35th Annual Meeting Program - American College of Toxicology

Transcription

American College
of Toxicology
35 Annual Meeting
Program
th
Orlando, Florida
November 9–12, 2014
Hyatt Regency Grand Cypress
www.actox.org
Some Orlando photos are courtesy of Visit Orlando unless otherwise noted. Some photos by Harvey Smith Photography.
AMERICANCOLLEGE
COLLEGEOF
OFTOXICOLOGY
TOXICOLOGY
AMERICAN
Welcome! COLLEGE OF TOXICOLOGY
AMERICAN
Dear Colleagues and Guests,
2013–2014 COUNCIL
2013–2014 COUNCIL
PRESIDENT
PRESIDENT
2013–2014
COUNCIL
Drew A. Badger,
PhD, DABT
Drew A. Badger, PhD, DABT
PRESIDENT
PRESIDENT-ELECT
DrewMary
A. Badger,
DABT
PRESIDENT-ELECT
Ellen PhD,
Cosenza,
PhD,
Mary Ellen Cosenza,
PhD,
DABT,
RAC
DABT, RAC
PRESIDENT-ELECT
Mary Ellen
Cosenza,
PhD,
VICE
PRESIDENT
DABT,
PRESIDENT
Hanan N.VICE
Ghantous,
PhD,RAC
DABT
Hanan N. Ghantous, PhD, DABT
VICE PRESIDENT
SECRETARY
Hanan
N. Ghantous,
PhD,
DABT
SECRETARY
Grace
M. Furman,
PhD,
DABT
Grace M. Furman, PhD, DABT
SECRETARY
TREASURER
Grace M.
Furman,
PhD, DABT
Alan
M.TREASURER
Hoberman,
PhD,
Alan M. Hoberman,
PhD,
DABT,
ATS
DABT, ATS
TREASURER
Alan M. Hoberman,
PhD,
COUNCILORS
DABT,
COUNCILORS
Nancy R. Bordelon,
PhD, ATS
DABT
Nancy R. Bordelon, PhD, DABT
Alan P. Brown, PhD, DABT
COUNCILORS
Alan P. Brown,
PhD, DABT
Nancy
R. R.
Bordelon,
PhD,
DABT
David
Compton,
PhD,
DABT
David R. Compton, PhD, DABT
Alan P.Jerry
Brown,
PhD, DABT
F. Hardisty,
DVM
Jerry F. Hardisty, DVM
David R.Anthony
Compton,
DABT
L. PhD,
Kiorpes,
PhD,
Anthony L. Kiorpes,
DVM,PhD,
DABT
Jerry F. Hardisty,
DVM
DVM, DABT
Timothy J. McGovern, PhD
Anthony
Kiorpes, PhD,
Timothy
J. L.
McGovern,
PhD
DABT
Sandra L.DVM,
Morseth,
PhD
Sandra L. Morseth, PhD
Timothy
McGovern,
Melissa
C.J.
Rhodes,
PhD, PhD
DABT
Melissa C. Rhodes, PhD, DABT
Sandra
L. Morseth,
PhD
Patricia
C. Ryan,
PhD
Patricia C. Ryan, PhD
Melissa C. Rhodes, PhD, DABT
PAST PRESIDENT
On behalf of the American College of Toxicology, I would like to welcome you to ACT’s 35th
Annual Meeting at the Hyatt Regency Grand Cypress in sunny Orlando, Florida. I am proud
of this year’s meeting that includes a variety of applied and regulatory toxicology sessions,
as well as a venue that offers numerous opportunities for fun and professional networking. I
encourage you to review the schedule of scientific sessions and special events in this Program
so that you can make the most of the days ahead.
Sunday offers a variety of half-day Continuing Education (CE) courses as well as an extended
Study Director Short Course. If you have not already registered in advance and would like
to register for a course on-site, stop by the ACT Registration Desk outside of the Exhibit
Hall and we’ll be happy to assist you. A detailed description for each course can be found in
this Program.
We are pleased to present Monday morning’s Plenary lecturer, Deborah Blum, Pulitzer-Prize
Winner and Author of The Poisoner’s Handbook: Murder and the Birth of Forensic Medicine in
Jazz Age New York. Wednesday morning’s Plenary lecturer will be Dr. Alison Van Eenennaam
of University of California, Davis speaking on “Food and Feed Safety of Genetically Modified
Organisms: The Hype and the Facts.”
ACT’s Annual Meetings are known for being collegial, with many opportunities for professional networking and catching up with friends and colleagues. We officially kick off the
meeting on Saturday with a low stress and fun golf outing followed by a reception for all the
golfers. “Jazzicology,” our own home-grown band comprised of ACT members, is back this
year to entertain us during Sunday’s Welcome Reception, which is a ticketed event that is not
included in the price of the meeting registration. Don’t miss Monday’s Awards Luncheon and
evening Poster Reception, both of which are included in your registration fee.
New this year is the ToxTrot on Tuesday morning on a trail around the grounds of the Hyatt.
Whether you walk or run, it’s sure to be fun! Participation in the ToxTrot is free, but advance
registration is required. We’ve also added a breakfast reception for all meeting attendees in
the Exhibit Hall following the ToxTrot event and a wine tasting with incoming President
Mary Ellen Cosenza on Wednesday evening for ACT members only.
PAST PRESIDENT
During your daily breaks, I encourage you to visit the exhibitors at their booths in the Exhibit
Hall as they are a vital part of the meeting. You also will have the opportunity to peruse over
100 posters on display in the Exhibit Hall.
EDITOR-IN-CHIEF
I would like to extend a special thank you to Program Committee Chair Mary Ellen Cosenza
and Education Committee Chair Jerry Hardisty, and their committees, for planning an
outstanding program.
Patricia
C. Ryan,
PAST
PRESIDENT
Robin
C. Guy,
MS, PhD
DABT,
Robin C. Guy, MS,
DABT,
RQAP-GLP
RQAP-GLP
Robin C.
Guy, MS, DABT,
EDITOR-IN-CHIEF
EDITOR-IN-CHIEF
Mary BethRQAP-GLP
Genter, PhD,
Mary Beth Genter,
PhD,
DABT,
ATS
DABT, ATS
Mary Beth Genter,
PhD,
EXECUTIVE
DIRECTOR
DABT,
ATS
EXECUTIVE DIRECTOR
Nancy
Rollman
Nancy Rollman
Let’s have a great week!
EXECUTIVE DIRECTOR
Nancy Rollman
2013–2014 ACT President
1821 Michael Faraday Drive, Suite 300, Reston, Virginia 20190
1821 Michael
Faraday
Drive, Suite
300,acthq@actox.org
Reston, Virginia 20190
Telephone: 703.547.0875
Fax:
703.438.3113
Email:
Website: www.actox.org
Telephone: 703.547.0875 Fax: 703.438.3113 Email: acthq@actox.org Website: www.actox.org
Telephone: 703.547.0875 Fax: 703.438.3113 Email: acthq@actox.org Website: www.actox.org
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College of Toxicology
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Schedule of Events Overview
Saturday, November 8
12:00 PM–5:30 PM
ACT Golf Outing (Ticketed Event)
Grand Cypress
Golf Course
3:00 PM–5:00 PM
Registration Open
Registration Area #1
4:00 PM–6:00 PM
Speaker Ready Room Open
Poinciana B
5:00 PM–7:00 PM
ACT Council Meeting
Magnolia
Sunday, November 9
CE Continental Breakfast
Regency Hall
7:00 AM–9:00 AM
Poinciana B
7:00 AM–5:00 PM
Registration Open
8:00 AM–11:30 AM
CE 1: Best Practices in Toxicologic Pathology
Regency Hall
CE 2: Regulatory Toxicology—In the FDA and Beyond
Palm
CE 3: Drug Line Extensions: Nonclinical Testing and Solutions
Regency Hall
CE 4: Interpreting Adverse Clinical and Anatomic Pathology Results:
Putting It All Together
Regency Hall
8:00 AM–3:15 PM
Study Director Short Course
Regency Hall
9:15 AM–10:30 AM
CE Refreshment Break (See Course Details for Break Times)
Regency Hall
11:30 AM–1:00 PM
Lunch On Your Own
12:00 Noon–12:55 PM
Exhibitor-Hosted Program: Submitting Standardized SEND to the FDA:
Data Fitment and Review Considerations
Presented by: PointCross Life Sciences, Inc.
Regency Hall
12:00 Noon–4:30 PM
Exhibits and Poster Setup
Grand
Cypress Ballroom
12:00 Noon–1:00 PM
New Member Lunch (By Invitation Only)
Hydrangea
In the Event of Rain:
Portico West
12:00 Noon–2:00 PM
Poinciana B
1:00 PM–4:30 PM
CE 5: Toxicology and Pathology of the Respiratory System
Regency Hall
CE 6: (Q)SAR—A Tool for the Toxicologist
Regency Hall
CE 7: Managing Anti-Drug Antibody Responses during Biologics Drug
Development
Palm
CE 8: Metabolites: Guidance and Considerations in Drug Development
Regency Hall
2:30 PM–3:10 PM
CE Refreshment Break (See Course Details for Break Times)
Regency Hall
4:00 PM–4:45 PM
Student Poster Setup
Grand
Cypress Ballroom
5:00 PM–6:30 PM
Student Poster Judging
Grand
Cypress Ballroom
6:30 PM–8:30 PM
Welcome Reception Featuring Jazzicology (Ticketed Event)
The Wilderness
Portico West
1 OVERVIEW
7:00 AM–8:00 AM
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Schedule of Events Overview (continued)
OVERVIEW
Monday, November 10
6:45 AM–8:00 AM
Past Presidents' Breakfast (By Invitation Only)
Gardenia
7:00 AM–8:00 AM
Continental Breakfast
Grand Cypress
Ballroom
Prefunction Area
7:00 AM–9:00 AM
Poinciana B
7:00 AM–5:00 PM
Registration Open
8:00 AM–8:55 AM
Plenary Lecture: The Poisoner's Guide to Life
Speaker: Deborah Blum
Regency Hall
9:00 AM–12:00 Noon
Symposium 1: From Mice to Men, Development of Human Drugs and
Biologics under the Animal Rule
Palm
Symposium 2: What the AEL is the NOAEL?
Grand Cypress
Ballroom A
Symposium 3: Systems Toxicology: The Future of Risk Assessment
Magnolia
9:30 AM–12:00 Noon
Exhibits and Posters Open
Grand
Cypress Ballroom
10:20 AM–10:55 AM
Refreshment Break
(Exhibit Hall: See Session Details for Break Times)
Grand
Cypress Ballroom
10:20 AM–10:55 AM
Book Signing by Plenary Lecturer Deborah Blum
ACT Member
Lounge in the Grand
Cypress Ballroom
11:00 AM–2:00 PM
Poinciana B
12:00 Noon–2:00 PM
Awards Ceremony and Luncheon (Open to all Registrants)
Speaker: Anthony Dayan, Distinguished Scientist Awardee
Regency Hall
2:00 PM–5:00 PM
Symposium 4: Antidrug Antibody-Independent Immune Responses
to Biologics in Rodent Studies—Regulatory Success in Early Drug
Development
Palm
Symposium 5: Use of Humanized Mouse Models in DMPK and Safety Testing
of Compounds
Magnolia
Symposium 6: Targeted Cancer Therapeutics: Concepts and Strategies to
Improve Oncology Drug Development
Grand Cypress
Ballroom A
2:00 PM–7:00 PM
Grand
Cypress Ballroom
3:20 PM–3:55 PM
Refreshment Break
Grand
Cypress Ballroom
3:20 PM–3:55 PM
Meet Distinguished Scientist Awardee Anthony Dayan
ACT Member
Lounge in the Grand
Cypress Ballroom
5:30 PM–7:00 PM
Poster Session and Reception (Exhibit Hall)
Grand
Cypress Ballroom
2 th
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Annual Meeting
2014
Tuesday, November 11
ACT ToxTrot (Registration Required by October 30)
Portico West Patio
8:00 AM–9:00 AM
Breakfast Reception (Exhibit Hall)
Grand
Cypress Ballroom
8:00 AM–4:30 PM
Grand
Cypress Ballroom
8:00 AM–5:00 PM
Registration Open
8:00 AM–10:00 AM
Poinciana B
9:00 AM–12:00 Noon
Symposium 7: Breathe In, Breathe Out, It's Easy: What You Need to Know
about Developing Inhaled Drugs
Regency Hall
Symposium 8: Cardiovascular Safety Evaluation—In Vitro to Humans
Grand Cypress
Ballroom A
Symposium 9: Centrally Administered Compounds in Small and Large
Species—Dose Routes, Study Considerations, and Data Interpretation
Palm
10:10 AM–10:55 AM
Refreshment Break
Grand
Cypress Ballroom
12:00 Noon–1:30 PM
IJT Editorial Board Meeting
Magnolia
12:00 Noon–2:00 PM
Lunch On Your Own
12:00 Noon–1:30 PM
2015 Program Planning Meeting (All ACT Members Invited, Box Lunch
Provided. Sign Up at Registration Desk.)
Regency Hall
2:00 PM–5:00 PM
Symposium 10: Cytokines: The Good, the Bad, and the Deadly
Grand Cypress
Ballroom A
Symposium 11: Differentiating Adverse from Adaptive Changes in
Toxicology
Palm
Symposium 12: In Silico Methods for Mutagenicity Prediction vis-à-vis ICH
M7 Guidance
Regency Hall
3:20 PM–3:55 PM
Meet IJT Editor Mary Beth Genter
Booth 304
in the Grand
Cypress Ballroom
3:20 PM–3:55 PM
Refreshment Break
Grand
Cypress Ballroom
4:30 PM–7:30 PM
Exhibit and Poster Teardown (Exhibit Hall)
Grand
Cypress Ballroom
5:00 PM–6:30 PM
ACT Members’ Meeting (All ACT Members Invited)
Regency Hall
3 OVERVIEW
6:30 AM–7:30 AM
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Wednesday, November 12
OVERVIEW
7:00 AM–7:55 AM
Exhibitor-Hosted Program: Maintaining Quality and Regulatory
Compliance in a Global Setting
Presented by: WuXi AppTec
Grand Cypress
Ballroom H
Exhibitor-Hosted Program: Practicalities of Dermal Administration
Presented by: Huntingdon Life Sciences
Grand Cypress
Ballroom G
Exhibitor-Hosted Program: Zebrafish: Reshaping Toxicity Testing
Presented by: Charles River
Grand Cypress
Ballroom I
7:00 AM–8:00 AM
Continental Breakfast
Grand Cypress
Ballroom
Prefunction Area
7:00 AM–8:00 AM
Council Orientation
Magnolia
7:30 AM–1:30 PM
Registration Open
8:00 AM–12:00 Noon
Poinciana B
8:00 AM–8:55 AM
Plenary Lecture: Food and Feed Safety of Genetically Modified Organisms:
The Hype and the Facts: Speaker: Alison Van Eenennaam, PhD
Grand Cypress
Ballroom D
9:00 AM–12:00 Noon
Symposium 13: Novel Therapeutics in Oncology: Recent Advances
and Considerations for Nonclinical Safety Evaluation
Palm
Symposium 14: Applied Nanotoxicology
Grand Cypress
Ballroom A
Symposium 15: Stem Cells Research
Grand Cypress
Ballroom B
Symposium 16: Safety Assessment Updates for Preventive Vaccines
and Vaccine Adjuvants
Grand Cypress
Ballroom C
10:20 AM–11:00 AM
Refreshment Break (See Course Details for Break Times)
Grand Cypress
Ballroom
Prefunction Area
12:00 Noon–12:55 PM
Exhibitor-Hosted Program: Demonstration of New Expert Alert System
for In Silico Assessment of Impurities under ICH M7 Guidelines
Presented by: Leadscope Inc.
Grand Cypress
Ballroom H
Exhibitor-Hosted Program: Evaluation of Electronic Cigarettes
in Testing Tobacco-Related Products
Presented by: Battelle
Grand Cypress
Ballroom G
Exhibitor-Hosted Program: Seizure Liability, qEEG and Sleep Quantification
in Nonclinical Drug Development: Regulatory and Scientific
Considerations
Presented by: CiToxLAB
Grand Cypress
Ballroom I
12:00 Noon–1:30 PM
ACT Council Meeting
Magnolia
12:00 Noon–1:30 PM
Lunch On Your Own
1:30 PM–4:30 PM
Symposium 17: Hot Topics
Grand Cypress
Ballroom D
3:00 PM–3:20 PM
Refreshment Break
Grand Cypress
Ballroom
Prefunction Area
5:00 PM–6:30 PM
Wine Tasting: Meet the 2015 ACT President, Mary Ellen Cosenza
(Open to All ACT Members, Pre-Registration Required)
Grand View Terrace
4 American College of Toxicology
35th
Annual
Meeting
Program Content
President’s Welcome �� Inside Front Cover
Schedule of Events Overview �� 1
General Information
General Information
Venue �� 6
Internet Access �� 6
Room Reservations �� 6
Parking �� 6
Transportation �� 6
Climate �� 6
Attire �� 6
Registration Information �� 6
Restaurants �� 6
Photography Policy �� 6
Hotel Map �� 8
Resort Map �� 9
Special Events�� 10
2014 Awards �� 12
Program Agenda
Continuing Education Courses
Study Director Short Course�� 17
Morning CE Courses �� 18
Afternoon CE Courses �� 22
Scientific Sessions
Monday Morning Sessions �� 27
Monday Afternoon Sessions �� 34
Tuesday Morning Sessions �� 40
Tuesday Afternoon Sessions �� 46
Wednesday Morning Sessions �� 53
Wednesday Afternoon Session �� 62
Abstracts
Orlando
2014
Poster Sessions
ACT Poster Presentations �� 63
100 Series—General Toxicology �� 64
200 Series—Regulatory �� 70
300 Series—Safety Evaluation Nonpharmaceuticals�� 73
400 Series—Toxicology Methods �� 80
500 Series—Safety Evaluation Pharmaceuticals �� 93
Author Index �� 102
Exhibit Information
Exhibitor Directory �� 108
Exhibit Hall Map �� 136
Exhibitor-Hosted Programs �� 137
Reference
Council Listing ��
Committee Listings ��
Headquarters Staff ��
Past Presidents ��
ACT Award Recipients ��
Corporate Members ��
Welcome New Members ��
ACT Charter Members ��
ACT Distinguished Fellows ��
5 138
140
145
146
147
148
149
149
149
GENERAL INFO
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General Information
Venue
Transportation
Hyatt Regency Grand Cypress Resort
Theme Park Transportation
The Hyatt Regency Grand Cypress provides complimentary
transportation to and from Walt Disney World,® Universal
Orlando® and Sea World. Please contact the Concierge
directly for scheduled times.
One Grand Cypress Boulevard, Orlando, FL, 32836
Telephone: 407.239.1234 | Fax: 407.239.3800
ACT 35th Annual Meeting Registrants will enjoy the Hyatt
Regency Grand Cypress where they will be secluded in the heart
of it all. The Hyatt Regency Grand Cypress is set in Orlando theme
park country near Lake Buena Vista, while being surrounded by
21 acres of shimmering lakes and lush landscaping.
Resort Transportation
A complimentary shuttle runs continuously around the resort
from 6:30 am–11:00 pm daily.
Hertz
Options during downtime are numerous. The Hyatt Regency
Grand Cypress is located just one mile from Walt Disney
World® Resort and five miles from Sea World®, and offers a
complimentary shuttle to both. The Hyatt Regency Grand
Cypress also offers an impressive collection of on-site activities.
From world-class championship golf and tennis to luxury spa
services and leisurely afternoons sailing on the private lake; you
may have to stay longer just to experience it all!
The Hyatt Regency Grand Cypress offers an ideal destination
for the stimulating scientific exchange at this year’s ACT
Annual Meeting.
Internet Access
There will not be Wi-Fi Internet access available in the meeting
rooms or Exhibit Hall. ACT will have an Internet Café located near
the registration area, which will be available during registration
hours. The café will include several computers with Internet
access. If you are staying at the hotel, the room rate includes
basic Internet access (wireless and wired) in your guest room.
Room Reservations
Meeting Rate
• $189 single/double occupancy
• Check-in time is 4:00 pm and check-out time is 11:00 am.
Waived Resort Fee
For all attendees staying at the hotel the $10 Hotel Program
Fee has been waived. The Hotel Program Fee provides use
of hotel activities and amenities including: hard-wire and
in-room basic wireless Internet (WiFi will not be accessible
in the session rooms or Exhibit Hall), in-room laptop safe,
intra-property transportation, unlimited use of the Health
Club, 9-hole Pitch and Put course (balls and clubs included),
golf driving range access, court time at the Racquet Club
(racquet and balls included), basketball, volleyball, rock
climbing wall, non-motorized boats, as well as resort bicycles.
Complimentary theme park shuttle to Disney, SeaWorld,
Universal Studios/Island of Adventure (please check with the
hotel concierge regarding shuttle times).
Parking
• Self-Parking, Fee: $11 with in/out privileges
• Valet Parking, Fee: $23 with in/out privileges
• Event Only (day) parking, Fee: $6
Located on property at the Hyatt Regency Grand Cypress,
Hertz is offering special meeting rates to ACT meeting
attendees. Reservations can be made online or by calling
Hertz directly at 1.800.654.2240 or 405.749.4434. Please
provide CV#022L4090. To talk to the Hertz desk at the Hyatt
Regency Grand Cypress, please call 407.238.5309.
Climate
Orlando’s average temperature in November is a high of 79
degrees and a low of 59 degrees. November is one of the driest
months of the year.
Attire
Meeting attire is business casual. The meeting rooms may be
cool, so be sure to dress with a lightweight layer. Additionally,
comfortable shoes for walking are advisable.
Registration Information
The registration fee includes the American College of Toxicology
Awards Luncheon on Monday, continental breakfast Monday
through Wednesday, all refreshment breaks, and a Monday
evening poster session and reception. Additional registration
fees are required for Continuing Education courses, for the
Sunday evening Welcome Reception, and for the Golf Outing.
If you have registered prior to October 15, you will receive your
name badge, course ticket(s), and qualifying ribbons in the mail.
You will not need to stand in the registration line if you received
these in advance. You may pick up the Program and your badge
holder on-site.
Restaurants
The Hyatt Regency Grand Cypress offers a variety of dining
options in addition to in-room dining. The hotel’s restaurants
offer spectacular settings and present inspiring backdrops for the
delectable culinary creations from their talented chefs. Should
you require assistance with reservations at any of their dining
outlets before or during your stay, we encourage you to use
Hyatt’s dedicated E-Concierge service online.
Photography Policy
ACT meeting attendees are asked to strictly adhere to the
photography policy while participating in sessions and while in
the Exhibit Hall. As a courtesy to our speakers, poster presenters,
and exhibitors, ACT asks that participants refrain from electronic
capture of any and all presented material unless given written
permission from the proprietary. Any person who does not
comply with the policy may be asked to leave the event.
6 The network for
ACT members only!
Access interACT from the ACT homepage to:
•Build your
MyPage profile
•Upload your CV
•Find an ACT member
•Access your
communities
•Read the ACTalks blog
and stay in touch!
Access the interACT community today!
Visit www.actox.org
7 T +1 407 239 1234
F +1 407 239 3800
grandcypress.hyatt.com
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Hotel Map
FLOOR PLAN
Ground Level
HYDRANGEA
GENERAL INFO
One Grand Cypress Boulevard
Orlando, FL 32836
USA
FEDEX
OFFICE
HYDRANGEA
PATIO
LOBBY / SALON
ELEVATOR
ORCHID
PARKING
ToxTrot
Meeting Area
GARDENIA
SERVICE /
LOADING AREA
MEN
G
PATIO
LOBBY
LEVEL
BOARD
ROOMS
HIBISCUS
I
H
OFFICE 1
Exhibit Hall
CAMELLIA
GRAND CYPRESS BALLROOM
MEN
WOMEN
TO MAIN
LOBBY
PORTICO
WEST
PREFUNCTION AREA
PORTICO
EAST
WOMEN
D
E
F
LOBBY LEVEL MEETING ROOMS
MEN
A
REG
2
SOUTH
BUS ARRIVAL / DEPARTURE
B
DRESSING
ROOM
REG
1
C
Registration
B
REG
4
REG
3
4
3
2
JACARANDA
WOMEN
REGENCY HALL
6
7
E
8
B
A
B
POINCIANA
C
MAGNOLIA
A
5
14th Floor
D
OUTDOOR
PATIO
ATRIUM
ROOM
1
MEN
Awards
Luncheon
A
PALM
UP TO LOBBY
F
SERVICE LOADING
C
C
Speaker Ready
Room
RESTROOM
FOYER
D
9
SERVICE CORRIDOR
LA COQUINA*
Note: * La Coquina Entrance on lobby level
07.13
8 9 WETLANDS
OPENSPACE
SOUTH 9
RACQUET
CLUB
WESTERN STABLE
RIDING TRAILS
WETLANDS
OPENSPACE
SR 535
NORTH
JACARANDA
GOLF
ACADEMY
RECEPTION CENTER
EAST 9
VILLAS
OF GRAND
CYPRESS
CLUB HOUSE
DRIVING
RANGE
AREA
HIGHLIGHTED
ON THIS MAP
EXECUTIVE
MEETING
CENTER
NORTH 9
VILLAS
EQUESTRIAN
CENTER
SR 535
NEW COURSE 18
HYATT
REGENCY
GRAND
CYPRESS
WETLANDS
OPENSPACE
I-4WEST
WEST
I-4
SR 535
I-4
Western
Trail Ride
Camellia
Gardenia
Orchid
Hibiscus
Grand View Terrace
29
29
21
22
23
24
25
26
27
28
29
Racquet
Ball
Basketball
Court
Lakside
Marina
Ground Floor Level Entry
Cascade
La Coquina
Palm Cafe and General Store
On The Rocks
Health Club
Game Room
Pitch ‘n Putt
Racquet Club
Ground Floor Level
16
17
18
19
20
Atrium/Lobby Level
Meeting Space
One Grand Cypress Blvd. • Orlando, FL 32836 USA
407-239-1234 • www.hyattgrandcypress.com
Parking
Tennis
Pro Shop
Tennis Courts
Trellises Lounge
La Coquina Entry
Cascade Entry
White Horse Sports Bar & Grill
Hemingway’s
Hurricane Lounge
Lamont’s Shop
Accents Shop
Concierge/Guest Services
Guest Elevators
Front Desk/Registration
Hemingways/Recreation Area Exit
Camp Hyatt Child Care Center
Business Center
Grand Cypress Salon Entry
TODISNEY
DISNEY
TO
THEMEPARKS
PARKS
THEME
WETLANDS
OPENSPACE
GRAND CYPRESS
RESORT PROPERTY
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Atrium/Lobby Level
30
31
32
33
34
35
36
37
38
39
40
Pitch ‘n Putt
Course
28
28
Palm
Poinciana
Magnolia
Regency Hall
Grand Cypress Ballroom
Pre-Function Area
Portico Area
Jacaranda
Cypress Point Pavilion
Wilderness Area
Theme Park Bus Depot
Jogging Trails
Stables/Barn
N
Spa
Riding Trails
Grand Cypress Blvd.
Ballroom and Hotel
Self Parking
Pitch ‘n Putt
Check in
Lower Level Meeting Space
21
21
Pool
27
27
Spa
Meeting
Space
Spa
55
25
26 25 66
26
Pool
Firepit
Towel Hut
Boat and Bike
Rental
Heated Pool
Meeting
Rooms
Lake Windsong
Beach
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Rooms
Atrium
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Meeting
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Entrance to
Bus Parking
Theme
Park Bus
Depot 17
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Hyatt
Regency
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Cypress
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Meeting Space
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Hotel Arrival
and Valet Parking
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Exit to
Grand Cypress Blvd.
Hotel Main
Entrance
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38
Wilderness
Area
Heliopad
Grand Cypress Blvd.
Main
Gate
Welcome
Reception
To I-4
39
39
Jogging Trails
SR 535
To Villas of Gra
nd Cypress, Gra
Golf Club and
Equestrian Ce nd Cypress
nter, (1.5 mil
es)
2014
Resort Map
GENERAL INFO
Hyatt Regency Grand Cypress
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Special Events
Golf Outing
Poster Session and Reception
Saturday, November 8
12:00 Noon–5:30 PM
Grand Cypress Golf Course
$125
Sponsored by HistoTox Labs and WIL Research
(Advance registration required
and space is limited)
Monday, November 10
5:30 PM–7:00 PM
Sponsored by SAGE
(Open event, all registrants invited)
This is the opportunity to discuss the latest research findings and
methodology with poster presenters and visit with exhibitors during
a reception with wine and light fare. Reception is included in the
Annual Meeting registration fee.
Arrive in Orlando early and enjoy a day on the golf course with
other ACT Annual Meeting attendees. This is a great way to build
relationships in a relaxed atmosphere while enjoying the beautiful
Florida weather on a classic golf course. This event is played in a fun
format that accommodates all levels of golfers.
ACT’s Inaugural ToxTrot
The event will take place on the Jack Nicklaus Signature New Course
at the Grand Cypress Golf Club. Set in the midst of an open meadow,
the New Course is Jack Nicklaus’ tribute and homage to the famed
Old Course at St. Andrews, Scotland.
The $125 fee per player includes 18 holes with cart, practice balls,
club storage and cleaning, a light reception, and participant door
prizes. Club Rentals are available for $50 per set and shoe rentals are
available for $20 per pair.
Welcome Reception
Sunday, November 9
6:30 PM–8:30 PM
The Wilderness
In the event of rain: Portico West
$50
(Ticketed event)
6:30 AM–7:30 AM
Portico West Patio
(Free event, registration by October 30 required)
ACT is holding its first ToxTrot at this year’s 35th Annual Meeting! Join
members from ACT’s Council as they “trot” through the property of
the Hyatt as the sun rises. This event is a 3.1-mile loop where you can
walk, trot, or run. There is no fee for this event and you will receive
a free t-shirt while supplies last to wear on the day of the ToxTrot.
There will be Hyatt staff at the finish line to give you your trot time,
if you are interested. You will receive your bib Tuesday morning, so
please arrive early to the event.
This is a great opportunity to meet fellow ACT members and
network, all while burning a few calories. We will also be raffling off
a complimentary 2015 ACT Annual Meeting registration after the
event for participants who complete the Trot!
ACT Members’ Meeting
After a stimulating day of Continuing Education, mingle with your
colleagues at a special dinner in the Wilderness area under the stars.
You will relax to the smooth sounds of “Jazzicology,” a combo of ACT
members appearing again by popular demand. Be sure to purchase
your $50 ticket in advance as space is limited. Your ticket includes a
fabulous barbeque dinner and two drink tickets.
5:00 PM–6:30 PM
Regency Hall
(All ACT members invited)
Awards Ceremony and Luncheon
Wine Tasting with 2015 ACT
President Mary Ellen Cosenza
Monday, November 10
12:00 Noon–2:00 PM
Regency Hall
(Open event, all registrants invited)
The Distinguished Scientist Award recipient Dr. Anthony Dayan will
provide the keynote presentation at this lunch, which is included in the
Annual Meeting registration. Other award recipients will be recognized
and the Furst Award for the best student poster at the meeting will be
announced. See page 12 for award recipients.
Come to the meeting to hear the latest ACT business and provide
feedback for the future.
5:00 PM–6:30 PM
Grand View Terrace
In the event of rain: Grand Cypress Ballroom G
(Free event for ACT members only, advance
registration required)
Come meet the incoming 2015 ACT President Mary Ellen Cosenza
and share your thoughts on the ACT Annual Meeting over a glass
of wine! This wine tasting event is a new opportunity to network
with fellow ACT members while getting to know the incoming ACT
President. Wine and light fare will be provided.
This is a free event for all ACT members and advance registration
is required.
10 Don’t Miss
the Welcome Reception
Sunday, November 9
The Wilderness
In the Event of Rain: Portico West
6:30 PM–8:30 PM
$50 Ticket
After a stimulating day of Continuing Education courses, mingle with
your colleagues at a delicious barbecue dinner under the stars.
You will relax to the smooth sounds of Jazzicology, a combo
of ACT members appearing again by popular demand.
www.actox.org
11 GENERAL INFO
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2014 Awards
2014 Awards will be presented at the Awards Ceremony and Luncheon on Monday, November 10 at 12:00 noon–2:00 pm in the
Regency Hall. This event is open to all attendees (members, nonmembers, and exhibitors, etc.). For a historical listing of award
recipients, see page 147 or visit www.actox.org/aboutact/pastrecipients.asp.
committee), and longstanding support of the College's
activities. The recipient must be a member of ACT.
ACT Distinguished
Scientist Award
ACT recognizes Norman N. Kim, MS, DABT as the
2014 Service Awardee.
The ACT Distinguished Scientist Award recognizes an
individual (not necessarily a member of ACT) who has made
outstanding contributions to toxicology, its relationship
to the regulation of chemicals, and/or the improvement of
public health. The DSA winner becomes the Keynote Awards
Luncheon Speaker at the Annual Meeting.
ACT recognizes Anthony Dayan, Emeritus
Professor, MBBS (Hons) MD as the 2014
Distinguished Scientist Awardee.
After gaining a degree in Pharmacology and
Physiology, Dr. Dayan qualified as a physician in
1959 and specialized in pathology and neuropathology after
various internships. He was a member of staff of the Hospital
for Sick Children and National Hospitals for Nervous Diseases,
London, from 1965–1973 when he joined the Wellcome
Foundation Research Laboratories as a toxicologist, later
becoming Head of Toxicology. In 1984, Dr. Dayan moved to
become the first Professor of Toxicology and Head of the DH
Department at Barts Hospital until his first retirement in 1998.
Whilst at Barts and subsequently he was a member of many
UK, EC, WHO and other international scientific advisory
committees concerned with all aspects of the safety of
human and veterinary drugs, medical devices, foods, air, and
pesticides as well as advanced therapies, such as the products
of biotechnology and gene therapy. He has also consulted
widely in those fields for companies and research bodies.
Dr. Dayan has been Chairman or President of the British
Toxicology Society, HESI and ILSI Europe, and of the
Comparative Medicine Section of the Royal Society of
Medicine and a member of its Board of Directors.
Dr. Dayan's academic career included directing and
examining PhD and MD candidates in several universities in
Britain and Europe, organizing an international collaborative
study of immunotoxicity test methods and running an annual
training course for WHO.
ACT Service Award
The ACT Service Award recognizes an individual for their
long-term dedication to ACT including but not limited to
service to the College (e.g., Councilor, officer, committee
member), frequent participation and contribution to
the Annual Meeting (speaker, chairperson, organizing
Norman Kim has been an active member of
the American College of Toxicology (ACT) since
2001. He has served in numerous capacities
for ACT, which have included positions on the Nominating
Committee (2005), Councilor (2007–2009), Membership
Committee (Chair, 2008–2009), Treasurer (2011–2013),
Finance Committee (Chair, 2011–2013), Publications
Committee (2011–2013), Resource Committee (2013), and
Program Committee (2014). As the Treasurer and Chair
of the Finance Committee, the College’s finances were
well managed. The College’s assets and investments were
stabilized during the turbulent economic times, appropriately
allocated to provide a more diverse investment portfolio,
and greatly enhanced to better support the future needs of
the College and to further benefit the ACT members. Many
of the financial functions occurred during the challenging
and critical stages of growth for the College when numerous
organizational changes and new initiatives took place.
Norman has supported ACT in many other roles that included
organizing and chairing various Symposia and Continuing
Education courses at the ACT Annual Meetings. He has also
served on the Organizing Committees of the ACT-hosted
toxicology training courses in the US (2010–2013) and in the
UK (2013–2014) on behalf of ACT.
Mr. Kim is currently a Director of Preclinical Safety at Biogen
Idec, covering multi-functional roles since 2011. He has
managed several toxicology programs, and currently is the
head of the Discovery Toxicology group and the interim-lead
of the Preclinical Safety department. He has over 25 years
of experience in the field of toxicology. He was previously
employed at Inotek Pharmaceuticals as the head of preclinical
development working on ophthalmology programs, at
Sepracor as a director of toxicology coordinating pulmonary
and CNS programs, at Alkermes where he provided preclinical
research and development support on drug delivery of
proteins and small molecules, and at Arthur D. Little where he
was a study director in genetic toxicology. He has worked on
numerous INDs in the US, and CTAs and CTNs internationally.
He has successfully been involved in several NDA and MAA
processes, including approvals of drugs for multiple sclerosis
(Tecfidera), asthma (Xopenex HFA MDI), chronic obstructive
pulmonary disease (Brovana), insomnia (Lunesta), and growth
hormone deficiency (Nutropin Depot). He has a number of
patents issued. He received his MS degree in biomedical
12 science specializing in toxicology from the Northeastern
University and BA degree in biology from the University of
Rhode Island. He is a member of the Society of Toxicology,
and participates on various external preclinical subcommittees
including Efpia’s Preclinical Development Committee, PhRMA’s
Clinical and Preclinical Development Committee, and HESI’s
Neurotoxicity Biomarkers and Cardiotoxicity Committees. He
is certified by the American Board of Toxicology (ABT), and
currently serves on the Board of Directors at ABT (2014–2018).
ACT Carol C. Lemire
Unsung Hero Award
2014
ACT Young Professional Award
The ACT Young Professional Award recognizes an ACT
member with no more than 10 years of full-time employment
experience since completing the highest degree (not
including postdoctoral training). Nominee must have
demonstrated outstanding service to the College, including
serving as an officer, councilor, committee member, and/or
frequent participation and contribution at the Annual Meeting
or any other College activity (i.e., speaker, chairperson,
organizing committee, etc.).
ACT recognizes Ilona G. Bebenek, PhD as the 2014
Young Professional Awardee.
The ACT Carol C. Lemire Unsung Hero Award recognizes an
ACT member or staff who has made substantive unrecognized
contributions to ACT. The nominee should have demonstrated
on-going willingness to help in ACT activities generally behind
the scenes.
ACT recognizes Kok-Wah Hew, PhD, DABT as the
2014 Carol C. Lemire Unsung Hero Awardee.
Dr. Hew is a Scientific Director at the Global Drug
Safety Research and Evaluation Department of
Takeda Pharmaceutical Company. He received
his PhD in Anatomy and Cell Biology from the University of
Michigan, Ann Arbor, Michigan. After graduation, he worked
as a Study Director in Reproductive Toxicology at Ciba-Geigy
Corporation and Novartis Pharmaceuticals Corporation. He
also served as the Manager of Reproductive Toxicology at
Springborn Laboratories; Senior Manager, and subsequently
Associate Director in the Nonclinical Drug Safety Evaluation
Department of Purdue Pharma; and Director of Toxicology at
Emisphere Technologies, Inc. He has more than 20 years of
experience in drug safety assessment, with special interests
in reproductive toxicology and juvenile animal toxicity
studies. In addition to authoring numerous toxicology reports
and regulatory documents, he is also the lead or co-author
of a number of peer-reviewed journal articles and book
chapters. Dr. Hew was a member of the Editorial Board in the
Reproductive Toxicology journal, and is currently a member of
the Editorial Board of the International Journal of Toxicology
as well as the Journal of Toxicological Sciences. Since 2010, he
is the Course Director and a speaker of the annual weeklong
course Toxicology for Industrial and Regulatory Scientists,
hosted by the American College of Toxicology (ACT). Dr. Hew
is a Diplomate of the American Board of Toxicology. He is also
a member of ACT, Society of Toxicology (SOT), Teratology
Society, Japanese Teratology Society, Middle Atlantic
Reproduction and Teratology Association (MARTA), and
the Developmental and Reproductive Toxicology Technical
Committee in Health and Environmental Sciences Institute
of the International Life Sciences Institute. In the SOT and
Teratology Society, he has served on various committees,
including the Chair of the Continuing Education Committee in
both societies. He is also a past president of MARTA.
Dr. Ilona Bebenek is a toxicologist at the U.S.
Food and Drug Administration, in the Division
of Transplant and Ophthalmology Products,
Center for Drug Evaluation and Research. She was previously
employed at ChemRisk/Cardno as a scientific consultant. She
completed her PhD in Molecular Toxicology at University of
California, Los Angeles. Her principal areas of training and
expertise include mechanisms of inflammation and regulatory
pathways in asthma, radiation biology, gene regulation,
mechanisms of carcinogenesis and regulatory toxicology.
Ilona won ACT’s Furst Best Student Poster Award in 2011
and was invited to participate in ACT’s strategic meeting in
June 2011 and 2012, which included service on the ad hoc
rebranding committee. She is currently chair of ACT’s webinar
subcommittee and a member of the Education Committee.
13 GENERAL INFO
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ACT President’s Award for
Best Paper Published in
the International Journal of
Toxicology
ACT International Travel Grants
The ACT President's Award recognizes the authors of the best
paper published in International Journal of Toxicology issues 5
and 6 of the previous year through and including IJT issue 4
(July–August) of the current year. The Publications Committee
carefully considered nominations for this award.
TOXICOLOGY
Volume 33 | Number 1 | January/February 2014
Authors: Jessica L. Price, T. Scott Manetz,
Jeffry D. Shearer, Robert V. House
Official Journal of the American College of Toxicology
IJT33_1_Covers.indd 1
2014�� Solange Costa, Portugal
Giorgia Del Favero, Italy
Deepak Dhakal, Nepal
Maria Elisa Peichoto, Argentina
Yeshvandra Verma, India
ACT North American Graduate
Fellowships
2014�� Julie Castaneda, University of California,
Los Angeles
Theresa Lansdell, Michigan State
Caroline Moore, University of California, Davis
2014.........International Journal of Toxicology:
Volume: 32(5): Pages 327–335,
September/October 2013
INTERNATIONAL JOURNAL OF
2014
ACT Student Travel Awards
2/3/14 1:01 PM
A limited number of graduate Student Travel Awards for
current students will be awarded based on merit of abstracts
and completed applications.
Paper Title: “Preclinical Safety Assessment of a Recombinant
Plague Vaccine (rF1V)”
2013�� International Journal of Toxicology: Volume: 31(5):
Pages 423–429, September/October 2012
Authors: Sudhir A. Shah, Madhav G. Paranjpe, Phillip I. Atkins,
Eias A. Zahalka
2014�� Winners to be announced at the Awards Luncheon
on Monday, November 10.
2013�� Shailender Singh Chauhan, Jamia Millia
Islamia, India
Chand Basha Davuljigari, Sri Venkateswara
University, India
Heidi Hsieh, University of Cincinnati,
United States
Chitrada Kaweeteerawat, University of California,
Los Angeles, United States
Paper Title: “Reduction in the Number of Animals and the
Evaluation Period for the Positive Control Group in Tg.rasH2
Short-Term Carcinogenicity Studies.”
ACT Furst Award
The Furst Award, established through a generous contribution
from the late Dr. Arthur Furst, is given to the best student
poster presentation at the Annual Meeting. The Furst Award is
determined by a panel of judges during a dedicated judging
session at the Annual Meeting but must participate in the
separate judging poster session.
2014�� Winner to be announced at the Awards Luncheon
on Monday, November 10.
2013�� Julie Castaneda
Institution: University of California,
Los Angeles
Poster Title: Distribution Patterns for the CB2
Receptor Vary between Human B-Cells, T-Cells,
and Malignant Cell Lines
14 Call for 2015 Awards
ACT Award Nominations
are Now Open
Each year, the American College of Toxicology
awards well-deserving individuals who have
contributed
to the field of toxicology and/or to ACT.
Visit the ACT website for the
Awards Nomination Form and the
full list of awards offered.
Send completed application, and CV if applicable,
to acthq@actox.org
attention “Awards Nomination.”
Deadline is March 31, 2015
15 2014 Awards Ceremony
and Luncheon
Monday, November 10
12:00 Noon–2:00 PM
Regency Hall
(Open Event, All Registrants Invited)
Join us as we celebrate this year’s outstanding awardees for their efforts to
advance the College and the field of toxicology. ACT’s Distinguished Scientist
Award recipient Dr. Anthony Dayan will provide the keynote presentation.
Monday, November 10
5:30 PM–7:00 PM
Sponsored by SAGE Publications
(Open Event, All Registrants Invited)
Discuss the latest findings and methodology with poster presenters
and network with exhibitors and fellow colleagues during a reception
with wine and light fare.
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PROGRAM AGENDA
Continuing Education (CE) courses are 3.5 hours each and are held either Sunday morning (AM) or Sunday afternoon (PM) with
the exception of the Study Director Short Course, which runs 7.25 hours (Study Director Short Course fee includes a boxed lunch).
Preregistration is required and seating is limited.
CONTINUING EDUCATION COURSE
Study Director Short Course
8:00 AM–3:15 PM
Regency Hall
SESSION CHAIRS: Barbara J. Mounho-Zamora, ToxStrategies,
Inc., Bend, OR, and
Heather Dale, Covance Laboratories Inc., Madison, WI
This Continuing Education course will review the essential aspects of the role and responsibilities of the study director. For
the first half of the course, the presentations will include topics relevant for study directors including a review and history of
the GLP regulations, managing and addressing the challenges of multisite studies, and selection of relevant animal models
for toxicology studies. The second half of the course will include more detailed review of specific toxicology studies, including
immunotoxicology, reproductive and developmental toxicology, and safety pharmacology. This course is an excellent
introduction for the new study director, as well as a refresher course for experienced study directors. All students will receive a
certificate for course participation that can be used for continuing education credits.
8:00 AM–8:10 AM
Introduction: The Study Director
Barbara J. Mounho-Zamora, ToxStrategies Inc., Bend, OR
8:10 AM–8:50 AM
GLP Regulations: History and Roles of the Study Director
Barbara Randolph, Biotechnical Services, Inc., Chattaroy, WA
8:50 AM–9:30 AM
Animal Models for Toxicology Studies
Scott E. Boley, MPI Research, Mattawan, MI
9:30 AM–10:10 AM
Managing Multisite Studies
Tom Beck, SNBL USA, Ltd., Everett, WA
10:10 AM–10:30 AM
Break
10:30 AM–11:10 AM
Immunotoxicity Assessment in Preclinical Safety Studies
Greg Bannish, Huntingdon Life Sciences, East Millstone, NJ
11:10 AM–11:50 AM
Safety Pharmacology in Human Pharmaceutical Development
R. Dusty Sarazan, Data Science International, St. Paul, MN
11:50 AM–12:50 PM
Lunch (boxed lunch provided)
12:50 PM–1:40 PM
Reproductive Toxicology
Alan M. Hoberman, Charles River Laboratories, Horsham, PA
1:40 PM–2:20 PM
Clinical and Anatomic Pathology for Standard Preclinical Toxicology Studies:
Data Integration and Interpretation
Kevin McDorman, Charles River Laboratories, Frederick, MD
2:20 PM–3:00 PM
What It Means to Be a Study Director—Managing the Issues and the Unexpected
Heather Dale, Covance Laboratories Inc., Madison, WI
3:00 PM–3:15 PM
Wrap Up
17 SUNDAY
Supported by an educational donation provided by:
Charles River Laboratories
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Morning CE Courses
CONTINUING EDUCATION COURSE— CE 1
Best Practices in Toxicologic Pathology
8:00 AM–11:30 AM
Regency Hall
SESSION CHAIRS: Kenneth A. Schafer, Vet
Path Services, Inc., and
Robert C. Sills, NTP/NIEHS, Research Triangle Park, NC
SUNDAY
Sponsored by the Society of Toxicologic Pathology and
Supported by educational donations provided by:
Experimental Pathology Laboratories, and Vet Path Services, Inc.
During this session, Society of Toxicologic Pathology (STP) members will present information from a few of the key guidance
documents. The guidance documents that have been selected are those that deal with basic issues in study design and
interpretation that toxicologists and pathologists can use in their conduct and reporting of toxicity studies. STP has provided a
number of best practice guidance documents, STP recommendations, and points to consider in the “Regulatory Forum” section
of the society's journal, Toxicologic Pathology. These publications are intended to provide guidance to toxicologic pathologists
and other interested scientists on issues that involve Data Interpretation/Management, Study Design, Study Reports/Peer
Review and several guidance documents dealing with organ systems and tissues that require unique approaches for evaluation.
The STP strives to collaborate with allied global organizations for many of these position papers.
8:00 AM–8:10 AM
Introduction: Regulatory Forum: Best Practices, Points to Consider and
STP Recommendations
Robert C. Sills, NTP/NIEHS, Research Triangle Park, NC
8:10 AM–8:50 AM
Use of Animal Models of Human Disease for Nonclinical Safety Assessment of
Novel Pharmaceuticals
Ronnie L. Yeager, AbbVie, Inc., North Chicago, IL
8:50 AM–9:35 AM
Assessment of Circulating Hormones in Nonclinical Toxicity Studies:
General Concepts and Considerations
Dinesh Stanislaus, GlaxoSmithKline, King of Prussia, PA
9:35 AM–10:10 AM
Break
10:10 AM–10:50 AM
Evaluation of Organ Weights for Rodent and Non-Rodent Toxicity Studies
Kenneth A. Schafer, Vet Path Services, Inc., Mason, OH
10:50 AM–11:30 AM
Pathology Peer Review in GLP Toxicology Studies
Rani Sellers, Albert Einstein College of Medicine, Bronx, NY
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CONTINUING EDUCATION COURSE—CE 2
Regulatory Toxicology—In the FDA and Beyond
8:00 AM–11:30 AM
Palm
SESSION CHAIRS: Patricia Frank, Patricia
Frank & Associates, Inc., Evanston, IL and
Shayne C. Gad, Gad Consulting Services, Cary, NC
Gad Consulting Services and Patricia Frank & Associates, Inc.
8:00 AM–8:10 AM
Introduction: Regulatory Toxicology
Patricia Frank, Patricia Frank & Associates, Inc., Evanston, IL
8:10 AM–8:50 AM
Interacting with FDA—A Regulatory Specialist's Viewpoint
Stacy N. Suberg, RBR, Ltd., Woodbury, MN
8:50 AM–9:35 AM
Interacting with CDER
Patricia Frank, Patricia Frank & Associates, Inc., Evanston, IL
9:35 AM–10:05 AM
Break
10:05 AM–10:45 AM
Interactions with CBER
Lauren Black, Charles River Laboratories, Reno, NV
10:45 AM–11:25 AM
Interacting with CDRH—The Devices Division of the FDA
Shayne C. Gad, Gad Consulting Services, Cary, NC
19 SUNDAY
Many toxicologists are intimately involved in the design, conduct, and reporting of nonclinical studies. However, many of these
professionals have a limited understanding of what happens to these reports after the studies have concluded. The aim of this
course is to discuss the details of regulatory toxicology both from the perspective of regulatory affairs specialists and regulatory
toxicology with an emphasis on drugs and devices. A discussion of the role that toxicologists play in the regulatory environment
will be presented considering both US and ex-US regulations. A regulatory affairs specialist will explain what regulators expect
from toxicologists and regulatory toxicologists will explain their role in interactions with drug, biologic and device regulatory
bodies. A panel discussion of all the presenters will answer specific questions from the participants.
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Drug Line Extensions: Nonclinical Testing and
Solutions
8:00 AM–11:30 AM
Regency Hall
SESSION CHAIRS: David R. Jones, MHRA,
London, UK and
Paul Baldrick, Covance Laboratories Ltd., Harrogate, UK
the American College of Toxicology
SUNDAY
This Continuing Education course will examine what nonclinical testing needs to be considered for drug line extensions and/or
new formulations. Talks will include EU and US regulatory agency experiences in this area along with a perspective on nonclinical
strategy and solutions for line extension development. In addition, case examples will be given for which additional nonclinical
testing was needed for a change to the original drug. The session will appeal to toxicologists working in the pharmaceutical
arena and also possibly consumer healthcare products.
8:00 AM–8:05 AM
Introduction
Paul Baldrick, Covance Laboratories Ltd, Harrogate, UK, and David R. Jones, MHRA, London, UK
8:05 AM–8:40 AM
EU Experiences with Line Extensions: From Initial Regulatory Contact
to Marketing Application
David R. Jones, MHRA, London, UK
8:40 AM–9:15 AM
US Experiences with Line Extensions: From Initial Regulatory Contact
to Marketing Application
Timothy J. McGovern, US Food and Drug Administration, Silver Spring, MD
9:15 AM–9:45 AM
Break
9:45 AM–10:20 AM
Nonclinical Strategy and Solutions for Line Extension Development
Paul Baldrick, Covance Laboratories Ltd, Harrogate, UK
10:20 AM–10:55 AM
Nonclinical Program to Support Modification to an Existing Well-known Formulation
Alan Christensen, Novo Nordisk A/S, Denmark
10:55 AM–11:30 AM
Nonclinical Program to Support Change of Formulation and
Administration Route of a GLP-1 Analogue
Charlotte Weimann, Novo Nordisk A/S, Denmark
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Interpreting Adverse Clinical and Anatomic
Pathology Results: Putting It All Together
8:00 AM–11:30 AM
Regency Hall
SESSION CHAIRS: Mary Jane Hinrichs, MedImmune,
Gaithersburg, MD and
Lila Ramaiah, Huntingdon Life Sciences, East Millstone, NJ
MedImmune and the American College of Toxicology
8:00 AM–8:10 AM
Introduction
Mary Jane Hinrichs, MedImmune, Gaithersburg, MD
8:10 AM–9:00 AM
Relations, Associations, Interactions and Causations: Principles for Correlating
Anatomic Pathology (AP) and Clinical Pathology (CP) Findings in Toxicology Studies
Lila Ramaiah, Huntingdon Life Sciences, East Millstone, NJ
9:00 AM–9:40 AM
Interpretation of Toxicity Findings through the Combination of Clinical and Anatomic
Pathology Data: Inflammation/Immunotoxicology
William Iverson, MedImmune, Gaithersburg, MD, and Elizabeth Skuba, Novartis Institutes
for Biomedical Research, East Hanover, NJ
9:40 AM–9:55 AM
Break
9:55 AM–10:40 AM
Interpretation of Toxicity Findings through the Combination of Clinical and Anatomic
Pathology Data: Peripheral Blood Cytopenias
William Iverson, MedImmune, Gaithersburg, MD, and Elizabeth Skuba, Novartis Institutes
for Biomedical Research, East Hanover, NJ
10:40 AM–11:30 AM
Diagnostic Utility and Interpretation of Traditional and Nontraditional Biomarkers
of Kidney and Liver Injury
Daniela Ennulat, GlaxoSmithKline, King of Prussia, PA
21 SUNDAY
This course will discuss the integrative approach required to interpret safety findings in toxicology studies. Specific focus will be
placed on the need to evaluate the data in its entirety, as neither clinical nor anatomic pathology can be relied upon in isolation
to fully understand the relationship between study findings and the test article. As such, the course content will involve a
collaborative effort between clinical and anatomical pathologists, who will discuss how they work together to interpret and
draw correlations between clinical pathology and anatomic pathology safety findings. The approaches used to interpret organspecific findings and diagnose common systemic physiologic processes will be described using a combination of general
principles and case examples. This course is intended for those interested in expanding their understanding of the approaches
used to interpret test-article related findings in nonclinical safety studies.
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EXHIBITOR-HOSTED PROGRAM
12:00 Noon–12:55 PM
Regency Hall
See page 137 for more information.
12:00 Noon–1:00 PM
New Member Luncheon (By invitation only)
Hydrangea
Afternoon CE Courses
SUNDAY
Toxicology and Pathology of the Respiratory
System
1:00 PM–4:30 PM
Regency Hall
SESSION CHAIRS: Daniel T. Kirkpatrick, WIL Research, Ashland, OH and
Torrie A. Crabbs, Experimental Pathology Laboratories, Inc., Research Triangle Park, NC
Experimental Pathology Laboratories, Inc. and WIL Research
The respiratory tract is a common target organ in toxicology studies. In order to determine the toxicological significance of
effects in the nose, larynx, trachea, and lung, it is important to understand the basic structure and function of these tissues.
Designing protocols for inhalation toxicology studies also requires knowledge of the current methods for inhalation exposure
of laboratory animals and evaluating respiratory structures and function. The first presentation will cover inhalation exposure
systems and administration techniques, and methods for generation and characterization of exposure atmospheres. The
remainder of the session will include detailed reviews of nose, larynx, trachea, and lung of common laboratory species. There
will also be a discussion on biomarkers, different tools used to determine related effects, and spontaneous and induced changes
observed in each part of the respiratory tract.
1:00 PM–1:10 PM
Introduction
Daniel T. Kirkpatrick, WIL Research, Ashland, OH
1:10 PM–1:50 PM
Considerations in Assessing the Impact of the Aerosolization of Drugs and Toxicants
in Respiratory Toxicology: It Is All About the Dose
Matthew D. Reed, Lovelace Respiratory Research Institute, Albuquerque, NM
1:50 PM–2:35 PM
Biomarkers for Respiratory Tract Toxicity Evaluation
James Michael Randazzo, WIL Research, Ashland, OH
2:35 PM–3:10 PM
Break
3:10 PM–3:50 PM
Anatomy and Toxicologic Pathology of the Upper and Lower Respiratory Tract
Torrie A. Crabbs, Experimental Pathology Laboratories, Inc., Research Triangle Park, NC
3:50 PM–4:30 PM
Immunohistochemical, Morphometric, and Stereological Evaluation of the
Respiratory Tract
Danielle L. Brown, WIL Research, Hillsborough, NC
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(Q)SAR—A Tool for the Toxicologist
1:00 PM–4:30 PM
Regency Hall
SESSION CHAIRS: Samantha Gad-McDonald, Gad
Consulting Services, Raleigh, NC and
Thomas J. Steinbach, Experimental Pathology Laboratories, Inc., Raleigh, NC
Experimental Pathology Laboratories, Inc. and Gad Consulting Services
1:00 PM–1:45 PM
(Q)SAR Basics: Understanding (Q)SAR Models and their Predictions
Naomi L. Kruhlak, US Food and Drug Administration, Silver Spring, MD
1:45 PM–2:30 PM
Practical Applications of (Q)SAR in Toxicology
Samantha Gad-McDonald, Gad Consulting Services, Raleigh, NC
2:30 PM–3:00 PM
Break
3:00 PM–3:45 PM
(Q)SAR and the Regulator
Mark W. Powley, US Food and Drug Administration, Silver Spring, MD
3:45 PM–4:30 PM
Applications and Pitfalls of (Q)SAR in Safety Assessments
Nigel Greene, Pfizer Inc., Groton, CT
23 SUNDAY
(Quantitative) Structure-Activity Relationships (Q)SAR methodologies use predictive computer modeling based on pre-defined
rules or statistical tools to correlate biologic activity with the molecular structure or properties of a compound. (Q)SAR has
applications in risk assessment, drug discovery, and regulatory decision making. Pressure within industry to reduce the cost
of drug development and societal pressure for government regulatory agencies to produce more accurate and timely risk
assessment of drugs and chemicals has necessitated the use of (Q)SAR. Producing a high-quality (Q)SAR model depends on
many factors including the choice of statistical methods and descriptors, and the quality of the data input into the model.
Understanding how a (Q)SAR model is developed and applied is critical to the successful use of such a powerful tool. This
session will cover, from a toxicologist’s perspective, how to interpret (Q)SAR results; how regulatory agencies use and interpret
(Q)SAR; practical applications of (Q)SAR in toxicology; and potential future application of (Q)SAR.
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Managing Anti-Drug Antibody Responses during
Biologics Drug Development
1:00 PM–4:30 PM
Palm
SESSION CHAIRS: Joerg Bluemel, Genentech,
Inc., South San Francisco, CA, and
Suzanne Wolford, Covance Laboratories Inc., Madison, WI
SUNDAY
Covance Laboratories Inc. and MedImmune
Immunogenicity of biotechnology-derived pharmaceuticals is frequently observed in nonclinical studies but can also affect
clinical development. Anti-Drug antibodies (ADA) are endogenous antibodies directed against a therapeutic protein, which
can also cross-react to other endogenous epitopes. The presence of ADA can have various biological consequences ranging
from no biological relevance, to impact on pharmacokinetics or pharmacodynamic or even the occurrence of toxicities due to
ADA. The impact of the occurrence of ADA on development strategies, their relevance for risk assessment and the necessity of
mitigation strategies is highly dependent on their functional consequences.
1:00 PM–1:45 PM
Biology, Relevance, and Impact of Anti-Drug Antibodies (ADA) during
Development of Biopharmaceuticals
Janice Lansita, ToxStrategies, Inc., Baltimore, MD
1:45 PM–2:30 PM
Bioanalytical Characterization of Anti-Drug Antibodies (ADA)
Ian Skitt, Covance Laboratories Inc., North Yorkshire, United Kingdom
2:30 PM–3:00 PM
Break
3:00 PM–3:45 PM
Toxicological Consequences of Anti-Drug Antibodies (ADA), Their Correlation
to Presence of ADA and Impact on Risk Assessment
T. Scott Manetz, MedImmune, Gaithersburg, MD
3:45 PM–4:30 PM
Strategies to Overcome /Minimize the Formation of Anti-Drug Antibodies (ADA)
in Nonclinical Studies
Simone M. Nicholson, MedImmune, Gaithersburg, MD
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Metabolites: Guidance and Considerations
in Drug Development
1:00 PM–4:30 PM
Regency Hall
SESSION CHAIRS: Holly Dursema, Boehringer
Ingelheim Pharmaceuticals, Inc, Ridgefield, CT and
Kate E. Lane, Cubist Pharmaceuticals Inc., Lexington, MA
Cubist Pharmaceuticals Inc.
1:00 PM–1:45 PM
Metabolites in Drug Development: Current Guidance
Clay B. Frederick, CBF Safety Assessment Consulting LLC, Dresher, PA
1:45 PM–2:30 PM
Metabolites in Drug Development: Assessment of Metabolites Present
in Animals and Humans
John-Michael Sauer, Critical Path Institute, Tuscon, AZ
2:30 PM–3:00 PM
Break
3:00 PM–3:45 PM
Disproportionate/Unique Metabolite: Case Study
Douglas A. Keller, Sanofi US, Bridgewater, NJ
3:45 PM–4:30 PM
Metabolites in Drug Development: An FDA Perspective
Carol M. Galvis, US Food and Drug Administration, Silver Spring, MD
6:30 PM–8:30 PM
Welcome Reception
(Ticketed Event) See page 10 for more information
25 The Wilderness
Portico West
SUNDAY
This course will review guidance that currently exists for nonclinical assessment of metabolites discovered during drug
development. This topic has matured over the last five years, therefore a review of the existing guidance and their application
is timely. The objective of this course is to provide participants with an understanding of guidance and tools they may use to
investigate human metabolites encountered during development. The first speaker will review current guidance documents
and present ways to incorporate those assessments into drug development. The second speaker will discuss use of this
guidance in assessment of a metabolite that is present in both animals and humans. The third speaker will discuss assessment
of a disproportionate human metabolite and/or unique human metabolite. The final speaker will provide FDA perspective on
evaluation of human metabolites. Time will be allotted for discussion of each aspect. The staging of the speakers has been done
to familiarize the audience with guidance and progress them through the challenges that may be encountered in metabolite
assessments. This course will be of interest primarily to members in the pharmaceutical field.
Experts in the Exhibit Hall
Monday
Morning Break: Plenary Lecturer Deborah Blum will be in the ACT Member Lounge
to sign your copy of The Poisoner’s Handbook
Afternoon Break: Come congratulate ACT’s Distinguished Scientist Awardee
Anthony Dayan in the ACT Member Lounge
Tuesday
Come to the Exhibit Hall in the afternoon and meet the Editor of ACT’s
International Journal of Toxicology, Mary Beth Genter at the SAGE Exhibit Booth (#304)
She’ll have tips for:
•
publishing in the Journal
•
reviewing manuscripts
•
preparing Symposium Overview manuscripts
ACT Members’ Meeting
Tuesday, November 11, 5:00 PM–6:30 PM
ACT Members Only
Join your colleagues for the annual Members’ Meeting.
Hear important reports from:
• President Drew A. Badger
• President-Elect
Mary Ellen Cosenza
• Treasurer Alan Hoberman
• Membership Committee Chair
Timothy McGovern
• Nominating Committee Chair
Robin C. Guy
• Publications Committee Chair
Mary Beth Genter
• And new initiatives!
Be an active member of
the American College of Toxicology and participate!
No registration required.
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6:45 AM–8:00 AM
Past Presidents' Breakfast
2014
Gardenia
(By invitation only)
Monday Morning Sessions
PLENARY LECTURE 1
The Poisoner's Guide to Life
8:00 AM–8:55 AM
Regency Hall
DEBORAH BLUM
PULITZER-PRIZE WINNER AND AUTHOR OF THE POISONER’S HANDBOOK:
MURDER AND THE BIRTH OF FORENSIC MEDICINE IN JAZZ AGE NEW YORK
Deborah Blum is the Pulitzer Prize–winning author of five books, most recently The Poisoner’s
Handbook: Murder and the Birth of Forensic Medicine in Jazz Age New York, which was named as one of
the top one-hundred books of 2010 by Amazon. A highly acclaimed science journalist and former
president of the National Association of Science Writers, Deborah is also co-editor of A Field Guide for
Science Writers. Her work has been translated into more than a dozen languages, optioned for film,
and has appeared in numerous publications, including The New York Times, Slate, The Washington
Post, the Los Angeles Times, The Guardian, Discover, and Health. She also writes about chemistry and
culture for the Public Library of Science in her blog, Speakeasy Science.
MONDAY
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SYMPOSIUM 1
From Mice to Men, Development of Human Drugs
and Biologics under the Animal Rule
CHAIR: John V. Wade, Battelle,
9:00 AM–12:00 Noon
Palm
Columbus, OH
CO-CHAIR: Owen McMaster,CDER/US Food and Drug Administration, Silver Spring, MD
Battelle Memorial Institute
The animal efficacy rule was finalized in 2002 and applies to the development of drugs to reduce or prevent serious lifethreatening conditions caused by exposure to lethal or permanently disabling toxic agents; including chemical, biological,
radiological, or nuclear (CBRN) substances. The studies conducted under the animal rule are used to support approval of
treatments, as human clinical trials are generally not feasible or unethical. The characterization and development of animal
efficacy models is critical to the success of drugs or vaccines being developed under the animal rule. This session will provide
an introduction to the animal rule, the qualification requirements for animal efficacy models development, and case studies of
development programs for therapeutics and vaccines.
S1–1
9:00 AM–9:35 AM
Overview of the Animal Rule
Barbara J. Mounho-Zamora, ToxStrategies, Bend, OR
S1–2
9:35 AM–10:05 AM
Animal Model Qualification Process and the Medical
Countermeasures Initiative
Owen McMaster, US Food and Drug Administration, Silver Spring, MD
S1–3
10:05 AM–10:35 AM
Development of Brincidofovir for the Treatment of Smallpox
under the Animal Rule
MONDAY
Lars C. Trost, Chimerix, Durham, NC
S1–4
10:35 AM–10:55 AM
Break
10:55 AM–11:30 AM
Utilizing Well-Characterized Drug Development Tools for The Assessment
of Medical Countermeasures: Anthrax Antitoxins
Gabe Meister, Battelle, Columbus, OH
S1–5
11:30 AM–12:00 Noon Development of an Anthrax Vaccine under the Animal Rule: A Case Study
Barbara J. Mounho-Zamora, ToxStrategies, Bend, OR
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S1–1
The Animal Rule (21 CFR 314.600 for drugs; 21 CFR 601.90
for biological products) provides regulation and a licensure
pathway that allows FDA to grant marketing approval for
candidate therapeutic products where it is neither ethical
nor feasible to conduct traditional human efficacy studies. In
such cases, a therapeutic product may be granted marketing
approval based on adequate and well-controlled animal studies
for the demonstration of clinical efficacy. There are several
novel biological products under clinical development that
may fall under the Animal Rule. For example, vaccines against
microbial pathogens that might be used in biological warfare
fall under the Animal Rule, and use animal studies (vs. human)
may be performed for the demonstration of clinical efficacy.
Several criteria, however, such as characterization of the
pathophysiological mechanism of toxicity of the pathogen and
selection of endpoints of efficacy used in the animal studies,
must be fulfilled in order for the FDA to consider using animal
studies to provide substantial evidence of clinical effectiveness.
This presentation will provide an overview of the Animal
Rule and challenges in bridging animal protection data to
human efficacy.
S1–2
S1–3
The talk will discuss potential challenges in developing
drugs under the Animal Rule by tracing the development of
Brincidofovir for treatment of smallpox, including technical
and project management issues. The development of relevant
animal models, which is frequently in collaboration with
academic or government institutions, and the subsequent
transfer of models to qualified nonclinical testing facilities
capable of conducting GLP-compliant studies will be discussed.
Challenges in the design of animal efficacy protocols, in
particular, establishing inclusion/exclusion criteria, study
blinding, and objective euthanasia criteria, of particular
importance to studies in which prevention of mortality is the
primary endpoint. The talk will conclude by touching briefly on
the unique regulatory challenges associated with the Animal
Rule, lack of precedence often chief among them, and scaling
to a human dose from doses proven effective in animal models.
S1–4
Battelle, with funding support from NIAID DMID/OBRA and
BARDA, has worked to establish well-characterized drug
development tools (small and large animal models) to assess
the effectiveness of anthrax adjunct therapies in support of
regulatory submissions. Preliminary studies assessed the clinical
and physiological parameters following exposure to Bacillus
anthracis Ames strain spores in New Zealand White (NZW)
rabbits and cynomolgus macaques to build a clinical profile of
disease and define appropriate therapeutic markers utilized
as “triggers” for treatment in subsequent efficacy studies.
Pilot efficacy studies validated the use of specific diagnostic
markers and pivotal efficacy studies were conducted to further
confirm the use of the markers. An FDA Anti-Infective Drugs
Advisory Committee was convened to discuss the Biologic
License Application (BLA) for the first monoclonal antibody
(antitoxin) to treat inhalational anthrax. During the discussion,
and confirmed by the voting results, the Advisory Committee
agreed that the effectiveness observed in the nonclinical
efficacy studies would be predictive of efficacy in humans.
The US FDA approved the first antitoxin for the treatment of
inhalational anthrax on December 14, 2012. Conforming to the
requirements set forth in 21 CFR 314.600 for drugs and 21 CFR
601.90 for biologicals, well-characterized drug development
tools are needed for drugs to be approved to treat serious or
life-threatening conditions caused by exposure to lethal or
permanently disabling toxic biological, chemical, radiological,
or nuclear substances.
S1–5
Anthrax is a serious disease that is highly contagious and can
affect both animals and humans. Anthrax is caused by bacteria
called Bacillus anthracis (B. anthracis), which is a gram positive,
facultative anaerobic, rod-shaped, highly pathogenic bacterium
that has the ability to form endospores. Due to the durability
of the endospores, B. anthracis can be easily aerosolized, and
therefore, has the potential to be weaponized and pose a threat
for use in biological warfare. This presentation will review a
case study of the development of an anthrax vaccine under
the Animal Rule, including the animal studies demonstrating
efficacy as well as the nonclinical safety assessment studies.
29 MONDAY
Acceptable animal models have not been developed for many
chemical, biological, radiological, nuclear, and infectious
disease threat agents. The FDA's Animal Model Qualification
Program (AMQP) encourages the qualification of animal models
that simulate the human disease or condition resulting from
these agents. For an animal model to be qualified, there must,
among other things, be a well-understood pathophysiological
mechanism of the challenge agent and its attenuation by
the medical countermeasure (MCM). The AMQP evaluates
animal models based on data from the human disease or
condition and data from animal model natural history studies.
Qualification of an animal model implies that FDA has accepted
that a specific animal species given a specific challenge agent
by a specific route produces a disease process or condition that
corresponds to the human disease or condition of interest. This
qualified model may subsequently be used for efficacy testing
in development programs for multiple investigational drugs
for the same disease or condition. This session will discuss
FDA's Animal Model Qualification Program including (1) The
conditions under which an animal model may be qualified,
(2) Characterization of the animals and challenge agent (3)
Required procedural information (4) Triggers for intervention
(5) Primary and secondary endpoints. This talk will close with
the activities of the medical countermeasures initiative since its
formation in 2010.
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SYMPOSIUM 2
What the AEL is the NOAEL?
9:00 AM–12:00 Noon
Grand Cypress
Ballroom A
CHAIR: Joy A. Cavagnaro, Access
BIO, Boyce, VA
CO-CHAIR: Lisa D. Beilke,Toxicology Solutions, Inc., San Diego, CA
MPI Research and the American College of Toxicology
Is the NOAEL different in the eyes of a pathologist vs. a toxicologist, a clinical reviewer/FIH clinical investigator—the animal?
Does clinical indication impact NOAEL and/or application of a NOAEL to a clinical indication? The pharmacological activity
that is outside the projected therapeutic profile of a new drug may include a spectrum of functional effects, which are not
hazardous and are reversible. Minor, albeit undesirable, effects should therefore be distinguished from unintended reactions
that are pertinent to toxicity and that may lead to target organ effects. In this way, pharmacodynamic activity, which is integral
to the therapeutic action of a drug, may be viewed differently from activity, which is not indispensable for efficacy. In this
respect, structural (morphological) changes in organs or tissues of potentially irreversible nature are of particular concern. For
that reason, histopathology has remained the most consistent criterion by which target organs are identified and NOAELS are
set. This session will draw out the common points that scientists often debate on this subject, particularly as exemplified by case
examples. There will also be an interactive session where data will be presented and the audience will have an opportunity to
vote on whether a NOAEL has been demonstrated.
S2–1
9:00 AM–9:40 AM
Recommended Practices for Defining and Communicating Adversity
for Nonclinical Study Data
James A. Popp, Stratoxon LLC, Lancaster, PA
S2–2
9:40 AM–10:20 AM
Determining Adverse Histopathology using a Weight of Evidence Approach
MONDAY
Daniel J. Patrick, MPI Research, Mattawan, MI
S2–3
10:20 AM–10:40 AM
Break
10:40 AM–11:20 AM
NOAEL Selection and Risk Assessment for Biologics
and Other Nontraditional Small Molecules
Laine Peyton Myers, OND/OAP/DAVP/CDER/US Food and Drug Administration,
Silver Spring, MD
S2–4
11:20 AM–12:00 Noon When Should Pharmacology/Superpharmacology Be Considered
Adverse (Ever?)
Christopher Horvath, bluebirdbio, Cambridge, MA
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S2–1
Identifying and communicating a NOAEL continues to be
a central issue related to toxicology studies prepared for
regulatory submission. As the term indicates, the NOAEL
is based on the identification of an adverse effect. The lack
of concurrence in what constitutes an adverse effect and
the inconsistencies around the communication of adverse
effects continue to be the basis of difficulties and differences
of opinion amongst practicing toxicologist and toxicologic
pathologists, despite many published attempts to address the
topic. The Society of Toxicologic Pathology (STP) developed
a set of recommended practices to serve as a guide for
determining and communicating adversity in nonclinical
studies more effectively with the goal of reducing confusion
regarding the use of the NOAELs in the future. In addition, the
recommended practices address the role of the toxicologist
and toxicologic pathologist in assessing potential human risk
based on adverse findings. The STP recommended practices
will be presented advocating a more consistent approach to
addressing adverse findings so that reliance on the NOAEL
may not be needed over time.
S2–3
A NOAEL is commonly used as a benchmark for the first-inhuman studies for pharmaceuticals. NOAEL determinations
hinge on multiple endpoints (e.g., histopathology panel,
in vitro-binding assays). Many times, the Sponsor and the
Agency will agree on the endpoints and the First in Human
dosing will proceed as scheduled. For small molecules, the
path forward is relatively uncomplicated. On occasion, the
FIH dose for these small molecules may be confounded (e.g.,
host resistance study outcomes, immunomodulator effects).
Moreover, for biological products and other nontraditional
small-molecules, there are certain challenges during drug
development that may confound defining a NOAEL. Biologic
products have confounding variables (small group size,
immunogenicity, species specificity/relevance) that may
confound data interpretation. Furthermore, some applications
include data using a surrogate molecule and/or a transgenic
species used in calculating a NOAEL. Lastly, other molecules
(e.g., oligonucleotide-based drugs) can often present speciesspecific issues that may confound the determination and/
or interpretation of the NOAEL. This talk will discuss unique
challenges to NOAEL selection and interpretation of the
NOAEL into risk assessment during drug development.
S2–4
For biologics, which must be tested in a pharmacologicallyrelevant species, toxicology studies generally assess safety
by using pharmacologic (comparable to anticipated human
doses) and superpharmacologic doses. The intent is to
maximize the pharmacodynamic response and to explore
whether secondary or “super” pharmacology occurs at
higher doses. Thus, at every dose level some effects will
be observed. Establishing a NOAEL in these settings may
be challenging. At pharmacologically-relevant doses, the
intended pharmacology may not be adverse, while at higher
doses, the intended effects may be adverse, and at some doses
it may be unclear whether the observed effects are adverse.
Additionally, the same effects may be considered acceptable
(nonadverse) in one patient population (e.g., cancer) and
considered not acceptable (adverse) in another population
(e.g., autoimmune disease).
An additional complication for determination of NOAELs for
biologics is the occurrence of immunogenicity and immunerelated events. Most human biologics are immunogenic in
animals, including monkeys. Anti-Drug antibodies (ADA)
can precipitate a wide range of effects in animals that may
have little or no relevance to human safety assessment.
For example, ADA may be associated with evidence of
immune stimulation, formation of intravascular or tissue
immune complexes, infusion or hypersensitivity reactions,
development of glomerulonephritis and/or neutralization
of an endogenous protein. Some of these events may be
adverse in animals, and would be adverse if they were to occur
in humans, yet their occurrence in animals is not predictive
of the risk to humans. Due to the immune-mediated nature
of such events, when they occur they are often not dosedependent (e.g., are idiosyncratic). Paradoxically, the highest
dose might provide a NOAEL while the lowest dose might
not. In some cases, the immune-related events can be clearly
demonstrated to be unique to animals, in which case the any
immune-based NOAEL might not be relevant to humans. This
talk will attempt to explore such issues, and may raise more
questions than it answers.
31 MONDAY
S2–2
This presentation will discuss the thought process a
toxicologic pathologist might employ when distinguishing
histopathologic changes that could be considered adverse,
nonadverse or somewhere in between. The overall
determination is based on a weight of evidence approach
utilizing multiple criteria, as well as the subjective scientific
opinion of the pathologist. Case examples with representative
photomicrographs, associated clinical pathology, and other
relevant data will be presented.
2014
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SYMPOSIUM 3
Systems Toxicology: The Future of Risk Assessment
CHAIR: John Michael Sauer, Predictive
9:00 AM–12:00 Noon
Magnolia
Safety Testing Consortium (PSTC), Tucson, AZ
CO-CHAIR: A. Wallace Hayes,Harvard School of Public Health, Andover, MA
Philip Morris International R&D
The vision of the National Research Council report on Toxicity Testing in the 21st Century is becoming a reality as modern
high-content and high-throughput technologies are applied. The approach can improve the toxicological assessment of a
wide range of substances including those developed for example by the pharmaceutical, chemical, cosmetic, and tobacco
industries. This symposium will share the results from leading researchers in the field to underpin the revolution that is taking
place in toxicology.
S3–1
9:00 AM–9:40 AM
Translating Systems Toxicology-Based Assessment into Risk Management
Thomas Hartung, John Hopkins University, Bloomberg School of Public Health,
Baltimore, MD
S3–2
9:40 AM–10:20 AM
Experimental Enablers: The Pan-Omics View
Marcel Leist, University of Konstanz, Germany
S3–3
10:20 AM–10:40 AM
Break
10:40 AM–11:20 AM
Computational Enablers: From Data Integration to Dynamic Modeling
Thomas B. Knudsen, US Environmental Protection Agency, Research Triangle Park, NC
MONDAY
S3–4
11:20 AM–12:00 Noon Implementing Systems Toxicology Approaches
Julia Hoeng, Philip Morris International R&D, Neuchâtel, Switzerland
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S3–1
This presentation is intended to set the scene for the
symposium by defining Systems Toxicology, spelling out its
aim(s) and explaining how it can and must be part of the new
paradigm for risk assessment and risk management.
S3–2
This presentation is intended to define key experimental
enablers of Systems Toxicology and how they can be applied
in various experimental settings from in vitro to clinical studies.
It will cover the main *omics technologies as well as highcontent screening using in vitro systems.
2014
S3–3
This presentation is intended to define key computational
enablers of systems toxicology and how they can be applied
in various settings ranging from Big Data management to
the simulation of complex pathways of toxicity and adverse
outcomes in a virtual organism.
S3–4
This presentation is intended to present how an integrated
systems toxicology program can be implemented in an
industry setting and present three case studies where it was
applied in vitro, in vivo and in the clinic.
MONDAY
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12:00 Noon–2:00 PM
Awards Ceremony and Luncheon
2014
Regency Hall
(Included in registration fee) See Page 10 for more information.
Monday Afternoon Sessions
SYMPOSIUM 4
Antidrug Antibody-Independent Immune
Responses to Biologics in Rodent Studies—
Regulatory Success in Early Drug Development
CHAIR: Krishna P. Allamneni,Jazz
2:00 PM–5:00 PM
Palm
Pharmaceuticals, Inc., Palo Alto, CA
CO-CHAIR: Joy A. Cavagnaro,Access
BIO, Boyce, VA
Due to the advances in recombinant protein technologies and subsequent development of rodent-crossreactive biologic
agents for therapeutic use in humans, a rising trend is noted for rodent toxicology studies for biologics. The development
of binding, sustaining/neutralizing antidrug antibodies and subsequent safety or efficacy liabilities are well recognized. This
symposium highlights the emergence of immune reactions in rodents that cannot be definitively attributed to immunogenicity
of the biotherapeutic agents. A high-level overview of the pathophysiology of immune system in rodents, clinical presentation
of immune reactions and differential diagnosis are discussed as a framework to assess risk. Plausible mechanisms of antidrug
antibody-independent immune responses in rodents are explored. Available tools to evaluate, characterize, and/or confirm
immune reactions specific to mice, rats, monkeys and their limitations are presented. Case examples of clinical development in
the context of rodent-specific immune responses are presented. A comprehensive view of the regulatory perspective on such
rodent-specific immune responses in the context of first-in-human risk assessment is presented.
S4–1
2:00 PM–2:15 PM
Overview
MONDAY
Krishna Allamneni, Jazz Pharmaceuticals, Inc., Palo Alto, CA
S4–2
2:15 PM–2:50 PM
Clinical Impact of Rodent-Specific Immune-Related
Reactions to Human Proteins
Joy A. Cavagnaro, Access BIO, Boyce, VA
S4–3
2:50 PM–3:20 PM
Non-ADA Mediated Anaphylactoid Reactions in Toxicology Studies
with Rodents
Krishna Allamneni, Jazz Pharmaceuticals, Inc., Palo Alto, CA
S4–4
3:20 PM–3:55 PM
Break
3:55 PM–4:25 PM
Immunotoxicoloogy Tools to Characterize Species-Specific Immune Reactions
Florence G. Burleson, Burleson Research Technologies, Inc., Morrisville, NC
S4–5
4:25 PM–5:00 PM
Regulatory Perspectives on the Rodent-Specific Immune Reactions
Jane Sohn, US Food and Drug Administration, Silver Spring MD
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S4–1
Problem statement is presented along with industry trends
on the prevalence of GLP studies in rodents for biologics.
A high-level overview of the physiology of immune system
in rodents, types of immune reactions, species differences,
in-life, clinical pathology and histopathology presentation,
differential diagnosis, relevance to humans is discussed as a
framework to assess risk. S4–2
It is acknowledged in ICHS6(R1) that immunogenicity
assessments are [only] conducted to assist in the interpretation
of toxicity study results (e.g. immune-mediated reactions
such as immune complex-related, vasculitis, anaphylaxis,
etc.) and are not relevant in terms of predicting potential
immunogenicity of human or humanized proteins. However
as rodents are increasingly being defined as relevant species
in early development programs there has been a higher
incidence of unexpected fatal acute infusion reactions which
may or may not correlate with antibody development that
have negatively impacted clinical development. Case studies
will be presented highlighting specific findings, consequences
and risk mitigation strategies to support clinical use.
S4–4
Biotherapeutics now make up greater than 50% of the
pharmaceutical pipeline. Unintended adverse immune
reactions following administration of biotherapeutics have
been observed in animal studies and man. These adverse drug
reactions may be hypersensitivity reactions that are antidrug
antibody (ADA) mediated, or idiosyncratic drug reactions
(IDRs). Non-ADA-mediated reactions include pseudoallergy
and cytokine release syndrome. In these type of reactions
the timing of observations, sample type, and timing of
acquisition are critical parameters. This symposium will review
these critical parameters, as well as the methods and assays
currently available to evaluate, or try to predict, unintended
adverse immune reactions. Gaps will be identified and future
directions discussed.
S4–5
Rodent toxicology studies are increasingly required for the
development of biologic products as scientific advances have
led to biologics with crossreactivity to rodents. The presentation
will focus on the review of biologics products on a case-bycase basis. Case studies of biologics with crossreactivity to
rats, with immune reactions will be presented. Each case
will highlight hypothetical analysis of data, and the review
process within CDER.
35 MONDAY
S4–3
Multiple case studies are presented of clinical candidates that
are not immunomodulatory in action. Clinical candidates
demonstrated high nanomolar affinity to targets in rodents
and in vivo functional activity in rodent models. Therefore,
rodents were considered biologically relevant for preclinical
safety assessment to enable first-in-human clinical trials. This
presentation details the transient immune reactions noted
in the toxicology studies with mice and rats. Results of the
subsequent investigational studies conducted to evaluate the
mechanistic basis of the immune reactions are discussed with
a focus on plausible hypotheses and regulatory package for
the clinical candidates.
2014
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SYMPOSIUM 5
Use of Humanized Mouse Models in DMPK
and Safety Testing of Compounds
CHAIR: Alema Galijatovic Idrizbegovic,Merck
CO-CHAIR: Charles Roland Wolf,University
2:00 PM–5:00 PM
Magnolia
& Co, West Point, PA
of Dundee, Dundee, United Kingdom
Taconic
The use of traditional laboratory animals to predict human outcomes in pharmacokinetics, drug-drug interaction or toxicity of
compounds is often limited by the significant differences which exist between animals and man. In order to address this issue
a lot of efforts have been made by various groups over the last years to generate humanized mouse models, which are more
predictive for various aspects of drug responses in humans. One approach is the generation of genetically humanized mice
expressing single or multiple human proteins involved in drug metabolism and disposition, such as xenobiotic receptors, drug
metabolizing enzymes and transporters. Another strategy involves the replacement of mouse with human tissue, resulting, for
example, in humanized mice for the liver and/or immune system.
This symposium provides the current status and discusses the future perspectives in the field of humanized mouse models
from the user’s perspective. It will be of interest to scientists involved in commercial drug development, particularly working
in drug metabolism and toxicology, academic researchers, as well as regulators evaluating data generated during safety
testing. Furthermore, with potential applications for risk assessment of chemicals and food ingredients, it will provide relevant
information to scientists in the chemical and consumer healthcare industries.
S5–1
2:00 PM–2:30 PM
Nearly Human—The Potential of Chimeric Mice with Livers Colonized
with Human Hepatocyte
Ian D. Wilson, Imperial College London, South Kensington, London, United Kingdom
MONDAY
S5–2
2:30 PM–3:05 PM
Application of Humanized Mouse Models to Study Anticancer Drug Efficacy
and Toxicity
Charles Roland Wolf, University of Dundee, Medical Research Institute, Ninewells, Dundee,
United Kingdom
S5–3
3:05 PM–3:35 PM
Utility of Humanized Mice in the Assessment of Biological Drug Products
Kristina Howard, US Food and Drug Administration, Silver Spring, MD
S5–4
3:35 PM–3:55 PM
Break
3:55 PM–4:25 PM
Humanized Mouse Models—Applications in Preclinical Testing
Alema Galijatovic-Idrizbegovic, Merck & Co, West Point, PA
S5–5
4:25 PM–5:00 PM
Regulatory Perspective on Alternative Animal Models
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S5–1
There are now a number of commercially available mouse
models where the liver has been largely repopulated with
human hepatocytes. These so called "chimeric" humanized
mice have an obvious potential for the investigation of
hepatic human metabolism and toxicity of drugs and other
xenobiotics. The emerging data suggest that such models do
indeed provide "human-like" metabolic data and as such these
chimeric animal models clearly merit further investigation.
Our experiences of using liver humanized mouse models,
based on colonization the livers of uPA-SCID or FRG mice
with human hepatocytes, will be described together with
selected published investigations that have employed these
models. Particular emphasis will be given to applications
in toxicology, and an attempt will be made to put these
models into context with alternative methods, such as in
vitro tools. The state of development of these chimeric mouse
models will be considered and their advantages and current
limitations will be discussed.
S5–2
The efficacy of currently used and emerging anticancer drugs
can often be intimately linked to their rate of metabolism by
enzymes such as the cytochrome P450-dependent monooxygenases. Also, the effectiveness of these drugs is often
limited by the emergence of drug resistance or drug side effects.
2014
S5–4
Transgenic mice humanized for key human proteins involved
in metabolism, and chimeric mice with highly humanized
livers can serve as models to address and evaluate metabolites
formed uniquely in humans as well as models to evaluate
endogenous metabolites to improve human safety prediction
from preclinical species. In addition rasH2 transgenic mice
carrying human c-Ha-ras oncogene in addition to the
endogenous murine Ha-ras oncogene, which are highly
susceptible to tumor formation, allow for rapid carcinogenicity
evaluation as an alternative to 2-year mouse carcinogenicity
studies, and are enabling significant changes to rodent
carcinogenicity testing strategy being discussed through ICH.
This talk will focus on the utility of these models to improve
and accelerate preclinical development of molecules and
reduce attrition of molecules in the clinical studies due to
metabolism and toxicology.
S5–5
This brief presentation will review the role of standard and
alternative animal models in drug development. Examples
of existing and potential applications as well as regulatory
expectations of alternative models will be discussed. Focus
will be placed on testing to support safety assessment.
S5–3
Testing of biological drug products for safety and efficacy in
animal models has been difficult to assess because common
models such as rodents, canines and nonhuman primates
do not necessarily share common biological receptors with
humans. Immunologically humanized mice offer the ability to
test the efficacy and safety of biological drug products in an in
vivo model of the human immune system. This talk will present
results of biological drug product testing in this model.
37 MONDAY
We have been using mouse models humanized for the
major P450s involved in drug disposition in man as well as
the transcription factors, which regulate their expression to
establish the role of these enzymes in defining the outcome
of the anticancer drug therapy. Our work has involved
studies into a range of tyrosine kinase inhibitors which
are either hepatotoxic or where drug resistance is a major
limiting factor in drug efficacy. In this presentation our
work in this area, including studies on the B-Raf inhibitor
vemurafenib, will be described.
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2014
SYMPOSIUM 6
Targeted Cancer Therapeutics: Concepts and
Strategies to Improve Oncology Drug Development
CHAIR: Vijayapal Reddy, Eli
2:00 PM–5:00 PM
Grand Cypress
Ballroom A
Lilly and Company, Indianapolis, IN
CO-CHAIR: Elaine Knight,National
Cancer Institute, Rockville, MD
Over the last decade, the focus for anticancer drug discovery has shifted from traditional cytotoxic agents (with significant
and well characterized toxicities) to rationally designed, molecularly-targeted pharmaceuticals. Of the new anticancer drugs
approved by the US Food and Drug Administration (FDA) since 2000, a majority have been targeted therapies, compared with
only few traditional chemotherapeutic agents. The safety data derived from studies of approved targeted pharmaceuticals
provide a wealth of information on the nature of toxicities identified in both nonclinical species and in patients. In many cases,
the toxicity profile of a targeted therapeutic is closely linked to the biological consequences of modulating the intended
targets. Continued advancement in our understanding of mechanisms of toxicity should provide a better understanding of the
relationships between drug efficacy and toxicity, and possibilities for better clinical management of toxicity. This symposium
will provide an overview of the advances in cancer biology that have facilitated discovery of anticancer drug targets or improved
candidates for drug development. The symposium also will include an overview of approaches to nonclinical safety evaluation
and tailored clinical evaluation of anticancer agents. Last, the session will include a regulatory perspective and regulatory
challenges for both small and biologic targeted cancer pharmaceuticals. This topic should be interested to a broad range of
attendees including those from industry, academia, government and clinical, and healthcare professionals.
2:00 PM–2:15 PM
Introduction: Targeted Cancer Therapies: Concepts and Strategies
to Improve Oncology Drug Development
MONDAY
Elaine Knight, NCI/National Institutes of Health, Rockville, MD
S6–1
2:15 PM–2:50 PM
Cancer Biology and the Discovery of Targeted Therapies
Alan C. Rigby, ImClone Systems, a Wholly-owned subsidiary of Eli Lilly and Company,
New York, NY
S6–2
2:50 PM–3:25 PM
Targeted Anticancer Pharmaceuticals: Off-Target and On-Target Toxicities
Vijayapal Reddy, Eli Lilly and Company, Indianapolis, IN
S6–3
3:25 PM–3:45 PM
Break
3:45 PM–4:30 PM
Transforming the NCI Experimental Therapeutic Program as It Relates
to Clinical Evaluation of Targeted Therapies
S. Percy Ivy, NCI/National Institutes of Health, Rockville, MD
S6–4
4:30 PM–5:00 PM
Regulatory Perspective on the Development of Targeted
Anticancer Therapeutics
Todd R. Palmby, CDER/US Food and Drug Administration, Silver Spring MD
5:30 PM–7:00 PM
See Page 10 for more information.
38 Exhibit Hall
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S6–1
An overview of the advances in cancer biology that have
facilitated discovery of anticancer drug targets or improved
candidates for drug development.
S6–2
Continued advancement in our understanding of mechanisms
of toxicity of targeted anticancer pharmaceuticals should
provide a better understanding of the relationships between
drug efficacy and toxicity, and possibilities for better clinical
management of toxicity.
S6–3
determination must use greater than cycle 1 adverse events
to established non-DLT based, but rather all grades of adverse
events to define a safe and tolerable dose to be used in future
studies. This presentation will present the challenges and
approaches that need to be developed for development of
MTAs. New and novel trial designs will need to be developed
as drug development proceeds in the 21st century.
S6–4
The development of anticancer therapeutics that are
designed to affect specific pathways known to be modulated
or deregulated in tumors or necessary for maintaining the
tumor phenotype is an exciting concept that has had many
successes in recent years. Nevertheless, many regulatory
challenges arise in these drug development programs due
to the specific nature of the products or diseases that they
are being used to treat. This presentation will discuss ICH
regulatory guidances S9, S6(R1) and M3(R2)relevant to the
development of targeted anticancer therapeutics and when
consideration should be given to the scope and specific
recommendations of each. Regulatory challenges that FDA
faces with these development programs include the often
chronic administration in patients, use in adjuvant or first-line
treatment settings, timing of nonclinical studies to support
use in certain patient populations, developmental and
reproductive toxicology studies with monoclonal antibodies,
antibody-drug conjugates, immunomodulators and products
affecting epigenetic pathways.
Toxicities observed in
clinical trials and in the post-marketing setting for recent
development programs of small molecule targeted anticancer
therapeutics were not always observed in nonclinical studies
conducted with current animal models, indicating a need for
better predictivity. Issues involved in identifying potential
clinical toxicities will be discussed including integration
of pharmacology data and considerations for the design
and conduct of nonclinical toxicology studies. Clinical trial
design for small molecule targeted anticancer therapeutics
may need to evolve due to emergence of toxicities in clinical
trials following many weeks to months of administration,
particularly with regard to how the Phase2/3 clinical dose is
selected. FDA is evaluating current practices by stakeholders
for conducting adaptive design Phase 1 clinical trials aimed
at identifying a recommended Phase 2 dose, integration of
nonclinical data into dose evaluation past the first-in-human
dose, integration of clinical pharmacology data and exposureresponse relationships and design and conduct of Phase 2
clinical dose-fnding trails.
39 MONDAY
The National Cancer Institute’s Experimental Therapeutics
Program performs the early clinical evaluation of molecularly
targeted agents (MTAs) that they hold under IND for cancer
treatment. NCI performs most of this work using two new
networks of investigators with expertise in phase 0, 1, and 2
clinical trials for drug development. The NCI’s Experimental
Therapeutics Clinical Trials Network is primarily focused on
clinical trials that are used to determine the dose, schedule and
safety of new drugs used for the first time in human subjects.
These trials will typically focus on the pharmacokinetics,
pharmacodynamics and response to treatment for the
new agents. The development of MTAs also involves the
identification and initial evaluation of biomarkers that can be
used to select patients for enrollment or to be assigned to a
specific treatment. The development of MTAs has brought
with them dramatic successes and new challenges for drug
development. Prior to 2000, development was focused on
cytotoxic chemotherapies and dose determination based on
safety and tolerability using a maximum tolerated dose that hit
rapidly dividing cancer cell and relatively spared normal tissue.
Development of MTAs is now focused on the determination
of an optimal biological dose which may not cause dose
limiting toxicity. Adverse events detected and described
during the conduct of early clinical trials of small molecule
targeted anticancer therapeutics are often not predicted
by the nonclinical studies using the current animal models.
MTAs are expected to cause both on target and off target
toxicity and also cause chronic low grade or DLT in cycles of
treatment beyond the first cycle of therapy. Using DLT only to
determine the recommended phase 2 dose, has led to doses
that are licensed for specific indications, but not tolerable for
extended administration. The definition of new paradigms for
pre-clinical evaluation IND directed pharm/tox are needed.
Likewise, clinical paradigms for recommended phase 2 dose
2014
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Annual Meeting
6:30 AM–7:30 AM
ACT's Inaugural ToxTrot
2014
Portico West Patio
(Free event, registration by October 30 required)
8:00 AM–9:00 AM
Breakfast Reception
Grand Cypress
Ballroom
(Open event)
Tuesday Morning Sessions
SYMPOSIUM 7
Breathe In, Breathe Out, It's Easy: What You Need
to Know about Developing Inhaled Drugs
CHAIR: Jeff Tepper, Tepper
9:00 AM–12:00 Noon
Regency Hall
Nonclinical Consulting, San Carlos, CA
CO-CHAIR: Jim Blanchard,Aradigm, Hayward, CA
Lovelace Respiratory Research Institute, Huntingdon Life Sciences, and Seventh Wave Laboratories
It's no surprise that toxicologists feel unprepared for their first development program using an inhaled drug. Understanding
of the area requires knowledge of lung anatomy, cell biology, respiratory physiology, particle physics and plumbing. Although
Paracelsus informed us that the dose makes the poison and thus is of paramount importance, in the context of an inhaled
drug, the "dose" is not easily defined. This symposium will attempt to demystify and provide background information
enabling you to understand the issues and challenges associated with the assessment of respiratory safety pharmacology
and designing an inhalation toxicology program. First, an overview examining ventilation, how to measure it, its influence on
dose and the perturbations observed with inhalation exposure will be covered. The topic of dose will be further explored to
better understand the assumptions and methods associated with determining drug deposition and clearance to arrive at lung
dose. Next, the techniques used to deliver aerosols to animals in a physiologically appropriate manner, as well as the devices
used to conserve test article, will be examined. With dose and inhalation exposure covered, species-specific histopathologic
lesions, both common background and toxicologically significant lesions, will be discussed. Finally, insight into how regulators
synthesize and evaluate these complex findings to assess clinical safety risks will be presented.
S7–1
9:00 AM–9:35 AM
Overview: It Sucks and Blows, Lung Function
Jeff Tepper, Nonclinical Consulting, San Carlos, CA
S7–2
9:35 AM–10:05 AM
Dose is Dose, Right? Determining Pulmonary Dose in Clinical
and Nonclinical Studies
Philip Kuehl, Lovelace Respiratory Research Institute, Albuquerque, NM
S7–3
10:05 AM–10:35 AM
You Need How Much!!! Test Article Conservation During In Vivo
Inhalation Studies
TUESDAY
Stuart Cracknell, Huntingdon Life Sciences, Somerset, NJ
S7–4
10:35 AM–10:55 AM
Break
10:55 AM–11:30 AM
Tour of the Respiratory Tract with Stops at Sites of Toxicological Significance
Kristen Nikula, Seventh Wave Laboratories, LLC, Chesterfield, MO
S7–5
11:30 AM–12:00 Noon Regulatory Considerations in Nonclinical Safety
Evaluations of Inhalation Drugs
Luqi Pei, US Food and Drug Administration, Silver Spring, MD
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S7–1
For inhalation studies, the respiratory tract is generally the
site most likely to show evidence of toxicity, but not all toxicity
manifests as morphologically observable injury. Functional
changes, which can occur with inhalation exposure, can range
from acute life threatening to more subtle changes in ventilation
and breathing pattern that can alter the dose and distribution
of an inhaled drug. The rationale, interpretation and practical
application of lung-function tests that are, or can be, used
in laboratory animals, is the focus of the presentation. These
tests provide analogues of clinical pulmonary function tests
conducted on humans. Because measurements of respiratory
rate and tidal volume are typically measured as part of the
safety pharmacology assessment, attention is given to the
theory behind how changes in lung volume and flow occur.
Additionally, methods to estimate (allometry) and measure
lung function by plethysmography, pneumotachography and
telemetry in animals will be explained. Functional changes that
may manifest with inhalation products, including changes in
ventilation, lung irritation, bronchoconstriction, restrictive,
obstructive and diffusional changes will be briefly reviewed.
Finally, strategies for the assessment of lung function within the
context of the ICH-S7A guideline as well as techniques to enhance
the detection of functional changes where concern has been
raised will be discussed.
S7–2
S7–3
Inhaled drug delivery to conscious animal models has always
used many times more test article than is actually delivered
to the respiratory tract. Half of this effect is associated with the
inconvenient reality that animals breathe out as well as in. Even
this “loss” as well as everything else associated with the delivery
of inhaled aerosols is subject to some measure of control. The
magnitude of systematic losses is typically greatest for dry
powder formulations but poor efficiency can also be a feature of
liquid droplet deliveries. Losses and inefficiencies occur in both
the initial aerosol generation process and in the aerosol delivery
systems used to bring the atmosphere product to the breathing
zone. Enhancing the efficiency of test article usage can enable
the completion of critical proof of concept and IND-enabling
inhalation investigations with significantly smaller quantities
of an active moiety than would be necessary when employing
standard laboratory techniques. This is especially important early
in test article development when the quantities available are
commonly both limited and produced at the highest unit cost due
to lab scale manufacture. Based on recent experience conducting
programs in which test article costs substantially exceed the cost
of running the in vivo studies themselves, this presentation will
concentrate on those techniques that have been found to be
effective when test article conservation in inhalation studies has
been a critical component of program survival. While focusing
on methods of aerosol generation, exposure system design and
aerosol delivery, factors related to study and program design as
well as study logistics will also be considered.
S7–4
The respiratory system, which comprises the largest mucosal
surface of the body, can be divided into two portions based on
anatomy and physiology: the conducting airways (nose, pharynx,
larynx, and tracheobronchial airways) and the respiratory portion
(respiratory bronchioles, alveolar ducts, and alveolar sacs).
Injury due to inhaled toxicants occurs when innate defenses
are overcome. The location and type of injury depends on the
physiochemical characteristics of the toxic agent, site-specific
tissue dosimetry, and the metabolic capabilities and sensitivity
of the cellular components of the respiratory tissue. Respiratory
system macroscopic and microscopic anatomy, particularly as
it relates to toxicant-induced injury and tissue responses, will
be presented. The inhalation of highly water-soluble chemicals
or large particles typically cause injury in the upper respiratory
tract whereas poorly soluble chemicals and small particles
cause injury in the centriacinar region. Highly reactive gases
and certain nanoparticles cause injury in both upper and lower
respiratory sites and toxicants that are metabolically activated
cause injury at the site of metabolism. Species-related differences
in functional anatomy of the respiratory tract that affect the
response to toxicant exposure among preclinical species used
in safety studies and humans will be discussed. Lastly, common
background findings in preclinical species as well as examples of
toxicant-induced lesions will be illustrated.
S7–5
Regulatory nonclinical safety evaluations play a unique role in
the development of inhalation drug products. These evaluations
present challenges to regulatory and research scientists because
of special characteristics associated with inhalation products.
The products generally require complex delivery devices and
involve aerosol sciences and engineering. Device, dosage forms,
formulations, and delivery mechanics are variable. The anatomy
and physiology of the respiratory system in animals and humans
have their own special feature, and responses to inhaled materials
in animals and humans may be species-specific. The design
and conduct of inhalation toxicity studies also requires special
knowledge, skills, facility, and equipment. It is often difficult to
accurately assess the local and systemic exposures of animals and
humans to inhaled drugs. All of these characteristics may affect
the evaluation and interpretation of findings of inhalation toxicity
studies in animals. Regulatory scientists should consider these
features when conducting the nonclinical safety evaluation of
inhalation drug products.
41 TUESDAY
Pulmonary dose has been and continues to be an area of
research and debate. Pulmonary dose can be calculated based
on relatively standard calculations, which include multiple
inherent assumptions. While there is precedence for the use of
these calculations, they require assumptions to be made within
them. Current trends in inhalation drug delivery have increased
the needs for more accurate empirical data in quantifying
pulmonary dose. In principle, there are two methods used to
empirically quantify pulmonary dose: deposition imaging and
pharmacokinetic analysis. Both empirical methods have strengths
and weaknesses. Pharmacokinetic analysis in a nonclinical study
can include lung tissue and systemic plasma measurements
while in a clinical setting only includes systemic plasma. Systemic
plasma, albeit a routine and established measurement, is an
indirect method to quantify pulmonary dose. This inherently
increases the potential for variability and can decrease utility of
plasma measurements. Deposition imaging, typically conducted
by SPECT/CT, can be used in both clinical and nonclinical studies
with minimal differences. Deposition imaging has the advantage
that it is a direct measurement of the dose at the site of deposition.
The disadvantage is that imaging modalities quantify a radiotracer,
not the drug. Therefore, the homogeneity of the radiotracer and
the drug must be validated in vitro in order to quantify pulmonary
dose in vivo. Overall, determining pulmonary dose throughout
clinical and nonclinical studies is a manageable task. Risk-based
choices must be made as to the accuracy of dose needed and the
methods most appropriate to quantify pulmonary dose.
2014
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2014
SYMPOSIUM 8
Cardiovascular Safety Evaluation—
In Vitro to Humans
9:00 AM–12:00 Noon
Grand Cypress
Ballroom A
CHAIR: Norman Kim, Biogen
Idec, Cambridge, MA
CO-CHAIR: Chris Mathes,ChanTest Corporation, Cleveland, OH
ChanTest Corporation
A new scientific testing paradigm for drug-induced cardiac safety was proposed by a consortium sponsored by Cardiac Safety
Research Consortium (CSRC), Health and Environmental Sciences Institute (HESI), and the US Food and Drug Administration
(FDA). The proposal instituted Comprehensive In vitro Proarrhythmia Assays (CiPA) that provided a framework for a shift from the
current testing guidelines as outlined in ICH S7B (nonclinical) and ICH E14 (clinical) to include novel assays in human cells and
in silico models of cellular electrophysiological effects to evaluate proarrhythmic drugs. Additional concepts besides CiPA have
also been proposed. This symposium will review the most current cardiovascular testing paradigm of potential therapeutics in
consideration of the regulatory guidelines. The current ICH S7B discusses nonclinical testing strategy for cardiovascular safety.
These include consideration of chemical/pharmacological class of the molecules, outcomes of in vitro assays (notably hERG
inhibition), in vivo cardiovascular study, and other related toxicology studies where cardiovascular endpoints are evaluated. The
ICH E14 provide clinical assessment of potential QTc prolongation. Nonclinical and available clinical safety information provide
the basis of an integrated cardiovascular risk assessment of molecules. The focus of the ICH guideline has been centered
around QT/QTc intervals and potential arrhythmia. Based on the available information, it is apparent that cardiovascular testing
paradigm should include more than the hERG inhibition assay and evaluation of other ion channels should be considered along
with the newer novel assays such as induced pluropotent-derived human stem cells for a more comprehensive cardiovascular
evaluation. The screening of molecules during early discovery and development phases could be better utilized and optimized
for cardiovascular evaluation. This session will introduce and review these in vitro assays and nonclinical in vivo evaluation.
Current pharmaceutical and regulatory thinking process of cardiovascular evaluation will be discussed, including a proposal
of modification/elimination of ICH guidelines S7B and E14. Experiences with CiPA in the cardiovascular evaluation will
be further discussed.
9:00 AM–9:10 AM
Introduction
Norman Kim, Biogen Idec, Cambridge, MA, and Chris Mathes, ChanTest Corporation,
Cleveland, OH
S8–1
9:10 AM–9:40 AM
Cardiovascular Safety Assessments During Drug Development:
Current Approach and the Need for a New Paradigm
Philip Sager, Stanford University, San Francisco, CA
S8–2
9:40 AM–10:10 AM
In Vitro Cardiovascular Safety—Discovery Screen to GLP Studies
Bernard Fermini, Pfizer, Groton, CT
TUESDAY
S8–3
10:10 AM–10:30 AM
Break
10:30 AM–11:00 AM
Integrated Systems for Evaluation of Cardiovascular Electrophysiology Safety:
Secondary In Vitro Assays and In Vivo Evaluations
Gary Gintant, AbbVie Inc., North Chicago, IL
S8–4
11:00 AM–11:30 AM
Regulatory Thinking of the Current Guidelines on Cardiovascular Evaluation—
Beyond QTc
Norman Stockbridge, US Food and Drug Administration, Silver Spring, MD
S8–5
11:30 AM–12:00 Noon Experiences with Elements of Comprehensive In Vitro Proarrhythmia Assay (CiPA)
Arthur “Buzz” Brown, ChanTest Corporation, Cleveland, OH
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S8–1
The current approach, outlined in ICH S7B and E14, to cardiac
arrhythmia risk is focused on preclinical and clinical assessments:
1) the effect of new chemical entities on the hERG encoded IKr
current and QTc prolongation in animals and 2) measuring QTc
prolongation at supratherapeutic exposures in humans, typically
during Phase 2 of development. While this approach has largely
eliminated the unanticipated presence of new torsadogenic
drugs entering the market, it has become clear that there are
important limitations to this methodology. Block of hERG alone
is often insufficient in predicting delayed repolarization and
hERG-related prolongation of repolarization does not necessarily
translate into human torsade de pointes risk. Increases in the
QTc interval are highly sensitive but not very specific for the
prediction of ventricular proarrhythmia risk. The use of the hERG
repolarizing ionic current assay (in early nonclinical development)
and QTc interval prolongation (in later nonclinical and clinical
development) as gatekeepers for the continued development
of a new chemical entity has likely led to the inappropriate
discontinuation of development programs for drugs with
potentially high public health benefits. The talk will focus on
these key issues and a potential new approach to drug-induced
arrhythmia development.
S8–2
During the past two decades, a number of noncardiovascular
drugs have had their label revised or have been withdrawn from
the market because of unexpected post-marketing reports of
sudden cardiac death associated with a prolongation of the QT
interval on the electrocardiogram and increased propensity
to develop a ventricular tachyarrhythmia called Torsades de
Pointes. Compound withdrawal not only indicates that a risk has
been posed to patient safety, but also results in a significant loss
of invested time, money and resources. In a majority of cases,
QT prolongation results from inhibition of the delayed rectifier
potassium current IKr or hERG. Consequently, assessment of
cardiac ion-channel activity of new chemical entities is now an
integral component of drug discovery programs. However, it has
recently become apparent that the current ion channel paradigm
(mostly based on hERG screening) may not assess the end point
of primary concern (i.e. ventricular proarrhythmia), and a shift in
paradigm has been proposed. In this presentation we will review
a typical ion channel cardiovascular safety strategy and examine
some of the methods and assays used from the exploratory to the
GLP stages. We will put the data generated from these assays in
context with translation to in vivo correlates, and take a critical
look at some of the newer assays and methodologies that strive
to address gaps present in the existing paradigm, such as the
inability to adequately assess the proarrhythmic potential of
new chemical entities.
S8–3
“best practice” in vivo studies (e.g., telemetry studies) coupled with
the use of so-called “secondary assays” (e.g. repolarization assays
and studies with human stem-cell derived cardiomyocytes) to
enhance or understanding of drug effects represents a reasonable
approach for understanding cardiovascular liabilities early in
drug discovery, guiding compound selection and subsequent
clinical studies. This presentation will discuss considerations
of how to best blend secondary and in vivo assays to inform on
cardiovascular risk assessments.
S8–4
The current ICH S7B and E14 guidelines have been the mainstay
of the preclinical and clinical cardiovascular testing paradigm.
Although ICH S7B and E14 provide the basis of the cardiovascular
safety testing, this evaluation scheme has limitations. The
measurement of QTc prolongation is highly sensitive but not
specific for predicting ventricular proarrhythmia risk of a drug,
and may inappropriately assign a drug with a Torsades de Pointes
(TdP) liability. In addition to the inhibitors of rapidly activating
delayed rectifier potassium current (IKr), there are other factors
that may lead to QTc prolongation.
This presentation will provide a regulatory perspective of
cardiovascular assessment during drug development, including
a brief history of molecules that have been removed from the
market due to TdP risk, basis of how the current ICH guidelines was
instituted, limitations of the current guidelines, regulatory views
of various proposals of integrative proarrhythmia evaluations,
and future direction of cardiovascular testing. Examples will be
provided where applicable.
S8–5
The regulatory paradigm for nonclinical cardiac risk assessment
has shifted from delayed repolarization, hERG block and QT
prolongation to involvement of major human cardiac ion
channels and proarrhythmic effects on human cardiomyocytes.
To test whether multiple ion channel effects (MICE) were
superior to hERG alone, automated gigaseal patch clamp was
used to measure the concentration-responses of hERG, hNav1.5
and hCav1.2 to torsadogenic and non-torsadogenic drugs and
compared the predictivity of a variety of logistic regression (LR)
models. The LR model for hERG was significantly inferior to the
best MICE LR model. Many of these drugs were tested on induced
pluripotent stem cell (iPSC)-derived cardiomyocytes using manual
patch clamp to record action potential duration (APD) and a multielectrode array (MEA) to record 2D propagation. With the latter,
spike amplitude, beat rate and field potential duration (FPD) were
measured. Drugs that are positive for Torsade de Pointe (TdP+)
drugs prolonged FPD and at higher concentrations produced
early after depolarization (EAD) and arrhythmias. Negative TdP
drugs had no effects. When an impedance device (xCELLigence)
was used to measure cytoxicity and contractile changes, a good
correlation was evident with anticipated drug effects. The results
of this multi-faceted approach are being integrated to provide
a hypothetical mechanism of action that can be applied to
predicting cardiac risk in the clinic.
43 TUESDAY
There is a need to establish robust approaches to ensure the
selection of drug candidates with safe cardiovascular profiles
through a combination of in vitro and in vivo mechanism-based and
integrated studies. Understanding the strengths and limitations of
2014
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SYMPOSIUM 9
Centrally Administered Compounds in Small and
Large Species—Dose Routes, Study Considerations,
and Data Interpretation
CHAIR: Sven Korte, Covance
9:00 AM–12:00 Noon
Palm
Laboratories GmbH, Münster, Germany
CO-CHAIR: Teresa L. Wright,Shire, Lexington, MA
Covance Laboratories Inc., Tox Path Specialists, LLC, and Shire
Many diseases affecting the central nervous system (CNS) are inadequately treated by traditional systemic delivery methods,
partly because of the inability to bypass the blood-brain barrier. Delivery of large molecules, cells, and other novel therapies
directly to the nervous system via intrathecal injection and/or implanted catheters overcomes this obstacle and administers
the treatments close to the target region. Clinical experience using direct CNS administration of compounds for pain relief
and chemotherapy has grown over the past decades, suggesting the same technologies can be applied to the treatment of
degenerative and inherited disorders. Administration of drugs directly into the CSF may involve some risk, including reaction
of the spinal cord or brain tissue adjacent to the device. The preclinical studies used to evaluate the safety of CNS administered
compounds must differentiate between the effects of the delivery method, the therapy, and the combination. Reliable, wellcharacterized animal models for CNS administration of test articles have been developed which enable nonclinical development
of these potential therapeutics. This session will discuss the technical challenges of preclinical intrathecal studies, design of
studies and nonclinical programs, evaluation of results, and considerations for special endpoints in the studies.
S9–1
9:00 AM–9:40 AM
Development of CNS Administered Biologics: Overview, Challenges,
and a Case History
Brian R. Vuillemenot, BioMarin Pharmaceutical Inc., Novato, CA
S9–2
9:40 AM–10:20 AM
Methodology of Central Drug Delivery and Cerebrospinal Fluid Collection
in the Sheep, Dog and Rat Model
Eric Adams, Northern Biomedical Research, Inc., Spring Lake, MI
S9–3
10:20 AM–10:40 AM
Break
10:40 AM–11:20 AM
Procedures for Intrathecal Drug Delivery and CSF Sampling in Nonhuman
Primates Studies
Sven Korte, Covance Laboratories GmbH, Münster, Germany
S9–4
11:20 AM–12:00 Noon Morphologic Assessment of Studies Involving Direct Delivery to the Central
Nervous System
TUESDAY
Mark T. Butt, Tox Path Specialists (TPS), LLC, Frederick, MD
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S9–1
This presentation will begin with an overview of theoretical
considerations relevant to direct CNS administration,
including blood brain barrier structure, CSF dynamics,
routes of administration, delivery devices, and relevant
disease indications. Design of nonclinical toxicology and
pharmacology studies and IND/CTA enabling programs for
CNS administered therapeutics will be discussed, with a focus
on relevant regulatory guidelines. Finally, a nonclinical case
history of a CNS-administered enzyme replacement therapy
currently in clinical trials will be presented to illustrate some
of these concepts.
S9–2
This presentation will introduce surgical techniques and
methodology surrounding drug delivery and CSF collection
in the sheep, dog and rat animal model. Emphasis will be on
stereotactic surgery techniques, the importance of performing
pilot studies, various drug delivery systems as well as CSF
collection methods. Intraparenchymal, intracerebroventricular
and intrathecal surgery models will be discussed along
with existing and novel CSF collection techniques. These
techniques will include cisterna magna and lumbar puncture
in anesthetized animals (sheep, dog, and rat) as well as serial
and continuous CSF collection in conscious rats.
2014
S9–3
The effects of CSF (cerebrospinal fluid) infused compounds
in large animal models will be reviewed. The presentation
will focus on animal selection, surgical techniques, and study
considerations in nonhuman primate studies undergoing
continuous or slow bolus injection by the lumbar, cisterna
magna or ventricular route. Commonly observed spontaneous
and induced changes observed in the in-life phase of
regulatory studies and under European housing conditions
will also be presented. Furthermore, the assessment of juvenile
toxicity in cynomolgus monkeys represents an emerging
field, requiring the application of established techniques
in 12-month old (or even younger) monkeys. The feasibility
and precaution measurements when conducting this type of
studies will be presented.
S9–4
This presentation will introduce the challenges and optimal
techniques used to assess the structural changes in the brain
and spinal cord associated with the direct delivery of various
test articles to the intrathecal space or directly to the brain
parenchyma. The sectioning schemes, staining methodologies,
embedding techniques, and special techniques for quantitative
assessments will be discussed and illustrated. Sample gross
and microscopic changes associated with the various delivery
techniques will be shown, along with examples of lesions
associated with various classes of test articles.
TUESDAY
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Annual Meeting
12:00 Noon–1:30 PM
IJT Editorial Board Meeting
12:00 Noon–1:30 PM
2015 Program Planning Meeting
2014
Magnolia
Regency Hall
(All ACT members invited. Sign up at the registration desk.
Box lunch provided.)
Tuesday Afternoon Sessions
SYMPOSIUM 10
Cytokines: The Good, the Bad, and the Deadly
CHAIR: Thulasi Ramani, Huntingdon
2:00 PM–5:00 PM
Grand Cypress
Ballroom A
Life Sciences, Somerset, NJ
CO-CHAIR: Carol S. Auletta,Huntingdon
Life Sciences, Somerset, NJ
Huntingdon Life Sciences
Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. This symposium
presents an overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for
evaluating these important entities. Cytokines play a broad role to help the immune system respond to diseases, and drugs
which modulate their effect have led to some amazing therapies. Cytokines may be “good” when stimulating the immune
system to fight a foreign pathogen or attack tumors. Other “good” cytokine effects include reduction of an immune response,
for example Interferon beta reduction of neuron inflammation in patients with multiple sclerosis. They may be “bad” when their
expression causes inflammatory diseases, such as the role of TNF-alpha in rheumatoid arthritis or asthma and Crohn’s disease.
Therapeutic modulation of cytokine expression can help the “good” cytokines to generate or quench the immune system,
and block the “bad” cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody
therapeutics can cause “ugly” cytokine release, which can be deadly. Well-designed toxicology studies should incorporate
careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discusses
lessons learned in cytokine toxicology using case studies and suggests future directions.
2:00 PM–2:10 PM
Cytokine Explosion: Rocking the World of Toxicology
Thulasi Ramani, Huntingdon Life Sciences, Somerset, NJ
S10-1
2:10 PM–2:40 PM
Therapeutic Cytokine-Blocking Antibodies
Daniel Weinstock, Janssen Research and Development, Spring House, PA
S10-2
2:40 PM–3:10 PM
Safety Evaluation of Cytokine Therapeutics: Translation of Preclinical Data
to the Clinic
Barbara Mounho-Zamora, ToxStrategies Inc, Bend, OR
S10-3
3:10 PM–3:40 PM
Targeting Cytokine Pathways to Treat Disease
TUESDAY
Patricia Ryan, MedImmune, Gaithersburg, MD
S10-4
3:40 PM–4:00 PM
Break
4:00 PM–4:30 PM
Beyond TeGenero—Development of Targeted Therapeutics without
Deadly Consequences
Theodora Salcedo, Bristol Myers Squibb Company, New Brunswick, NJ
S10-5
4:30 PM–5:00 PM
Cytokines as Biomarkers for Immunotoxicity
Gregory Bannish, Huntingdon Life Sciences, Somerset, NJ
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S10–1
Antibodies and their derivatives comprise a growing segment
of approved products for treatment of a wide variety of human
diseases. Soluble cytokines and their receptors make excellent
targets for therapeutic intervention based on extensive
documentation of their roles in specific diseases. Antibodies
against tumor necrosis factor (TNF), human epidermal growth
factor receptor 2 (HER2) and epidermal growth factor receptor
(EGFR) are “blockbuster drugs.” Additional validated cytokine
targets for treatment of human diseases include interleukin-1
(IL-1), IL-2 receptor (IL-2R), IL-6R, IL-12, IL-23 and receptor
activator of nuclear factor-κB ligand (RANKL). Development
strategies for large molecule therapeutic proteins with
immunomodulatory effects require understanding of the
effector functions of the therapeutic molecule as well as the role
of the targeted cytokine and/or it’s receptor(s) in the normal
and diseased states. Preclinical and clinical development
strategies strive to characterize safety and efficacy. ICH S6
(Preclinical Safety Evaluation of Biotechnology-derived
Pharmaceuticals) and ICH S8 (Immunotoxicity Studies for
Human Pharmaceuticals) provide guidance for development
of immunodulatory biologics. Unfortunately, treatment
of patients with immunomodulatory agents sometimes
may result in unwanted adverse consequences. Thorough
knowledge of the mechanism of action of the therapeutic
molecule and the biology of the cytokine target are required for
efficient development strategies and ultimate therapeutic use.
S10–3
Biologics that impact cytokine pathways are promising
therapies for a variety of diseases including cancer,
autoimmunity and inflammation. This presentation will
describe several case examples of biologics that target
cytokine pathways. In each case, the special considerations
required in designing and interpreting nonclinical safety
studies for biologics, which either induce cytokines or block a
key cytokine pathway as part of their mechanism of action will
be described. In each of these case examples, consideration of
the expected pharmacology was important to appropriately
interpret nonclinical safety results given that the majority of
the toxicities for these types of biologics arise from on-target
excessive pharmacodynamics.
S10–4
TGN1412 is a monoclonal antibody that binds to CD28 and has
agonistic activity on cytokine release. Although it was studied
preclinically, it was administered in the clinic (in 2006) with
disastrous consequences. It made the term “cytokine storm”
a household word in toxicology circles. This presentation will
provide an update on advances in the science associated with
“cytokine storm,” and describe strategies used successfully
to develop targeted therapeutics that can be safely
administered to humans.
S10–5
Cytokine evaluation is often included in preclinical studies
for the assessment of immunotoxicity. The increasing use of
these evaluations reflects the increased understanding of the
role of cytokines in the immune response, the modulation of
cytokines following inflammatory events, and the increased
ability to measure cytokine levels through new technologies.
However, significant challenges exist which can include
temporal expression, low systemic expression, complexity,
redundancy, species, strain, and inter-animal variability, and the
limited knowledge and reagent availability for immunological
evaluations in common toxicity species. This presentation will
discuss significant advances in primate cytokine evaluation,
including intracellular evaluation of cytokine expression to
delineate lymphoid subpopulations, evaluation of cytokine
levels in sera at sub-pg/mL concentrations, evaluation of
cytokine mRNA expression, evaluation in skin biopsies, and a
validated 24-plex cytokine panel. Many of these advances will
allow for establishment of biomarkers in preclinical studies that
will improve the ability to monitor for immunopharmacology
and toxicity in clinical studies.
47 TUESDAY
S10–2
Cytokines are a unique class of regulatory proteins that play
a critical role in maintaining and regulating immunologic
systems. Excessive production of certain cytokines, however,
can lead to pathological consequences. Advancement in
cytokine research has lead to the development of cytokine
therapeutics (i.e., cytokine antagonists) for the treatment
of various diseases. Modulation of the immune system by
cytokine therapeutics, however, can result in adverse clinical
consequences, especially with chronic administration. The
preclinical safety evaluation of cytokine therapeutics is a
critical component in understanding the potential adverse
effects associated with cytokine therapeutics. Identifying
relevant assays and incorporating safety parameters in
toxicology studies for cytokine therapies can be challenging,
particularly in understanding the relevance of the preclinical
data to the patient population. Additionally, it is critical to
understand the potential toxicities and impact on the immune
system associated with chronic administration of the cytokine
therapeutic, which may not be possible to demonstrate in
animal studies. This presentation will review the types of
assays and parameters used in the preclinical safety evaluation
of cytokine therapies. The challenges in understanding the
relevance of the data to the patient population and how these
challenges are managed with approved cytokine therapeutics
will also be discussed.
2014
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SYMPOSIUM 11
Differentiating Adverse from Adaptive Changes
in Toxicology
CHAIR: Anthony L. Kiorpes,River
2:00 PM–5:00 PM
Palm
Bluff Associates, LLC, Bloomington, MN
CO-CHAIR: Arun R. Pandiri,Experimental
Pathology Laboratories, Inc., RTP, NC
Experimental Pathology Laboratories, Inc., and BASi
An important question in the practice of toxicology is, “what is an adverse finding”? Central to what every toxicologist does is
the interpretation of a large experimental data set to arrive at a no-observed-adverse-effect level (NOAEL). In many cases, the
difference between an adverse (pathological) finding from one that is adaptive (physiological) is not obvious. Specifically, this
symposium will explore what are adverse findings and what differentiates them from normal physiological or adaptive changes
from whole-animal, organ, molecular, and regulatory perspectives. The topic is timely as recent meetings, working groups, and
papers have attempted to address this issue. The intended audience is the general toxicologist regardless of industry segment.
S11-1
2:00 PM–2:40 PM
A Whole-Animal Overview of Adaptive versus Adverse Change
Peter C. Mann, Experimental Pathology Laboratories, Inc., Seattle, WA
S11-2
2:40 PM–3:20 PM
Identifying Adverse Organ Responses: The Liver as Paradigm
Robert R. Maronpot, Maronpot Consulting, LLC, Raleigh, NC
S11-3
3:20 PM–3:40 PM
Break
3:40 PM–4:20 PM
Using Toxicogenomics in Assessing Adaptive versus Adverse Effects
Russell Thomas, US Environmental Protection Agency, National Center for Computational
Toxicology, Research Triangle Park, NC
S11-4
4:20 PM–5:00 PM
Differentiating Adaptive and Adverse Changes: A Regulatory Perspective
TUESDAY
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S11–1
The first talk will introduce the problem of differentiating
adaptive, physiological changes in test systems from
nonadaptive, adverse, or pathological changes that are
toxicologically meaningful. The perspective of this talk will be
at the level of the whole organism. Practical examples will be
given as part of the talk.
S11–2
This talk will focus on acute, intermittent, delayed, and chronic
adverse responses at the organ system level using the liver as
a model organ. The talk will include practical biomarkers and
will demonstrate the integrating of meaningful endpoints in
supporting an overall conclusion of adaptive, physiological
change vs nonadaptive, pathological or adverse change.
The talk will discuss predictive value (clinical relevance) of
meaningful endpoints and the difference between adverse
changes or findings that are reversible versus those changes
or findings that are not reversible. Case studies will be used to
make key points practical and meaningful.
2014
S11–3
This talk will focus on using toxicogenomic technologies
to assess adaptive versus adverse effects in toxicological
research. Transcriptomic alterations are usually noted
before the manifestation of histological changes and
at usually lower doses. The challenging aspect of using
toxicogenomics for assessing adaptive versus adverse effect
is that not all transcriptomic alterations result in an adverse
effect. This presentation will discuss the concepts of NOTEL
(no observable transcriptional effect level) and TBMDL
(transcriptional benchmark dose level), and its relationship to
traditional toxicology end points. Examples will be discussed
to demonstrate the value of using toxicogenomics in assessing
adaptive versus adverse effects.
S11–4
Identification of a no-observed-adverse-effect-level (NOAEL)
from a toxicity study is a key component in identifying
acceptable human exposure to a particular test article. One
aspect of this exercise is distinguishing between adaptive and
adverse effects. This talk will focus on the question of adverse
versus adaptive changes from a regulatory point of view
with an emphasis on pharmaceutical drug development. The
primary points of discussion will include the issues regulators
need to consider in evaluating toxicity data that are generated
in support of clinical development programs and the
information needed to support a “nonadverse” interpretation
of clinical or pathological changes. Case examples will be
discussed to illustrate the key issues in distinguishing adaptive
versus adverse responses from a regulatory perspective.
TUESDAY
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SYMPOSIUM 12
In Silico Methods for Mutagenicity Prediction
vis à vis ICH M7 Guidance
CO-CHAIR: Joel Bercu,Amgen,
CO-CHAIR: Vijay K. Gombar,Eli
2:00 PM–5:00 PM
Regency Hall
Inc., Thousand Oaks, CA
Lilly and Co., Indianapolis, IN
The manufacture of the active pharmaceutical ingredient (API) of a drug involves a number of starting materials, reagents,
and intermediates. Many of these chemicals could be potentially genotoxic and may end up as impurities in an API. It is the
responsibility of the sponsor pharmaceutical company (Pharma) to identify, control, and assess risk posed by these potential
genotoxic impurities (GTIs). Given that a GTI meets regulation on its limits, the ICH M7 draft guidance (Guidance) permits use of
in silico approaches in contrast to experimental assessment of mutagenicity.
Now that more than two years have passed since the Guidance was issued, the present symposium seems timely and important
to share and learn about (1) what are regulatory expectations around use of in silico methods, (2) which in silico methods
Pharma companies are using, and why, for compliance, (3) what developments have taken place by developers of in silico tools
and methods, and most importantly (4) case studies on risk assessment by Pharmas highlighting their experience in the use of
their chosen in silico methods. There could not be a more suitable forum than the ACT Annual Meeting, which brings together
important stakeholders, for discussion and shared learning around these salient topics.
S12-1
2:00 PM–2:25 PM
Risk Characterization of Mutagenic Impurities
Joel Bercu, Amgen, Thousand Oaks, CA
S12-2
2:25 PM–2:50 PM
Regulatory Implementation of ICH M7
S12-3
2:50 PM–3:15 PM
Living with ICH M7: The Practical Application of Two In Silico Systems
in Screening for GTIs
Nigel Greene, Pfizer, Inc, Groton, CT
S12-4
3:15 PM–3:45 PM
ICH M7: Risk Assessment with In-House and Off-the-Shelf In Silico
Mutagenicity Predictors
Robert A. Jolly, Lilly Corporate Center, Indianapolis, IN
S12-5
3:45 PM–4:05 PM
Break
4:05 PM–4:35 PM
Using In Silico Tools for the Assessment of Genotoxic Impurities
Chris Barber, Lhasa Limited, Holbeck, Leeds, England, United Kingdom
S12-6
4:35 PM–5:00 PM
Physico-Chemical Modulation of DEREK Structural Alerts
TUESDAY
Vijay K. Gombar, Eli Lilly and Co., Indianapolis, IN
5:00 PM–6:30 PM
ACT Members' Meeting
(All ACT members invited.) See page 10 for more information.
50 Regency Hall
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S12–1
Pharmaceutical companies have processes to ensure potential
exposure to impurities would not be of toxicological concern.
Developments in science and regulatory guidance have
allowed companies to characterize the risk of DNA reactive
(mutagenic) impurities. These impurities are of particular
concern since they are assumed to have no threshold. In silico
assessments are an important part of the risk characterization
process: hazard assessment. Computational assessments
facilitate screening of actual and potential impurities and
identify compounds requiring additional investigation. If
an impurity is determined to be mutagenic, then it must be
controlled to an acceptable dose following patient exposure.
The threshold of toxicological concern (TTC) is considered
a dose, which is of negligible excess cancer risk to patients
assuming a mutagenic impurity is also a potent carcinogen.
Chemistry uses the TTC to demonstrate process removal
of an impurity to a negligible level. In conclusion, in silico
technologies are a part of the risk characterization process
for mutagenic impurities as it triggers further follow-up if an
impurity is predicted to have mutagenic potential.
S12–2
The draft ICH M7 guideline provides recommendations for
assessing and controlling mutagenic impurities in drugs. For
many impurities lacking empirical data, mutagenic potential
can be established using (Q)SAR. Per the draft guideline,
a (Q)SAR analysis should include prediction of bacterial
mutagenicity (i.e., Ames assay) using 2 complementary
methodologies. Expert knowledge may also be used to add
perspective to the (Q)SAR prediction and support the overall
decision-making process.
The presentation will focus on regulatory expectations of
impurity evaluations. Specific points of emphasis will include
components of an appropriate (Q)SAR analysis, the utility and
role of expert knowledge, as well as recommendations for
reporting results. The current FDA Office of New Drugs review
process and regulatory decision making will also be covered.
pharmaceutical intermediates we have examined the relative
predictive performances of some popular commercial systems
that are in common use across the pharmaceutical industry.
We have explored how these systems can be combined under
the draft ICH M7 guidance to enhance the detection of DNA
reactive molecules.
S12–4
Recent ICH M7 draft guidance states that at least two in silico
models (e.g., rules-based method and a QSAR approach),
with complementary approaches, be used with expert
knowledge for assessing potential mutagenicity of chemicals
constituting the synthetic routes of pharmaceutical APIs. We
have conducted detailed evaluation of commercial off-theshelf (COTS) packages and compared them with in-house
models. We also investigated whether we can improve the
accuracy of in silico mutagenicity predictions by adding
proprietary data for training models. An optimization benefit
analysis was done to identify the best mutagenicity predictors
for risk assessments.
S12–5
The nascent ICH M7 guidelines allow for the submission of in
silico predictions of mutagenicity from 2 orthogonal systems
following expert review. In order to support this review, such
tools need to provide transparent and scientifically sound
predictions with sufficient supporting information to allow
the expert to understand why a prediction is made, how
confident the user should be, and what evidence supports
that conclusion. This talk will focus on the questions an expert
should ask of the models and how such information can be used
to come to an overall conclusion. It will be illustrated using two
predictive tools—Derek Nexus, an expert system and Sarah
Nexus, a statistical approach to the prediction of mutagenicity.
S12–6
The focus of this investigation is the structural alerts (SAs) of
mutagenicity underlying the in silico expert system, Derek
Nexus (DN). The presence of a mutagenicity SA indicates
mutagenic potential of a test compound and many DN
SAs have been reported to be fairly accurate. We parsed
clean, uniform data of Ames assay results for 8541 diverse
compounds through DN to examine the hit rate and accuracy
of DN SAs. We observed that many SAs had higher prevalence
in nonmutagenic compounds. We analyzed each of the 23
DN SAs that hit on more than 10 nonmutagenic compounds
by Recursive Partitioning (RP) to identify physico-chemical
modulators of SAs that lead to higher accuracy in predicting
mutagens. The RP trees for each of these 23 DN SAs will be
presented and discussed for possible modification of rules.
51 TUESDAY
S12–3
The current Step 2 document outlining the ICH M7 guidelines
for the assessment and control of DNA reactive impurities in
pharmaceutical products includes the use of in silico prediction
systems as part of the hazard identification and risk assessment
strategy. This is the first internationally agreed guidance
document to include the use of computational approaches.
The current proposal requires the use of two complimentary
approaches, an expert rule-based method and a statistical
algorithm. In addition, the draft guidance calls for the output
from these computer-based assessments to be reviewed using
expert knowledge to provide additional support or resolve
conflicting predictions. Using a data set of 800 chemicals and
2014
You’re Invited to a Members-Only
Wine Tasting
Wine tasting Full page ad
with 2015 ACT President
Mary Ellen Cosenza
Wednesday, November 12 • 5:00 PM–6:30 PM
Grand View Terrace
Hyatt Regency Grand Cypress, Orlando, Florida
Come meet the incoming
2015 ACT President Mary Ellen Cosenza
and share your thoughts on
the ACT Annual Meeting
over a glass of wine and light fare.
This is a free event for
all ACT members and
advance registration
is required.
www.actox.org
52 th
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7:00 AM–7:55 AM
Wednesday Morning Sessions
PLENARY LECTURE 2
Food and Feed Safety of Genetically
Modified Organisms: The Hype and
the Facts
8:00 AM–8:55 AM
Grand Ballroom D
ALISON VAN EENENNAAM
COOPERATIVE EXTENSION SPECIALIST, ANIMAL GENOMICS AND BIOTECHNOLOGY, DEPARTMENT OF ANIMAL SCIENCE,
UNIVERSITY OF CALIFORNIA, DAVIS
Dr. Alison Van Eenennaam is a Cooperative Extension Specialist in the field of Animal Genomics and
Biotechnology in the Department of Animal Science at University of California, Davis. She received a
Bachelor of Agricultural Science from the University of Melbourne in Australia, and both an MS in
Animal Science, and a PhD in Genetics from UC Davis. The mission of her extension program is “to
provide research and education on the use of animal genomics and biotechnology in livestock
production systems.” Dr. Van Eenennaam works particularly with the beef cattle industry and has
developed a variety of extension programming for producers on topics ranging from marker-assisted
and whole-genome enabled selection. Her outreach program focuses on the development of sciencebased educational materials outlining the uses of animal genomics and biotechnologies in livestock
production systems, including the controversial biotechnologies of genetic engineering (GE) and
cloning. She has given over 250 invited presentations in 17 states and 7 countries, and has served on several national
committees including the USDA National Advisory Committee on Biotechnology and 21st Century Agriculture, (2005–
2009), and as a temporary voting member of the 2012 FDA Veterinary Medicine Advisory Committee meeting on the
AquAdvantage salmon, the first GE to be evaluated for entry into the food supply. Dr. Van Eenennaam received the
“National Award for Excellence in Extension” from the American Association of Public and Land-Grant Universities in 2010.
53 WEDNESDAY
EXHIBITOR-HOSTED PROGRAMS
WEDNESDAY
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SYMPOSIUM 13
Novel Therapeutics in Oncology: Recent Advances
and Considerations for Nonclinical Safety
Evaluation
CHAIR: Hadi Falahatpisheh, Pfizer,
9:00 AM–12:00 Noon
Palm
Pearl River, NY
CO-CHAIR: Paul Moore,MacroGenics, Rockville, MD
In the early 1980s, monoclonal antibodies were considered to have the potential to revolutionize cancer therapy through
selective and specific targeting of tumor-associated antigen-positive cells. However, this concept has met with limited clinical
success in oncology at this stage.
These limitations led to the development of novel therapeutics such as antibody-drug conjugates, bispecific mAbs and cancer
vaccines. ADCs combine the specificity of a mAb for a tumor-associated antigen with the potency of a novel generation cytotoxic
agent and ensure selective tumor cell killing while reducing toxicity. Bispecific antibodies are designed to bind simultaneously
to 2 different epitopes, such as a tumor antigen and a receptor on an immune effector cell with the objective to redirect effector
cells to cancer cell killing. Therapeutic cancer vaccines take advantage of the individual's immune system to target tumor cells.
This symposium will review the recent advancements for these emerging modalities and will also highlight specific
considerations and challenges associated with the nonclinical safety evaluation of these molecules.
We believe this symposium will be of value to a broad range of participants, including academic and industry researchers
working in oncology, as well as toxicologists or regulatory scientists focusing on development of anticancer drugs.
S13-1
9:00 AM–9:40 AM
Antibody Drug Conjugates: Recent Developments and Future Perspectives
Laurie Tatalick, Seattle Genetics, Bothell, WA
S13-2
9:40 AM–10:20 AM
Advances in Bispecific Antibodies Facilitating Novel Therapeutic Opportunities
Paul Moore, MacroGenics, Rockville, MD
S13-3
10:20 AM–10:40 AM
Break
10:40 AM–11:20 AM
Nonclinical Safety Evaluation of Novel Ab-based Therapeutics for Oncology
Magali Guffroy, Pfizer, Pearl River, NY
S13-4 11:20 AM–12:00 Noon Using the Power of the Immune System to Target Cancer
David W. Clarke, Pfizer, Pearl River, NY
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Years of research and continuous optimization of the
different parts of ADCs have led to a robust ADC pipeline
(over 30 ADCs currently in clinical development) and the
recent FDA approvals of Kadcyla (Genentech/ ImmunoGen)
and ADCETRIS (Seattle Genetics). In this presentation, the
recent breakthroughs in research and development of ADC
modality will be discussed.
S13–2
Monoclonal antibodies have provided breakthrough
medicines for various diseases spanning cancer, autoimmunity
and infectious disease. Their ability to selectively bind
and interfere with a single target provides benefits over
conventional therapy in terms of selectivity and specificity.
Bispecific antibody technology provides an opportunity to
extend this selectivity to dual targets, heralding opportunity
to intervene in disease either through co-engagement of
multiple pathways or cell types. Dual Affinity ReTargeting
(DART) molecules are one such technology, which have
been successfully designed to overcome limitations of prior
bispecific antibodies in terms of manufacturability, stability
and pharmacological properties. In this presentation, the
preclinical development of bispecific DART molecules for
cancer and autoimmunity will be presented showcasing their
ability to dual target independent pathways or cell types
simultaneously for therapeutic benefit.
S13–3
The increasing molecule complexity of novel biotherapeutic
modalities, such as antibody-drug conjugates and bispecific
T-cell engagers, and specific considerations related to the
targeted cancer patient population lead to the design of
tailored nonclinical safety strategies that incorporate the
most current international regulatory guidelines and rely
on sound scientific principles. The presentation will first
review and discuss major aspects of nonclinical development
including selection of appropriate nonclinical species, design/
duration of general toxicity studies and new developments in
immunosafety testing, along with reproductive toxicology and
carcinogenicity assessments. We will also emphasize the need
for efficient clinical development and the greater risk tolerance
in patients when addressing life-threatening conditions. The
presentation will then highlight major safety issues with these
new therapeutic modalities and the predictivity/limitations of
the nonclinical studies.
S13–4
For many years the prospect of using the immune system
to target cancer cells has been a goal. To date the approach
has primarily been through passive immunization and
the administration of mAb. There have been a number of
attempts looking at active immunization, but to date this
approach has met with limited success. Generating anticancer
immunity is a multistep challenge which needs to generate a
significantly higher immune response to be able to overcome
tolerance to a self antigen, maintain the immune response,
and modulate the immune suppression present in the tumor
microenvironment. Many different approaches including
autologous tumor cell vaccines, allogenic tumor cell vaccines,
dendritic cell vaccines, protein- and peptide-based vaccines,
and genetic vaccines have been evaluated in nonclinical and
clinical studies and will be reviewed. Each of these approaches
will have unique nonclinical studies, which pose a challenge
to understanding the nonclinical safety of these cancer
immunotherapy regimens.
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Antibody-drug conjugates (ADCs) represent an innovative
and promising strategy for selective cancer treatment that
combines the specificity of a monoclonal antibody (mAb)
for a tumor-associated antigen with the potency of novel
cytotoxic agents. Through targeted delivery of cytotoxins
to cancer cells, ADCs are expected to be associated with
increased efficacy, reduced systemic toxicity, and therefore
improved therapeutic index.
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SYMPOSIUM 14
Applied Nanotoxicology
9:00 AM–12:00 Noon
Grand Cypress
Ballroom A
CHAIR: Dave Hobson,LoneStar
CO-CHAIR: Robin C. Guy,Robin
PharmTox, LLC, Bergheim, TX
Guy Consulting, LLC, Lake Forest, IL
Nanomaterials, including nanoparticles and nanoobjects, are being incorporated into everyday products at an increasing rate.
These products include consumer products of interest to toxicologists such as pharmaceuticals, cosmetics, food, food packaging,
household products, etc. The manufacturing of products containing or utilizing nanomaterials in their composition may also
present potential toxicologic concerns in the workplace. The molecular complexity and composition of these nanomaterials
is ever increasing and the means and methods being applied to characterize and perform useful toxicologic assessments are
rapidly advancing. This session will include presentations by experienced toxicologists in the nanotoxicology community that
are focused on the applied aspect of the discipline toward supporting state of the art toxicologic assessments for food products
and packaging, pharmaceuticals and medical devices, inhaled nanoparticle and gastrointestinal exposures and addressing
occupational safety and health issues and concerns.
S14-1
9:00 AM–9:35 AM
Introduction to Applied Nanomaterial Toxicology and Applied Nanotoxicology
for Pharmaceuticals and Medical Devices
Dave Hobson, LoneStar PharmTox, LLC, Bergheim, TX
S14-2
9:35 AM–10:05 AM
Assessing the Biological Fate of Ingested Nanomaterials
Steve Roberts, University of Florida, Gainesville, FL
S14-3
10:05 AM–10:35 AM
Nanoparticles as an Emerging Environmental and Occupational Hazard—
Toxicology Prospective
Anna A. Shvedova, CDC-National Institute for Occupational Safety and Health,
Morgantown, WV
S14-4
10:35 AM–10:55 AM
Break
10:55 AM–11:30 AM
Consumer Product Example: Strategies for Setting Occupational Exposure
Limits for Engineered Titanium Dioxide Nanomaterials
David Warheit, DuPont Haskell Laboratories, Newark, DE
S14-5 11:30 AM–12:00 Noon Applied Considerations for Safety Assessment of Food Products and Food
Packaging Containing Nanomaterials
Robin C. Guy, Robin Guy Consulting, LLC, Lake Forest, IL
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The biological activity of ingested nanomaterials depends
to a large extent on reactions and interactions that occur
both within the gastrointestinal tract and the body.
This presentation provides an overview of experimental
approaches for examining nano particle behavior in the gut,
as well as uptake into and distribution within the body.
S14–3
Advancements in nanotechnology field with broad
applications and manufacturing of nanomaterials raise the
issue of their potential adverse health effects particularly
in occupational and environmental settings. Carbonaceous
nanoparticles (CNP) have a wide scope of uses, ranging
from cosmetics and toiletry products, biomedicine, polymer
chemistry, composites employed in vehicles and sports
equipment, to integrated circuits for electronic components.
The lung is the major portal of unintended CNP entry into
the human body potentially leading to pulmonary damage,
inflammation, oxidative stress, fibrosis, and granuloma
formation. By employing proteomics and lipidomics analyses,
in vivo ESR spin-trapping technology, redox assessments of
antioxidant balance, and quantitative morphometry (including
collagen) in wild-type and genetically manipulated mice, we
were able to reveal the major pathways through which CNP —
in doses relevant to potential occupational exposures—exert
their toxic effects in the lung and distant organs of exposed
animals. The talk will address important issues of comparative
respiratory outcomes of CNP and asbestos, particularly with
regards to pulmonary injury and potential carcinogenicity.
Finally, the mechanisms of toxicity will be discussed in
the context of current regulations in environmental and
occupational settings. Acknowledgements: supported by
National Institutes of Health 008282, NORA 92700Y, 7th
Framework EU: FP7-NMP-2007.
S14–4
Lessons learned from practical development of methods
to evaluate toxicological effects from inhaled nanomaterial
exposures using a consumer product example. The
presentation will describe a bridging approach to estimate
OELs for three types of nano-TiO2 particulates based on
comparative intratracheal instillation toxicity studies in rats.
Toxicity profiles for the nanoparticulates were compared with
that for control materials (pigment-grade TiO2 particles) for
which an extensive database of long-term, animal inhalation
data and epidemiological data exists.
S14–5
More and more, companies are considering using nano-sized
materials in their food products and food packaging. These
new food ingredients exhibit benefits for the consumer; and
some of these benefits will be discussed. However, they also
bring about chemical, functional, and possibly toxicological
differences as compared to their micro-sized counterparts.
New applications are being developed that may take food
contact items to the next level of food safety. As with any new
ingredient, safety assessments need to be conducted on each
of these new ingredients. This discussion will focus on practical
aspects of safety assessment for the development of foods
and food contact items, which contain nano-sized materials.
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A brief overview and background of the session topics with
examples of applied nanotoxicology for pharmaceutical
and medical device products will be provided. State of
the art toxicology approaches being used with success for
these nanomaterials applications will be presented as well
as examples of past problems and current challenges with
conducting safety evaluations using various models and
gaining regulatory approval.
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SYMPOSIUM 15
Stem Cells Research
9:00 AM–12:00 Noon
Grand Cypress
Ballroom B
CHAIR: Kathleen A. Funk,Experimental
Pathology Laboratories, Inc., Sterling, VA
CO-CHAIR: Maralee McVean,Pre-Clinical
Research Services, Inc., Fort Collins, CO
Experimental Pathology Laboratories, Inc. and Pre-Clinical Research Services, Inc.
Stem cells have great potential in basic research and are being slowly integrated into toxicological research. This symposium
will provide an overview of the state of the field, stem cell models, describe allogeneic stem cell treatments and issues of
immunogenicity associated with protein therapeutics, and then concentrate on stems cell uses in regenerative medicine
focusing on lung and testing strategies on engineered tissues from a pathologist’s perspective.
S15-1
9:00 AM–9:35 AM
Where Is the Field of Regenerative Medicine Going?
Alan Trounson, Monash University, Victoria, Australia
S15-2
9:35 AM–10:20 AM
Applications of Stem Cell Technologies in Drug Discovery
Kyle Kolaja, Cellular Dynamics, Madison, WI
S15-3
10:20 AM–10:40 AM
Break
10:40 AM–11:20 AM
Pathology Techniques to Aid the Development and Understanding of Advanced
Therapy Medicinal Products (ATMPs)
Klaus Weber, AnaPath GmbH, Oberbuchsiten, Switzerland
S15-4 11:20 AM–12:00 Noon Advancing Engineered Lung Tissues to the Clinic: Considerations for Animal
Models and Toxicology Studies
Thomas Petersen, United Therapeutics Corporation, Research Triangle Park, NC
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This talk will serve as an introduction to the applications of
stem cell derived tissues toxicology applications in preclinical
discovery. The talk will highlight activities related to stem
cell-derived cardiomyocytes, their use to predict arrhythmia
and regulatory evaluation as well as the latest efforts related
to predicting teratogenicity, hepatotoxicity, and neuronal
toxicity. In addition, the prospect of genetic diversity of iPScell derived tissues in applied research will be discussed.
S15–3
Histopathologic analysis can help choose relevant animal
models, consider species specificity on a molecular, cellular
and tissue level, illuminate immunogenicity issues, detect
possible adverse effects, and the safety and suitability of all
structural components.
S15–4
Engineered lung tissues offer a potential solution to the
shortage of available organs for lung transplantation. This
presentation will cover on the following topics: 1) A scientific
update on the latest advancements in the generation of
functional engineered lungs; 2) A discussion of ex vivo
assessments of pulmonary function; 3) A discussion of the
challenges of transplantation studies using engineered lungs;
and 4) the impact on selection of animal models and the
design of toxicology studies.
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S15–1
Overview of stem cells and their characteristics and the ability
of stem cell technologies to represent proper organ physiology
and predict response to disease states and therapies.
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SYMPOSIUM 16
Safety Assessment Updates for Preventive
Vaccines and Vaccine Adjuvants
CHAIR: David W. Clarke,Pfizer,
CO-CHAIR: Jayanthi Wolf, Merck
9:00 AM–12:00 Noon
Grand Cypress
Ballroom C
Pearl River, NY
& Co, West Point, PA
With the development of more refined vaccine antigens there has been a need to help boost the immune response through the
addition of adjuvants into the formulation. The objective of this session is to review the rationale for the inclusion of adjuvants
in a vaccine and some of the unique challenges that the inclusion of an adjuvant brings to the nonclinical evaluation of the final
vaccine product. The session will include both the industry perspective on the nonclinical development of vaccines, but also the
regulatory framework under which the work is conducted.
S16-1
9:00 AM–9:25 AM
Rationale for Use of Adjuvants in Vaccines and Overview of Adjuvant Classes
and Pathways
Jayanthi Wolf, Merck, West Point, PA
S16-2
9:25 AM–9:50 AM
Regulatory Considerations in the Safety Assessment of Vaccine Adjuvants and
Adjuvanted Vaccines
Carmen Custodio, US Food and Drug Administration, Silver Spring, MD
S16-3
9:50 AM–10:20 AM
Industry Approaches to the Evaluation of Adjuvants and Immunostimulators
Ozzie Berger, GlaxoSmithKline Vaccine, King of Prussia, PA
S16-4
10:20 AM–10:45 AM
Safety Considerations for Adjuvants including Update from HESI Meeting
on Adjuvants and Autoimmunity
Sarah Gould, Sanofi-Pasteur, Marcy L’Etoile, France on behalf of The International Life
Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI)
S16-5
10:45 AM–11:00 AM
Break
11:00 AM–11:30 AM
Maternal Immunization and Nonclinical Safety Assessment
Martha Leibbrandt, Novartis Vaccines, Cambridge, MA
S16–6
11:30 AM–12:00 Noon Safety Assessment of Residuals and Contaminants in Vaccines
Deborah L. Novicki, Novartis Vaccines, Cambridge, MA
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The Office of Vaccines Research and Review (OVRR) is
responsible for regulatory review of new Investigational New
Drug Applications (INDs) and Biologics License Applications
(BLAs) for preventive vaccines and therapeutic vaccines
for infectious disease indications. Through this review
process, OVRR ensures that vaccines are safe, effective, pure,
and potent, as specified in Title 21 of the Code of Federal
Regulations, Sections 312, 600, and 610. This presentation will
review the key components in nonclinical and clinical safety
assessment of investigational vaccines regulated by OVRR,
with a focus on product testing and characterization, and
pharmacology and toxicology study design considerations, for
vaccines with novel adjuvants. In addition, updates on clinical
trial design considerations, including demonstration of the
“added benefit” of the adjuvant, adjuvant dose selection, and
safety monitoring will be discussed briefly.
S16–3
This talk will provide a global overview of the regulatory
framework for the nonclinical evaluation of adjuvant
systems and immunostimulants; and describe study designs
and species selection for local tolerance, repeated dose,
mutagenicity, reproductive/developmental toxicity, and safety
pharmacology. It will also address considerations outlined in the
2013 WHO Guidelines regarding the nonclinical assessment of
autoimmunity and hypersensitization and the inconsistencies
between EMA and WHO guidelines for nonclinical assessment
of adjuvant systems and immunostimulants.
S16–4
Questions are often raised about the safety of vaccine
adjuvants, particularly in relation to autoimmunity or
autoimmune disease(s)/disorder(s) (AID). The International Life
Sciences Institute (ILSI) Health and Environmental Sciences
Institute (HESI) formed a scientific committee (which included
industry, regulators and academics), which included technical
experts from academia, government regulatory agencies and
industry to consider adjuvant safety and conducted a wide
literature review and a two-day workshop. This presentation
will summarize the groups considerations relating to key
identified topics, which were as follows: 1) oil-in-water
emulsions and Toll-like Receptor (TLR) agonists adjuvants, 2)
use of animal models and 3) biomarkers for the evaluation and
prediction of AID and key issues including: the value of animal
models of autoimmunity for studying novel vaccine adjuvants;
whether there is scientific evidence indicating an intrinsic risk
of autoimmunity with adjuvants, or a higher risk resulting from
the mechanism of action; and if there is compelling clinical
data linking adjuvants and AID.
S16–5
Routine vaccination of a pregnant woman for the purpose of
protecting her unborn child against the effects of influenza,
tetanus and pertussis is now common in many parts of the
world. However, regulatory expectations for the type of
nonclinical data needed to support maternal immunization
with novel vaccine candidates or recently approved vaccines
vary across geographies. Strategies, insights and examples
pertaining to the design of reproductive and developmental
toxicity studies for vaccines indicated for pregnant women in
a global setting will be presented.
S16–6
The talk will provide background information and an overview
of the existing regulatory framework for the assessment of
residuals and contaminants in vaccines. It will provide a basis,
which can be used to formulate a general approach for the
safety assessment of residuals and contaminants in vaccines.
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Vaccine adjuvants are substances that are used in conjunction
with a vaccine antigen to increase or modulate the specific
immune response to the vaccine antigen in order to enhance
the clinical effectiveness of the vaccine. This presentation will
provide a rationale for the use of adjuvants in vaccines. An
overview of different adjuvant classes will be presented, with
a focus on the current understanding about mechanisms of
action and pathways used for immune stimulation.
2014
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EXHIBITOR-HOSTED PROGRAMS
12:00 Noon–12:55 PM
Wednesday Afternoon Session
SYMPOSIUM 17
Hot Topics
1:30 PM–4:30 PM
Grand Cypress
Ballroom D
CHAIR: Timothy J. McGovern,US
Food and Drug Administration, Silver Spring, MD
CO-CHAIR: Melissa C. Rhodes,GlaxoSmithKline,
Research Triangle Park, NC
SciLucent
1:30 PM–2:00 PM
FDA Tobacco/eCig Initiatives
Michael Orr, US Food and Drug Administration, Silver Spring, MD
2:00 PM–2:30 PM
Update on Biosimiliars
Barbara Mounho-Zamora, ToxStrategies Inc., Bend, OR
2:30 PM–3:00 PM
Animal Rights Extremists
John Sancenito, INA Security, Harrisburg, PA
3:00 PM–3:20 PM
Break
3:20 PM-3:30 PM
Update on FDA/CDER Guidances, Initiatives; ICH Activities
3:30 PM–3:45 PM
PETA Questions the Value of AAALAC Accreditation—What Is Going on Here?
David G. Serota, MPI Research, Mattawan, MI
3:45 PM–4:15 PM
Update on Activities around the Ebola Outbreak
Beth Leffel, Leffel Consulting Group, Washington, DC
4:15 PM–4:30 PM
FDA Perspectives on Ebola Issues
Christopher Ellis, US FDA/CDER, Silver Spring, MD
5:00 PM–6:30 PM
Wine Tasting with 2015 ACT President
Mary Ellen Cosenza
(Free event for ACT members only, advance registration
required) See page 10 for more information.
62 Grand View Terrace
In case of rain:
Grand Cypress G
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ACT Poster Presentations
Posters may be in place as early as Sunday afternoon and will be displayed from Monday through Tuesday at 4:30 pm.
Designated authors (indicated in the Poster description by an underline) will present their poster during the Poster Reception
Monday, November 10 from 5:30 pm to 7:00 pm. Please join this session to engage with the authors and see some of the latest
work in the field. (ACT is not responsible for posting, removing, or storing posters.)
ABSTRACTS
Posters are located in the Grand Cypress Ballroom.
100 Series—General Toxicology
200 Series—Regulatory
300 Series—Safety Evaluation Nonpharmaceuticals
400 Series—Toxicology Methods
500 Series—Safety Evaluation Pharmaceuticals
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Poster Abstracts
Poster abstracts are indicated with letters preceding the poster number: Poster (P), Student Travel Award (STP), North American Graduate
Fellowship (GFP), and International Travel Grant (IGP).
100 Series—General Toxicology
P101
Veterinary Pharmacovigilance Survey Conducted in Tamil
Nadu State, India—A Status Report.
G. Sarathchandra1,2. 1Pharmacovigilance Laboratory for Animal
P103
Prevalence and Incidence of Cataracts in a Population of
Yucatan Miniswines after Induction of Type I Diabetes.
C. Hanks1, A. Ingerson1, M. Freeman1, S. Schlink1, L. Delaney1, S.
Renna1, L. Brown1, A. Stricker-Krongrad1, J. Liu1, A. Tellez Cruz2,
S. Rousselle2, J. Wicks2, G. Bouchard1. 1Sinclair Research Center
ABSTRACTS
Feed and Food Safety, Chennai, Tamilnadu, India, 2Tamil Nadu
Veterinary & Animal Sciences University, Chennai, Tamilnadu, India
Veterinary pharmacovigilance monitors the safety of veterinary
medicines, including vaccines (VAC) used for the prophylaxis,
diagnosis or treatment of diseases in animals once they reach
the market after authorization. In India, there is no present
government policy to survey and evaluate adverse drug events
(ADEs) / Pharmacovigilance programme for veterinary medicines.
Therefore, essential information such as frequency, severity
of treated animal ADEs and reliable data about frequent ADEproducing drugs remains unknown. The objective of the study
was to assess and communicate risks and benefits in the market.
Ultimately to educate the veterinarians and the stakeholders
on the safety and efficacy of veterinary drugs and biologicals.
A 12-month period pilot study was conducted to monitor the
ADE for frequently used drugs (labeled/extra labeled drugs). A
survey protocol consisting of a questionnaire about used drugs
in livestock was developed; the questionnaire was distributed
to 300 veterinarians of Tamil Nadu state. The veterinarians were
instructed to voluntarily report on the various types of drugs used
and the ADEs, if any observed. More than 37% ADEs were related
to antimicrobials, antiparasitic and anti-inflammatory agents. A
further 27% of ADEs were due to vitamins and feed additives. Two
cases of ADEs observed in FMD vaccination, in cattle and canine
Parvo vaccine in dogs. In poultry, tiamulin and salinomycin ADEs
induced serious mortality. The present study warrants for the
need of sustained veterinary pharmacovigilance programmes
in livestock for timely ADEs presenting drug detections and
drug safety improvement.
P102
Withdrawn
LLC, Auxvasse, MO, USA, 2Alizee Pathology, LLC, Thurmont, MD, USA
Cataracts as a consequence of chronic diabetes is considered a
leading cause of legal blindness in humans in the United States and
is also observed frequently in aged diabetic populations (>65%).
Objective: Assess postinduction (PI) onset of ocular
cataract(s) in a colony of over 266 castrated, male, diabetic,
Yucatan miniature swine.
Methods: Diabetic miniature swine were routinely screened by
the veterinary staff for clinical ocular abnormalities including
visible ‘mature' cataracts.
Results: Over the course of a 6 month period, the prevalence was
30% (80 positive animals out of 266 animals). The most recent
incidence (past 2.5 months) was 20.4% (38 positive animals with
60 affected eyes from pool of 186 previously negative animals).
Eighteen animals had bilateral and 20 animals had unilateral
cataracts (OD: 31; OS: 29). Cataract onset ranged from 2 to 19
months PI with an average of 11 months PI. Cataracts were
detected earlier in animals when euglycaemia was intentionally
less controlled, which supports the current predominant theory
of glycation-induced cataract development. Interestingly, swine
unlike human are not capable of glycating their hemoglobin due
to the lack of penetration of glucose into the red cells. Miniswine
with cataracts appear to function acceptably well despite the
assumed visual handicap.
Conclusions: Diabetic Yucatan miniature swine commonly
manifest with cataracts on average at 11 months postinduction.
Insulin regimen and glucose control are strong factors in the
prevalence and incidence of cataracts in diabetic miniswines. The
diabetic miniswine would provide a good model for preventative
or therapeutic cataract therapies.
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P104
Reproductive and Developmental Toxicology Assessment of
Oral Dietary Calcium Formate in Yucatan Miniature Swine.
T. Madsen1, D. Hobson2, C. Selby1, G.P. Georges4, R.
Hanzlik3, D. Brocksmith1, A. Stricker-Krongrad1, J. Liu1, G.
Bouchard1. 1Sinclair Research Center, LLC, Auxvasse, MO, USA,
LoneStar Pharm Tox, LLC, Boern, TX, USA, 3University of Kansas,
Lawrence, KS, USA, 4NephroTech 1, LLC, Shawnee, KS, USA
2
Calcium Formate (CaF) is being considered as a dietary
calcium supplement.
Objective: Assess the reproductive/developmental toxicity
of oral dietary CaF.
Results: Female fertility index/group ranged from 80-100%. Total
fetuses delivered were 174 with 170 livebirths. Piglet viability
was good. Length of gestation, birth weights and body weight
change were comparable. Litter size was robust (range 5.4-7.1) for
all groups. CaF supplementation was associated with decreased
food intake in both parents in the high dose group and with
decreased weight gain in both parents during the premating
phase of the study. These between group differences persisted
through the gestational phase for the females, but were not
statistically significant. CaF supplementation was also associated
with increased serum calcium levels in both parents. Although
statistically significant, the magnitudes of these differences were
small, and well within the normal physiologic ranges.There were
no significant findings of developmental/reproductive toxicity
related to dietary exposure to CaF.
Conclusion(s): Decreased food intake, decreased weight
gain during premating phase, and increased serum calcium
were associated with oral dietary CaF administration. These
findings were consistent with previous research, and/or
represented expected responses to the administration of oral
CaF supplementation.
P105
Toxicokinetic Approaches to Improving Accuracy of Drug
Withdrawal Times in Food Producing Animals to Avoid Toxic
Violative Tissue Residues.
J. Riviere1, Z. Lin1, M. Li1. Institute of Computational Comparative
Medicine, Kansas State University, Manhattan, KS, USA1
Monitoring for potentially toxic violative chemical residues in
meat, milk and eggs is the primary regulatory tool to ensure
chemical food safety in edible products from food producing
animals. Although analytical approaches to monitoring residues
have dramatically improved (2012 multi-residue MS/MS
methods), toxicokinetic models used to establish drug withdrawal
times (WDT) to avoid violative residues have not changed since
their inception decades ago. WDTs are determined in healthy
animals with a number of simplifying assumptions related to
analysis of tissue depletion data (single log-linear decay, constant
parent-drug to metabolite ratios, breed or disease effects on
depletion kinetics) that are violated when animals are given label
doses in field conditions; further exacerbated if drugs are legally
administered off-label when increased dosages are used to treat
resistant pathogens. Two toxicokinetic-modeling techniques
can be used to make WDT estimation more realistic relative to
variability seen in field conditions; physiological-based (PBPK) and
mixed-effect population pharmacokinetic (PopPK). Both allow
incorporation of disease effects on distribution (protein binding),
elimination or biotransformation based on published literature;
approaches could be considered meta-analysis tools that allow
relevant data to be incorporated in WDT estimations. Efficiency
of these approaches were assessed using published and new
experimental data from tissue depletion studies on penicillin-G,
oxytetracycline and flunixin in cattle and swine. Results using both
PBPK and PopPK modeling for all drugs suggest that disease and
dosing route changes have major impact on WDT and could result
in residue violations even when label dosages are employed.
(Supported by FARAD USDA-NIFA 2013-41480-21001)
P106
Interaction of Silver and Gold Nanoparticles with Proteins,
Biocorona Formation and Its Impact on Cellular Toxicity.
N. Monteiro-Riviere1, A. Sasidharan1, R. Chen1, J. Riviere1. Kansas
State University, Manhattan, KS, USA1
Nanoparticles (NP) interact with proteins to form a protein
corona in biological fluids that can influence their biodistribution.
The dynamic interaction of the protein corona with NP may
significantly affect the bio-identity of the NP, thereby leading
to diverse biological outcomes at the cellular level. Since NPprotein interactions decide the fate of a NP in vivo, understanding
the complexity and dynamic interaction of the NP-protein
formation is imperative. Time dependent adsorption kinetics
of the protein corona were conducted with lipoic acid and BPEI
coatings of 40 and 80nm silver (AgNP) and gold NP (AuNP). Ag
and AuNP's were exposed to human serum albumin (HSA; 40mg/
mL), fibrinogen (2mg/ml), immunoglobulin G (IgG; 12mg/ml) and
transferrin (2.5mg/ml) at their physiological concentrations from
6-24h. These studies indicated that irrespective of size or surface
chemistry, rapid and prominent binding of HSA corona formed
over both surface coatings with AgNP causing a slight increase
in size, without aggregation. In contrast, the fibrinogen corona
showed a time dependent decrease in NP stability leading to
aggregation at 6h at 37°C. Interestingly, the transferrin corona
induced aggregation in 80nm AuNP, while 40nm AuNP remained
stable at 24h at 37°C. Further, the impact of the biocorona
formation with human epidermal keratinocytes (HEK) and human
vascular endothelial cells (HUVEC) were affected. Our results
suggest that NP-protein interaction significantly affects the
agglomeration and surface charge that further modulates the
cellular responses in HEK and HUVEC.
65 ABSTRACTS
Experimental Procedures: Sixty (30 male and 30 female)
sexually mature minipigs were gender paired for breeding and
randomized into 3 groups of 10 pairs receiving untreated control,
low dose (2.25% CaF), and high dose (4.5% CaF) in the daily
diet. Standard reproductive and developmental variables were
assessed, including clinical, gross, and microscopic pathology
(parents and piglets).
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P107
In Silico Toxicity Evaluation of Marine Molecules with
Antifungal Profile.
Castro HC1, Santos TAN1, Mendonça AT2, Cabral LM2, Rodrigues
CR2. 1Post-graduation Programs in Science and Biotechnology and
ABSTRACTS
Pathology, Federal Fluminense University, Niterói, Rio de Janeiro,
Brazil. 2Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio
de Janeiro, Brazil.
The fungi resistance against the antimicrobials is currently the
major challenge for a proper infection treatment. Literature
describes several new antifungals from natural sources such as
marine organisms, but the toxicological aspects are still unknown
due to the difficult on isolating and testing them. Since the use
of in silico toxicology tools may help in selecting new molecules
for further in vitro and in vivo toxicological evaluation, our
purpose was to characterize the in silico toxicological properties
of 19 marine products with antifungal potential described in
the last 5 years to guide the selection for further in vitro and in
vivo studies. In this work we also compared these molecules
with antifungals in use such as fluconazole and voriconazole.
Thus we used the programs for toxicological prediction, LAZAR
and OSIRIS for evaluating 19 marine products that vary on the
structural complexity degree (high, medium and low). The lowest
risk toxicity profile was observed for nine compounds, including
those of low complex structure (e.g. halogenated furans and
curcudiol) showing a promising profile for future in vivo studies.
Differently two compounds, including cucurphenol presented
the highest risk profile and lower priority for in vitro and in vivo
evaluations. This theoretical study reinforced the use of these
tools as a step that may be included as a laboratory routine for
studying marine compounds and others of difficult obtention but
with high biological potential for human treatment. This step may
help in selecting and identifying the potential of these molecules
as safer antifungals agents.
P108
A Comparison of the Type of Spontaneously Occurring
Microscopic Lesions in the Göttingen and Chinese Bama
Minipig.
T. Zhou1, S. McPherson1, X. Yang1. Wuxi Apptec, Suzhou, China1
The minipig is often used in regulatory preclinical toxicology
studies as the choice of the nonrodent species. It presents a
favorable profile as a nonrodent toxicology model in terms of the
similarity to man and also in terms of applicability to different
study types (Bode et al 2010). Studies for general toxicology
programs can be performed by oral, dermal, parenteral and
inhalation routes. Physiologically the minipig also has advantages
for use in reproductive and safety pharmacology studies.
In USA and Europe the Göttingen minipig is often selected,
whilst in China the Bama pig is usually the strain of choice.
Histopathological data from control animals from toxicology
studies using the Bama at Wuxi Apptec Suzhou were compared
to published data for the Göttingen minipig. The type of lesions
and also systems affected were compared to see if there were any
notable differences between the two strains of animals. Generally
the findings between the two strains were similar. However, one
notable difference between the two strains of minipig was that for
the Bama minipig the presence of hyaline droplets accumulation
2014
(minimal to moderate) in the glomerulus of the kidney, this hasn't
been reported in the Göttingen pig.
P109
Evaluation of Background Tumor Incidence in rasH2 Mice
and Clinical Pathology Data from rasH2 Non-Transgenic and
Transgenic Mice.
K. Bonnette1, M. Morse1. Charles River, Spencerville, OH, USA1
A 26-week carcinogenicity study in rasH2 (CByB6F1-Tg(HRAS)2JIC)
mice is recognized by ICH S1B (Testing for Carcinogenicity of
Pharmaceuticals) as an alternative to a conventional 2 year bioassay
in mice. The conduct of these studies is dependent on a low
number of background tumors in controls and a notable number of
background tumors in concurrent positive controls. Additionally,
clinical pathology measurements are often collected during the
28-day carcinogenicity range-finding studies to monitor toxicity
and pharmacology endpoints. In these range-finding studies,
rasH2 hybrid (or nontransgenic littermates) mice are typically used
as they are genetically similar to their transgenic littermates and
the absence of the transgene does not impact toxicity. Therefore,
we wanted to determine if our facility's background incidence of
neoplastic findings in the rasH2 mouse is within expected limits
reported in the literature. Additionally, we wanted to establish
clinical chemistry and hematology historical control ranges for
both transgenic and nontransgenic rasH2 mice and to compare
them to the CD-1 mouse historical reference ranges as this strain
of mouse is typically used in 2 year bioassays. Our results indicate
that our incidence of common neoplastic findings was similar to
those published in the literature. Additionally, we determined
that the majority of clinical pathology parameter ranges were
similar between the strains of mice; however, when older rasH2
transgenic mice were compared to younger nontransgenic
littermates, and age matched CD-1 mice, some parameters (e.g.
aspartate aminotransferase, aspartate aminotransferase, alkaline
phosphatase) demonstrated wider ranges.
P110
The Postnatal Development and Growth of the CardioRespiratory System in Sprague-Dawley Rats.
A. Apreutese1,2, C. Gordon1, R. Foster3, A. Graham1, B. Palate3,
J. Haruna1, M.O. Benoit-Biancamano2. 1CiToxLAB North America,
Laval, Quebec, Canada, 2Faculté de Médecine Vétérinaire, Université
de Montréal, St-Hyacinthe, Quebec, Canada, 3CiToxLAB France, Évreux
CEDEX, France
The purpose of this study was to investigate the histomorphological
changes of the cardio-respiratory system in rat pups over
the first month of life. The heart weight and the heart weight
relative to body weight ratio were calculated for 51 rats over 13
timepoints, ranging from postnatal day 1 (PND1) to PND30. For
each timepoint, whenever possible, equal number of females
and males were used. The aortic wall progressively increased
in thickness throughout the duration of our study as a result of
an accumulation of extracellular matrix (collagen and elastic
fibers). Postnatally, the cardiac volume essentially increased by
cardiomyocyte hypertrophy, which showed a more mature
appearance around PND21. In the newborn myocardium, mitotic
figures and apoptotic bodies were frequently seen, increased on
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complicated, and is affected by systems level effects such as
multiple feedback processes within and between the various onand off-target pathways. These systems level processes are often
impossible to reconstruct in vitro as they involve many cell types,
tissues, and organs systems throughout the body. We show here
that through mathematical modeling we were able to identify, in
silico, molecular properties that are critical to driving functional
selectivity. The models, although simple, capture the key systems
pharmacology needed to understand the balance between
known on- an off- target effects. Surprisingly, in this case, the key
driver of functional selectivity is not the affinity of the drugs but
rather the pharmacokinetics, with drugs having a short half-life
predicted to be the most functionally selective.
P111
Histomorphologic Features of Neonatal and Juvenile
Uro-Genital Development in Sprague-Dawley Rats.
A. Apreutese1,2, C. Gordon1, R. Foster3, A. Graham1, B. Palate3,
J. Haruna1, M.O. Benoit-Biancamano2. 1CiToxLAB North America,
P113
Prediction of Severity and Clinical Outcome of Poisoning in
India by Multiple Clinical Scoring Systems.
S. Churi1, M. Ramesh1. JSS University, Mysore, Karnataka, India1
Laval, Quebec, Canada, 2Faculté de Médecine Vétérinaire, Université
de Montréal, St-Hyacinthe, Quebec, Canada, 3CiToxLAB France,
Évreux, France
This study describes the histomorphologic key postnatal
developmental events occurring in the uro-genital system of rat
pups from birth to postnatal day 30 (PND30). Tissues were collected
from 51 rats, using equal numbers from each sex whenever
possible, at PND1, 2, 4, 6, 8, 10, 14, 17, 21, 24, 26, 28, and 30. Our
study revealed that nephrogenesis in rats ceased by PND14, while
few mitoses were still observed at the cortico-medullary junction
at PND21. Individual cell death and mitoses were abundant at
birth and followed a centripetal pattern (from outer cortex to
medulla), accompanying developing renal structures. At PND26,
the ovary exhibited a sharply demarcated cortico-medullary
junction. Between PND21-PND26 numerous apoptotic ova were
present. The first uterine glands became visible around PND14,
whereas scattered apoptotic epithelial cells were still present up
to PND26. By PND24, the superficial layer of the vaginal epithelium
was multifocally composed by large cells containing a mucinous
material mixed with few apoptotic cells. At birth, the seminiferous
tubular epithelium was 1 to 2 layers thickened, composed of
spermatogonia and Sertoli cells. A seminiferous lumen was rarely
seen and the interstitium was abundant and hypocellular. The
pachytene spermatocytes were observed around second week
of life, while the first round spermatids became visible on PND30.
The description of these major histological features of the male
and female uro-genital systems from birth to PND30 will serve
as valuable histological historical database that will be useful in
pediatric drug development.
Objective: Descriptive and prognostic evaluation scales (scoring
systems), which are widely accepted worldwide, can be used to
predict the severity and mortality rate of poisoning. We sought
to assess the efficacy of GCS, PSS, APACHE II and SAPS II systems
in predicting the severity and clinical outcome of pesticides,
medicines and household products poisoning in India.
Methods: One-year study (total patients = 198) was conducted
at Indian tertiary-care teaching hospitals. GCS scores were
calculated according to motor response to pain, and verbal and
eye responses. PSS scores were calculated according to signs
and symptoms of various systems and metabolism. APACHE II
and SAPS II scores were calculated using the worst physiologic
values in the first intensive care unit day. Based on the scores,
the severity and clinical outcome of poisoning was predicted.
Pearson correlation and Chi-square test were used to assess the
statistical significance.
Results: A majority of patients (n = 173, 87.4%) with mild to
moderate predicted severity were recovered from poisoning.
Patients with severe predicted illness were either discharged with
severe illness (n = 14, 7.1%) or morbidity (n = 3, 1.5%) or expired
(n = 8, 4%). There was a significant (P<0.05) association between
the actual clinical outcome and scores of scales. There was also a
moderate correlation between scoring systems (r = 0.61, P<0.01),
indicating that tested scales provided similar efficacy.
Conclusion: The study demonstrated essential sensitivity and
excellent efficacy of these scoring systems to predict the severity
and clinical outcome of poisoning in India.
P112
A Systems Pharmacology Approach to Understand Efficacy
and Toxicity to Optimize Therapeutic Window.
J. Apgar1, J. Burke1. Applied BioMath, Winchester, MA, USA1
Most commonly the selectivity of a compound is defined in an in
vitro or cellular assay, and it is thought of as principally a function
of the binding energy of the drug to its on-target and off-target
proteins; however, in vivo functional selectivity is much more
67 ABSTRACTS
PND4 and showed a diffuse pattern. At birth, the trachea was lined
by immature columnar ciliated epithelial cells, and submucosal
glands became visible around one week after birth. The newborn
rat has no alveoli and breathes with smooth, large gas exchange
units termed "primary saccules". An intense interstitial cellular
proliferation was observed in the lungs between PND6 and
PND14, when the majority of alveoli are separated by new
secondary septa, formed from the primary walls. These changes
were accompanied by few mitoses and/or individual apoptotic
cells. The findings described herein suggest that the cardiorespiratory system of rats is immature at birth. The data generated
will serve as background historical database that will be valuable
when performing postnatal developmental toxicity studies.
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STP114
Mechanisms of Acetaminophen-Induced Cell Death in
Primary Human Hepatocytes.
Y. Xie1, M. R. McGill1, K. Dorko1, S. C. Kumer1, T. M. Schmitt1, J.
Forster1, H. Jaeschke1. University of Kansas Medical Center, Kansas
ABSTRACTS
City, USA1
Acetaminophen (APAP) overdose is the most prevalent cause
of acute liver failure in western countries. Numerous studies
have been conducted to investigate the mechanisms of injury
after APAP overdose in various animal models; however, the
relevance of these mechanisms for humans remains unclear.
Here we investigated APAP hepatotoxicity using freshly isolated
primary human hepatocytes (PHH) from either donor livers or
liver resections. PHH were exposed to 5mM, 10mM or 20mM APAP
over a period of 48 hours and multiple parameters were assessed.
APAP dose-dependently induced significant hepatocyte necrosis
starting from 24h, which correlated with the clinical onset of human
liver injury after APAP overdose. Interestingly, cellular glutathione
was depleted rapidly during the first 3h. APAP also resulted in
early formation of APAP-protein adducts (measured in whole
cell lysate and in mitochondria) and mitochondrial dysfunction,
indicated by the loss of mitochondrial membrane potential
after 12h. Furthermore, APAP time-dependently triggered c-Jun
N-terminal kinase (JNK) activation in the cytosol and translocation
of phospho-JNK to the mitochondria. Both co-treatment and
post-treatment (3h) with the JNK inhibitor SP600125 reduced JNK
activation and significantly attenuated cell death at 24h and 48h
after APAP. The clinical antidote N-acetylcysteine offered almost
complete protection even if administered 6 hours after APAP and
a partial protection when given at 15h. Conclusion: These data
highlight important mechanistic events in APAP toxicity in PHH
and indicate a critical role of JNK in the progression of injury after
APAP in humans. The JNK pathway may represent a therapeutic
target in the clinic.
IGP115
Comparative Study of Muscular Regeneration after Necrosis
Induced by Philodryas patagoniensis and Bothrops alternatus
Snake Venoms.
M.E. Peichoto1, M.N. Sánchez1, G.P. Teibler2, S.L. Maruñak2, O.C.
Acosta2. 1Instituto Nacional de Medicina Tropical, Puerto Iguazú,
Argentina, 2Facultad de Ciencias Veterinarias, Universidad Nacional
del Nordeste, Corrientes, Argentina
According to studies carried out with Bothrops (Viperidae)
venoms, poor muscle regeneration is evidenced when tissues are
affected by hemorrhage as this affects the microvascular supply
of nutrients and oxygen necessary to accomplish a successful
regeneration. On the other hand, the process of muscular
regeneration after injury induced by Philodryas patagoniensis
(Colubridae) venom (PpV) - which exhibits higher hemorrhagic
activity than Bothrops alternatus venom (BaV) - has never been
studied before. Thus, the purpose of this work was to evaluate
and compare the regeneration of skeletal muscle fibers after
necrosis induced by these two venoms. Mice were injected
into the gastrocnemius muscle with 40 µg of either PpV or BaV.
2014
After 1, 3, 7, 14 and 28 days of inoculation, muscle fragments
were extracted to have a qualitative histological assessment of
the regeneration by staining sections with Hematoxylin-Eosin
and Gomori's One-Step Trichrome. Samples showed an earlier
appearance of regenerating fibers in muscles injected with
BaV than with PpV. These results were consistent with those
evaluating fibrosis, which showed an earlier and a higher amount
of muscle tissue substituted by collagen fibers in PpV samples.
These differences could be related with the different hemorrhagic
activities exhibited by both venoms, and it would be the cause of
the deficient muscular regeneration observed in P. patagoniensis
envenomation, both experimentally and clinically. On the whole,
these observations help us to understand the local pathological
effects associated with viperid and colubrid envenomings, and
they should be considered in both diagnosis and prognosis
of snakebite victims.
IGP116
Nanotoxicity of Arsenic Trioxide in Liver and Kidney of
Laboratory Rats.
Y. Verma1, S.V.S. Rana1, Kavita Rana1. C.C.S. University, Meerut, UP,
India1
The impact of nanoparticles on human health and the
environment is largely unknown, although many studies are
under way in different parts of the world. While the small size of
particles is what makes nanotechnology so useful in medicine and
industry it is also one of the main factors that might make them
potentially dangerous to human health. Arsenic is known human
carcinogen. The adverse effects of Arsenic (III)(encapsulated with
PLGA) nanoparticles cannot be predicted from known toxicity
of bulk materials. We hypothesized that the noval properties
may allow harmful interactions with biological system with the
potential to generate toxicity. Therefore toxicological evaluation
of arsenic trioxide is critical to establish the full in vitro potential
of nanomedicine. Present paper describes the results on
protein, MDA, GSH, GSSG, GST and CYP-450 in liver and kidney
of laboratory rats treated with arsenic trioxide encapsulated
with PLGA nanoparticles. Results also established the liver and
kidney as accumulative organs for arsenic trioxide nanoparticles.
Present study on toxicity of Arsenic (III) encapsulated with PLGA
nanoparticles in rat expected to be useful from health risk of point
of view among occupational workers involved in the manufacture
and processing of nanoparticles and in general population using
products containing these nanoparticles.
GFP117
The Impact of B-Cell Activation on Cb2 Expression.
J. Castaneda1, A. Harui1, S. Kiertscher1, M. Roth1. University of
California, Los Angeles, Los Angeles, CA, USA1
Cannabinoids, the primary bioactive constituents of marijuana,
activate cannabinoid receptor CB2, which is expressed on
the surface of human B cells but not T cells. The toxicity of
cannabinoids on immune function remains to be determined. In
preliminary studies, human tonsillar B cell subsets were analyzed
for the expression of cell surface CB2 by flow cytometry. While
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GFP118
Exposure to Neurotoxicant Results in Parkin-Dependent
Changes in Proteasome Activity in Brain Regions Containing
Differentially Susceptible Dopaminergic Neurons.
T. Lansdell1, J.L. Goudreau2, K.J. Lookingland3. 1Dept. of
Neurology Michigan State University, East Lansing, USA, 2Dept.
of Pharmacology and Toxicology, Michigan State University, East
Lansing, MI, USA, 3Center for Integrative Toxicology, Michigan State
University, East Lansing, MI, USA
Parkinson disease (PD) is a neurodegenerative disorder in which
motor symptoms result from the loss of nigrostriatal dopamine
(NSDA) neurons, while those in the mediobasal hypothalamus
are spared. The pattern of dopamine (DA) neuron susceptibility
to neurodegeneration can be recapitulated with neurotoxicant
exposure, including acute and chronic treatment with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone.
Expression of parkin mRNA and protein increases in the medial
basal hypothalamus following MPTP exposure, a change that is
temporally linked to the phenotypic and functional recovery of
tuberoinfundibular dopamine (TIDA) neurons in the mediobasal
hypothalamus. In contrast, there is no increase in parkin mRNA
or protein in the ventral midbrain following MPTP exposure and
these neurons do not recover function or phenotype. Parkin is an
E3 ubiquitin ligase with an N-terminal ubiquitin like domain that
can directly modulate the activity of the proteasome.
69 ABSTRACTS
naïve (IgD+/CD38-/CD27-) and quiescent memory (IgD-/CD38-/
CD27+) B cells expressed cell surface CB2, activated B cells (IgD-/
CD38+/CD27dim) expressed low to no detectable surface CB2. We
initially hypothesized that B cell activation might be responsible
for down-regulation of CB2. Tonsillar B cells were therefore
exposed for seven days in vitro to mega-CD40L and IL-4. This
treatment promoted expression of the CD27 activation marker
by all B cell subsets but also led to a selective down-regulation of
cell surface CB2 only on activated memory B cells - not naïve cells
still expressing IgD. Our findings suggest that CB2 is differentiallyregulated in naïve versus isotype-switched B cells. In ongoing
experiments, isolated naïve B cells (>98% purity) will be activated
with or without triggering by anti-IgD to examine differences in
CB2 expression that occur before/after Ig isotype selection. Cells
will also be treated with selective CB2 agonists and antagonists
to determine the impact on isotype switching and the resulting
expression of Ig subtypes. These experiments will establish a
model system for examining the two-way interaction between
CB2 receptors and signaling events that lead to B cell activation
and differentiation.
2014
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200 Series—Regulatory
P200
Selected Excipients Tested for Their Potential to Induce
Hemolysis In Vitro in Different Species.
M. Festag1, A. Eichinger-Chapelon1, C. Hager1, R. Kopf2, K.
Ravuri2, C. Sarron-Petit1. 1F. Hoffmann-La Roche Ltd, Roche
ABSTRACTS
Pharmaceutical Research and Early Development, Pharmaceutical
Sciences, Roche Innovation Center Basel, CH - 4070 Basel, Switzerland,
2
F. Hoffmann-La Roche Ltd., Pharmaceutical Technical Development,
CH - 4070 Basel, Switzerland
Six different surfactants were studied in minipig, dog,
cynomolgus monkey or human whole blood to identify the
concentration where a disintegration or permeabilization of red
blood cell membranes resulting in hemolysis and the release of
hemoglobin would occur.
Serial dilutions of N-Dodecyl-β-D-maltoside (DDM), Polysorbate
20 (PS20), Polysorbate 80 (PS80), Poloxamer 188 (P188), Kolliphor
HS15 (Solutol), and N-Octyl-β-D-glucopyranoside (OGP) in 0.9%
NaCl as the vehicle were prepared. The different concentration
ranges were incubated with blood from the selected species
and released hemoglobin was photometrically measured at 540
nm. Results were expressed in % hemolysis extrapolated from an
internal standard curve.
A less than 5% hemolysis was measured at concentrations of
≤0.195 mg/mL DDM, ≤3.75 mg/mL PS20, ≤9.36 mg/mL PS80 in
dog blood and at higher concentrations in the other investigated
species, ≤100 mg/mL (highest test concentration) P188 (≤80 mg/
mL in monkey blood), ≤6.25 mg/mL (highest test concentration)
Solutol, and ≤1.56 mg/mL OGP in the tested species. A strong
hemolysis (up to 100%) was induced by DDM and OGP at
≥1.563 mg/mL and ≥6.25 mg/mL, respectively in all investigated
species. There was no major species difference identified in
causing hemolysis at the investigated concentrations of the
different surfactants.
Due to the static nature of this in vitro assay compared to the in
vivo situation determined concentrations are rather seen as a
hazard than true risk assessment.
P201
Value Added: A Case Study Where Unconventional Endpoints
(Bone Composition and Bone Turnover Biomarkers) Provided
Early Signals for Safety Monitoring in a Two-Week General
Toxicology Dog.
R. Yeager1, Y. Luo2, Y. Tian3, B. Hooker2, T. Cole2, A. Tovcimak2, K.
Barnhart1, K. Whitney1, C. Graff3, R. Stoffel4, D. Honor1, R. Garg1,
S. Fossey1. 1Preclinical Safety, AbbVie, Inc., North Chicago, IL, USA,
Imaging, AbbVie, Inc., North Chicago, IL, USA, 3Drug Metabolism,
AbbVie, Inc., Worcester, MA, USA, 4Immunology Discovery, AbbVie,
Inc., Worcester, MA, USA
2
Early preclinical toxicology studies for small molecules generally
consist of 5 to 14 days of dosing in a rodent and nonrodent
species and are typically designed to evaluate for test item-related
effects on a standard panel of clinical pathology parameters and
an abbreviated tissue list for histopathology. This case study
demonstrates the value of including additional/unconventional
endpoints, specifically bone marrow fat, bone mineral density
(BMD) and serum P1NP (total procollagen type 1 N-terminal
propeptide; a bone formation biomarker), on a two-week
dosage range-finding toxicology study in Beagle dogs with a test
compound that may have a bone-related effect.
Pathology findings from the standard clinical pathology panel
and abbreviated tissue list for histopathology were considered
nonadverse and were generally consistent with expected
pharmacology. At the high dose, there was a significant increase
in the bone marrow fat fraction from L4 vertebrae body. A similar
trend was observed in the marrow from femoral diaphysis, but
was not statistically significant. There was no significant test
item-related effect on BMD. At all three dose levels, serum P1NP
levels were decreased by approximately 80% on Dosing Day 14
compared to baseline.
There was a strong inverse correlation between increased bone
marrow fat fraction and decreased serum P1NP, which provided
an early signal for undesirable pharmacology-related changes
in bone. For test compounds that may have a bone-related
effect, these additional study endpoints can be used for future
compound safety screening in preclinical species and possibly be
applied in clinical trials as safety monitoring biomarkers.
P202
An Improved Workflow to Perform In Silico Mutagenicity
Assessment of Impurities as per ICH M7 Guideline.
R. Saiakhov1, S. Chakravarti1, A. Sedykh1. MultiCASE Inc,
Beachwood, OH, USA1
Purpose: Use of in silico tools is one of the central points of ICH
M7 guideline. However computational assessment of DNA
reactive impurities is still challenging. Purpose of this study
is to develop and apply an effective workflow using a QSAR
statistical system and a quantitative read across methodology
to obtain reliable genotoxicity assessments adhering to the
ICH M7 recommendations. The novel multi-tier methodology
provides the detailed information of toxicity alerts and reduces
false positives, false negatives while increasing the test coverage.
This in silico approach can be successfully used for assessment of
mutagenicity of new drug candidates, impurities and metabolites.
Method and Data: CASE Ultra is a QSAR statistics based computer
program that automatically extracts structure-activity knowledge
from chemical databases and applies the knowledge for
predicting activity in test chemicals. Several models, developed
by MultiCASE Inc alone and within Research Cooperation
Agreement with Center for Drug Evaluation and Research of FDA
were utilized, as well as a read across technique for quantitative
prediction of toxicity that uses the neighborhood profiles of
chemicals. A multi-tier approach in combining several models
and read across engine for bacterial mutagenicity evaluation
resulted in significant improvements in the sensitivity, specificity
and coverage. The details of the methodology and results of
prediction for a large external test set are presented.
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Results of the Study: The improvements in the predictive
performance as a result of the effective workflow is demonstrated
for various scenarios of mutagenic impurity assessments, using an
external validation set.
P203
Safety Assessments of Food Ingredients Require
Consumption Analysis.
R. Matulka1, A. Morales1, S. Ulm1. Burdock Group, Orlando,
FL, USA1
P204
Defining Components of an Expert Review necessary for ICH
M7 Compliant Submissions.
G. Myatt1, R. Daniel Benz2, K. Cross1. 1Leadscope, Columbus, Ohio,
USA, 2OmnyCorp, Rockville, MD, USA
The recently published International Conference on Harmonisation
(ICH) M7 guideline includes the use of in silico analysis to qualify
actual or potential impurities as nonmutagenic. According to
M7, two methodologies, one rule-based (structural alerts) and
one statistical-based (QSAR models), should be used and the
outcome reviewed using expert knowledge. This expert opinion
can "...provide additional supportive evidence on relevance of
any positive, negative, conflicting or inconclusive prediction..."
This poster outlines a list of items to consider as part of the
expert evaluation, starting with an assessment of the quality of
any available laboratory data on the impurity. In the absence
of such data, the results of applying expert alerts and statistical
QSAR models covering both A:T and G:C mutations should be
evaluated, including: 1) applicability domain considerations, 2)
definitions and relevance of alerts and structural features used in
the QSAR models, 3) mechanistic rationale, 4) the quality of data
supporting the prediction results, and 5) the relevance of any
deactivating fragments. The expert analysis should also describe
how the results from the two methodologies were combined into
an overall consensus prediction. Information on chemical analogs
may also be included in this expert opinion. Other considerations,
including arguments based on the chemical environment of
alerting substructures as well as changes to limits based on in vivo
data should be discussed when appropriate. This poster presents
a semi-automated framework to rapidly generate expert opinions
that are transparent, consistent and traceable.
P205
Ensuring Regulatory Acceptable (Q)SAR Models and Expert
Alerts for ICH M7 Reflect Proprietary Chemical Space.
K. Cross1, N. Kruhlak3, G. Myatt1, L. Stavitskaya3, A.
White2. 1Leadscope, Columbus, OH, USA, 2GlaxoSmithKline, Ware,
Hertfordshire, UK, 3US Food and Drug Adminstration, Silver Spring,
MD, USA
The International Conference on Harmonisation (ICH) M7
guideline permits the use of two in silico methodologies to
qualify any actual or potential drug impurities as nonmutagenic.
Statistical models and expert alerts built from public domain
knowledge and data are used for ICH M7 assessments as they
provide the necessary transparency and are sufficiently predictive
for this purpose. Knowledge from proprietary data increases the
specificity for selected chemical classes as well as expands the (Q)
SAR models' applicability domain. This leads to less laboratory
testing and synthesis of the impurity for the sponsor. We have
investigated the use of proprietary data made available through
confidentiality agreements directly with pharmaceutical sponsors
to identify potential solutions to specific model predictivity issues,
and are working towards the release of appropriate knowledge,
compounds, and experimental data necessary to solve the (Q)
SAR issue while preserving model transparency. The end result
will be a regular transfer of knowledge for use in the development
of (Q)SAR statistical models and incorporation of those data into
the Leadscope alert-based expert system. This poster outlines
the collaborative program for sharing data and knowledge
for inclusion in regulatory acceptable public models without
releasing any confidential business information. The process for
knowledge sharing through the use of structural fingerprints for
several compound classes will be discussed. A case study will be
presented where, as a result of the incorporation of knowledge
derived from proprietary data, the specificity of a model to
predict primary aromatic amines was increased by 15% with no
decrease in sensitivity.
71 ABSTRACTS
The safety of food ingredients has recently come into question,
generated by an incomplete understanding of the safety
assessment process necessary to determine that a potential food
ingredient meets the standard of a "reasonable certainty of no
harm" under the intended conditions of use. Critical to the safety
assessment is the analysis of potential exposure on a daily basis,
based on the categories of foods to which it will be added. With
the use of our proprietary consumption software, we are able
to calculate the mean, median, 90th and 95th percentile intake
of an ingredient consumed, utilizing the USDA two-day food
consumption survey data set entitled "What We Eat in America"
obtained through the National Health and Nutrition Examination
Survey (NHANES) every two years. We calculate the potential
90th percentile intakes by gender and different age groups, as
determined by the survey data to represent consumption by
different subpopulations of US consumers. The 90th percentile
level of food intake is a purposeful exaggeration built into the
analysis. The consumption data provides an estimated daily
intake (EDI) which can then be compared to the acceptable daily
intake (ADI), derived from the lowest No Observed Adverse Effect
Level (NOAEL) from safety studies conducted with the ingredient.
A basic criterion for determining the safety of a food ingredient
is that the EDI must not exceed the ADI. Because risk is based
on both hazard and exposure, our analysis of the animal safety
data and our consumption software support the "safety-in-use"
of food ingredients.
2014
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P206
SEND Architecture Facilitates Harmonization and Integration
of Data from Multiple LIMS and Controlled Terminology
Versioning.
F. Mura1, R. Buchanan2, M. Wasko2, C. Wuermlin1,
L. Kaufman2. 1PDS Preclinical Data Systems, Inc, Basal, Switzerland,
P207
Comparative Pharmacology of iPSC-Derived Cardiomyocytes
Assessed by Conventional Current Clamp and Multi-Electrode
Array (MEA).
A. Bruening-Wright, C. Obejero-Paz, N. Federov, J. Kramer, A.
Brown. ChanTest Corporation, Cleveland, OH, USA
PDS Preclinical Data Systems, Mt Arlington, NJ, USA
2
ABSTRACTS
2014
FDA guidances for submission of clinical and nonclinical data
in standard electronic format are expected to become binding
towards the end of 2016. Preparing for the nonclinical standard,
SEND (Standard for the Exchange of Nonclinical Data) is a process
that involves participation of multiple preclinical departments
in addition to IT. Producing SEND compliant datasets requires
consistency of metadata across all domains regardless of data
source/ LIMS used for data collection. Correlations between
records from different XPT files are required for data interpretation,
as is inclusion of all data collected for a toxicology study: in-life,
bioanalytical, pk, clinical pathology, postmortem, and planned
and actual study design. A SEND solution must also map a
sponsor’s terms to CDISC controlled terminology, along with the
ability for versioning based on frequent controlled terminology
releases/ updates. We wish to report a web-based software
architecture for SEND that accomplishes the aggregation,
harmonization, and translation of data from different sources
into one complete SEND dataset including all XPTs, define files,
and validation report. The architecture involves input from LIMSspecific or file-based adaptors, which are then processed through
an engine that maps data to appropriate variables and domains;
harmonizes metadata between domains, consolidates comments,
specifies relationships, and performs controlled terminology
translation. Controlled terminology versioning is managed with a
self-learning technology that avoids the time-consuming activity
of remapping terms that have not changed. Trial information
is provided to the engine through a specialized applicationprogramming interface (API), and expert tools were developed to
allow study-specific customization.
The goal of this research was to compare drug effects on the
electrophysiological properties of iPSC-derived cardiomyocytes
(Axiogenesis Cor.4u cells) using two techniques; MEA and
conventional (manual) patch clamp in current clamp (CC) mode.
MEA experiments were performed using a Maestro instrument
from Axion BioSystems (Atlanta, GA). CC experiments were
done using MultiClamp 700 A and B amplifiers in cells grown
in 35 mm culture dishes covering an area of approximately 1
cm2. Both MEA and CC experiments were carried out at 35°C
in the absence of serum. Field potential and action potential
durations were prolonged by hERG channel blockers (terfenadine,
dofetilide, cisapride) and shortened by calcium channel blockers
(verapamil and nifedipine). The electrical activity in both
preparations was abolished by tetrodotoxin at comparable
concentrations (3–10 μM).
Our results indicate that field potential changes observed in MEA
studies parallel the changes observed in action potentials recorded
in comparable culture conditions. As a corollary, CC experiments
can be used as a follow up technique to further characterize
pharmacological mechanisms observed in MEA studies.
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2014
300 Series—Safety Evaluation Nonpharmaceuticals
P300
Metabolic and Endocrine Disorders in Rats Exposed to
Malathion: Risk of Diabetes Type 2 Induction.
R. Rezg2, B. Mornagui3, S. El-Fazaa1, N. Gharbi1. 1University
of Tunis El Manar, Faculty of Sciences of Tunis, El Manar, Tunisia,
2
University of Monastir, High Institute of Biotechnology of Monastir,
Monastir, Tunisia, 3University of Gabes, Faculty of Sciences of Gabes,
Gabes, Tunisia
The aim of this study was to investigate the effects of subchronic
exposure to malathion, on metabolic parameters and
hypothalamic corticotropin-releasing hormone (CRH) mRNA
expression. Malathion was administered to Wistar rats by gavage
for 32 days at a dose of 100 mg/kg bw/day.
Malathion intoxication decreases hepatic Glycogen Phosphorylase
activity and increases Hexokinase activity with a rise in hepatic
glycogen rate. Malathion decreased hepatic proteins and lipid
contents that could be associated to liver gluconeogenesis.
We have recorded a significant decrease in muscular glycogen
rate, which indicates a stimulated glycogenolysis.We suggest
that malathion can caused a turnover of glucose by its release
through a succession of glycogenolysis and gluconeogenesis,
which involves abnormal hyperglycaemia and its storage via
glycogenesis, in subchronic exposure to an OP compound.
Continued repetition of this circle exhausts the metabolic control
system, resulting in insulin resistance. Also, Malathion exposure
induced a significant decrease CRH mRNA. This result is in
accordance with that of diabetic type 2 rat model.
We conclude that OP, the most widely used classes of pesticides
present an important risk factor to diabetes type 2 induction.
P301
Integrated Use of Biomarkers (Oxidative Stress Biomarkers
and Genotoxicity) in Mussels Lamellidens marginalis for
Assessment of Monocrotophos Toxicity.
A. Mundhe1, S. Pandit1. University of Pune, Pune, Maharashtra,
India1
Genotoxic studies evaluate the effects of pollutants on organisms
and consequently, their implications on human health.
Monocrotophos (MCP), an organophosphate pesticide is widely
used in India for control of various pests. The present study
is undertaken to evaluate the oxidative stress and genotoxic
potential of MCP on Lamellidens Marginalis and repair of the
damaged DNA after exposure.
The results clearly indicated that exposure to MCP caused increase
in the number of damaged nuclei in gill cells. After the recovery
period, a significant reduction in the number of damaged nuclei
was observed indicating repair. Our findings suggest that MCPinduced oxidative stress may, partly, be contributing to genotoxic
damage of gill cells.
P302
Toxicology and Risk Assessment of Chemical Mixtures.
M. Krishan1, A. Kretser1. International Life Sciences Institute North
America, Washington, DC, USA1
Evaluating potential health risks posed by exposures to multiple
chemicals is challenging for toxicology research and risk
assessment (RA). Problem formulation is complex and mixturesRA
frameworks vary greatly among agencies. This study 1) describes
RA approaches for chemical mixtures; 2) characterizes differences
in RA frameworks; and 3) assesses regulatory acceptance of these
frameworks with a focus on food mixtures. Reviews were completed
for mixture RA paradigms used by US federal agencies, nonprofit
organizations (WHO, IPCS) and international agencies (EU). There
are significant overlaps and differences between paradigms and
there appears to be no single unified approach. Considering the
current challenges in food mixtures, a hypothetical case study was
conducted using a tiered screening approach and hazard index
method to evaluate the effects of mixtures in foods. A hypothetical
new bean product is being considered to replace pinto beans for a
food program. Component levels of the following differ between
old beans (OB) and new beans (NB) (assuming a 10% decrease):
cadmium, deltamethrin, cyfluthrin; and bisphenol A levels are the
same in OB and NB. Noncancer health effects following chronic
oral exposure were evaluated. First tier provided a crude filter
using the most recent and conservative health reference values
for mixture components. Some assumptions in the first tier were
refined in the second tier. Components were grouped based
on health effects and biomonitoring data was used to estimate
exposure in the second tier. Results indicate that tiered approach is
a useful way of rapidly screening the effects of chemical mixtures.
The animals were exposed to 5.25 mg/l of MCP for 7 days and after
treatment, allowed to recover for 4 days in pesticide-free water.
The involvement of oxidative stress was examined by estimation
of Thiobarbituric acid reactive substances (TBARS); increase in the
73 ABSTRACTS
Diabetes type 2 is recognized as a global major public health
problem. Obesity, lifestyles and rich diets in fats are known
risk factors for this disease, but recent evidence also points to
environmental toxicants as an important factor to Diabetes type
2 induction. Our attention has turned to the organophosphate
pesticides (OP), which represent 50% of all the insecticide use
worldwide and especially to Malathion.
levels of TBARS was recorded in the gill, muscle, foot and mantle
tissues. Cellular antioxidant defences i.e. antioxidant enzyme
activities like catalase, superoxide dismutase, glutathione-Stransferase and glutathione reductase were used as biomarkers
of oxidative stress. Altered activities of antioxidant enzymes were
observed in the tissues exposed to MCP. There was a significant
recovery in the above parameters in the tissues after the recovery
period. To monitor genotoxicity of MCP, we used micronucleus
and comet assay. Significant DNA damage was measured in
terms of the Olive tail moment in gill cells of treated animals and
compared to control.
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P303
High-Content Screening Analysis of the Biological Impact of
Harmful/Potentially Harmful Constituents of Tobacco Smoke.
I. Gonzalez Suarez1, D. Marescotti1, S. Acali1, S. Johne1, S.
Frentzel1, C. Mathis1, J. Hoeng1, M. Peitsch1. Philip Morris
ABSTRACTS
International R&D, Neuchâtel, Switzerland1
Exposure to cigarette smoke (CS) causes lung toxicity and increases
the risk of developing chronic obstructive pulmonary disease
and cancer. CS is a complex aerosol with over 6000 chemicals,
thus it is difficult to determine individual contributions to overall
toxicity, as well as the molecular mechanisms by which smoke
constituents exert their effects. Previously [1], we performed a
systems toxicology evaluation of a subset of 14 CS constituents
categorized as harmful/potentially harmful by the Food and
Drug Administration. Here, we investigated the biological impact
of additional 34 CS constituents, on normal human bronchial
epithelial (NHBE) cells. Cytotoxicity was evaluated using and
impedance-based, multi-electrode array system. Furthermore,
a High Content Screening (HCS) analysis platform was used to
measure 13 multi-parametric indicators of cellular toxicity over
a wide range of concentrations and at different time points.
Toxicity profiles varied dramatically among the different tested
CS constituents, with EC50 values ranging between 0.01-10mM
after 24h of exposure. Based on HCS results, the most important
toxicity mechanisms were: DNA damage/growth arrest, oxidative
stress, mitochondrial stress and apoptosis/necrosis. Some CS
constituents did not induce a toxic response in NHBE cells despite
the high doses tested. In summary, combination of multiple
HCS endpoints allows to investigate the biological impact of CS
constituents in a rapid and reproducible manner, while gaining
insight on the molecular mechanisms activated upon exposure.
1. Gonzalez Suarez et al. (2014) Systems biology approach for
evaluating the biological impact of environmental toxicants in
vitro. Chem Res Toxicol 27: 367-376.
P304
Investigating the Performance of an In Silico Salmonella
Mutagenicity Model with HPHCs from Tobacco Products and
Tobacco Smoke
L.G. Valerio Jr.1, R.P. Yeager1. US FDA Center for Tobacco Products
(CTP), Office of Science, Division of Nonclinical Science, Silver Spring,
MD, USA1
In silico toxicology approaches are of interest as risk-based
nontesting strategies, to reduce the necessity to conduct animal
studies, and accelerate knowledge on potential toxicities of
chemicals when experimental toxicology testing are absent or
equivocal. This research assessed the utility of a novel in silico
quantitative structure-activity relationship model to predict
Salmonella mutagenicity of constituents from tobacco products
and tobacco smoke. The model is trained with 8,700 chemicals
in the computational platform, Symmetry. The computation uses
k-nearest neighbors and Logistic regression algorithms, and the
Mold2 molecular descriptor software. Harmful and potentially
harmful constituents (HPHC) from tobacco products and tobacco
smoke (FR 20034, 77:64, 2012) can be an integral part of the
nonclinical toxicological risk assessment process at FDA/CTP.
The research examined the model's predictive performance and
chemical space with HPHCs. All HPHCs were within the model
2014
applicability domain, indicating sufficient chemical representation
with tobacco constituents. Predictive performance characteristics
showed 90% sensitivity, 0% false positive rate, 10% false negative
rate, and a 93% concordance overall in predicting DNA reactive
mutagens, and nonmutagens with the model. These screening
results show the knowledge base in the model is capable of
predicting tobacco constituents known to cause DNA damage
that leads to mutations and potentially cancer, suggesting its
potential usefulness for analyzing other constituents when
study data are unavailable. This study is also supportive of the
application of computational predictive models as tools for
rapid decision-support to inform nonclinical risk assessments
on potential genotoxic/carcinogenic hazard of new chemicals
in tobacco products.
P305
Effects of Cigarette Smoke Exposure on the Insulin
Resistance-Related Metabolic Changes in the High-Fat
Diet-Fed ApoE Knock-Out Mice.
A. Iskandar1, D. Sharma2, S. Boue1, H. De Leon1, B. Phillips2,
M. Cabanski1, E. Veljkovic1, N. Ivanov1, J. Hoeng1, M.
Peitsch1. 1Philip Morris International R&D, Neuchâtel 2000,
Switzerland, 2Philip Morris International Reserach Laboratories, Pte
Ltd., Singapore 117400, Singapore
Insulin resistance (IR) has been linked to cigarette smoking
and it is known to contribute to diabetes and lipid disorders.
Cigarette smoke (CS) induces inflammation and weakens
immune responses, both of which can exacerbate diabetes and
atherosclerosis development. We examined the effects of CS
exposure on IR-related metabolic changes in the ApoE-deficient
mouse, a model of dyslipidemia and atherosclerosis that has been
shown to exhibit accelerated development of diabetes upon
a high fat diet (HFD) feeding. Female ApoE-/- mice were fed a
HFD for 11 weeks and were exposed to CS from 3R4F or filtered
air (sham). Fasting glucose and insulin levels, aortic plaque
area, serum levels of lipids and metabolic analytes, muscle and
liver transcriptomes, as well as plasma and liver lipidomes were
analyzed. CS-exposed mice had lower fasting glucose levels than
sham-exposed mice, while insulin levels remained unchanged.
Aortic plaque areas were increased in the CS-exposed group
as compared to mice from the sham group. Lipidomics analysis
showed increased levels of plasma and liver cholesterol esters,
ceramides and sphingomyelins. Transcriptomics analysis
suggested that CS exposure upregulated xenobiotic metabolizing
enzymes and suppressed inflammatory/immune responses. Our
results indicate that CS exposure interfered with the regulation
of plasma glucose levels and increased plaque formation in
ApoE-/- mice. The observed gene transcription changes within
various metabolic pathways in the CS-exposed mice may account
for the increased atherogenic lipids in the plasma and liver. The
mechanistic links among xenobiotic metabolism, suppression
of immune responses and diabetogenesis in the CS-exposed
ApoE-/- mice remain to be elucidated.
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P306
Characterization of microRNA Expression Patterns and
their Target Genes to Discover Potential Biomarkers for
Hepatacaciongenesis after Exposed to Thioacetamide in Rats.
Y. Wang1, C. Castro2, B. Gong1, Y. Morikawa3, J. Yan1, T. Uehara3,
T. Chen1, W. Tong1. 1National center for Toxicological Research,
USFDA, Jefferson, AR, USA, 2University of North Carolina, Charlotte,
NC, USA, 3Shinonogi & Co., Ltd., Osaka, Japan
P307
TRENDS in Human Adverse Events Associated with Pyrethroid
Insecticides.
F. Suarez1. Syngenta Crop Protection, Greensboro, North
Carolina, USA1
Poison control centers have been shown to reduce the number of
unnecessary emergency room visits due to poisoning incidents.
American Poison Control Center (APCC) reports indicate that
the number of reported incidents involving human exposure
associated with pyrethroid insecticide exposure have been
increasing annually; however, the proportion of cases treated
at health care facilities (HCF) has not changed substantially. To
further understand the reasons for seeking medical attention
after incidental exposure to one pyrethroid (lambda-cyhalothrin
L-C), data collected over a 10 year period was extracted from an
adverse incidents report database (PROSAR). The information was
analyzed in terms of demographics, case severity, primary route
of exposure, and primary symptom or health concern. Results
were compared with an evaluation of L-C human adverse events
conducted by the US EPA; and with peer-reviewed published
information available through PubMed. The majority of cases
reported were from dermal exposures, were categorized as minor,
and did not require medical attention. However, a number of cases
reported inhalation exposures. Although observed less frequently
than dermal exposures, most of these cases were categorized as
moderate, and were more frequently treated at HCF. Content
analysis of the description of the exposure event identified odor
perception as a common theme in several of these cases. These
findings suggest that recording patient's perception of chemical
odors as evidence of exposure via inhalation could introduce bias
in the interpretation of trends from adverse incidents control data
P308
Comparison of the Biological Impact of Cigarette Smoke and
a Prototypic Modified Risk Tobacco Product on Human versus
Rat Primary Normal Bronchial Epithelial Cells.
U. Kogel1, C. Poussin1, D. E. Messinis2, S. Frentzel1, C. Mathis1,
J. Hoeng1, M. C. Peitsch1. 1Philip Morris International R&D, Philip
Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland,
ProtATonce Ltd, Scientific Park Lefkippos, Patriarchou Grigoriou &
Neapoleos 15343 Ag. Paraskevi, Attiki, Greece
2
Smoking causes serious, fatal diseases such as lung cancer,
cardiovascular and chronic obstructive lung diseases. Along
with the current global paradigm change for safety assessment
of consumer products, PMI R&D is working towards creating an
integrative, systems biology-based approach for the evaluation
and risk assessment of modified risk tobacco products (MRTPs).
With the view to investigate the level of translatability between
rodent and human biology, we exposed normal human bronchial
epithelial (NHBE) cells and its rat counterpart normal rat bronchial
epithelial (NRBE) cells to total particulate matter (TPM) generated
from a prototypic modified risk tobacco product (pMRTP) and
from the reference cigarette 3R4F for four hours.
Exposure to the same dose of TPM from the 3R4F resulted in twice
as many differential expressed genes in NHBE cells compared with
NRBE cells (FDR<0.05, FC>0). The exposure to the same dose of
pMRTP resulted in a weak transcriptional response in both species.
A computational-modeling approach based on tissue-specific
biological networks identified proliferation, apoptosis, and
senescence as the most perturbed molecular processes after
exposure of NHBE cells to TPM of the 3R4F. Cell stress were
impacted to a lesser extent. In NRBE cells the most perturbed
biological processes are the cell stress, followed by proliferation
and senescence. These processes are much less perturbed after
exposure to pMRTP in both species.
In conclusion, after 3R4F exposure the highest species correlation
is found for the cell stress sub-network NFE2L signaling. Exposure
to pMRTP induces very low biological effects in both species.
75 ABSTRACTS
Given the widespread roles of miRNA cross various biological
processes, understanding their patterns of expression in chemical
treatment across different doses and treatment durations will
provide insights into the role of miRNA underlying toxicity. In
this study, an integrated analysis of miRNAs expression with their
target mRNAs was conducted to investigate the dynamic nature
of miRNA-mediated regulating modules in rat livers exposed to a
thioacetamide at multiple dose levels and treatment durations. At
each dose- and time-point, both miRNAs and mRNA expression
profiling of the same rat livers were generated with next
generation sequencing and microarray, respectively. Comparison
of differentially expressed miRNA and mRNAs revealed distinct
dose- and time-dependent characteristics of two RNA features. We
found that two miRNAs, miR-34a and miR-100 were consistently
differentially expressed across all the doses and time-points
examined. To our knowledge, miR-100, was firstly reported in rat
liver in this study which is thought to be negatively regulating the
mammalian target of rapamycin (mTOR), a central regulator of cell
metabolism, growth, proliferation and survival. This suggests that
miR-100 could potentially be used as biomarkers or therapeutic
targets for liver cancer and drug-induced liver injury (DILI).
Finally, the integrative analysis based on computational target
prediction and miRNA/mRNA profiling defined a network of
putative functional miRNA-target regulatory relations supported
by expression data. These findings demonstrated the potential
application of miRNAs as biomarkers to assess liver carcinogenicity
and DILI at the early stage of drug discovery and development.
2014
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P309
A Meta-Analysis of Human Organotypic Respiratory Cultures
Exposed to Whole Cigarette Smoke.
P. Leroy1, C. Mathis1, M. Cabanski1, A. Iskandar1, R.
Kostadinova1, S. Frentzel1, D. Kuehn1, S. Majeed1, C. Merg1,
A. Elamin1, E. Guedj1, R. Dulize1, G. Vuillaume1, Y. Xiang1, F.
Martin1, W. K. Schlage1, M. C. Peitch1, J. Hoeng1. 1Philip Morris
ABSTRACTS
International R&D, Philip Morris Product SA, Neuchâtel, Switzerland
The development and the use of human three-dimensional in vitro
models that closely mimic in vivo biology are of great interest to the
scientific community to address some of the limitation of species
translatability and further support the reduction, refinement,
and replacement framework of animal use in laboratory. Human
organotypic epithelial tissue cultures (e.g., bronchial, nasal),
grown at the air-liquid interface, are particularly attractive to
assess the impact of airborne toxicants exposure, including
pollutants and cigarette smoke (CS). As organotypic tissue
models are currently still expensive and not always accessible for
small laboratories, having a well-defined experimental design is
essential for scientifically sound outcomes. We investigated the
‘reproducibility' of different molecular endpoints collected after
CS exposure of human organotypic bronchial and nasal epithelial
cultures obtained from different production batches as well as
from different donors. The following endpoints were assessed
after different postexposure time points of 28 min exposure to air
(Sham control) or to different dilutions of mainstream CS (3R4F
- Health Canada regimen): cytotoxicity (AK assay), cytochrome
P450 (CYP1A1/1B1) activity, pro-inflammatory markers secretion
(MAP), histological assessment, and gene expression changes.
The statistical analysis shows the impact and the contribution of
the use of various donors, of different production batch, and of
multiple exposure smoke experiments.
P310
Integration of cII and Pig-a Mutation and Micronucleus
Endpoints into the Big Blue® Transgenic Mouse Mutation
Assay: Results for Benzo(a)pyrene (BaP) and N-Ethyl-Nnitrosourea (ENU).
R. Young1, H. Dinesdurage1, D. Bruning1, L. Stankowski1, R.
Kulkarni1, T. Lawlor1, M. McKeon1, Y. Xu1, S. Avlasevich2, D.
Torous2, S. Dertinger2, M. Aardema3. 1BioReliance, Rockville, MD,
USA, 2Litron Laboratories, Rochester, NY, USA, 3Marilyn Aardema
Consulting, LLC, Fairfield, OH, USA
Integration of multiple genotoxicity endpoints into repeat-dose
rodent studies provides broad assessment of genotoxic potential
of different modes of action while reducing the use of animals.
Using male Lambda LIZ/lacI C57BL/6 homozygous (Big Blue®)
transgenic mice, we examined the induction of cII mutations in
liver and bone marrow, micronuclei in blood reticulocytes and
mature erythrocytes (mnRET and mnNCE, respectively), and Pig-a
mutant phenotype reticulocytes and erythrocytes (RETCD24- and
RBCCD24-, respectively). Animals were treated with olive oil (5 mL/
kg/day for 28 days), BaP (50 mg/kg/day for 28 days), or ENU (40
mg/kg/day on Days 1, 2 and 3), with sacrifice on Day 31. Significant
increases (p<0.001) in cII mutant frequencies were observed
for BaP in liver (4.89-fold) and bone marrow (4.15-fold), and for
ENU in liver (17.7-fold) and bone marrow (10.6-fold). Peripheral
blood was collected ~3 hours before sacrifice and analyzed for
2014
Pig-a mutant phenotype and micronucleus frequencies by flow
cytometry using MutaFlow® and MicroFlow® kits, respectively
(Litron Laboratories). BaP induced significant increases (p<0.001)
in mnRET, mnNCE, RETCD24- and RBCCD24- (1.56-, 2.11-, 616 , and 101fold, respectively). ENU induced significant increases (p<0.001)
in mnNCE, RETCD24- and RBCCD24- (1.40-, 1050-, and 208-fold,
respectively). As expected, mnRET were not elevated by ENU
(p>0.05) due to the long interval between last administration and
blood harvest. This study demonstrates the robustness of the Big
Blue® Mouse Mutation Assay to detect induced mutagenesis by
a direct acting mutagen and one requiring metabolic activation.
This work also demonstrated the ability to integrate additional
endpoints for mutation and clastogenicity.
P311
Effects of Cigarette Smoke Extracts from a Prototypic
Modified Risk Tobacco Product on Chemotaxis and
Transendothelial Migration of Human Monocytes.
M. van der Toorn1, S. Frentzel1, M. Peitsch1, J. Hoeng1, H. De
Leon1. Philip Morris International, Neuchâtel, NE, Switzerland1
Introduction. Although it is well-established that cigarette
smoking increases cardiovascular risk, the mechanistic links
between cigarette smoke and atherogenesis are poorly
understood. Aim. We determined the effects of cigarette smoke
aqueous extracts (CSE) from 3R4F, a conventional cigarette,
and a prototypic modified risk tobacco product (pMRTP) on
monocyte chemotaxis and migration through a monolayer of
human coronary artery endothelial cells (HCAEC). Methods.
CSE were generated by smoke-bubbling RPMI media (sbMedia)
from 3R4F and pMRTP according to Health Canada standards.
Endpoints included cytotoxicity (cell death assessed by 7-AAD
staining followed by FACS analysis), inflammation (cytokine
measurements), THP-1 cell migration (Boyden chambers), and
transendothelial migration (TEM) determined by real-time
impedance. Results. Direct treatment of THP-1 cells with increasing
concentrations of sbMedia from 3R4F and pMRTP induced dosedependent increases in cytotoxicity (cell death) and inflammation
(IL-8, TNF-α release). Pretreatment of THP-1 cells or HCAEC with
sbMedia from 3R4F and pMRTP decreased stromal cell-derived
factor 1 (SDF1)-mediated migration and TEM in a dose-dependent
manner. SbMedia from 3R4F was ~20 times more potent than
sbMedia from pMRTP for all endpoints. Conclusion. sbMedia from
3R4F or pMRTP cigarettes induced dose-dependent responses
in assays of inflammation, cytotoxicity, chemotaxis and TEM. Our
findings indicate that CSE from a pMRTP are far less cytotoxic and
less proinflammatory than CSE from conventional 3R4F cigarettes.
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P312
Application of Systems Pharmacology to Identify Exposure
Response Markers in Peripheral Blood After Switching to
a Candidate Modified Risk Tobacco Product: The Tobacco
Heating System 2.1 (THS 2.1).
F. Martin1, M. Talikka1, C. Haziza1, M. Peistch4, J. Hoeng5, J.
Ancerewicz6. 1Philip Morris International, Neuchatel, Switzerland,
Philip Morris International, Neuchatel, Switzerland
2
By analyzing the whole blood transcriptome of the study subjects
and leveraging previously identified genes that exhibited a
response to smoking in blood, we derived a classification tool
using statistical learning methods. The classifier consisted of
eight genes anddifferentiated users of THS 2.1 from smokers of
CC with a specificity and sensitivity of 0.81 and 0.74, respectively.
In conclusion, our systems pharmacology approach showed that
the impact of switching to THS 2.1 can be detected in 5 days
in whole blood transcriptome, thus providing a sensitive and
noninvasive tool to assess exposure-response. These data alone
do not substantiate reduced risk, and a range of further studies,
including clinical studies, are being conducted on MRTPs.
P313
MicroRNA Profiling of Hepatocellular Carcinomas in B6C3F1
Mice Treated with Ginkgo biloba Extract by Gavage for 2
Years.
H. Yamashita1, A. Pandiri2, S. Bhusari3, K. Shockley4, S.
Peddada4, K. Gerrish5, C. Rider3, M. Hoenerhoff3, R. Sills3. 1Taisho
Pharmaceutical Co. Ltd., Saitama, Japan, 2Experimental Pathology
Laboratories, Research Triangle Park, NC, USA, 3National Toxicology
Program, National Institute of Environmental Health Sciences
(NIEHS), Research Triangle Park, NC, USA, 4Biostatistics Branch,
NIEHS, Research Triangle Park, NC, USA, 5Molecular Genomics Core
Laboratory, NIEHS, Research Triangle Park, NC, USA
Ginkgo biloba leaf extract (GBE) has been used for centuries
in traditional Chinese medicine and today is used as an herbal
supplement touted for improving brain function and for its
antioxidant and anticancer effects. Exposure of B6C3F1 mice to
GBE in the 2-year National Toxicology Program (NTP) bioassay
resulted in a dose-dependent increase in hepatocellular
carcinomas (HCC). We have previously reported increased Ctnnb1
mutations and alterations in Wnt/Ctnnb1 signaling in GBEinduced HCC compared to spontaneous HCC in vehicle controls.
MicroRNAs (miRNAs) are small noncoding RNAs that are often
dysregulated in various diseases including cancer. To identify
key miRNAs that modulate GBE-induced hepatocarcinogenesis,
we examined the global miRNA expression using Affymetrix
GeneChip® miRNA 3.0 arrays and 2-pairwise analyses (n=5/group)
comparing GBE-induced HCCs and spontaneous HCCs with
vehicle control age-matched normal livers from B6C3F1 mice.
We observed 16 and 3 unique differentially expressed miRNAs in
GBE-induced HCC and spontaneous HCC, respectively. Ingenuity
Pathway Analysis of the miRNA and mRNA array data from these
tumors demonstrated altered molecular pathways associated
with hepatocarcinogenesis, cell cycle progression, cell migration
and cell proliferation. Additionally, miR-31, miR-145, miR-329 and
miR-433, which were uniquely expressed in GBE-induced HCC, are
known to regulate Wnt/Ctnnb1 signaling. Since the differentially
altered miRNAs were unique to either GBE-induced HCC or
spontaneous HCC, we plan to examine liver samples from the
90-day GBE study to see if these miRNAs could serve as potential
biomarkers for GBE exposure or chemical-induced carcinogenesis.
P314
28-day Toxicity Study of 3-monochloropropane-1,2-diol in
CB6F1-nonTgrasH2 Mice.
S.J. Park1, B.S. Lee1, E. Ju Jeong1, K.S. Moon1. Korea Institute of
Toxicology, Daejeon, Republic of Korea1
3-monochloropropane-1,2-diol (3-MCPD) is a food processing
contaminant that occurs in a wide range of foods. Several studies
have evaluated the toxicological properties of 3-MCPD, but its
carcinogenic potential has been controversial. In the present
study, 28-day oral dose range finding in CB6F1-nonTgrasH2 mice
was conducted to investigate a potential toxicity of 3-MCPD and
also determine dose levels for following 26-week carcinogenicity
study using TgrasH2 mice. The test article was administered once
daily by oral gavage to male and female mice at dose levels of 0,
25, 50, and 100 mg/kg/day for 28 days. The standard toxicological
evaluations were conducted during the in-life and postmortem
phase. In mortality, three males and one female died during the
study period, and toxic symptoms such as thin appearance and
subdued behavior were observed with corresponding significant
decreases of mean body weight and food consumption in the
100 mg/kg/day groups. Furthermore, relative and absolute
weights of spleen, thymus, seminal vesicle and prostate in the
100 mg/kg/day groups were significantly lower than those of
the control groups. Treatment-related microscopic findings were
germ cell degeneration in testis (≥25 mg/kg/day), vacuolation
in brain and sciatic nerve (≥50 mg/kg/day), basophilic tubule in
kidney (100 mg/kg/day), and cardiomyopathy (100 mg/kg/day).
These findings are in good agreement with previous studies. In
conclusion, the target organ was determined to be brain, nerve,
kidney, testis and heart, and the no observed adverse effect level
(NOAEL) of 3-MCPD was considered to be 25 mg/kg/day or less in
males, and 25 mg/kg/day in females.
77 ABSTRACTS
Establishing exposure-response markers is imperative for the
assessment of candidate modified risk tobacco products (MRTPs)
against conventional combustible cigarettes (CC). Biomarkers
derived from the primary site, such as the airway, require invasive
sampling, whereas blood offers a noninvasive alternative for the
general population. Various diseases and exposures, including
cigarette smoke, have been shown to alter the molecular profile of
the blood. To identify exposure-response relationships, we have
conducted a whole genome Affymetrix microarray analyses from
blood derived from a clinical study comparing smokers switching
from CC to candidate MRTP THS 2.1, and from smokers who
continued smoking their own CC for 5 consecutive days. Theopenlabel, randomized, controlled, 2-arm parallel group recruited 42
healthy smokers of both genders, aged between 23 and 65 years
andwas conducted according to Good Clinical Practices (GCP) and
is registered on ClinicalTrials.gov,
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P315
Safety Assessment of Fruit Body Extract of Clitocybe nuda:
Cytotoxicity and Genotoxicity Studies.
M. Qiao1, T. Ren1, T.S. Huang1, J. Weese1, A. Gardner1, J.T. Chen2,
J.W. Huang3. 1Department of Poultry Science, Auburn University,
has not been previously documented in alcohol intoxication. He
appears to have the highest reported BAC in a surviving pediatric
patient. Hemodialysis, as recommended by poison control, was
impracticable due to the presence of shock. The rapid drop in
BAC, magnesium, and potassium levels may be due rapid volume
expansion during fluid resuscitation rather than more rapid
elimination of alcohol by an alternative pathway.
Clitocybe nuda (C. nuda) is an edible mushroom which is promising
to be developed either as novel natural food antimicrobials or as
new functional food due to various bioactive components found
in its fruit body extract recently; however, little or no toxicity
information about its fruit body extract is available. In this study,
the cytotoxic potential of its fruit body ethanol extract (freeze
dried and heated dried) was investigated with both MTT assay
and Neutral Red Uptake assay in embryonic fibroblast BALB/3T3
and human hepatoma (HepG2) cell lines. IC50 value was calculated
based on the concentration-response curves ranged from 0.045
-100 mg/ml after 48 h exposure, and acute oral LD50 value was
estimated from IC50 value obtained in 3T3 NRU assay based
on the prediction model. Moreover, potential genotoxic effect
of the extract was evaluated with two standard genotoxicity
assays: in Ames assay, a set of Salmonella tester strains (TA98,
TA100, TA1535, TA1537 and TA1538) were treated with fruit
body extract aqueous sample with 5 different concentrations
ranged from 50 to 5000 µg/plate, with and without S9 mix as an
external enzymatic metabolizing system; in cytokinesis-blocked
micronucleus cytome (CBMN-cyt) assay, number of micronucleus
(MN) in binucleated HepG2 cells was examined after exposure to
the fruit body extract within 0.045 -100 mg/mL in medium for 24
hours. Results suggested that C. nuda fruit body ethanol extract is
nongenotoxic in vitro and with little cytotoxic effect.
STP317
Protective Role of Sildenafil against Carbon TetrachlorideInduced Nephrotoxicity by Augmenting the Availability of
Nitric Oxide and Antioxidant Enzymes.
S. Goyal1, N. Verma1, S. Sharma1. School of Pharmacy and
Auburn, AL, USA, 2Division of Plant Pathology, Taiwan Agricultural
Research Institute, Taichung, Taiwan, China, 3Department of Plant
Pathology, National Chunghsing University, Taichung, Taiwan, China
ABSTRACTS
2014
P316
Arrhythmias and Electrolyte Abnormalities in Binge Alcohol
Consumption: Supportive Management and Survival.
H. Shakir1, T. The1. 1The Children’s Hospital at Saint Peter’s University
Hospital, New Brunswick, NJ, USA, 2Drexel University College of
Medicine, Philadelphia, PA, USA
A 17 years old college student was admitted from our emergency
room after binge drinking in a frag party with a blood alcohol
level (BAC) of 815 mg/dL. He was comatose (GCS=3/15),
hypothermic (rectal temperature 94.9 F), cyanotic with an oxygen
saturation of 69% and a shallow breathing rate of 12/min. His
heart rate was 73/min with a sinus rhythm. He was emergently
intubated and mechanically ventilated. Upon rewarming,
his blood pressure (BP) dropped to 65/28. Despite receiving
multiple fluid boluses, increasing his maintenance intravenous
infusion of Ringer Lactate to 200-300ml/hr, and increasing his
Dopamine and Epinephrine intravenous infusion, his blood
pressure remained labile. Whenever, we were able to raise his BP
to normotensive levels, he developed massive diuresis and his BP
dropped again. He developed severe hypokalemia, hypocalcemia,
hypoalbuminemia, hypomagnesaemia and accelerated junctional
rhythm with tall peak T waves. At about 10 hours postadmission,
with the last magnesium sulfate bolus and his BAC dropping
below 500 mg/dL, the accelerated junctional rhythm resolved
and his blood pressure stabilized. Accelerated junctional rhythm
Emerging Sciences, Baddi University of Emerging Sciences and
Technology, Village- Makhnumajra, City- Baddi, State- Himachal
Pradesh, India1
Introduction: Nephrotoxicity in experimental animal can be
induced by CCl4¬¬ (Carbon tetrachloride), which is a colorless,
volatile and nonflammable liquid of industrial use. Free radicals
are generated due to the metabolic transformation of CCl4¬¬
that results in prominent changes in the morphology of kidney,
including tubulointerstitial fibrosis and vascular congestion.
The present study was designed to investigate the possible
mechanism involved in protective effect of sildenafil (PDE5 inhibitor) in CCl4¬¬ induced nephrotoxicity. Material and
Methods: Wistar albino rats of either sex (180-260g), n=6
were employed in the study. Nephrotoxicity was induced by
administration of carbon tetrachloride (0.5 ml/kg, s.c.,) for 28
days. Serum creatinine, BUN, urinary microproteins, TBARS,
nitrite/nitrate and reduced glutathione estimations were done
as hallmarks of renal functioning. Results: Administration of CCl4
induced prominent changes in morphology of kidney, including
tubulointerstitial fibrosis and vascular congestion, increases in
serum creatinine, BUN, urinary microproteins, and renal tissue
TBARS levels in comparison to normal control. It also decreased
reduced glutathione and tissue nitrite/nitrate levels. Sildenafil
treatment (0.4 and 0.8 mg/kg) antagonized the effect of CCl4
induced renal intoxication dose dependently. L-NAME (Nitric
oxide synthase inhibitor) treatment significantly reversed the
effect of Sildenafil treatment. Conclusion: Therefore, it may be
concluded from the above findings that Sildenafil has a protective
effect in prevention of renal injury by increasing the availability
of nitric oxide and antioxidant enzymes. Impact statement: Based
upon our evaluation, Sildenafil shows a promising result for the
treatment of CCl4 induced Nephrotoxicity.
STP318
Investigating Cellular and Molecular Pathogenesis
of Hydrocarbon Oil-Induced Lung Hemorrhage and
Inflammation.
P. Prasad1, I. Valera1, M. Fishbein1, R. Raj Singh1. University of
California (UCLA), Los Angeles, CA, USA1
Exposure to toxic substances (isocyanates/pesticides),
recreational drugs (crack cocaine), pharmaceuticals, organ
transplantation, and inflammatory diseases (vasculitis, lupus)
may result in inflammation/hemorrhage in lungs, called diffuse
alveolar hemorrhage (DAH). With no effective treatment,
it is invariably fatal. Limited access to human tissue and/or
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IGP319
Occupational Exposure to FA: Genotoxicity, Immunotoxicity,
and Susceptibility.
S. Costa1, J. García-Léston3, S. Silva1, B. Laffon3, B. Porto4,
J.P.s Teixeira1. 1National Institute of Health, Environmental Health
Department, Porto, Portugal, 2ISPUP, Institute of Public Health, Porto,
Portugal, 3University of A Coruña,Toxicology Unit, Department of
Psychobiology, A Coruña, Spain, 4University of Porto, ICBAS, Institute
of Biomedical Sciences Abel Salazar, Porto, Portugal
Formaldehyde (FA) is a high-volume production chemical
produced worldwide with a large range of industrial and
medical uses. The highest level of human exposure to FA occurs
in occupational settings. Eighty-five workers from anatomy
pathology laboratories exposed to FA and 87 nonexposed controls
took part in the study. Air monitoring was performed in worker’s
breathing zone and the level of FA-exposure in air was estimated.
Genotoxicity was evaluated in peripheral blood lymphocytes
(PBLs) by means of cytogenetic alterations, DNA damage (comet
assay) and T-cell receptor mutation assay. Percentages of different
lymphocyte subpopulations were selected as immunotoxicity
biomarkers. In addition, the effect of polymorphic genes of
xenobiotic metabolising enzymes and DNA repair enzymes on
the endpoints studied were determined. The mean level of FAexposure was 0.38±0.03 ppm. All cytogenetic endpoints and DNA
damage evaluated by comet assay were significantly increased in
PBLs of FA-exposed workers compared to controls. The exposed
group also presented significant alterations in %cytotoxic T
lymphocytes, NK cells and B lymphocytes in comparison with
control group. Results from susceptibility biomarkers suggest that
polymorphisms in CYP2E1, GSTP1 and GSTM1 are associated with
increased genetic damage in FA-exposed subjects. Also FANCA
significantly altered the level of genetic damage induced by FA
exposure, revealing a potential novel repair pathway involved
in the repair of genetic lesions caused by FA-occupational
exposure. This work is supported by FCT under the grants SFRH/
BD/46929/2008 and PTDC/SAU-ESA/102367/2008.
IGP320
Pesticide Residues in Strawberries.
D. Dhakal1, R. R. Regmi Dhakal2, S. K. Raut2. 1Patan Multiple
Campus, Institute of Science and Technology, Tribhuvan University,
Lalitpur, Nepal, 2National Society of Toxicology Nepal, Lalitpur, Nepal
The research work was carried out in Okharpauwa and Kakani
VDCs of Nuwakot district, Nepal during 2013. Strawberries are
becoming the single most important commodity in improving
the living standards of local farmers. It instigates hybrids which
demands relatively large amount of chemical fertilizers, and are
susceptible to diseases & pests in this fruit. For the better control of
those attacks, farmers were indiscriminately applied the pesticides
on the area. Moreover, farmers has been using pesticides in
their own way by means of bare hands to their farms, rather
than adopting advised application procedures & safe handling
methods. Six representative samples were taken from 20 different
points. The samples were extracted in ethyl acetate and cleaned
up by DSPE with PSA and pesticide residues analyzed by a gas
chromatograph coupled with GC-EI-MS/MS. Final confirmation
of the positive findings using two MRMtransitions and accurate
quantification was performed by LC-MS/MS using a hybrid triple
quadrupole linear ion trap mass spectrometer. Pesticideresidue
has detected in 83.33% sample like Chlorothalonil, Dicofol,
Endosulfan - α, Endosulfan - β, Parathionand 100% sample
identified with Fenpropathrin. The T-Testsrevealed that not
significant in the case of Dicofol and Fenpropathrin since p > 0.05.
Moreover, 83.33% sample has observed with residue greater than
the tolerance level in Chlorothalonil & Pyrathion, whereas only
33.33% of the samples were noticed with residue greater than the
tolerance level in Dicofol but others residues were identified lower
than the tolerance level of EU.
79 ABSTRACTS
lack of animal models have prevented investigations into its
pathogenesis, until recently, when investigators detected DAH in
two otherwise normal mouse strains, C57BL/6 (B6) and C57BL/10,
exposed to hydrocarbon oil [2,6,10,14-tetramethylpentadecane
(TMPD)]. TMPD is a component of crude/mineral oils, laxatives,
diesel exhaust, and cosmetics. The broad goal in this project is
to investigate the role of immune cells and immune-response
genes in the pathogenesis of DAH using the TMPD model. We
have found that intraperitoneal administration of TMPD (0.5 ml)
led to pneumonitis/vasculitis/hemorrhage in lungs of B6 mice
within 2-4-weeks in 72% of 29 TMPD-exposed versus none of
23 controls (saline or control oil n-hexadecane). 50% of animals
died within 3-4 weeks post-TMPD exposure. Flow cytometry data
showed significant increase in plasmacytoid dendritic cells (pDC)
in bone marrow (BM), and myeloid DCs (mDC) in lungs of TMPD
exposed mice versus controls. To investigate whether TMPD
triggers epigenetic changes in immune response genes, lungs
from 3 groups of mice (saline, nhexadecane, TMPD) are being
analyzed via microRNA and mRNA microarrays for differential
gene expression. Future studies, will analyze whether elevated
mDCs in lungs secrete pro-inflammatory cytokines locally,
whereas pDCs in BM stimulate B1and marginal zone B cells, the
first cell populations to encounter antigens acquired through
peritoneum and blood.
2014
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2014
400 Series—Toxicology Methods
P400
Geometric Determinants of Full Thickness Wound Healing in
Adult Male Yucatan Miniature Swine.
D. White, C. Brandt, T. Madsen, C. Hanks, L. Brown, A. StrickerKrongrad, J. Liu, G. Bouchard. Sinclair Research Center, LLC,
observations up to 1 hour post administration without the need
for additional or continuous sedation.
Auxvasse, MO, USA
ABSTRACTS
Objective: We assessed the relationships between wound healing
rates vs. initial size and shape of full thickness wounds.
Methods: Each of 3 minipigs had 9 full thickness paraspinous
wounds created. The wounds were comprised of all combinations
of 3 sizes (10, 20 and 30 cm2) with 3 shapes (square, circle
and equilateral triangle - apex pointing to spine). During
dressing changes, all wounds were photographed and
planimetric measurements of total wound areas and areas of
epithelialization were obtained.
Time to complete healing was determined by clinical observation
and photographic documentation. Linear healing rate and distance
were determined from changes in planimetric measurements
of area and perimeter using the following calculations: Results:
Although larger wounds took longer to heal than smaller ones,
there was no appreciable association with wound shape, e.g.
average healing times for 10 cm2 wounds were 33, 35 and 33 days
for circles, squares and triangles respectively.
Absolute wound healing rates were calculated using planimetric
data. There was a strong correlation between healing rate and
initial wound area. Mean healing rates were 2.1, 2.6 and 3.3 cm2
per week for 10, 20 and 30 cm2 wounds, respectively. These
differences did not appear to be affected by wound shape.
Conclusions: Linear healing rates in adult Yucatan MS were largely
unaffected by initial wound size or wound shape. This confirms
the appropriateness of this test system for further preclinical
wound healing studies.
P401
Sublingual Dose Administration In Rabbits.
K. Polhamus1, S. Blechinger1. MPI Research, Mattawan, MI, USA1
The rabbit is an increasingly in demand model for the assessment
of mucosal irritation due to sublingually administered substances.
The purpose of this study was to develop an effective technique
for sublingual dose administration in rabbits, which minimized
leakage, mimicked swallowing, and allowed for subsequent tissue
assessments with limited repeat sedation. Animals were sedated
with 0.5 mg/mL intramuscular injection of Dexdomitor® at a
dosage of 0.25 mg/kg and placed into a mechanical head restraint
device, which supported the upper jaw and head. The lower jaw
and tongue were retracted and tinted tap water administered
via syringe into the sublingual cavity at volumes up to 100 µL.
Assessments of leakage were performed visually and followed by
a saline rinse to mimic saliva and swallowing. Tissue examination
was conducted at timed intervals from 0.5 to 6 hours post dose,
to determine the need for additional sedation for appropriate
assessment of mucosal irritation. The use of the head restraint
and sedation regime allowed for the administration of up to 50
µL of liquid with minimal leakage and the assessment of timed
P402
Characterization of T-dependent Antibody Response (TDAR)
to Keyhole Limpet Hemocyanin (KLH) in the Göttingen
Minipig®.
V. Peachee1, M. Smith3, M. Beck2, D. Stump2, K. White
Jr.1. 1ImmunoTox, A Division of AIBioTech, LLC, Richmond, VA, USA,
2
WIL Research, Ashland, OH, USA, 3ImmunoTox, Inc., Richmond,
VA, USA
Recently, there has been a renewed interest in the use of the
minipig as an alternative to dogs and nonhuman primates for
conducting toxicological assessments in nonrodent species.
Since the T-dependent antibody response (TDAR) is one of
the most widely-accepted assays used in the assessment of
immunocompetence, the present study was undertaken to
characterize the primary and secondary TDAR to keyhole limpet
hemocyanin (KLH) in the Göttingen Minipig®. Following primary
immunization with either 2 or 10 mg KLH, anti-swine IgM and
IgG ELISAs were optimized and individual animal responses were
evaluated over time. Immunization with 10 mg KLH on Day 0
promoted primary IgM responses that peaked 6 to 9 days after
antigen administration, while primary IgG levels peaked on Days
13 or 14. Secondary IgG antibody levels (following secondary
injection with 2 mg KLH on Day 14) plateaued on Days 20-22.
Anti-KLH antibody levels were decreased in minipigs treated
with cyclophosphamide (CPS), a known immunosuppressant, at
doses ranging from 12.5 - 50 mg/kg/day, while antibody levels
in animals treated with 2.5 mg CPS/kg/day were similar to levels
in saline-treated swine. These results demonstrate that the
Göttingen Minipig® can be a useful alternative nonrodent species
to the dog and the nonhuman primate for evaluating the TDAR to
KLH in regulatory assessments of immunotoxicity.
P403
Spermatogenesis in the Göttingen Minipig: Assessing the
Onset of Puberty.
N. Navratil1, E. Taberner2, B. Jasmin1, M. Salerno1, B. Grambo1,
G. Althouse2. 1Marshall BioResources, North Rose, NY, USA,
University of Pennsylvania, Kennett Square, PA, USA
2
As the use of the Göttingen Minipig for toxicological studies
increases, there is a need to define age of puberty. The purpose
of this study was to evaluate the testis tissue from young
Göttingen Minipigs to determine age at puberty, which was
defined in this study as the majority presence of elongated
spermatids in the seminiferous tubules/tubule lumen. Paired
tissue samples from both testes were collected from 24 male
minipigs ranging in age from 5-8 weeks (e.g., 6 boars assessed/
week of age). All animals were weaned at 4 weeks of age, and
subsequently housed with age-matched males on a 12-hour
light/dark cycle prior to tissue collection. These young males had
no contact with mature breeding boars so as to avoid influence
on their reproductive development. Tissues were harvested and
immersed in Bouin's fixative, followed by histological sectioning
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and H&E staining. Microscopic examination was performed to
determine number of each cell type (e.g., primary spermatocytes,
round and elongated spermatids, sperm in lumen) in 100
seminiferous tubules. Elongated spermatids were predominantly
observed in the tubules of 12 of the 24 males; this included
3 males at 6 weeks of age, 3 males at 7 weeks of age, and in all
samples (N=6) collected from males at 8 weeks of age. A highly
significant (p<0.01) correlation between boar age and presence
of elongated spermatids was observed (rs = 0.78). Based on these
results, puberty in male Göttingen Minipigs appears to begin at a
younger age than previously cited in the literature.
Chemotherapy-induced peripheral neuropathy (CIPN) is a
progressive condition featuring pain, numbness, tingling, and/or
muscle weakness often felt in the feet/hands. Despite an average
incidence rate of 30-40% in the clinic, nonclinical toxicity studies
often fail to detect CIPN. Thus, the aim of the present study was
to adapt an established rodent CIPN model, vincristine-induced
PN, into an assay that could be used to predict the occurrence of
PN and applied to standard toxicity studies. Von Frey filaments
were used to assess changes in mechanical sensitivity and testing
was adapted according to the literature in order to make the
assessment more amenable to incorporation into a toxicity study.
Three baseline measurements were performed using filaments
with bending forces of 4 g, 8 g, and 15 g applied to the plantar
hind paw. Withdrawal responses were counted and expressed
as an overall percent response. Following baseline, animals were
administered vehicle or vincristine (50 or 100 µg/kg, i.p.) once daily
for 10 days. Mechanical sensitivity was assessed again on days 7,
14, and 22. A time-dependent increase in mechanical sensitivity
to all 3 filaments was observed in both vincristine treatment
groups when compared to vehicle. These findings suggest that
this assessment may be useful for the nonclinical detection of
CIPN and could be amenable to use on toxicity studies.
P405
Co-Culture Assay for the Identification and Investigation of
Dermal Sensitizers (EPI-DC).
G. DeGeorge1, M. Troese1, L. Pratt1, M. Piehl1, P. Hayden2, S.
Ayehunie2. 1MB Research Laboratories, Spinnerstown, PA, USA,
activation surface marker CD86+ >1.5-fold over vehicle controls,
as measured by flow cytometry. Results: for IL-18, basal secretion
in vehicle control co-cultures was 28.8 pg/ml. Treatment of Epi-DC
with NBB yielded IL-18 concentrations that peaked at 0.2% NBB,
resulting in a release of 166.4 pg/ml (12.9-fold increase). A dosedependent increase of CD86+ pDC was observed with treatment
of NBB ranging from 0.05% to 0.2% NBB, peaking at a 2.9-fold
increase in CD86 detection. At 1.0% Eugenol, increases of 1.7fold over control was observed in CD86 expression. Thus, in this
initial evaluation, the Epi-DC co-culture model has been shown to
be a useful and predictive tool for identifying dermal sensitizers
without the use of animals.
P406
A Highly Differentiated 3D Epidermal Skin Model to
Characterize Skin Sensitizers in Mixtures.
L. Pratt1, M. Troese1, G. DeGeorge1. MB Research Laboratories,
Spinnerstown, PA, USA1
Strong support exists in the consumer products, pharmaceutical
and cosmetics industries to develop in vitro assays to identify skin
sensitizers. We have adapted the keratinocyte interleukin-18 (IL18) response assay developed by Corsini and colleagues (2009)
for use with epiCS®, a highly-differentiated 3D epidermal model.
The IL-18 assay measures release of this cytokine into the culture
medium of treated tissues over 24 hours, by ELISA. Results are
expressed as a Stimulation Index (SI) when compared to vehicle
control treatment; an SI value of >1.5 was considered indicative
of a positive sensitizer response. Four vehicles - Ethanol, AOO
4:1, Ethanol:DMSO 4:1, and Petrolatum - were compared for
effects on three sensitizers (dinitrochlorobenzene, eugenol
and citral). Ethanol:DMSO 4:1 yielded the highest SI values for
the three sensitizers. The basal amount of IL-18 release for all
vehicles ranged from 1.1 pg/ml to 17 pg/ml. DNCB consistently
produced the highest SI values with the vehicles. In Ethanol, doseresponses were observed for DNCB, nitrobenzylbromide and
p-phenylenediamine, while cinnamic alcohol and resorcinol were
negative. Resorcinol in AOO 4:1 was clearly positive (SI = 2.7). The
irritant/nonsensitizers phenol and glycerol were both negative
(SIs < 1.5). Hair dyes ranging from light brown, dark brown and
black colors were tested neat on the epiCS® tissues. An increase
in IL-18 (> 71 pg/ml) over sham-treated controls (13 pg/ml) was
observed in all dyes (SI values 5.7, 6.0 and 6.8). Further work is
necessary to investigate different categories of chemicals and
mixtures to improve the prediction model.
MatTek Corporation, Ashland, MA, USA
2
To investigate the mechanism of dermal sensitization, a co-culture
model of human keratinocytes and dendritic cells was developed
and tested. This model (Epi-DC) consists of a 3D epidermal
organotypic tissue, EpiDerm™, grown atop a suspension culture
of plasmacytoid dendritic cells (pDC) in medium that allows for
normal viability, expression of IL-18, and expression of activation
marker CD86 on the surface of pDC. Test chemicals were dosed
topically on the EpiDerm™ tissue for 24 hours. Criteria for change
in biomarkers indicating a positive sensitizer included: (1) an
increase of IL-18 release into the culture medium of >1.6-fold
over vehicle, or (2) an increase in the percentage of pDC-bearing
81 ABSTRACTS
P404
Development of a Nonclinical Assessment of ChemotherapyInduced Peripheral Neuropathy That Can Be Applied to
Standard Rat Toxicity Studies.
C. Tyszkiewicz1, A. Foote1, K. Cannon1. Pfizer Inc., Groton, CT, USA1
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P407
Circulating miRNA-133a, miR-133b, and miR-1 as Potential
Sensitive Biomarkers of Myotoxicity.
J. Calvano1, A. Lo1, J. DiPiero2, B. Murphy1, C. Hixon1, R.
Mangipudy1, M. Tirmenstein1. 1Bristol-Myers Squibb, New
of thrombocytopenia for surviving animals ranged from 12-25
d (cyno) and 10-24 d (rhesus). ANC and PLT reached nadir for
surviving animals 14-19 d and 14-16 d, respectively, for cynos and
on 13-15 d and 14 d, respectively, for rhesus.
Brunswick, NJ, USA, 2Bristol-Myers Squibb, Lawrenceville, NJ, USA
ABSTRACTS
2014
Drug-induced myotoxicity is a significant concern in drug
development. Plasma myotoxicity biomarkers including fatty
acid binding protein-3 (FABP3), myosin light chain-3 (Myl3), and
aspartate aminotransferase (AST), lack sensitivity and specificity,
which can limit their utility as biomarkers of skeletal muscle
toxicity. Published literature evaluating circulating miRNAs as
biomarkers of skeletal muscle injury is limited. Male SpragueDawley rats received a single intraperitoneal injection of
mitoxantrone (10 mg/kg), an antineoplastic anthracenedione, or
vehicle. FABP3, Myl3, skeletal muscle troponin (sTNI), and AST were
compared to miRNAs miR-133a, miR-133b, and miR-1 in serum.
These miRNAs were identified as muscle-enriched by screening a
tissue panel from untreated rats. Although no treatment-related
histopathologic findings were observed in the soleus or quadricep
muscle, heart, liver or kidney samples examined microscopically
at 4, 24 or 48 hours after mitoxantrone administration, there were
significant increases in mean sTNI in mitoxanthrone treated rats
at all timepoints (4, 24, and 48 hours) examined. Other indices of
skeletal muscle injury such as mean FABP3, MYL3, and AST were
not significantly elevated in mitoxantrone treated rats. Serum
levels of miRNA-133a, miR-133b, and miR-1 were increased 4
and 24 but not 48 hours postdose following mitoxantroneinduced skeletal-muscle injury. The amplitude of these increases
was similar to that observed for the traditional sTNI biomarker
of muscle injury at the 4 and 24 hour timepoints. The highest
increases were noted with miR-133a and miR-133b. Our results
suggest that muscle-enriched miRNAs are as sensitive as sTNI and
may serve as an additional biomarker of myotoxicity.
P408
Hematopoietic Characteristics of the Macaque (Rhesus vs
Cynomolgus) following a Single Dose of Irradiation.
R. Love1, N. Makori1, R. Manning1, S. Glaza1, T. Beck1, K.
Fukuzaki1, R. Nagata2. 1SNBL USA, Ltd., Everett, WA, USA, 2Shin
Nippon Biomedical Laboratories, Ltd., Kagoshima, Japan
In continuing efforts to develop well defined animal models
for the acute radiation syndrome under the FDA Animal Rule
(21CR314, subpart 1), total body irradiation was applied to six
cynomolgus (cyno) macaques given full supportive care at a
dose of 7.55 Gy and sixteen rhesus macaques at a dose of 7.25 or
7.75 Gy using a bilateral 6 MV linear accelerator photon radiation
source at 0.80 Gy min-1.
Results: 50% of cynos (7.55 Gy) were euthanized by d 37 and
38% (7.25 Gy) to 50% (7.75 Gy) of rhesus were euthanized by d 19
post-irradiation. Study endpoints, in addition to survival, included
cell nadirs and day/duration of neutropenia (ANC <500µL, ANC
<100µL) and thrombocytopenia (PLT <20,000µL). ANC was <500
μL-1 8 d (cynos) or 6-7 d (rhesus) and <100 μL-1 10-12 d (cyno) or
9-12 d (rhesus) after irradiation. ANC of survivors recovered to
≥100 μL-1 by 22 d (cyno) or 19-21 d (rhesus) and to ANC ≥500
μL-1 by 22-25 d (cyno) or 21-24 d (rhesus). PLT count was <20,000
μL-1 12-25 d (cyno) or 10-11 d (rhesus) after irradiation. Duration
Overall the response of the cynomolgus and rhesus macaques
to a single application of irradiation were similar, suggesting the
cynomolgus macaques may be a species utilized in future acute
radiation syndrome studies.
P409
Isolation of Granulocyte Colony Stimulating Factor (G-Csf)
Mobilized Peripheral Blood Mononuclear Cells By Apheresis
of Blood from the Rhesus Macaque.
N. Lalayeva1, R. Love1, R. Rose1, N. Makori1, R. Manning1, S
Glaza1, T. Beck1, K. Fukuzaki1, R. Nagata2. 1SNBL USA, Ltd, Everett,
WA, USA, 2Shin Nippon Biomedical Laboratories, Ltd., Kagoshima,
Japan
Apheresis facilitates collection of stem cells or other blood
components (such as platelets) in the peripheral blood that are
subsequently used in the research of blood production and
repopulation of blood producing cells for therapies such as for
acute radiation syndrome and certain types of bone marrow
cancers. Mobilization and apheresis of rhesus macaque blood,
however, has proven to be technically challenging due to the
inefficient mobilization response after in vivo G-CSF treatment
and the high extracorporeal blood volumes required for harvest
of these cells. In this study, one animal was administered
Neupogen® at a dose of 50 µg/kg once daily for 5 days. Apheresis
was performed on the 6th day using the AmicusTM Separator with
MNC Collection (Fenwal Inc). Primary assessments of the collected
blood included PBMC isolation, hematology and flow cytometry.
White blood cells in the fresh apheresis product were higher
than in the preapheresis product. The increase in lymphocytes,
monocytes and basophils in the apheresis product was greater
than the neutrophils. Flow cytometry data showed an upward
trend in the absolute counts of CD45+ CD34+, CD45+ CD34high
and CD45+ CD34high CD117+ hematopoietic stem cell populations
following Neupogen® administration. Using the ACK lysis buffer
procedure to remove red blood cells, 1.325 x 109 PBMCs were
isolated from 8 mL of apheresis product vs 2 to 2.5x107 PBMCs
recovered via a standard isolation procedure. These results
confirmed appropriate apheresis and product collection methods
were selected, thus establishing a reliable apheresis method
in the rhesus macaque.
P410
Evaluating Immunogenic Responses in Cynomolgus Monkeys
with a Serum Biochemistry Analyzer.
R. Early1, M. Chen1, W. Lv1, H. Pei1, S. McPherson1. Wuxi Apptec,
Suzhou, China1
Immunogenic responses to immunoactive agents have historically
been analyzed using ELISA methods and, whilst sensitive and
precise, are often time-consuming and expensive. In the present
study, responses in IgM, IgG, IgA, C3 and C4 to IM injections
of keyhole limpet hemocyanin (KLH) in female cynomolgus
monkeys (2 per treatment) were analyzed using a Hitachi 7180
Biochemistry Analyzer. The data was normalized to pretest values
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and compared to the control animals. Treatments consisted of a
single IM injection of saline (controls); 5 mg/kg KLH (KLH Low);
or 15 mg/kg KLH (KLH High). Serum was collected on Days -6, -2,
6, 8, 10, 12, 14, 16, 18, 20, 23 and 28 following the KLH injection.
P411
Renal Safety Pharmacology: Characterization of a
Non-Rodent Model with Water Loading Using a Positive
Control Agent.
S. Authier1, S. Abtout1, E. Troncy2. 1CiToxLAB, Laval, Quebec,
Canada, 2University of Montreal, St-Hyacinthe, Quebec, Canada
Introduction: Renal safety pharmacology is commonly
performed in rodents but limited data is available for nonrodents.
A canine model of renal safety pharmacology with water loading
was characterized. Methods: Male beagle dogs (n=6) received
furosemide (0.3, 3 and 10 mg/kg) or control in a crossover design
with a 7 day wash-out. Water loading (30 ml/kg) and urinary
bladder emptying were completed prior to each treatment.
Each treatment session was divided into baseline (0-6 h and
6-24 h) and postdose collections (0-2 h, 2-4h, 4-6h and 6-24h).
Biochemistry was evaluated at 6h and 24 hours post dose. Urine
volume (ml/kg), specific gravity, plasma and urine biochemical
parameters, water consumption and food consumption were
assessed. Glomerular filtration rate, water clearance and excretion
fraction were calculated to evaluate renal function. Results:
Water loading increased urine output and glomerular filtration
rate (0-6 h). Furosemide (0.5, 3 and 10 mg/kg) induced a dose
dependent increase in urine output at 0-6 h. The 24h urine
volume was moderately increased (+60.7%) with furosemide at
10 mg/kg compared to control. from 0-6 h, furosemide increased
free water clearance, urinary excretion of sodium, calcium and
chloride, decreased urine osmolarity and specific gravity. Water
consumption increased and was proportional to urine output
while food consumption decreased slightly at high dose (10 mg/
kg) only. Conclusion: Renal safety pharmacology in a canine model
with water loading enabled identification of pharmacodynamic
effects following administration of a diuretic. The canine model
represents a valid alternative when this species is justified.
P412
Practicalities of Dermal Dosing: The Practical Aspects of Dose
Administration in Minipigs and Rats.
T. Ramani1, L. Jun-Hsiang1, C. Savidge1, T. Jones1, C.
Auletta1. Huntingdon Life Sciences, Somerset, NJ, USA1
Dermal administration to animal models presents multiple
challenges. Ingenuity is needed to achieve dermal exposure that
closely mimics the human exposure and provides an adequate
margin of safety. Because of the limited area for exposure to test
articles, it is often necessary to administer dermal formulations at
the maximum feasible dose volume, which may differ for different
materials and for different species. Procedures and calculations
for determination of body surface area and the area to be covered
by dermal formulations methods (10%) may vary from laboratory
to laboratory. Comparisons and significance of the differences are
discussed in this presentation. Procedures for open, occluded and
semi-occluded administration of dermal formulations also vary
from laboratory to laboratory. Advantages and disadvantages of
collars, jackets and various wrapping materials/procedures are
discussed and procedures currently in use at HLS are described.
P413
Jacketed External Electroencephalographic (EEG) Telemetry
Monitoring in Conscious Beagle Dogs and Cynomolgus
Monkeys: Qualification of a Central Nervous System Safety
Testing Model.
S. Authier1, M. Pouliot1, L. Bassett1, R. Forster1, E.
Troncy2. 1CiToxLAB, Laval, Quebec, Canada, 2University of Montreal,
St-Hyacinthe, Canada
Introduction: Implanted EEG monitoring by telemetry was
reported in nonclinical studies but noninvasive with freely
moving EEG recordings by telemetry as used in humans was
not previously reported in nonrodents. Methods: A system for
noninvasive continuous EEG-video monitoring by telemetry
was qualified in dogs and nonhuman primates. EEG traces were
obtained in Beagle dogs and cynomolgus monkeys using short
electrophysiology needles in a Cz-Oz configuration from the 1020 system connected to a telemetry transmitter. An intravenous
infusion (1.7 mg/kg/min) of pentylenetetrazol (PTZ) was used
to characterize the model for seizure detection. Results: The
incidence of signal artifacts was low (<5% of total EEG traces) and
adequate for EEG interpretation. Non-invasive EEG monitoring
was associated with a higher incidence of signal artifacts than
surgically implanted EEG telemetry. The power of the EEG spectral
bands was lower than values obtained from surgically implanted
EEG leads but with comparable ratios between each band (delta,
theta, alpha, sigma and beta). EEG traces showed normal profiles
for the species evaluated with circadian changes. Upon PTZ
infusion onset, paroxysmal EEG activity was observed with the
expected trace morphologies (e.g. isolated sharp waves, repeated
sharp waves, increased synchrony). PTZ induced ictal activity
showed expected characteristics with a dominant frequency
at Fast Fourier Transform (FFT) ranging from 3-6 Hz in dogs and
monkeys. Conclusion: Noninvasive EEG monitoring by telemetry
in freely moving animals was confirmed to be adequate to
monitor normal, preictal and ictal CNS activity in conscious Beagle
dogs and nonhuman primates.
83 ABSTRACTS
A dose-dependent response in IgM was observed beginning on
Day 6and was approximately 1.6-fold greater (zenith on Day 10)
in the KLH Low animals and 2.6-fold greater (zenith on Day 8)
in KLH High animals, compared to the normalized control data.
Generally, there was no clear relationship to KLH injection in the
IgG, IgA, C3 or C4 analytes. However, one KLH Low animal was
noted for greater increases in IgA (1.3 fold greater on the Day 10
zenith), C3 (1.8 fold greater on the Day 14 zenith) and C4 (3.1 fold
greater on the Day 16 zenith) relative to the controls and other
KLH-treated animals. In conclusion, the samples were rapidly
analyzed using the Biochemistry Analyzer (less than one day) and
was considered advantageous for rapidly screening samples for
immunogenic responses when compared to ELISA methods.
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P414
Left Ventricular Pressure (LVP) Assessment Screening Models:
Comparison of High Definition Telemetry in Free-Moving with
Anesthetized Rats.
S. Authier1, A. Ascah1, R. Forster1, L. Bassett1, E.
Troncy2. 1CiToxLAB, Laval, Quebec, Canada, 2University of Montreal,
ABSTRACTS
St-Hyacinthe, Quebec, Canada
Introduction: Nonclinical models to screen for cardiac contractility
changes are used in drug development. Methodology: Left
ventricular pressure (LVP) was measured in the conscious and
anesthetized rats by direct catheterization of the LV apex. Results
from conscious and anesthetized animals with the same positive
control agents were compared. Results: Average dP/dt max
observed during day time (7949 ± 890 mmHg/sec) and night
time (9906 ± 1689 mmHg/sec) confirmed the circadian changes
associated with normal activities. Pharmacological agents known
for their contractility enhancer (Dopamine and Sotalol) or lessener
(KCl) properties produced the expected effect on dP/dt max in
both models. In the anesthetized model Sotalol (6 mg/kg, IV) and
KCl (0.34 mEq/kg, IV) induced a reduction in dP/dt max of -23%
and -21%, respectively compared to control. Dopamine induced
a dose dependent increase in dP/dt max (+11% at 0.05 mg/kg
and +34% at 0.1 mg/kg) in anesthetized rats. In the conscious
rats, Sotalol (6 mg/kg, IV) and KCl (0.34 mEq/kg, IV) were also
associated with a decrease in dP/dT max. Dopamine (IV) induced
a dose dependent increase in dP/dT max (at 0.05 mg/kg and at
0.1 mg/mg) in conscious rats. Discussion: Our results suggest
that the anesthetized rat model may be more sensitive than the
conscious model to detect drug induced contractility changes.
The conscious model enables repeated administration which is
often required to increase sensitivity of the assay. Left ventricular
pressure (LVP) monitoring in free-moving or anesthetized rats
represent applicable methodologies for nonclinical safety
evaluations in drug development.
P415
Electroencephalography (EEG) in Sprague-Dawley Rats
and Cynomolgus Monkeys: Superintervals to Increase
Model Sensitivity.
S. Authier1, L. Bassett1, M. Pouliot1, E. Troncy2, R.
Forster1. 1CiToxLAB, Laval, Quebec, Canada, 2University of Montreal,
St-Hyacinthe, Canada
Introduction: Application of super-intervals to EEG data from rats
and nonhuman primates was evaluated to enhance sensitivity
in safety pharmacology. Methods: Cynomolgus monkeys and
Sprague Dawley rats with EEG and EMG telemetry transmitters
were used for EEG spectral analysis. Data variability was calculated
for data bins of increasing durations from 1 to 480 min over 24-hour
periods. The impact of data bin durations on intrinsic variability
was assessed and potential differences for daytime and night-time
data. Intrinsic EEG data variability was compared to cardiovascular
and respiratory data. Results: In cynomolgus monkeys, increasing
EEG data bins showed optimal variability reduction with a 60 min
bin duration, with lower variability during night-time compared
to daytime. In comparison, respiratory rate, tidal volume and heart
rate in cynomolgus monkeys showed progressive improvements
up to an interval duration of 480 min.. In Sprague Dawley rats,
EEG data bins also showed optimal variability reduction at 60 min
2014
without significant differences between day and night time. In
comparison, optimal data bin durations for respiratory rate and
tidal volume in rats was observed with bin duration of 5 min, with
progressive improvements up to an interval duration of 480 min
for heart rate.. Discussion: Super-intervals decrease variability for
respiratory, cardiovascular and EEG data. The benefit of increasing
in bin duration should be weighed against the potential dilution
of drug effects with unaltered data. The current analysis supports
a bin duration of 60 min for EEG data in rats and nonhuman
primates when pharmacologically relevant.
P416
Melanin Location in the Skin and Hair Appendages in the
Long Evans Rats: Relevance to Photosafety Evaluations.
M. Dougherty1, J. Baker2, M. Elliott2, T. Albers3,
D. Learn1. 1Charles River Laboratories Preclinical Services, Horsham,
PA, USA, 2Pathology Associates, Inc, Frederick, MD, USA, 3Charles River
Laboratories, Wilmington, MA, USA
The role of melanin in xenobiotic-induced ultraviolet radiation
(UVR)-induced phototoxicity is not clear. Melanin produced in
response to UVR exposure is classically considered a protective
adaptation to this exposure. There are references to melaninrelated amplification of phototoxicity, primarily using in vitro
models that has generated regulatory concern, but evidence of
this effect in vivo has not been reported. The ICH S10 Photosafety
Evaluation of Pharmaceuticals also recognizes that melanin
binding can increase local tissue concentration of xenobiotics
but that binding alone does not present a photosafety concern.
The Long Evans (LE) rat is the primary in vivo phototoxicity Test
System used in this Testing Facility to evaluate possible melaninbinding enhancement of phototoxicity, as both lightly and darkly
pigmented skin sites can be evaluated. Questions have been raised
regarding the anatomic location of the melanin visibly observed
in the skin of the LE rat. Should melanin not be present in the skin
but only in the hair appendages, and presuming that binding
could exacerbate phototoxicity, the relevance of the model to
humans could be questioned. Histopathological evaluation of
lightly and darkly pigmented skin revealed melanocytes located
at the dermal/epidermal junction in the darkly pigmented skin,
but absent in the lightly pigmented skin. The darkly pigmented
skin was less sensitive to UVR-induced erythema and edema,
demonstrating that the constitutive pigmentation, regardless
of location, was, as expected, protective. These results indicate
that the LE rat is a relevant model for potential melaninenhanced phototoxicity.
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P417
Modeling of Flow and Evolving Aerosol Particles Dynamics
for Computing Local Deposition in Air-Liquid Interface
Experiments.
A. Kuczaj1, M. Nordlund1, S. Majeed1, S. Frentzel1, J. Hoeng1,
M. Peitsch1. 1Philip Morris International R&D, Philip Morris Products
SA, Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland, 2Multiscale
Modeling and Simulation, Faculty EEMCS, University of Twente, AE
Enschede, The Netherlands
Deposition of aerosol is governed by the various physical
mechanisms (e.g., diffusion, impaction, sedimentation), and
implicitly is also dependent on the flow and surrounding aerosol
particles' thermal conditions. This is in particular important when
considering that aerosols consisting of liquid droplets are being
diluted with air as they may still evolve. Using Computational Fluid
Dynamics, a computational model of the well was constructed, in
which we considered flow with embedded droplets characterized
by its mean size droplet diameter. The simulations took in account
fully coupled equations for mass, momentum and energy in the
Euler-Euler framework as well as one-way coupling of gas and
liquid phase. For the account of the sedimentation the driftflux approach was used.
The numerical investigations indicated that the flow rate, droplet
diameter, diffusion and gravitational settling play significant
roles in the process of aerosol deposition. Simultaneously
the influence of impaction was found to be negligible at
considered droplet diameters.
P418
Qualification and Comparison of Big Blue® Mouse and Rat
Transgenic Rodent (TGR) Mutation Assays with N-Ethyl-NNitrosourea (ENU) and Benzo(a)pyrene (BaP).
R. Young1, H. Dinesdurage1, M. McKeon1, R. Elbekai1,
D. Bruning1, T. Lawlor1, M. Aardema2. 1BioReliance, Rockville, MD,
USA, 2Marilyn Aardema Consulting, LLC, Fairfield, OH, USA
Background mutant frequency in each tissue was similar in mice
and rats. Liver background mutant frequency was 43.6±6.2x10-6 in
mice and 43.4±8.8x10-6 in rats. Bone marrow background mutant
frequency was 38.1±14.2x10-6 in mice and 29.7±14.3x10-6 in rats.
In mice, significant (p<0.001) increases in mutant frequencies
were observed with BaP in liver (4.9-fold) and bone marrow (17.7fold) and ENU in liver (4.2-fold) and bone marrow (10.6-fold). In
rats, significant (p<0.001) increases in mutant frequencies were
observed with BaP in liver (5.8-fold) and bone marrow (9.6-fold)
and ENU in liver (3.6-fold) and bone marrow (6.8-fold). Both Big
Blue® mouse and rat systems are robust with the ability to detect
significant increases in mutagenicity in slow dividing (liver) and
fast dividing (bone marrow) tissues by a direct acting mutagen
and one that requires metabolic activation.
P419
Methods for Successful Intra-Vaginal Dosing in Rats RM.
R.M. Gendron1, P. Mansell1. Charles River Laboratories Preclinical
Services Montreal, Montreal, Quebec, Canada1
With an increase in the development of new drugs specifically
targeting female patients, including hormone replacement
therapies, contraceptives, anti-infectives and infertility therapies,
various forms of intra-vaginal administration (creams, gels,
suppositories and rings) have been developed for local and/or
systemic use. The intra-vaginal route presents advantages for
women, including a reduced need for daily administration (e.g. the
vaginal ring), user controlled administration, discreteness, single
treatments lasting for weeks or months, and treatment regimens
tailored to the individual. These advantages result in increased
compliance and a decrease in potential side-effects. Additionally,
the use of the vaginal route for drug delivery avoids first-pass
effects and provides optimum pharmacokinetic profiles. With this
focus on intra-vaginal delivery, there is also a need to successfully
and efficiently perform intra-vaginal dose administration in
nonclinical studies. Our laboratory has established procedures
required for intra-vaginal dosing of different formulations of
controlled-released drugs in Sprague Dawley rats. Due to the
limited surface area within the female reproductive tract of rats,
it was determined that the procedures and/or frequency of
application may need to be varied depending on the formulation,
dose level of the material to be delivered, and body weight of the
rat. It was also determined that for a successful study, procedures
were required to minimize loss of test material. In conclusion, our
laboratory has established procedures for intra-vaginal dosing in
Sprague Dawley rats that allows for accurate assessment of local
and systemic responses to drug exposure and allows for standard
observations to be evaluated in toxicology studies.
In vivo transgenic rodent (TGR) mutations assays are used to
follow up genotoxicity results with a suspected mutagenic mode
of action. One advantage of the Big Blue® model compared to
other TGR mutation models is that both mouse (C57BL/6 or
B6C3F1) and rat (Fisher 344) models are available. We qualified
both species to new OECD TG 488 standards and to permit
comparisons between the species. Homozygous male Big Blue®
C57BL/6 mice and F344 rats received olive oil vehicle (5 mL/kg/
day) or BaP (50 mg/kg/day) for 28 days or ENU (40 mg/kg/day
for mice or 20 mg/kg/day for rats on Days 1-3) with necropsy
on Day 31. Mutations in liver and bone marrow were evaluated.
85 ABSTRACTS
Understanding physical conditions that govern deposition of
aerosol droplets and its influence on the cell functioning is a key
step towards the ultimate goal to relate the exposure of inhaled
and deposited aerosols to health outcomes. This is important twofold, i.e., the same physical mechanisms are acting in much more
complex geometries (e.g., human airways), and simultaneously
acquired knowledge allows for improved in vitro inhalation
toxicology experiments. We present here our approach to model
the flow and evolving aerosol dynamics together with aerosol
deposition in a simple trumpet-like geometry frequently used in
in vitro exposure systems (e.g., Vitrocell®).
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P420
Intrathecal Administration and Cerebrospinal Fluid Collection
in the Juvenile Beagle Dog.
J. Douville1, F. Emond1, R. St-Jacques1, F. Claudia1, B.
Lise1. Charles River Laboratories, Preclinical Services Montreal,
ABSTRACTS
Senneville, Quebec, Canada1
Delivery of drugs directly into the cerebrospinal space is an
effective means to treat neurological diseases when systemic
delivery fails to reach the target or alleviate the symptoms.
Neurological disorders often appear or develop during childhood
and there is an increased interest in conducting nonclinical
studies in juvenile animals to mimic the age/life phase of the
target population. Additionally, these studies oftentimes require
collection of cerebrospinal fluid (CSF) to evaluate central nervous
system (CNS) drug concentrations or disease-specific biomarkers.
At this early growth stage, morphology of the weanling dog
presents particular challenges requiring refinement of our surgical
techniques. Also, our established approach for CSF collection
via the lateral ventricle in adult dogs necessitates modification,
including determination of stereotaxic coordinates and cranial
landmarks in juvenile dogs. Therefore, we investigated suitable
methods for accurate delivery of potential therapeutics to the
CNS and CSF collection in 9 to 11 week old dogs. An intrathecal
catheter was inserted via a microlaminectomy of the L5 vertebra
and a durotomy. Once the catheter was secured, a subcutaneous
pocket was made in the lumbar region, and the access port was
fixed to the muscle; the catheter was then fixed to the access port.
Different approaches were evaluated for CSF collection, including
direct puncture or catheter implantation into the cisterna magna
and implantation of a guide port for repeated sampling from the
lateral ventricle of the brain. Herein we describe the success rate
of our optimized approaches for both intrathecal delivery and CSF
collection in juvenile dogs.
P421
Comparative Evaluation of Background Data for the Incidence
of Foot Lesions In Sprague-Dawley Rats Housed in Different
Types of Caging.
S. Kwok1, P. Mansell1. Charles River Laboratories Preclinical Services,
Montreal, Senneville, Quebec, Canada1
Use of polycarbonate (solid-bottom) cages containing bedding
for rodents has been previously shown to provide improved
housing conditions with particular emphasis on a reduction in
the incidence of foot lesions known to occur in rats during the
conduct of chronic toxicology and carcinogenicity studies. The
background incidence of foot lesions was therefore compared
between metal wire and solid-bottom housed animals for
carcinogenicity studies conducted in our facilities with ad
lib fed Sprague Dawley Crl:CD(SD) rats. Data from 104 week
carcinogenicity studies performed in solid-bottom cages and
conventional metal (stainless-steel wire mesh or perforated
floor) cages was evaluated to investigate the relationship
between housing regimens, body weight as well as to compare
the incidence and onset of foot lesions. Characteristic clinical
signs associated with foot lesions considered in this comparative
assessment included limited hind limb usage, skin lesions, skin
papules, skin redness, skin scabs, and firm/soft swelling of the
hind limbs and/or hind paws. As anticipated, there was general
2014
reduction (0.02X to 0.6X) in the incidence and a delayed onset of
clinical signs associated with foot lesions in rats housed in solidbottom cages, when compared to rats housed in metal cages.
Incidence was shown to be positively correlated to bodyweight,
with higher occurrence and earlier onset of lesions being noted
in the heavier male population when compared to females.
Data from this laboratory was generally comparable to existing
literature and further supports use of solid bottomed cages for
chronic rodent studies.
P422
Long-Term Intrathecal Infusion/Sampling Via a Surgically
Implanted Access Port with Functional Observation Battery
Observation in Cynomolgus Monkeys.
R. Tavcar1, S. Authier1, M. Said Meghazzi1, S. Groom1, R.
Forster2. 1CiToxLAB North America, Laval, Quebec, Canada, 2CiToxLAB
France, Évreux, France
Intrathecal administration and sampling continues to be critical
in nonclinical pharmaceutical development for drugs that
must be delivered across the blood-brain barrier or to allow
sampling of cerebral spinal fluid (CSF). In alignment with the
3Rs we have refined a method to allow long term administration
and/or sampling. In addition, a modified function observation
battery (FOB) often conducted as part of the ICH S7A safety
pharmacology core battery, was developed for the evaluation
of neurological changes in nonhuman primates. A cerebrospinal
fluid catheter was inserted into the intrathecal space in the
vertebral lamina (L3) and connected to a vascular access port.
Implanted animals were first used for the evaluation of the
cerebrospinal pharmacokinetics of a pharmaceutical, with CSF
sampling over a period of 36 hours followed by a washout period
and ending with the 28 day continuous infusion feasibility Phase.
Following the 28 day period, the animals were euthanized for
histopathological evaluation. No neurological abnormalities
were observed and minimum to mild catheter-associated chronic
granulomatous inflammation was associated with the catheter
in the subarachnoid space at the injection/sampling site, next to
the spinal cord and spinal nerve roots. Similar moderate catheterassociated chronic granulomatous inflammation was also noted
along the catheter track beside the vertebral body and dorsal
spinal process below the lumbar muscles. In conclusion, the port/
catheters were patent for the duration of the experiments (over
100 days in total). Therefore the improved method was deemed
to be appropriate for long term toxicological, neurological and
pharmacokinetic evaluations in Cynomolgus monkeys.
P423
Repeated Intratracheal Powder Aerosol Delivery In SpragueDawley Rats.
M. Stoute1, A. Dumais1, S. Groom1, R. Tavcar1, R.
Forster2. 1CiToxLAB North America, Laval, Quebec, Canada, 2CiToxLAB
France, Évreux, France
Inhalation administration is a highly effective delivery route
allowing the bypass of first-pass metabolism and permitting
local delivery to the lungs but is expensive and requires large
quantities of material. We evaluated an alternative approach
using a novel device for repeated intratracheal administration
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P424
Human Whole Blood In Vitro Cytokine Release—How Does
Variability Impact Study Design?
C. Dumont1, R. Bourgeois1, K. Bryant1, E. Marcotte1, S. Lavallée1,
M.S. Christin-Piché1. Charles River, Senneville, Quebec, Canada1
Interpretation of in vitro cytokine release assays (CRA) can be
challenging. Appropriate study design and knowing the expected
variability are critical in a successful outcome. In this study, we
focused on the comparability of the response of 9 cytokines
following in vitro stimulation of human whole blood with an
anti-human CD3 (24 hours). Blood from up to 35 donors was
stimulated by soluble and dry-coated methods and data were
evaluated for inter-donor variability. The data collected over
different occasions were used to assess donor reproducibility.
Globally, the inter-donor variability was high and inter-day
variability was observed. However, the donors with the higher or
lower levels remained generally consistent between occasions.
Both stimulation formats showed similar inter-donor and interday variability. Detectable levels of cytokines were measured in
both assay format but differed significantly for some cytokines.
IL-1β was released at least 1.5X more using the soluble format
while IL-6, IL-8, IL-10 and IFNg were released at least 1.9X more
using the dry-coated format. The levels of IL-2, IL-12, TNF-a and
G-CSF were not significantly altered by the stimulation format. In
conclusion, based on the variability observed in CRA data, it is not
recommended to use less than 8 donors. The interpretation must
be conducted with caution as a positive or negative response in
this type of assay might not be representative of the response
obtained with all donors. Lastly, the choice of the cytokines
analyzed and the mode of action of the drug must be taken into
consideration when choosing the assay format.
P425
Comparative Photomicrographic Examination of Integument
from Eight Species of Mammals Including Two Lineages of
Research Miniswine.
L. Brown1, D. Kim3, C. Hanks1, S. Schnapp1, D. Brocksmith2, D.
White1, A. Stricker-Krongrad1, J. Liu1, G. Bouchard1. 1Sinclair
Research Center LLC, Auxvasse, MO, USA, 2Sinclair BioResources
LLC, Auxvasse, MO, USA, 3Veterinary Medical Diagnostic Laboratory,
Columbia, MO, USA
Introduction: Skin is the largest organ in the body. Animals
have skin which is generally similar to human skin, however,
species specific anatomical and biochemical differences exist.
The integument of animal models may vary in skin surface
topography, overall thickness and thickness of specific layers,
stratum corneum, epidermis, dermis density and collagen
content, regional blood flow, pelage (hair count), hair follicle
size or density, and sub-dermal characteristics. Determination of
which animal model most closely matches the skin of humans is
important for translational dermal research.
Objective/Rationale: Prepare magnified images of comparative
skin histology and perform simple image analysis for
differences or similarities.
Methods: Animal skin samples collected included Yucatan
miniswine, Hanford miniswine, Cynomolgus monkey, Beagle
dog, NZW rabbit, Hartley guinea pig, Sprague-Dawley rat,
and CD-1 mouse. The human skin image was acquired from a
medical school. Samples were fixed in neutral buffered formalin,
processed, sectioned, stained with H&E, examined by microscope
and photographed by veterinary dermatopathologist (DYK). The
resulting skin images generated by Olympus MicroSuiteTM were
compared side-by-side at equivalent magnification.
Results: Visual comparison of images suggest the skin of swine
and human look the most similar while the skin of rodents (rat,
mouse) has a much thinner epidermis. The skin of rabbit and
guinea pig appear to consist predominantly of hair shafts/hair
follicles combined with thin epidermis. Monkey and dog skin
were next most similar to the human skin.
Conclusion(s): The swine (Yucatan & Hanford) skin images are
visually most like those of the human images.
87 ABSTRACTS
(IT Rx). We performed single dose and 7 day repeat dose studies
with administration of air, PLGA (50/50 DL-lactide/glycolide
copolymer) (10 mg/day) or a pharmaceutical test item (10 mg/
day) to groups of 6 female Sprague Dawley rats. Only the results
of the air and PLGA control groups are presented. Repeated IT
Rx resulted in procedure-related lung changes in both control
groups, including perivascular/peribronchiolar infiltrate,
increased alveolar macrophages, and alveolar hemorrhage. These
changes were seen with higher incidence and/or severity in rats
receiving PLGA. Lung changes attributable to PLGA, but not seen
in the air control, included bronchioloalveolar inflammation,
bronchiolar epithelium hypertrophy/hyperplasia and/or erosion,
exudate/cellular debris in bronchioloalveoar lumens, foreign
material, foreign body granuloma, and necrosis with or without
trachea epithelium hypertrophy/hyperplasia and inflammation.
Although repeated IT Rx of dry powder aerosols was feasible
with this novel device, the lung mechanical damage and dose
delivery variation represented significant limitations. This
approach was not considered ideal for a 28-day regulatory study
with the pharmaceutical test item because of these limitations.
Repeated IT Rx of a dry powder aerosol in this way can be feasible
and cost effective alternative approach to inhalation exposure
during early discovery allowing for preliminary toxicological
and pharmacokinetic evaluation before committing to longer
term inhalation studies.
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P426
Application of a DNA Adductomics Software Platform to the
Investigation of DNA Damage in a Bacterium.
R. Kanaly1, A. Maeda1, R. Micheletto1. Yokohama City University,
P428
Comparison of Selected Clinical Pathology Parameters from
Sprague-Dawley Rats Sampled via Abdominal Aorta versus
Jugular Vein.
B. Attalla1, P. Mansell1. Charles River Laboratories, PreClinical
Yokohama, Japan1
ABSTRACTS
2014
DNA adductomics is an emerging field of toxicology that
was conceived of as a comprehensive top down approach to
detect DNA modifications in human tissues by utilizing liquid
chromatography coupled to electrospray ionization tandem
mass spectrometry (LC/ESI-MS/MS). A triple quadrupole MS is
used to detect the neutral loss of 2'-deoxyribose from positively
ionized modified 2'-deoxynucleosides by utilizing single reaction
monitoring mode transmitting the [M + H]+ > [M + H - 116]+
transition over a range of multiple predefined transitions. A
software platform to aid in the processing of DNA adductomics
data was written in Python and utilizes a UNIX/Linux-compatible
environment via a graphical user interface. This software was
applied in an investigation of DNA damage in the bacterium
Serratia marcescens when it was grown under different conditions.
A total of 250 SRM transitions were monitored and all data were
merged and converted into bubble-type chart adductome maps
that allowed for direct visual sample comparisons. The software
platform also enabled the creation of transition-specific data
plots that may be extracted from the large data sets. The utility
of this software as it is applied to DNA adductome analyses in the
context of bacterial DNA shall be presented.
P427
QT Interval Prolongation and ECG Restitution Assessment
Using Beat-to-Beat Method in the Minipig.
R. Brandon Borders1, K. Kearney1, B. Roche1, A. Fossa2. 1WIL
Research, Ashland, OH, USA, 2iCardiac, Brighton, NY, USA
The FDA has rejected many potential pharmaceutical agents
due to QTc prolongation as a surrogate marker for potential risk
of fatal arrhythmias but assessing arrhythmogenic risk based
solely on QTc prolongation is an inherently flawed decision in
the drug safety and development paradigm (Hondeghem et al
2008, Ranjan et al 2013). Though certain types of fatal arrhythmias
share a positive correlation to the delayed repolarization period,
QTc cannot discriminate the importance of changes in autonomic
state or define reference bounds for normal physiological states.
Fossa (et al 2006, et al 2010) has shown that the QT instability of
the QT-RR and QT-TQ interval (restitution) relationship assessed on
a beat-to-beat method is an important and often misunderstood
factor in arrhythmogenic risk analysis. Using beat-to-beat analysis
derived from ECG data is proving to be a more pragmatic screen
because: 1.) the technique discriminates proarrhythmic vs. safe
drugs despite QT prolongation because: it considers the changes
in QT interval in relationship to normal physiological reference
bounds, 2) it can examine beat-to-beat restitution (hearts ability
to recover from one beat to the next) quantifying the risk of the
QT-TQ heterogeneity leading to re-entrant arrhythmias. In order
to use restitution data as bridge between nonclinical and clinical
risk analysis, it is important to define the QT-TQ variability in each
of the common species used in drug development. The purpose
of this study was to observe changes in QT/TQ and RR restitution
relationship of mini-pigs during control and after exposure to
a QT prolonging drug.
Services, Montreal, Quebec, Canada1
Blood sampling for routine clinical pathology assessments in rats
can be performed using different sites and approaches, many
of which require sampling at termination. Refinement of blood
sample collection via direct jugular puncture has presented
an opportunity for nonterminal sample collection for these
assessments. This can allow for monitoring of clinical pathology
parameters over the course of the study as well as at termination.
A comparison of standard clinical chemistry, hematology and
coagulation parameters for samples from Sprague Dawley rats
where blood was drawn via jugular or abdominal aorta was done
to confirm that values obtained by either collection methods are
comparable. The rats used for the comparison were between 10
and 20 weeks old. Males and females were compared separately.
The data was gathered from studies where rats were group
housed, up to three animals per cage and fasted prior to the blood
collection procedure. There were no meaningful differences on the
hematology, clinical chemistry, or coagulation parameters from
fasted Sprague Dawley rats between 10 and 20 weeks old, when
sampled from the jugular vein or abdominal aorta. In conclusion,
both methods are considered suitable and the resultant data can
be appropriately compared within the same study or program.
P429
Optimization of T-Cell Dependant Antibody Response (TDAR)
Conditions for Juvenile Rat Toxicity Studies.
R. T. Laureano1, N. Collins1, J. Piccotti2, L. Morford3, S. Rochelle
Mikkelsen4. 1Celgene Corporation, Summit, NJ, USA, 2Celgene
Corporation, San Diego, CA, USA, 3WIL Research, Ashland, OH, USA,
Burlenson Research Technologies, Morrisville, NC, USA
4
For pediatric therapeutics where there is cause for concern
for the developing immune system, it is recommended that
immunotoxicity endpoints such as TDAR be added to the juvenile
study. However, there is little information on the appropriate KLH
dose for juvenile animals or the ability of immunosuppressive
therapeutics to quantifiably suppress the TDAR. To determine
the optimal KLH concentration for eliciting a TDAR in juvenile
rats and compare the response to adult rats, rats (n=8/sex/group)
were administered 0.1 or 0.3 mg KLH (IV) on PND 42 (juveniles)
or PND 70 (adults) and blood samples collected 6 and 21 days
postsensitization for anti-KLH IgM and IgG titers, respectively. To
investigate whether a immunosuppressive agent would suppress
a TDAR in juvenile animals, cyclophosphamide (8mg/kg/day)
was administered (IP) on PND 35-49 (juveniles) or PND 63-77
(adults). There were no remarkable differences in juvenile TDAR
between the 0.1 and 0.3 mg KLH doses. A statistically significant
increase in anti-KLH IgM production in adults compared to
juveniles was observed. Cyclophosphamide suppressed antiKLH antibody responses at both KLH dosages, except for the
IgG response in juvenile males, and adult females immunized
with 0.3 mg of KLH. These results indicate that a KLH dose of 0.1
mg could elicit a robust TDAR response in juvenile rats and the
response can be quantifiably suppressed with an appropriate
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dose of an immunosuppressive therapeutic. Anti-KLH IgM were
higher in adults. There was no difference in anti-KLH IgG response
between juveniles and adults; however, female titers were
generally higher than males.
P430
Comparative Specular Microscopy in Laboratory Animals
(Rabbits, Dogs, and Nonhuman Primates).
S. Wise1, Mark Vézina1. Charles River Laboratories Preclinical
Services Montreal, Senneville, Quebec, Canada1
P431
Assessment of Maximum Volume Injected Intramuscularly
to Rats.
M. Felx1, A. Varela1, S. Haile1, S. Y. Smith1. Charles River
Laboratories, Senneville, Quebec, Canada1
injecting ≤0.10 mL of Indian ink, the ink remained within rectus
femoris muscle with minimal leakage into the subcutaneous
tissue and some spread to surrounding muscles. Injection of
≥0.20 mL indicated that ink spread to the surrounding muscles
with increased leakage into the subcutaneous tissue. Based on
Faxitron radiographs of contrasting agent, gross examination
of the spread of injected ink, 0.10 mL was determined to be the
optimal volume that could be injected into the muscle with
minimal spread to the neighboring muscles and limited leakage
into the subcutaneous tissue.
P432
Flow Cytometry in Combination with Benchmark Dose
Software is a Powerful Tool for Evaluating In Vitro and In Vivo
Genotoxic Dose-Responses.
S. Bryce1, J. Bemis1, D. Torous1, S. Avlasevich1, S.
Phonetapswath1, J. MacGregor2, S. Dertinger1. 1Litron
Laboratories, Rochester, NY, USA, 2Toxicology Consulting Services,
Bonita Springs, FL, USA
Flow cytometry-based micronucleus (MN) scoring (In Vitro and In
Vivo MicroFlow®) is an efficient means of generating large datasets
that allow the study of dose-response relationships. We propose
that the utility of such data can be maximized by applying Point of
Departure-type analyses as provided by Benchmark Dose (BMD)
software (e.g., PROAST). For proof-of-concept, we compiled high
quality flow cytometric in vivo MN data for 7 diverse clastogens
that were evaluated in male rats exposed for 3 days with up to
9 dose levels of melphalan, chlorambucil, thiotepa, 1,3-propane
sultone, hydroxyurea, azathioprine, or methyl methanesulfonate.
These same chemicals were studied for in vitro MN responses by
treating TK6 cells with up to 20 concentrations in quadruplicate.
In vitro MN frequencies were determined via flow cytometric
analysis using a 96 well plate autosampler. In vivo and in vitro
MN frequencies were evaluated with PROAST, and the dose
corresponding to a doubling of baseline MN frequency (BMD100)
was calculated. The resulting analyses rank-ordered the in
vivo and in vitro potency of these chemicals, with melphalan
demonstrating the lowest BMD100 values and hydroxyurea and
1,3-propane sultone the highest. For these systemically available
chemicals, a direct relationship between in vitro and in vivo
BMD100 values was observed (R2=0.839). These results suggest
that flow cytometric scoring in combination with quantitative
approaches for dose-response modeling can be useful for risk
assessment and prioritization.
The objective of this experiment was to determine the maximum
volume that could be injected intramuscularly into the rectus
femoris of albino rats. To female albino rats, different volumes of
Indian ink and a contrasting agent (OmnipaqueTM) were injected
into the rectus femoris. The rats were 8 to 9 weeks at the time of
injection and weighed between 200 to 250g. Faxitron radiographs
were performed immediately post, 15 minutes post and 5 hours
post injection. At the location of the Indian ink injection, the skin,
subcutis and muscle were opened and the spread of the ink within
the muscle and the extent of leakage were evaluated. Faxitron
radiographs indicated that a ≤0.10 mL injection of OmnipaqueTM
was localized at the muscle area with minimal or no leakage.
Injections of ≥0.20 mL resulted in leakage outside of the
muscle and showed distal expansion cranially along the patella
and patellar ligament. Gross observations showed that when
89 ABSTRACTS
Specular microscopy is a noninvasive imaging technique that
allows visualization and morphological analysis of the corneal
endothelium (EC) layer, a monolayer of specialized cells covering
the posterior surface of the cornea that maintains the health and
transparency of the corneal stroma. Clinical instruments can be
used to monitor longitudinal in-life changes during nonclinical
toxicology studies following administration of drugs to the eye.
Our laboratory has used the noncontact Nidek CEM-530 specular
microscope to compare baseline cell density, pleomorphism (cell
shape), and central corneal thickness values in New Zealand White
rabbits, beagle dogs, and cynomolgus monkeys (NHP). Rabbits,
having the thinnest corneas, had the greatest EC density (2968 ±
235 cells/mm2, n=20 eyes) and highest percentage of hexagonal
cells (74% ± 2) of the three species. Conversely dogs, with the
thickest corneas, had the lowest EC density (2540 ± 105 cells/
mm2, n=20 eyes) and lowest percentage of hexagonal cells (66%
± 3). EC density in NHP was 2900 ± 351 cells/mm2 (n=10 eyes),
with 71% ± 7 hexagonal cells. In comparison, histomorphometric
evaluation of dual-stained (0.25% trypan blue and 0.2% alizarin
red S) fresh rabbit corneas produced density values 18% higher
than specular microscopy (3510 ± 351 cells/mm2, n=6 eyes). Due
to species-specific eye position and corneal curvature, the angle
of image capture is important for accuracy of specular microscopy
imaging and likely contributes to differences when compared to
histomorphometry. However the advantage of longitudinal data
obtained by specular microscopy outweighs this discrepancy and
potentially reduces animal use.
2014
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P433
Evaluation of the Use of Transponders in the Tg.rasH2
Mouse Model.
M. Paranjpe1, J. Belich1, R. Elbekai1. BioReliance by SAFC, Rockville,
ABSTRACTS
MD, USA1
Subcutaneous implantation of transponders is a commonly used
method for animal identification in preclinical studies involving
conventional rodents. However, no robust data is available to
support the use of subcutaneous transponders in the transgenic
Tg.rasH2 mice. The Tg.rasH2 mouse model is commonly used in
26-week carcinogenicity assessment studies, and the objective of
this study was to determine if implantation of glass encapsulated
microchip transponders increases the incidence of tumors in this
model over a 26-week period. Male and female Tg.rasH2 mice
were assigned to three groups. Group 1 consisted of mice in
which the transponders were implanted subcutaneously. Group 2
consisted of mice in which transponders were not implanted but
were subjected to subcutaneous injection procedure. The third
group consisted of mice that were implanted with transponders
but were also inoculated intra-peritoneally with positive control
material, urethane. In none of the mice was there any tumor
formation at the site of injection. The most common finding
was a cavity formation at the transponder site with surrounding
compressed connective tissue. In a few mice, there was infiltration
of inflammatory cells around these cavities. The incidence of
spontaneous tumors in these mice remained within the historical
control range. As expected, the positive control material, urethane,
induced pulmonary tumors and splenic hemangiosarcomas. It
is therefore concluded that the use of transponders Tg.rasH2
mice would not negatively impact the outcome of a 26-week
carcinogenicity study.
P434
Suitable Identification Method for Transgenic Hemophilia
Type A Mice (HA).
J. Forget1, L. Bernier1, E. Arlund2. 1Charles River Laboratories,
Montreal, Quebec, Canada, 2Somark Innovations, San Diego, CA, USA
Reliable identification of laboratory animals is critical to safety
assessment study conduct to generate quality data. Various
identification methods are available, including ear tags, manual
tattoos, and radio frequency identification devices (RFID);
however, most of these are not suitable for transgenic HA mice
as this model has less than 1% of normal factor VIII activity and
exhibit prolonged clotting times. Minor lesions induced by ear
tags, RFIDs or manual tattoos can result in excessive blood loss
leading to death within few hours.
The LabStamp tail tattoo system developed by Somark
Innovations was evaluated for its suitability. The system allows a
controlled depth of needle penetration and delivery of the ink at
the desired level; the mid dermal layer of the skin. Injury to blood
vessels is avoided therefore alleviating risks of hemorrhage in
these hemophilic mice.
This method was evaluated on 210 transgenic HA mice that
were 6 to 7 weeks of age at time of identification. Animals were
observed for up to 7 weeks during which time there were no
clinical observations associated with the identification procedure,
confirming absence of substantial damage to blood vessels at the
set depth of penetration. Integrity of legibility of the tattoo was
2014
also noted to be maintained throughout this 7 week period. The
automated characters of the LabStamp system also eliminated
risks of ambiguity in characters which may exist with manual
tattoo inscriptions.
The LabStamp system was therefore considered to provide
an appropriate identification method for use with transgenic
Hemophilia type A mice.
P435
Assessing Mitochondrial Liabilities Using Multiple Assays and
Specific Cell Types.
K. Gareau1, S. Qin1, J. Bradley1, C. Strock1. Cyprotex US, LLC,
Watertown, MA, USA1
Mitochondrial toxicity is one of the most important and widely
recognized liabilities associated with drug development. Although
this toxicity is well recognized, the proper selection of assays and
cell types is not well understood to assess the different types of
mitochondrial toxicity. Here we show that with the proper assays
and cell types, one can screen multiple mitochondrial toxicities.
The first assay which analyzes the maintenance of mitochondrial
potential utilizes primary rat hepatocytes and the mitochondrial
potential sensing dye, TMRE, which is a highly cell permeable
live cell dye. This assay will detect any compound that interferes
with the maintenance of potential which is necessary for the
production of ATP through the electron transport chain. Another
assay utilizes the HepG2 cell line and its dependence on glycolysis
for growth which is known as the Warburg effect. Here we show
that there is an increased sensitivity for mitochondrial toxins when
the HepG2 cells are grown in the presence of galactose. HepG2
cells grown in glucose can also be stained with the mitochondrial
dye, Mitotracker red, which can identify compounds which
stimulate an increase in the overall numbers of mitochondria due
to an interference in the production of energy through glycolysis.
A fourth assay analyzes cells for their expression of mitochondrial
coded proteins. This assay is effective for analyzing compounds
which interfere with the expression of mitochondrial coded
proteins such as antivirals and antibiotics. Overall, the selection of
cell type and assay are important for screening compounds and
identifying their liabilities.
STP436
High-Throughput Screening of Toxicity of 24 Metal Oxide
Nanoparticles in Escherichia Coli.
C. Kaweeteerawat1, A. Ivask2, R. Liu2, H. Godwin2. 1Molecular
Toxicology Interdepartmental Program, UCLA, Los Angeles, CA,
USA, 2UC Center for Environmental Implications of Nanotechnology
(UC-CEIN), Los Angeles, CA, USA
Nanotechnology has grown rapidly over the past decade,
promising benefits in diverse areas of society. However, the rate
of toxicological analysis of nanoparticles (NPs) has failed to keep
pace with new NP development, leading to concerns over the
potential biological toxicity and environmental contamination of
NPs. Here, we developed high-throughput screening assays as a
robust platform to rapidly determine magnitude and mechanisms
of toxicity of 24 metal oxide nanoparticles (MOx) in the bacteria E.
coli. A suite of sublethal assays, consisting of PI/SYTO, XTT, DiBAC,
and H2DCFDA, were used to measure viability, respiration rate,
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membrane potential, and ROS production, respectively. Growth
inhibition analysis revealed that 7 out of the 24 MOx NPs (ZnO,
CuO, CoO, Mn2O3, Co3O4, Ni2O3 and Cr2O3) exerted significant
toxicity, causing membrane damage and accumulation of ROS.
Moreover, in vitro ROS generation assays revealed that 5 out
of the 7 toxic particles (Mn2O3, CoO, Co3O4, Ni2O3 and CuO)
were strong oxidizing agents. Interestingly, both ZnO and CuO
dissolved at high levels after 24 hours in bacterial media (5.27%
and 7.89%, respectively), and their toxicity is likely augmented
by dissolved metal ions. Structure-Activity relationships (nanoSARs) indicated that hydration and conduction band energies
are strongly correlated with toxicity. Our data suggests that the
probability of toxicity for a given MOx NP increases when its
conduction band energy is closer to that of the redox potential for
biological molecules and as its hydration energy decreases.
Environmental Health, Cincinnati, OH, USA1
Zinc is both an essential and potentially toxic metal. It is widely
recognized that oral zinc supplementation can reduce the effects
of the common cold; however, there is strong clinical evidence
that intranasal zinc gluconate treatment for this purpose causes
anosmia, or the loss of the sense of smell, in humans. Using the
rat olfactory neuron cell line, Odora, we have investigated the
means by which zinc is toxic to olfactory neurons. Using RNAseq
and in silico analyses, we identified pathways associated with
oxidative stress, calcium regulation, and ATP generation as being
up-regulated upon zinc exposure. Many genes in these pathways
are polymorphic in humans, suggesting that individuals may
be differentially susceptible to zinc toxicity. We are currently
utilizing shRNA to reduce expression of polymorphic genes
that are involved in zinc metal response (Mt1/2), oxidative stress
(Gclm), and ATP generation (Akr1b) to demonstrate their critical
role in mediating zinc toxicity and to identify adaptive pathways
in response to reduction of expression of the respective genes.
We have also established the time course of recovery in wild-type
mice exposed to intranasal zinc gluconate. Future studies are
planned using metallothionein knockout mice and glutamatecysteine ligase knockout mice to test the hypothesis that these
knockout mice will show increased olfactory mucosal damage
and delayed histological and behavioral recovery in olfactory
neurons in response to intranasal zinc gluconate administration.
STP438
Cigarette Smoke-Induced BBB Toxicity under Normal and
altered Glycemia: Proteomic Assessment of BBB Endothelial
Dysfunction.
S. Prasad1, P. Naik1, M. A. Kaisar1, R. Sajja1, L. Cucullo1. Texas
Tech University Health Sciences Center, Amarillo, USA1
Cigarette smoking (CS) is a major risk factor for diabetes mellitus
(DM). Both DM and CS have independently been reported
to enhance the chances of cerebrovascular and neurological
disorders such as stroke and Alzheimer’s disease. However,
their combinatorial pathogenic potential through involvement
of common pathways lies unexplored. Previous studies from
our group show that BBB impairment by CS extracts (CSE) is
mediated through induction of vascular adhesion molecules,
pro-inflammatory cytokines and matrix metalloproteinases from
activated leukocyte and endothelial cells (EC). Similar levels
of BBB impairment was observed in BBB EC cultures following
exposure to hyperglycemia (HG). Thus, we hypothesized that
concomitant exposure to HG and CSE will impair the physiological
and functional (tight junctions) properties of BBB ECs in an
additive manner through common molecular mechanisms. For
this purpose, we assessed the impact of CSE on protein expression
levels in BBB EC. Herein we report the specific impact of CSE on BBB
EC dysfunction under normal and HG conditions. Upregulation of
junction proteins such as ZO-1, claudin-5 and VE-cadherin was
observed following the independent exposure to HG and CSE.
The resulting effect was further increased by co-exposure to both
conditions. Both Glut-1 and SGLT-1 was upregulated by CSE and
HG-CSE co-exposure (although to a lesser extent). We further
observed an additive increase of IL-6 and VEGF release following
HG-CSE co-exposure when compared to controls. In summary, our
results show an additive effect of CSE over HG exposure on BBB
ECs which suggests the involvement and potentiation of common
molecular mechanisms.
STP439
Protecting the BBB from Tobacco Smoke Damage Using
Popular Antioxidants Supplements: Is It Really Working?
M. A. Kaisar1, S. Prasad1, P. Naik1, L. Cucullo1. Texas Tech
University Health Sciences Center, Amarillo, Texas, USA1
We have recently shown that BBB exposure to soluble cigarette
smoke extract (CSE) at physiological concentrations triggers a
strong endothelial inflammatory response through induction
of vascular adhesion molecules, pro-inflammatory cytokines
and matrix metalloproteinases. Nrf-2- a transcription factor
involved in anti-oxidant response signaling was also increased
in CSE-exposed endothelial cells substantiating the role of the
ROS generation in BBB toxicity. We have also shown that loss of
BBB function and integrity following an ischemic/reperfusion
injury is significantly worsened by CSE and pretreatment with
α-tocopherol and/or ascorbic acid proved highly protective for
the BBB. Recent studies suggest that High mobility group box
1 (HMGB1) can be actively secreted in response to exogenous
and endogenous inflammatory stimuli including ROS. Whereas,
HMGB1 elicits inflammatory responses at the BBB by increasing
the expression of pro-inflammatory cytokines and MMP
activation. Based on these premises, our underlying hypothesis is
that prophylactic administration of antioxidants can reduce CSE
and/or inflammatory-dependent BBB damage. Thus the goal of
this study is to evaluate and rank the prophylactic BBB protective
effectiveness of 5 popular and readily available antioxidants
(Coenzyme Q10, Lipoic acid, Glutathione, Resveratrol and
Melatonin) against exposure to CSE using human BBB endothelial
cells. Our preliminary data analyzing the inflammatory response
(Il-6, VCAM-1 and E-selectin) of BBB endothelial cells to CSE
following antioxidant treatment suggest Resveratrol to be the
most effective. Interestingly no significant protective effect was
observed in response to GSH administration.
91 ABSTRACTS
STP437
Investigation of Zinc Toxicity in Olfactory Neurons Using In
Silico and Molecular Techniques.
H. Hsieh1, M.B. Genter1. University of Cincinnati, Department of
2014
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STP440
Comparative Analysis of Endogenous Gene Expression Levels
Across Human and Rat Primary Endothelial Cells.
C. Snyder1, A. Kauss1, E. Doudement1, V. Musinipally1, T. Ngo1, T.
Zabka1, H. Uppal1, D. Misner1, D. Dambach1, R. Pai1. Genentech,
ABSTRACTS
South San Francisco, CA, USA1
Endothelial cells (ECs) play important roles in regulation of blood
flow, nutrient exchange, vascular structure, and pathological
response. Different tissues and vascular networks possess unique
EC populations, each with distinct gene expression profiles and
functional capabilities. EC activation is a major mechanism in the
development of drug-induced vascular injury (DIVI), a preclinical
phenomenon that often delays or prevents drug candidates from
progressing through development. Translation of preclinical DIVI
to the clinic is poorly understood and no legitimate biomarkers
have been identified so far for its early detection. In an attempt
to select an appropriate EC type for developing an in vitro
screening tool, we first established the similarities and differences
across human and rat species using primary human and rat ECs
from more than 20 different organs and tissue types. Over 100
EC structure- and function-related genes were quantified in
isolated RNA using Taqman® probes. Expression levels relative to
endogenous controls were compared by hierarchical clustering.
We further validated some of these distinct profiles for tissuedependent protein expression using immunocytochemistry.
Our results show that about 40% of the genes analyzed were
consistently expressed across in both rat and human ECs. In
addition, protein expression data correlated well with individual
gene expression profile. Based on these comparative data,
changes in genes consistently expressed across rat and human
are being used to evaluate the effects of drugs known to induce
DIVI in a rat EC culture system.
IGP441
Evaluation of Functional Impairment of Neonatal Rat
Ventricular Cardiomyocytes In Vitro: An Atomic Force
Microscopy Study.
G. Del Favero1, V. Martinelli2, T. Lanzicher1, L. Mestroni3, O.
Sbaizero1. 1Department of Engineering and Architecture University
of Trieste, Trieste, Italy, 2International Center for Genetic Engineering
and Biotechnology (ICGEB), Trieste, Italy, 3University of Colorado
Cardiovascular Institute, Aurora, CO, USA
2014
nuclear cell elasticity (Controls 1.12x103 ±7.7x102 Pa vs 1 μM Cyt-D
1.09x103 ± 5.6x102 Pa) but a decrease in both cell viscoelasticity
behavior and adhesion strength of the cardiac cell to the AFM
probe. Moreover, contractile activity of cardiac cells in response
to mechanical stimulation was impaired at all concentrations
tested. We propose a panel of endpoints that may suggest early
cytotoxic events: namely morphology, elasticity, viscoelasticity,
adhesion and contractile activity that are directly related to the
ability of the cell to respond to the extracellular environment and
to mechanical stimulation.
GFP442
Detection of Algal Toxins in Water and Rumen Contents
Utilizing the Protein Phosphatase 1 Inhibition Assay.
C. Moore1, B. Puschner1. UC Davis School of Veterinary Medicine,
Davis, CA, USA1
Microcystins (MCs) are acute hepatotoxins of increasing concern
in drinking and recreational waters worldwide. Produced by bluegreen algae, MCs inhibit serine/threonine protein phosphatases
(PP) 1 and 2A, and are a major public health risk. A cost-effective
PP1 enzymatic assay using p-nitrophenyl phosphate was
developed to quickly assess water and rumen samples for PP1
inhibiting toxins. Significant inhibition was determined via a
linear model comparing increasing concentrations of sample
extract and the log-transformed ratio of the exposed rate of
PP1 activity to control rate of PP1 activity. In August 2013 a dog
became ill and died after swimming in Clear Lake, California.
Water samples were collected one to five weeks after clinical
signs developed. PP1 inhibition correlated with detected levels of
MC congeners MC-LR, -LA, YR and -RR via LC-MS/MS: week one
samples had the highest levels of all four MCs and had significant
potent PP1 inhibitor activity (p < 0.001), while week five samples
had trace amounts of MC-LR and no significant PP1 inhibition (p
< 0.1), with the slope of the linear models becoming less steep
with decreasing MC congener concentrations. In August 2013 six
cattle died in and around two ponds in Kentucky, with pond B
identified to contain potential toxin-producing algae. MC-LA, -LR,
-YR and –RR were not detected in Pond A (Pond B was not tested).
Pond B and all three tested rumen contents, but not Pond A, had
significant PP1 inhibition (p <0.001), showcasing the diagnostic
strength of using functional assays in conjunction with LC-MS/MS.
Compression, shear, and flexural stresses: cells physiological
environment is all but static and cellular ability to respond to
mechanical stimulation is crucial for its proper function. In this
light, there are increasing evidences that suggest how variation
of cell mechanical properties can be associated to cytotoxicity
[Zou et al., 2013 PlosONE 8(8):e73499; Del Favero et al., 2014
Toxicology Letters 225: 285-293; Dulińska-Molak et al., 2014
J Biomed Nanotechnol. 10(4):651-9 ]. In the present work, we
propose the use of Atomic Force Microscopy (AFM) as a tool for
assessing morphological and mechanical changes of primary
cultures of neonatal rat ventricular cardiomyocytes in response
to exposure to Cytochalasin D (Cyt-D). Cyt-D is a mycotoxin and
a well know cytoskeleton-disrupting compound, which blocks
actin polymerization. AFM was able to confirm cell morphology
alteration due to Cyt-D, with the appearance of granulation on
the cell surface; at the same time no apparent variation of the
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2014
500 Series—Safety Evaluation Pharmaceuticals
P500
Acute and Repeated Dose Toxicity Studies of Novel Pyridazine
Substituted S-Triazin-2-Thione Derivatives as New Class of
Antihypertensive Agent.
R. Mishra1, A. A. Siddiqui2, A. Husain2, M. Rashid2. 1School of
Pharmacy and Emerging Sciences, Baddi University of Emerging
Sciences and Technology, Makhnumajra, Baddi, Distt. Solan, Himachal
Pradesh 173205, India, 2Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard
Nagar, New Delhi 110062, India
P502
A Case of Acute Hepatic Failure due to Acetaminophen
verdose Treated with Molecular Absorbents Recirculating
System®.
B. K. Yang1, J. S. You1, Y. S. Joo1, S. P. Chung1, H. Schick
Lee1. Severance Hospital, Seoul, Republic of Korea1
We report on a patient who developed acute hepatic failure
despite intravenous N-acetyl cysteine therapy who was
treated with the Molecular Adsorbents Recirculating System
(MARS). She presented 20 hours after the ingestion of 13 g
of acetaminophen. The MARS is based on albumin dialysis
principle which can be applied for patients with acute
poisoning from drugs that have high protein-binding capacity
because of its ability to selectively remove from circulation
protein-bound toxins. The clinical toxicologist should be
consider this technology when treating patients with hepatic
failure following acetaminophen poisoning.
P501
Surveillance of Chloramphenicol Residues in Milk, Eggs, and
Chicken Meat By LCMSMS.
G. Sarathchandra1. 1Pharmacovigilance Laboratory for Animal
Feed and Food Safety, Chennai, India, 2Tamil Nadu Veterinary &
Animal Sciences University, Chennai, India
Chloramphenicol has been banned for use in all foodproducing animals by the European Union (EU), and Most
of the developed countries.. The EU recently set a minimum
required performance limit (mrpl) for chloramphenicol
determination at 0.3 μg/kg (ppb) in all foods of animal origin.
The growing food safety concerns call for intensive surveillance
of chloramphenicol in food products. The objective of the
study was to assess whether milk, eggs and chicken meat
produced by the livestock farmers in TamilNadu state of India
were contaminated with chloramphenicol residues. Liquid
chromatography/mass spectrometry (LC/MSMS) method was
employed for the determination of chloramphenicol (CAP)
93 ABSTRACTS
Pyridazines are important biologically active scaffolds, possessing
antihypertensive, cardiotonic, analgesic, anti-inflammatory,
antidepressant, antibacterial, anticancer, nephrotopic drugs,
antithrombic, diuretic and anti-HIV activities. Some new
7-substituted-phenyl-3,4,8,9tetrahydro-2H-pyridazino[1,6-a]
[1,3,5]triazin-2-thione derivatives were synthesized. Pyridazines
and its derivatives are known for their cardiovascular effects. To
support the safety of synthetic compound 7-substituted-phenyl3,4,8,9-tetrahydro-2H-pyridazino[1,6-a][1,3,5]triazin-2-thione
derivatives, it has been examined in an acute and in a 4-week
repeated dose toxicity study in rats. Animals were divided into
groups of 5 animals each. The compound (20mg/kg body weight
and 40 mg/kg body weight) was injected ip after suspending in
1% carboxymethylcellulose solution in single dose resulted in no
adverse events or mortality. Also, the compound administered
as a daily dose of 40 mg/kg for 4 weeks by gavage resulted
in no adverse events or mortality. No evidence or treatmentrelated toxicity was detected during both studies. Data analysis
of body weight gain, food consumption, clinical observations,
blood biochemical, haematology, organ weight ratios and
histopathological findings did not show significant differences
between control and treated groups. It is concluded that the
synthetic compound orally administered to rats was safe and that
no treatment-related toxicity was detected in both acute ip route
of exposure and repeated dose (4 weeks) oral route of exposure
(40 mg/kg of body weight) toxicity studies.
residues in milk, eggs, chicken muscle and liver, and kidney.
CAP was extracted from the samples with acetonitrile and
defatted with hexane. The acetonitrile extracts were then
evaporated, and residues reconstituted in 10mM ammonium
acetate--acetonitrile mobile phase and injected into the
LC system, and detection was by a triple quadrupole mass
spectrometer operated in selected reaction monitoring
(SRM) mode. The method studied was sensitive enough to
detect and quantify 0.050 ug/kg (ppb) chloramphenicol for
screening purposes, much lower than the Minimum Required
Performance Limit (MRPL) of 0.3 μg/kg imposed by European
Commission's regulation. The study revealed that most of the
samples were in compliance with MRL and growing awareness
amongst farmers to avoid banned antibiotic CAP.
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P503
AMG 595: A Novel ADC with Therapeutic Potential in
Glioblastoma.
M. Santostefano1, M. Engwall2, N. Everds1, R. Guzman2, V.
Chow3, V. Upreti3, K. Hamblett4, J. Hill5, H. Vargas2. 1Comparative
ABSTRACTS
Biology and Safety Sciences, Amgen Inc., Seattle, WA, USA,
2
Comparative Biology and Safety Sciences, Amgen Inc., Thousand
Oaks, CA, USA, 3Pharmacokinetics and Drug Metabolism, Amgen Inc.,
Seattle, WA, USA, 4Therapeutic Innovation Unit, Amgen Inc., Seattle,
WA, USA, 5Early Development, Amgen Inc., Thousand Oaks, CA, USA
AMG 595 is an antibody drug conjugate (ADC) composed of a
fully human anti-EGFRvIII specific IgG1 antibody conjugated
to the semi-synthetic derivative of maytansine (DM1), via a
noncleavable linker, MCC. AMG 595 is directed against the
unique splice junction epitope, only present in EGFRvIII, which
is expressed in a significant proportion of glioblastomas
(GBM). The antibody "backbone" does not cross react with
wild-type EGFR. AMG 595 induces tumor growth regression
in EGFRvIII-positive subcutaneous and orthotopicallyimplanted xenograft models. AMG 595 is internalized into
cells and catabolized into lysine-MCC-DM1 (the intracellular
active moiety), which binds tubulin and inhibits microtubule
polymerization. Nonclinical toxicology studies consisted of a
single-dose or 1-month rat IV study with AMG 595 or DM1,
respectively, and a 1-month cynomolgus monkey IV study with
AMG 595. The toxicity was consistent with the cytotoxic nature
of the maytansine (typical DM1 effects on highly proliferative
cell populations) and related to total DM1 dose delivered. The
highest nonseverely toxic dose in the monkey (10 mg/kg) was
used to set the clinical starting dose of 0.5 mg/kg. In a Phase
1 clinical trial in patients with EGFRvIII positive GBM, tumor
response (partial response) has been observed in 2 patients
with evidence of sustained stable disease in 3 patients. Adverse
events were consistent with data from other DM1 containing
ADCs. These data demonstrate that AMG 595 has biological
impact in Phase 1 and the safety profile is consistent with the
cytotoxic nature of DM1 and not related to the EGFRvIII.
P504
Safety Evaluation of the Anti-Ang2-TNFalpha Bispecific
Antibody in Cynomolgus Monkeys.
S. Nicholson1, W. Iverson1, S. Karanth2, J. Connor1, L. Yan1, X.
Chen1, N. Dimasi1, R. Faggioni1, P. Ryan1. 1MedImmune LLC,
Gaithersburg, MD, USA, 2Charles River Laboratories Preclinical
Services, Reno, NV, USA
2014
signs, or changes in food consumption, body weights,
injection site observations, physical examination parameters,
blood pressure, electrocardiology, ophthalmology or clinical
pathology (hematology, coagulation, clinical chemistry, and
urinalysis) parameters. However, histopathological evaluation
at the end of the dosing phase revealed axonal degeneration
and astrocyte hypertrophy of the dorsal funiculi at all levels
of the spinal cord at all dose groups. Incidence was 2/3 and
1/3 in the high and mid dose females respectively and 1/3 in
the low dose males. Lesions were characterized by multiple
dilated axons and associated enlarged astrocytes. There
appeared to be no damage to the blood brain barrier or the
vasculature in the spinal cord or in any other tissues examined
histopathologically.
P505
Chronic Repeat Dose Administration of Monoclonal
Antibody MEDI-557 in Cynomolgus Monkeys Results in
Immunogenicity-mediated Findings.
P. Ryan1, M. Rebelatto1, G. Robbie1, S. Ren1, R. Criste1, J. Rojko2,
R. Dixit1. 1MedImmune, Gaithersburg, MD, USA, 2CRL Pathology
Associates, Frederick, MD, USA
MEDI-557 is a Mab directed against the F protein of RSV with
three amino acid changes in the Fc region engineered to
prolong serum half-life. Toxicity of MEDI-557 was assessed in
a repeat dose study in cynomolgus monkeys with monthly
intramuscular or intravenous injection of 30 or 108 mg/kg to
cynomolgus monkeys for 6-months with a 20-week recovery
period. There were no adverse findings in any parameter
assessed. Histopathologic findings included hypercellularity
of the red pulp of the spleen which is a common finding
following administration of foreign proteins to monkeys
and may relate to clearance of antibodies or immune
complexes (IC) from circulation. A few animals had findings
of inflammation in the choroid plexus and the perivascular/
vascular region of the sciatic nerve. Selected tissues were
evaluated by immunohistochemistry to investigate the
possible immunologic/IC-basis for these findings. Granular
deposits of MEDI-557, monkey IgG or IgM were judged as
evidence of IC deposition and inflammatory changes in sciatic
nerve and choroid plexus were directly associated with the sites
of IC deposition. As outlined in ICH S6 guidance, these types
of immunogenicity assessments assist in the interpretation of
nonclinical results but are not relevant for predicting potential
immunogenicity in humans.
The toxicokinetics, pharmacodynamics, and potential toxicity
of MEDI3549, a novel human anti-Ang2-TNFa bispecific
antibody were evaluated in a GLP cynomolgus monkey
study. Animals were administered a single loading dose
intravenous infusion of MEDI3549 to avoid immunogenicity,
followed by subcutaneous injections, twice per week, at
18, 30, or 75 mg/kg for 13-weeks with a 12-week recovery
period. All but 3 animals in the low dose group maintained
exposure to MEDI3549 following 13 weeks of dosing. AntiDrug antibodies led to loss of exposure in these animals.
Administration of MEDI3549 did not result in any clinical
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P506
Leveraging Early Pharmacology Studies to Learn About
Relevant Safety Characteristics During Early Drug Discovery
—A Case Study.
S. Mohr1, A. Herrmann1, S. Kustermann1, R. Jagasia1, J.
Wichmann1, T. Singer1. Roche Innovation Center Basel, Basel,
Switzerland1
P507
Repeat Dose Toxicity Studies of 3-Bromopyruvate in Dogs
Following Intrahepatic Artery and Intraperitoneal Infusion.
C.S. Godin1, K.E. Engelke1, J.F. Geschwind2. 1Smithers Avanza,
Gaithersburg, MD, USA, 2Johns Hopkins University School of
Medicine, Baltimore, MD, USA
The anticancer efficacy of the pyruvate analog
3-bromopyruvate (3-BP) has been demonstrated in tumor
models, and has been shown to inhibit glyceraldehyde3-phosphate dehydrogenase resulting in a depletion of
intracellular ATP and cellular death. Thus, 3-BP may be a
potent and promising anticancer agent. Groups of dogs were
dosed during two 5-day intervals over 14 days. Each dose was
administered to the hepatic artery via a 2-hour infusion at 0,
0.25, 2.5 and 7.5 mg/kg/dose. Mortality occurred at doses of
7.5 mg/kg. Other test article-related effects included emesis,
decreased body weight and food consumption, elevated liver
enzymes and leukocytosis, macroscopic findings in the liver
and lymph nodes, and microscopic changes in the hepatic
artery, bile duct, peritoneum, lymph nodes, liver, gallbladder
and mesentery. The no-observed-adverse-effect level (NOAEL)
is less than 0.25 mg/kg/dose and the highest nonseverely
toxic dose (HNSTD) is <2.5 mg/kg/dose. In a separate study,
groups of dogs were dosed for 21 consecutive days via a
2-hour intraperitoneal infusion at doses of 0, 0.25, 2.5 and 5
mg/kg. No mortality occurred, and test article-related emesis,
decreased body weight and food consumption, decreased RBC
count, hematocrit, and hemoglobin, increased serum chloride,
and macroscopic and microscopic findings at the infusion
site, lymph nodes and peritoneum were noted. The NOAEL
is < 0.25 mg/kg/dose based on the microscopic changes in
the peritoneum (deposition of fibrin and fibrosis along with
inflammatory cells and hemorrhage) of all treated groups, and
the HNSTD is 2.5 mg/kg/dose.
P508
Two Tales: ADA-Mediated Toxicities in Mice and Monkeys
Treated with a Therapeutic Monoclonal Antibody.
J. Wheeler1, C. Thompson1, S. Eble1, D. Devona1, B. Wang1,
R. Li1, G. Rao1, S. Clark2, B. Philip2, T. Bunch2, H. Haggerty1, F.
Burleson3, W. Freebern1. 1Bristol-Myers Squibb, New Brunswick, NJ,
USA, 2Bristol-Myers Squibb, Mt. Vernon, IN, USA, 3Burleson Research
Technologies, Inc., Morrisville, NC, USA
During preclinical safety evaluation, apparent anti-drug
antibody (ADA)-mediated toxicities were observed in mice
and monkeys intravenously administered mAbX at 0, 10 or150
mg/kg weekly. Mice were found dead or moribund within 3
hours after repeated doses of 10 mg/kg mAbX, with the timing
of mortality indicative of ADA-mediated hypersensitivity
reactions. An investigative study was performed, with
continual observations following dosing, cohorts for scheduled
necropsies following the 3rd weekly dose, and analyses
including ADA, complement, mast cell protease-1, histamine,
bradykinin, tryptase, serotonin, and circulating immune
complexes. Mortality was reproduced in the 10 mg/kg group,
with morbidity occurring within 30 minutes after repeated
doses. A striking correlation between ADA responses and
incidence of clinical observations and mortality was observed,
although no correlations with tested chemical mediators were
found. These findings suggest that responses did not involve
IgE-mediated mast cell degranulation, further supporting an
IgG1 ADA-mediated hypersensitivity. ADA-mediated toxicities
were also observed in cynomolgus monkeys administered
mAbX. Two of 6 monkeys dosed at150 mg/kg had decreased
platelets following the second dose, with 1 euthanized on
Day 25 to further investigate concomitant decreases in food
consumption and body weight. These monkeys had the highest
ADA levels, and flow cytometric and immunohistochemical
analyses demonstrated mAbX/ADA complexes on platelets
and in spleen (germinal center lymphocytes and macrophages)
supporting that platelet decreases were likely due to mAbX/
ADA complex-platelet bound mediated splenic clearance. In
conclusion, these two ‘tales' highlight investigations used to
confirm toxicities in preclinical studies were ADA-mediated
and not direct effects of the mAb.
95 ABSTRACTS
Roche was able to significantly reduce the safety-related
attrition of selected clinical leads over the last couple of
years through safety representation at earlier phases of drug
discovery. Compound failure could be significantly reduced
by identifying potential target-related safety liabilities early on
via a thorough safety target assessment and the generation
of more predictive safety data. The importance of an early
safety assessment will be discussed using an innovative
project as case example. There is accumulating evidence that
neurogenesis in the adult hippocampus contributes to brain
physiology and disease. We developed a human embryonic
stem cell-derived neural precursor cell model for phenotypic
screening of compounds with neurogenic properties to
then translate into in vivo models of disease. from the start, a
tailor-made safety strategy was developed to optimize safety
and efficacy in tandem. In early pharmacology studies the
brain was used to evaluate efficacy based on hippocampal
neurogenesis while the peripheral organs were collected to
assess safety. The team identified molecules with excellent
properties in efficacy at the cellular and behavioral level.
But this came with the price of safety liabilities in form of
multi-organ tissue proliferation. from the start, the project
team realized safety would play a vital role and the project
was intensively supported by early and mechanistic safety,
ADME and discovery pathology. Moreover, the early project
toxicology leader was not only team member, but also sharing
project leadership equally with the chemistry and biologist
leader. Ultimately, this approach allowed implementing safety
readouts very early during drug discovery.
2014
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P509
An Approach to Assess the Potential Reproductive and
Developmental Toxicity of Anti-rHuPH20 Antibodies that are
Cross-Reactive to Species-Specific PH20 in the Mouse and
Rabbit.
R. Veneziale1, M. A. Printz1, F. Araiza1, J. Bahn1, B. J. Sugarman1,
B. Dietrich2, A. M. Hoberman3, J. A. Cavagnaro4, G. I. Frost1, F.
Drake1, D. C. Maneval1, P. J. Lapinskas1. 1Halozyme Therapeutics,
Inc., San Diego, CA, USA, Baxter Innovations GmbH, Vienna, Austria,
3
Charles River Laboratories Preclinical Services, Horsham, PA, USA,
4
Access BIO, Boyce, VA, USA, 5Intrexon Corporation, San Diego,
CA, USA
ABSTRACTS
2
Regulatory guidances do not currently provide specific
advice on assessing the potential safety risk of antibodies to
therapeutic proteins that have an endogenous counterpart.
A recombinant human PH20, rHuPH20, is used clinically to
facilitate the subcutaneous absorption of fluids and drugs
by rapid and transient degradation of hyaluronan in the
skin. PH20 is known to be expressed only in the adult male
reproductive tract on sperm, where it plays a nonessential
role in fertilization by aiding in the penetration of the sperm
through the hyaluronan-rich cumulus layer of the oocyte.
Recently, a single reference reported PH20 expression in
the central nervous system (CNS). Therefore anti-rHuPH20
antibodies may theoretically impact offspring fertility and
neurological development, if PH20 expression is confirmed
in CNS. In a pre/postnatal developmental toxicity study
of rHuPH20, conducted in mice, anti-rHuPH20 antibodies
were characterized and the potential impact on offspring
neurobehavioral development and fertility was evaluated.
Dedicated studies with anti-rHuPH20 antibodies were also
conducted in the rabbit to evaluate adult fertility, embryo-fetal
development, and postnatal development through adulthood
and mating. Anti-rHuPH20 antibodies generated in these
nonclinical species were cross-reactive to the species-specific
PH20 and could also cross-neutralize the PH20 hyaluronidase
activity in the rabbit. These studies did not detect any impact
of anti-PH20 antibodies on reproduction or development
including: adult fertility, embryo-fetal development or
offspring growth, neurological development or fertility. Life
cycle evaluations in both rodent and nonrodent species that
generate cross-react antibodies, provides a comprehensive
assessment of the potential effects of anti-therapeutic
antibodies on an endogenous protein.
2014
P510
Antibodies Generated to Recombinant Human PH20
Hyaluronidase, rHuPH20, Do Not Impact Fertility in Multiple
Species.
R. Veneziale1, M. A. Printz1, F. Araiza1, J. Bahn1, B. J. Sugarman1,
B. Dietrich2, A. M. Hoberman3, J. A. Cavagnaro4, G. I. Frost5, F.
Drake1, D. C. Maneval1, P. J. Lapinskas1. 1Halozyme Therapeutics,
Inc., San Diego, CA, USA, 2Baxter Innovations GmbH, Vienna, Austria,
3
Charles River Laboratories Preclinical Services, Horsham, PA, USA,
4
Access BIO, Boyce, VA, USA, 5Intrexon Corporation, San Diego,
CA, USA
The recombinant human PH20 hyaluronidase, rHuPH20,
is used clinically to facilitate the subcutaneous absorption
of fluids and drugs by rapid and transient degradation of
hyaluronan in the extracellular matrix of the skin. Endogenous
PH20, expressed in the adult male reproductive tract and
localized to the sperm membrane, plays a nonessential role in
fertilization by aiding in the penetration of the sperm through
the hyaluronan-rich cumulus layer of the oocyte. As a result
of PH20's role in fertilization, it was proposed as a target for
development of an immunocontraceptive vaccine; however,
this vaccine approach failed to impact fertility in mouse,
rabbit, monkey, and sheep, though reversible infertility was
observed in the guinea pig. Thus, a theoretical risk exists that
anti-rHuPH20 antibodies could bind sperm and impact fertility.
Nonclinical safety assessments of anti-rHuPH20 antibodies on
fertility were performed in a chronic monkey toxicity study,
fertility studies in male and female rabbits and in the postnatal
phases of reproductive toxicity studies in mouse and rabbit
offspring. Anti-rHuPH20 antibodies generated in nonclinical
species were cross-reactive to the species-specific PH20. In
monkeys and rabbits, these antibodies could cross-neutralize
the species-specific PH20 hyaluronidase activity. Anti-rHuPH20
antibodies had no effect on adult male or female fertility or on
the fertility of offspring exposed throughout development.
Our approach provides a comprehensive assessment of the
potential for effects of antibodies to a sperm antigen on
fertility and is consistent with the prevailing concept that
antibody responses to multiple sperm antigens are required
to impact fertilization.
P511
Pharmacokinetics and Metabolite Profile of Diclofenac and
Lumiracoxib in Mice.
C. E. Wilson1, K. Schreiter2, R. Wehr2, R. J. Riley1, A. Lewis1, A. P.
Dickie1, I. D. Wilson3. 1Evotec (UK) Ltd, Abingdon, UK, 2Evotec AG,
Göttingen, Germany, 3Imperial College, London, UK
Diclofenac and lumiracoxib are nonsteroidal anti-inflammatory
drugs (NSAIDs) taken or applied to reduce inflammation and
as an analgesic reducing pain in certain conditions. Both have
been associated with adverse drug reactions involving drug
induced liver injury (DILI). Diclofenac was first introduced in
the UK in 1979 and despite the potential for DILI is available
as a generic drug in a number of formulations. Lumiracoxib
is manufactured by Novartis, and whilst it was withdrawn
from many markets as a direct result of DILI, it is still available
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P512
Preclinical Safety Assessment of a Bile Acid Receptor Agonist
Intended for the Treatment of Type 2 Diabetes.
J. Horvath1, T. Dorr1, C. Hixson1, R. Mangipudy1, E. Dierks2,
K. Foster2, M. Orsini2, J. Smalley2, Q. Sun2, L. Buchanan2, J.
Li2, J. Panzica2, J. MacGuire3. 1Bristol-Myers Squibb Drug Safety
Evaluation, New Brunswick, NJ, USA, 2Bristol-Myers Squibb R&D
Discovery, Princeton and Hopewell, NJ, USA, 3Bristol-Myers Squibb
Veterinary Sciences, Hopewell, NJ, USA
Agonism of the G-protein-coupled bile acid receptor 1
(GPBAR1/TGR5) promotes GLP-1 secretion and was proposed
as a mechanism for the treatment of type 2 diabetes. BMSTGR5-A, a TGR5 agonist, was evaluated for nonclinical safety.
Mice given BMS-TGR5-A orally (2 weeks) had gallbladder
distension (a pharmacologically-mediated effect) and
minimal vacuolation of gallbladder epithelium (nonadverse)
whereas dogs developed marked hyperplasia/hypertrophy
of the walls of the extrahepatic bile ducts and gallbladder (no
NOAEL established) and at high doses, periductular edema/
fibrosis in the larger bile ducts in the liver and pancreatic
ducts. Additionally, cardiovascular (CV) safety studies in
these species showed significant increases in heart rate
and decreases in blood pressure (BP). To determine if these
effects were target-based, an investigative approach was
developed to evaluate BMS-TGR5-A with other TGR5 agonists
(> potency to BMS-TGR5-A but of different chemotypes).
Daily doses of BMS-TGR5-A and BMS-TGR5-B given to dogs
resulted in gallbladder concentrations of BMS-TGR5-B > BMSTGR5-A and no gallbladder pathology was observed with
BMS-TGR5-B. Following high single doses of BMS-TGR5-C
(chemotype with increased systemic bioavailability), TGR5
knock-out mice maintained normal sinus rhythm and BP
whereas wildtype controls had similar CV effects as noted
previously. TGR5 expression (qPCR) in gallbladder and heart
was also established. These results demonstrate that BMSTGR5-A-associated gallbladder toxicity was likely independent
of TGR5 whereas CV changes were likely a pharmacologic
TGR5-based class effect. Overall, the preclinical studies on
TGR5 agonists demonstrated the potential of TGR5 agonism
to treat type 2 diabetes, but also identified a specific risk of
pharmacologically-mediated hemodynamic changes.
P513
Measuring T-Cell Dependent and Independent Antibody
Responses (TDAR/TIAR) in the Cynomolgus Monkey:
Abatacept (CTLA4-Ig) and Methotrexate Lead to
Immunosuppression in a TDAR but not TIAR Response.
G. Bannish1, M. Perpetua1, T. Ziegelhofer1, A. Curran1, L.
Coney2. 1Huntingdon Life Sciences, East Millstone, NJ, USA,
Huntingdon Life Sciences, Huntingdon, Cambridgeshire, UK
2
The TDAR response is used to evaluate drug effects on the
immune system, assessing antigen presentation and T and
B lymphocyte function. Cynomolgus monkeys were injected
intradermally with 100 ug Keyhole Limpet Hemocyanin (KLH)
in the absence of adjuvant, injected subcutaneously with 6
limit of flocculation (LFU) of tetanus toxoid (TT), or injected
intravenously with 25 ug DNP-LPS. Animals were boosted
after approximately 2 months, and sera was collected twice
weekly to evaluate antibody responses. Animals developed
a detectable IgM response with mean inverse titers of 60,000
ten days following primary immunization. IgG responses were
detectable 14 days post primary injection with inverse titers of
66,000 and 7 days post secondary challenge with inverse titers
of over 316,000. Treatment of a cohort of these animals with
Abatacept led to a near elimination of antibody responses.
Antibody responses to KLH were reduced but not ablated
when treated with 1 mg/kg methotrexate via subcutaneous
injection. Maximal mean IgM responses to KLH 10 days
following primary immunization were reduced from 60,000 to
8,300. Maximal mean IgG responses to KLH were reduced from
316,000 to 191,000 with maximal responses delayed from
7 to 10 days post secondary KLH challenge. TIAR responses
were observed following treatment with the T-independent
antigen type 1 (Ti-1) DNP-LPS, with average inverse titers
of 26,000. Neither Methotrexate nor Abatacept treatment
reduced the magnitude of response, consistent with the lack
of need for T cell help.
97 ABSTRACTS
in a few countries, including Mexico, Ecuador and the
Dominican Republic. Given the need for reduced attrition in
drug development caused by DILI there is a need to develop
more predictive models of metabolism and toxicity including
both in vitro and in vivo model systems. One such in vivo
model is represented by the recently introduced "chimeric"
humanized mice, where human hepatocytes can replace up
to 90+% of the murine hepatocytes. Prior to studies in this
mouse model to investigate how well such mice recapitulate
the human metabolism for diclofenac and lumarocoxib it
was necessary to fully characterize the biotransformation of
these compounds in normal mice. The pharmacokinetics (PK)
and metabolite profile of diclofenac and lumiracoxib were
therefore investigated over 24h following the administration
of 10 mg/kg oral doses to male C57Bl/6 mice (n=3/compound).
The pharmacokinetics and metabolite profiling will form the
basis for further work using chimeric humanised and chimeric
murinised mice (FRG KO/c57Bl6 ; Yecuris, USA).
2014
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Annual Meeting
P514
Two-Year Oral Carcinogenicity Study of Udenafil, a Potent
Novel Phosphodiesterase-5 Inhibitor in B6C3F1 Mice.
K.S. Moon1, Y.B. Kim1, K.K. Kang2, E. J. Jeong1. 1Korea Institution of
ABSTRACTS
Toxicology, Daejeon, Republic of Korea, 2Dong-A ST Pharmaceutical
Company, Yong-In, Republic of Korea
Udenafil is a new PDE5 inhibitor that has been approved in
South Korea for the treatment of erectile dysfunction (ED).
As a part of safety evaluation program for human use, a twoyear oral carcinogenicity study was conducted to investigate a
tumoriogenic potential of Udenafil in mice. The test article was
given orally to male and female B6C3F1 mice (60 animals/sex/
group) once daily for at least 104 weeks at dose levels of 0, 30,
100/150 and 300/500 mg/kg for males, and 0, 50, 150 and 500
mg/kg for females. There were no test article-related changes
on survival rates, clinical signs, ophthalmology, and bone
marrow smear examination in either sex of any treated groups.
In addition, transient changes in body weights and food intake
were observed in males at 300/500 mg/kg/day and in females
at 500 mg/kg/day throughout the study. In microscopic
examination, there were no test article-related non-neoplastic
or neoplastic findings in all treatment groups. Therefore, it was
determined that there was no evidence of carcinogenicity of
the Udenafil, based on the incidence of benign and malignant
tumors in the study and the no-observed-adverse-effect level
(NOAEL) was considered to be 500 mg/kg/day.
P515
Gamma-Secretase Inhibitor BMS-708163 (avagacestat)
Decreases Beta Amyloid Levels in Brain and Cerebrospinal
Fluid in the APPSWE 2576 Hemizygous and Wild Type Mice.
C. Korgaonkar1, G. Pilcher1, V. Guss2, G. Cadelina2, J. Meredith2,
H. Gu3, B. Wang4, R. Bunch1, T. Sanderson1. 1Bristol-Myers Squibb
Company, Mt. Vernon, IN, USA, 2Bristol-Myers Squibb Company,
Wallingford, CT, USA, 3Bristol-Myers Squibb Company, Lawrenceville,
NJ, USA, 4Bristol-Myers Squibb Company, New Brunswick, NJ, USA
BMS-708163 (avagacestat), a gamma secretase inhibitor, was
evaluated in a transgenic mouse model that overexpresses
human Amyloid Precursor Protein (APP) and is used to study
amyloid lowering and microhemorrhage potential in the
brain. Avagacestat was dosed orally to B6;SJL Tg(APPSWE)2576
hemizygous mice (Tg2576) and wild type mice (Wt2576)
at 0, 100 or 300 mg/kg/day for 2 weeks to evaluate its
pharmacokinetic profile; plasma and brain concentrations of
avagacestat and its weakly active metabolite, BMS 737622; and
Aβ peptide (Aβ40 and Aβ42) levels in brain and cerebrospinal
fluid (CSF). The CSF and brain samples were collected at 5 and
10 hours post dose on Day 14. Plasma avagacestat AUC values
generally increased dose proportionally in Wt2576 mice. Mean
avagacestat plasma concentrations at 5 and 10 hours post dose
were similar for both strains. Brain (cerebellum) and plasma
avagacestat and BMS-737622 concentrations increased in a
dose-related manner with generally similar mean cerebellum/
plasma concentration ratios over time, across doses, and
between mouse strains. At 5 hours post dose, dose-dependent
decreases in brain Aβ40 levels relative to controls were noted
2014
in Tg2576 (up to 80%) and Wt2576 (up to 50%) mice. In Tg2576
mice, dose-dependent decreases in Aβ40 and Aβ42 levels in
CSF (up to 100%) relative to control were noted. Overall, brain
Aβ40 and Aβ42 reductions were higher in the Tg2576 mice
compared to the Wt2576 controls. Collectively, these data
confirmed that avagacestat was pharmacologically active in
Wt2576 and Tg2576 mice at doses that may be useful for the
evaluation of brain microhemorrhage potential.
P516
Biotherapeutics and Immune Reactions: What are the
Incidences and the Endpoints that Support an Immune
Response?
A. Prefontaine1, L. Bernier1. Charles River, Senneville, Quebec,
Canada1
Biotherapeutics are recognized to present a risk of eliciting
immune responses in nonclinical models and responses
range from the simple presence of antibodies to clinically
expressed adverse events. These immune reactions can
confound interpretation of test article toxicities and it is
therefore important to characterize the immune reactions in
these studies in order to support the occurrence of an immune
reaction. A review of historical data for studies conducted
with biotherapeutics in our facilities was performed with
respect to the incidences of positive ADA, clinical signs and
pathology findings in different species. Moreover, a summary
of investigations performed to demonstrate that the adverse
events were caused by an immune reaction was assessed
in order to define which endpoints provided supportive
evidence. Clinical signs indicative of an immune reaction were
observed in approximately 28% of studies where positive
ADAs were noted and ranged from nonadverse redness/
swelling of extremities (27%) to adverse respiratory effects
and/or death (73%). Four out of ten studies with adverse
reactions required additional investigative studies to further
demonstrate that the findings were caused by an immune
reaction. For these investigative studies, cytokines release,
complement factor and/or immunohistochemistry/immunocomplex assays were performed. Given the incidence in our
facilities of adverse immune reaction and investigative studies,
we consider that the addition of cytokine, complement factor,
or immunohistochemistry/immuno-complex to study designs
helps distinguish between compound toxicity from speciesspecific secondary immune reaction.
98 th
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Annual Meeting
P517
Simvastatin and Dipentyl Phthalate Display Different Modes
of Action but Exhibit Dose Additive Effects on Fetal Testicular
Testosterone Production in Sprague-Dawley Rats.
B. Beverly1, C. Lambright1, J. Furr1, H. Sampson1, G. Travlos2, P.
Foster2, B. McIntyre2, V. Wilson1, L. E. Gray Jr.1. 1US Environmental
Protection Agency, Research Triangle Park, NC, USA, 2National
Institute of Environmental Health Sciences, Research Triangle Park,
NC, USA
Abstract does not reflect the views of the EPA.
P518
Stem Cells and Regeneration of Toxic Liver Fibrosis.
A. F. Tohamy2, H. M.E. Imam1, A. F. Tohamy2, H. M.
Rezk3. 1Anatomy and Embryology Department, Faculty of Veterinary
Medicine Suez Canal University, Ismaillia, Egypt, 2Department of
Toxicology and Forensic Medicine, Faculty of Veterinary Medicine,
Cairo University, Giza, Egypt, 3Anatomy and Embryology Department,
Faculty of Veterinary Medicine Cairo University, Giza, Egypt
Aims: To investigate the potential therapeutic effect of
hUCMSCs on CCl4-induced induced liver fibrosis in rats.
Methods: Ninety adult female rats were used in this study,
sixty of them were injected with CCl4 (0.5ml/kg) to induce
liver fibrosis. hUCMSCs (CD34, CD45 and CD105) separated by
MiniMACS Separator and cultured for 14 days; then infused
into the rats' tail vein (1×106 cells/rat) after 72 h of the last CCl4
dose. Rats were divided into 4 groups (15 rats/each): control,
CCl4, CCl4 & hUCMSCs, and hUCMSCs. After 6th and 8th weeks
of treatment, blood samples were collected to assess liver
functions (ALT, AST, GGT and ALB) and level of Procollagen
III. Histopathological and immunohistochemical assessment
of liver were conducted using anti-human monoclonal
antibodies against CD34, CK19 and albumin.
Results: Antifibrotic effect of hUMSCs evidenced by a
significant decrease in (AST, ALT, GGT and liver Procollagen III
levels) and significant increase of serum albumin level in the
treated groups compared to CCl4 group at both 6th and 8th
weeks of therapy. Pathological findings revealed significant
increase in normal liver function in stem cell treated groups
compared to CCl4 group while there was no significant
difference between treated groups at the 6th and 8th weeks
post-therapy. Immunohistochemistry finding indicates
homing and differentiation of hUMSCs in the rats' liver and
expression of albumin.
Conclusion: Our findings indicate transplantation of hUCMSCs
may be a novel therapeutic approach for treating liver fibrosis.
Key Words: CCl4, liver fibrosis, mesenchymal stem cells and rat
STP519
Effects of Inflammation on Nilutamide-Induced Liver Injury.
A. Al Maruf1, P. O'Brien1. University of Toronto, Toronto, Canada1
Nilutamide (NIL) is used in the treatment of metastatic prostatic
carcinoma in association with castration. Its therapeutic use is
overshadowed by the rare development of hepatotoxicity that
occurs in approximately 0.5 to 1 % of patients. The mechanism
of NIL-induced hepatotoxicity is still unknown. Inflammation
caused by infections or endotoxins could activate NADPH
oxidase, which produces hydrogen peroxide (H2O2) and other
reactive oxygen species (ROS) and thus causing oxidative
stress. The potential molecular cytotoxic mechanisms of NIL
towards isolated rat hepatocytes were investigated in this
study using an in vitro oxidative stress inflammation model.
A significant increase in NIL-induced (400 µM) cytotoxicity,
ROS and H2O2 formation, and a decrease in mitochondrial
membrane potential (% MMP) was observed when
glutathione (GSH)-depleted hepatocytes were used and this
toxicity was decreased by the addition of N-acetylcysteine (a
GSH precursor). Catalase-inhibited hepatocytes also increased
NIL-induced cytotoxicity, while the direct addition of catalase
to the hepatocytes delayed cytotoxicity. When a nontoxic H2O2
generating system (glucose/glucose oxidase) with peroxidase
or Fe(II) (to simulate in vivo inflammation) were added to the
hepatocytes prior to the addition of NIL, an increase in NILinduced cytotoxicity, ROS formation and a decrease in % MMP
were observed that were reversed by 6-N-propyl-2-thiouracil
(a peroxidase inhibitor) or desferoxamine (an iron chelator),
respectively. Potent antioxidants, resveratrol (a polyphenolic
compound), and trolox (the water-soluble vitamin E
analogue) significantly decreased NIL-induced cytotoxicity,
ROS formation, and increased % MMP. These results raise the
possibility that inflammation may be another susceptibility
factor for drug-induced liver injury.
99 ABSTRACTS
Sex differentiation of the mammalian male reproductive tract
is driven, in part, by fetal androgen production. In utero, some
phthalate esters (PEs) alter fetal Leydig cell differentiation,
reducing the expression of genes associated with steroid
synthesis/transport, and consequently, lowering fetal
androgen levels. Simvastatin (SMV) is a cholesterol-lowering
drug that inhibits HMG-CoA reductase in the cholesterol
pathway. As cholesterol is a precursor of steroid hormone
biosynthesis, we hypothesized that in utero exposure to SMV
during the critical period of sex differentiation would lower fetal
testosterone (T) production without affecting genes involved
in cholesterol and androgen synthesis/transport. Secondly, we
hypothesized that a mixture of SMV and a PE would reduce
testosterone levels in an additive manner. Pregnant Sprague
Dawley rats were dosed orally with 0, 15.6, 31.25, or 62.5 mg/
kg/day SMV from gestational days (GD) 14-18, and fetuses
were evaluated on GD18. On GD18, fetal T and serum lipids
were reduced with increasing doses of simvastatin. Further,
PEs downregulate several genes in the fetal testes that were
unaffected by SMV treatment. Individual administration of
SMV (62.5 mg/kg/day) and DPeP (50 mg/kg/day) reduced
fetal T by 44% and 37% of control, respectively (p < 0.0001
versus control). When administered as a mixture, SMV and
DPeP reduced fetal T in an additive manner (19% of control; p
< 0.0001 versus control, SMV, and DPeP), demonstrating that
a mixture of chemicals can induce additive effects on fetal T
even though they display different modes of action.
2014
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American
Annual Meeting
STP520
Cognitive Effects of Simvastatin in the Rat
D. Miller1, M. B. Genter1. University of Cincinnati Department of
ABSTRACTS
Environmental Health, Cincinnati, OH, USA1
Statins are widely prescribed drugs primarily used to lower
cholesterol and decrease the risk of cardiovascular disease.
These drugs are generally well-tolerated; however there are
reports of patients developing confusion and memory loss,
which appear to be caused by statins. These reports were
considered significant enough for the US FDA to update the
warning label of all statins in 2012 to include the potential
for negative cognitive side effects. Interestingly, there are
also numerous reports regarding the neuroprotective
effects of statins in conditions such as stroke, subarachnoid
hemorrhage, multiple sclerosis, Alzheimer's and other
neurodegenerative diseases. There is considerable controversy
in the literature surrounding these contradictory effects. Given
the growing rate of cardiovascular disease in the population,
as well as the potential of statins to be used as treatment
in neurological illness and injury, the need arises to better
understand the mechanisms of action of statins in the brain.
We have completed a pilot study investigating the effects
of simvastatin demonstrating memory impairment in rats
in both the Barnes maze and novel object recognition tests.
These data will guide future experiments in which behavioral
assessments will be conducted, and gene expression changes
will be determined at the time that behavioral effects,
whether adverse or beneficial, are observed. Our findings
may eventually provide a further screen in drug development
to avoid negative cognitive effects as the next generation of
statins are developed, or identify target pathways to allow
optimization of existing statins to increase their effectiveness
in the treatment of neurological illness.
100 2014
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101 th
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Annual Meeting
2014
Author Index
Poster abstracts are indicated with letters preceding the poster number: Poster (P), Student Travel Award (STP), North American
Graduate Fellowship (GFP), and International Travel Grant (IGP).
ABSTRACTS
A
A Siddiqui, A.............................................P500
Aardema, M..................................P310, P418
Abtout, S....................................................P411
Acali, S........................................................P303
Acosta, O.C........................................... IGP115
Albers, T......................................................P416
Althouse, G...............................................P403
Ancerewicz, J............................................P312
Apgar, J.......................................................P112
Apreutese, A.....................P110, P110, P111
Araiza, F..........................................P509, P510
Arlund, E....................................................P434
Ascah, A......................................................P414
Attalla, B.....................................................P428
Auletta, C...................................................P412
Authier, S..........................P411, P413, P414,
.................................................. P415, P422
Avlasevich, S.................................P310, P432
Ayehunie, S...............................................P405
B
Bahn, J............................................P509, P510
Baker, J........................................................P416
Bannish, G.................................................P513
Barnhart, K................................................P201
Bassett, L............................P413, P414, P415
Beck, M.......................................................P402
Beck, T.............................................P408, P409
Belich, J.......................................................P433
Bemis, J.......................................................P432
Benoit-Biancamano, M.O.........P110, P111
Benz, R. D...................................................P204
Bernier, L........................................P434, P516
Beverly, B...................................................P517
Bhusari, S...................................................P313
Blechinger, S.............................................P401
Bonnette, K...............................................P109
Borders, R. B. R.........................................P427
Bouchard, G..........P103, P104, P400, P425
Boue, S........................................................P305
Bourgeois, R..............................................P424
Bradley, J....................................................P435
Brandt, C....................................................P400
Brocksmith, D...............................P104, P425
Brown, A.....................................................P207
Brown, L.............................P103, P400, P425
Bruening-Wright, A................................P207
Bruning, D.....................................P310, P418
Bryant, K.....................................................P424
Bryce, S.......................................................P432
Buchanan, R..............................................P206
Buchanan, L..............................................P512
Bunch, T......................................................P508
Bunch, R.....................................................P515
Burke, J.......................................................P112
Burleson, F.................................................P508
C
Cabanski, M..................................P305, P309
Cabral, L.M. ..............................................P107
Cadelina, G................................................P515
Calvano, J...................................................P407
Cannon, K..................................................P404
Castaneda, J........................................ GFP117
Castro, C.....................................................P306
Castro, H. C................................................P107
Cavagnaro, J. A............................P509, P510
Chakravarti, S...........................................P202
Chen, R.......................................................P106
Chen, T........................................................P306
Chen, J.T. J.................................................P315
Chen, M......................................................P410
Chen, X.......................................................P504
Chow, V.......................................................P503
Christin-Piché, M.S.................................P424
Chung, S.P..................................................P502
Churi, S.......................................................P113
Clark, S........................................................P508
Claudia, F...................................................P420
Cole, T..........................................................P201
Collins, N....................................................P429
Coney, L......................................................P513
Connor, J....................................................P504
Costa, S.................................................. IGP319
102 Criste, R.......................................................P505
Cross, K...........................................P204, P205
Cucullo, L.............................STP438, STP439
Curran, A....................................................P513
D
Dambach, D..............................................P118
De Leon, H.....................................P305, P311
DeGeorge, G.................................P405, P406
Del Favero, G....................................... IGP441
Delaney, L..................................................P103
Dertinger, S...................................P310, P432
Devona, D..................................................P508
Dhakal, D.............................................. IGP320
Dhakal, R. R.......................................... IGP320
Dickie, A.....................................................P511
Dierks, E......................................................P512
Dietrich, B......................................P509, P510
Dimasi, N....................................................P504
Dinesdurage, H............................P310, P418
DiPiero, J....................................................P407
Dixit, R.........................................................P505
Dorko, K.....................................................P428
Dorr, T..........................................................P512
Doudement, E..........................................P118
Dougherty, M...........................................P416
Douville, J..................................................P420
Drake, F...........................................P509, P510
Dulize, R.....................................................P309
Dumais, A..................................................P423
Dumont, C.................................................P424
E
Early, R........................................................P410
Eble, S.........................................................P508
Eichinger-Chapelon, A..........................P200
El-Fazaa, S..................................................P300
Elamin, A....................................................P309
Elbekai, R.......................................P418, P433
Elliott, M.....................................................P416
Emond, F....................................................P420
Engelke, K.E..............................................P507
Engwall, M.................................................P503
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Everds, N....................................................P503
F
G
García-Léston, J.................................. IGP319
Gardner, A.................................................P315
Gareau, K...................................................P435
Garg, R........................................................P201
Gendron, R.M...........................................P419
Genter, M.B.........................STP437, STP520
Georges, G.P..............................................P104
Gerrish, K...................................................P313
Geschwind, J.F..........................................P507
Gharbi, N....................................................P300
Glaza, S...........................................P408, P409
Godin, C.S..................................................P507
Godwin, H............................................STP436
Gong, B.......................................................P306
Gonzalez Suarez, I..................................P303
Gordon, C......................................P110, P111
Goudreau, J.L..................................... GFP118
Goyal, S..................................................STP317
H
Hager, C......................................................P200
Haggerty, H...............................................P508
Haile, S........................................................P431
Hamblett, K...............................................P503
Hanks, C.............................P103, P400, P425
Hanzlik, R...................................................P104
Harui, A................................................. GFP117
Haruna, J........................................P110, P111
Hayden, P...................................................P405
Haziza, C.....................................................P312
Herrmann, A.............................................P506
Hill, J............................................................P503
Hixon, C..............................P407, P512, P510
Hoberman, A. M......................................P510
Hobson, D..................................................P104
Hoenerhoff, M..........................................P313
Hoeng, J............................P303, P305, P308,
...........................P309, P311, P312, P417
Honor, D.....................................................P201
Hooker, B...................................................P201
Horvath, J..................................................P512
Hsieh, H.................................................STP437
Huang, T.S..................................................P315
Huang, J.W................................................P315
Husain, A....................................................P500
I
Imam, H. M.E............................................P518
Ingerson, A................................................P103
Iskandar, A.....................................P305, P309
Ivanov, N....................................................P305
Ivask, A..................................................STP436
Iverson, W..................................................P504
103 J
Jaeschke, H...............................................P428
Jagasia, R...................................................P506
Jasmin, B....................................................P403
Jeong, E.J.......................................P314, P514
Johne, S......................................................P303
Jones, T.......................................................P412
Joo, Y.S........................................................P502
Jun-Hsiang, L............................................P412
K
Kaisar, M. A..........................STP438, STP439
Kanaly, R.....................................................P426
Kang, KK.....................................................P514
Karanth, S..................................................P504
Kaufman, L................................................P206
Kauss, A......................................................P118
Kaweeteerawat, C..............................STP436
Kearney, K..................................................P427
Kiertscher, S........................................ GFP117
Kim, D..........................................................P425
Kim, YB........................................................P514
Kogel, U......................................................P308
Kopf, R.........................................................P200
Korgaonkar, C..........................................P515
Kostadinova, R.........................................P309
Kramer, J....................................................P207
Kretser, A....................................................P302
Krishan, M..................................................P302
Kruhlak, N..................................................P205
Kuczaj, A.....................................................P417
Kuehn, D....................................................P309
Kulkarni, R.................................................P310
Kumer, SC..................................................P428
Kustermann, S..........................................P506
Kwok, S.......................................................P421
L
Laffon, B................................................ IGP319
Lalayeva, N................................................P409
Lambright, C.............................................P517
Lansdell, T............................................ GFP118
Lanzicher, T.......................................... IGP441
Lapinskas, P. J...............................P509, P510
ABSTRACTS
Faggioni, R................................................P504
Federov, N.................................................P207
Felx, M.........................................................P431
Festag, M...................................................P200
Fishbein, M...........................................STP318
Foote, A......................................................P404
Forget, J......................................................P434
Forster, R...........................P413, P414, P415,
...................................................P422, P423
Forster, J.....................................................P428
Fossa, A.......................................................P427
Fossey, S.....................................................P201
Foster, R..........................................P110, P111
Foster, K......................................................P512
Foster, P......................................................P517
Freebern, W...............................................P508
Freeman, M...............................................P103
Frentzel, S.........................P303, P308, P309,
...................................................P311, P417
Frost, G...........................................P509, P510
Fukuzaki, K....................................P408, P409
Furr, J...........................................................P517
Graff, C........................................................P201
Graham, A.....................................P110, P111
Grambo, B..................................................P403
Gray Jr., L. E...............................................P517
Groom, S........................................P422, P423
Gu, H............................................................P515
Guedj, E......................................................P309
Guss, V.........................................................P515
Guzman, R.................................................P503
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2014
ABSTRACTS
Laureano, R. T...........................................P429
Lavallée, S..................................................P424
Lawlor, T.........................................P310, P418
Learn, D......................................................P416
Lee, B.S........................................................P314
Lee, H.S.......................................................P502
Leroy, P........................................................P309
Lewis, A......................................................P511
Li, M.............................................................P105
Li, R..............................................................P508
Li, J...............................................................P512
Lin, Z............................................................P105
Lise, B..........................................................P420
Liu, J.........................P103, P104, P400, P425
Liu, R.......................................................STP436
Lo, A.............................................................P407
Lookingland, K.J................................ GFP118
Love, R............................................P408, P409
Luo, Y...........................................................P201
Lv, W.............................................................P410
M
MacGregor, J.............................................P432
MacGuire, J................................................P512
Madsen, T.......................................P104, P400
Maeda, A....................................................P426
Majeed, S.......................................P309, P417
Makori, N......................................P408 , P409
Maneval, D. C................................P509, P510
Mangipudy, R...............................P407, P512
Manning, R....................................P408, P409
Mansell, P...........................P419, P421, P428
Marcotte, E................................................P424
Marescotti, D............................................P303
Martin, F........................................P309 , P312
Martinelli, V.......................................... IGP441
Maruf, A.A.............................................STP519
Maruñak, S.L........................................ IGP115
Mathis, C............................P303, P308, P309
Matulka, M. R............................................P203
McGill, M. R...............................................P428
McIntyre, B................................................P517
McKeon, M....................................P310, P418
McPherson, S................................P108, P410
Mendonça, A.T. .......................................P107
Meghazzi, M. S.........................................P422
Meredith, J................................................P515
Merg, C.......................................................P309
Messinis, D. E............................................P308
Mestroni, L........................................... IGP441
Micheletto, R............................................P426
Mikkelsen, S. R.........................................P429
Miller, D.................................................STP520
Mishra, R....................................................P500
Misner, D....................................................P118
Mohr, N. S..................................................P506
Monteiro-Riviere, N................................P106
Moon, K.S......................................P314, P514
Moore, C............................................... GFP442
Morales, A..................................................P203
Morford, L..................................................P429
Morikawa, Y...............................................P306
Mornagui, B..............................................P300
Morse, M....................................................P109
Mundhe, A.................................................P301
Mura, F........................................................P206
Murphy, B..................................................P407
Musinipally, V...........................................P118
Myatt, G..........................................P204, P205
N
Nagata, R.......................................P408, P409
Naik, P....................................STP438, STP439
Navratil, N..................................................P403
Ngo, T..........................................................P118
Nicholson, S..............................................P504
Nordlund, M.............................................P417
O
O'Brien, P...............................................STP519
Obejero-Paz, C.........................................P207
Orsini, M.....................................................P512
P
Pai, R............................................................P118
Palate, B..........................................P110, P111
Pandiri, A...................................................P313
104 Pandit, S.....................................................P301
Panzica, J....................................................P512
Paranjpe, M...............................................P433
Park, S.J.......................................................P314
Peachee, V.................................................P402
Peddada, S................................................P313
Pei, H...........................................................P410
Peichoto, M.E....................................... IGP115
Peitsch, M.............P303, P305, P308, P309,
.......................................P311, P312, P417
Perpetua, M..............................................P513
Philip, B.......................................................P508
Phillips, B....................................................P305
Phonetapswath, S..................................P432
Piccotti, J....................................................P429
Piehl, M.......................................................P405
Pilcher, G....................................................P515
Polhamus, K..............................................P401
Porto, B.................................................. IGP319
Pouliot, M. M................................P413, P415
Poussin, C..................................................P308
Prasad, P................................................STP318
Prasad, S...............................STP438, STP439
Pratt, L.............................................P405, P406
Prefontaine, A..........................................P516
Printz, M. A....................................P509, P510
Puschner, B.......................................... GFP442
Q
Qiao, M.......................................................P315
Qin, S...........................................................P435
R
Ramani, T...................................................P412
Ramesh, M.................................................P113
Rana, S.V.S............................................ IGP116
Rana, K................................................... IGP116
Rao, G..........................................................P508
Rashid, M...................................................P500
Raut, S. K............................................... IGP320
Ravuri, K.....................................................P200
Rebelatto, M.............................................P505
Ren, T...........................................................P315
Ren, S..........................................................P505
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Saiakhov, R................................................P202
Sajja, R. .................................................STP438
Salerno, M. ...............................................P403
Sampson, H. .............................................P517
Sánchez, M.N. ..................................... IGP115
Sanderson, T.............................................P515
Santos, T.A.N.............................................P107
Santostefano, M......................................P503
Sarathchandra, G........................P101, P501
Sarron-Petit, C..........................................P200
Sasidharan, A. .........................................P106
Savidge, C..................................................P412
Sbaizero, O........................................... IGP441
Schlage, W. K............................................P309
Schlink, S....................................................P103
Schmitt, T. M.............................................P428
Schnapp, S................................................P425
Schreiter, K................................................P511
Sedykh, A...................................................P202
Selby, C.......................................................P104
Shakir, H.....................................................P316
Sharma, D..................................................P305
Sharma, S..............................................STP317
Shockley, K................................................P313
Sills, R..........................................................P313
Silva, S.................................................... IGP319
Singer, T......................................................P506
Singh, R. R.............................................STP318
Smalley, J...................................................P512
Smith, M.....................................................P402
Smith, S. Y..................................................P431
Snyder, C....................................................P118
St-Jacques, R.............................................P420
Stankowski, L...........................................P310
Stavitskaya, L............................................P205
Stoffel, R.....................................................P201
Stoute, M...................................................P423
Stricker-Krongrad, A.................P103, P104,
...................................................P400, P425
Strock, C.....................................................P435
Stump, D....................................................P402
Suarez, F.....................................................P307
Sugarman, B. J.............................P509, P510
Sun, Q..........................................................P512
T
Taberner, E.................................................P403
Talikka, M...................................................P312
Tavcar, R.........................................P422, P423
Teibler, G.P............................................ IGP115
Teixeira, J.P............................................ IGP319
Tellez Cruz, A............................................P103
The, T...........................................................P316
Thompson, C............................................P508
Tian, Y..........................................................P201
Tirmenstein, M.........................................P407
Tohamy, A. F..............................................P518
Tong, W.......................................................P306
Torous, D........................................P310, P432
Tovcimak, A...............................................P201
Travlos, G...................................................P517
Troese, M........................................P405, P406
Troncy, E.................P411, P413, P414, P415
Tyszkiewicz, C..........................................P404
U
Uehara, T....................................................P306
Ulm, S..........................................................P203
Uppal, H.....................................................P118
Upreti, V......................................................P503
V
Valera, I..................................................STP318
105 Valerio Jr., LG............................................P304
van der Toorn, M.....................................P311
Varela, A.....................................................P431
Vargas, H....................................................P503
Veljkovic, E................................................P305
Veneziale, R...................................P509, P510
Verma, Y................................................. IGP116
Verma, N...............................................STP317
Vézina, M...................................................P430
Vuillaume, G.............................................P309
W
Wang, Y.......................................................P306
Wang, B......................................... P508, P515
Wasko, M....................................................P206
Weese, J......................................................P315
Wehr, R........................................................P511
Wheeler, J..................................................P508
White, A......................................................P205
White, D..........................................P400, P425
White Jr., K.................................................P402
Whitney, K.................................................P201
Wichmann, J.............................................P506
Wicks, J.......................................................P103
Wilson, C. E................................................P511
Wilson, I. D.................................................P511
Wilson, V.....................................................P517
Wise, S.........................................................P430
Wuermlin, C..............................................P206
X
Xiang, Y.......................................................P309
Xie, Y............................................................P428
Xu, Y.............................................................P310
Y
Yamashita, H.............................................P313
Yan, J...........................................................P306
Yan, L...........................................................P504
Yang, X........................................................P108
Yang, B........................................................P502
Yeager, R....................................................P201
Yeager, R.P..................................................P304
You, J.S........................................................P502
Young, R.........................................P310, P418
ABSTRACTS
Renna, S.....................................................P103
Rezg, R........................................................P300
Rezk, H. M. H.............................................P518
Rider, C.......................................................P313
Riley, R. J. R................................................P511
Riviere, J.........................................P105, P106
Robbie, G...................................................P505
Roche, B.....................................................P427
Rodrigues, C.R......................................... P107
Rojko, J....................................................... P505
Rose, R........................................................P409
Roth, M................................................. GFP117
Rousselle, S...............................................P103
Ryan, P.............................................P504, P505
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Z
ABSTRACTS
Zabka, T......................................................P118
Zhou, T........................................................P108
Ziegelhofer, T............................................P513
106 107 th
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Annual Meeting
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Exhibitor Directory
Exhibit Hall Hours:
Monday, November 10
9:30 AM–12:00 Noon
2:00 PM–7:00 PM
ACT Member Lounge
1821 Michael Faraday Dr., Suite 300
Reston, VA 20190
Contact: Nancy Rollman
8:00 AM–4:30 PM
Tel: 703.547.0875
Fax: 703.438.3113
Email: exhibits@actox.org
Website: www.actox.org
All participants are welcome to stop by the ACT Member Lounge to learn more about the College's educational programs and
webinars, view membership benefits, update your interACT profile, view the ACT's scientific journal, the International Journal of
Toxicology, and more.
Advinus Therapeutics Limited
EXHIBIT INFO
21-22, Phase II, Peenya Industrial Area
Bangalore, Karnataka 560 058
India
Contact: Ms. Y R Sapna
504
Tel: +91 80 28394959
Fax: +91 80 28394015
Email: sapna.r@advinus.com
Website: www.advinus.com
Advinus is an integrated Development Center promoted by the TATAs catering to pharma & Agro sectors. Located in India,
Advinus is a 22-yr GLP-accredited & AAALAC-certified lab with integrated CMC, DMPK, Safety Pharmacology & Toxicology
capabilities. We have a track record of submitting 30 INDs (USFDA -11) & >6000 standalone toxicology studies to global regulatory
bodies. We have conducted >50 carci studies including Transgenic mouse models. We comply with ICH, EPA, EEC, OECD, CIPAC
guidelines.
Alliance Pharma, Inc.
17 Lee Blvd.
Malvern, PA 19355
Contact: Bingbing Feng
218
Tel: 610.608.5917
Fax: 610.296.3153
Email: bfeng@alliancepharmaco.com
Website: www.alliancepharmaco.com
As a CRO, Alliance Pharma specializes in GLP and non-GLP studies for preclinical and clinical programs in the following areas:
small molecule LC-MS/MS bioanalysis of drugs, biomarkers and agrochemicals, large molecule immunoassays to support PK,
immunogenicity studies and biomarker analysis, cell based assays, drug metabolism and pharmacokinetics, and sample storage.
Antech GLP
600 Airport Blvd., Suite 500
Morrisville, NC 27560
Contact: Susan St. Clair
319
Tel: 253.277.0811
Email: Susan.Stclair@antechmail.com
Website: www.antechglp.com
Antech Diagnostics GLP offers a full-service, Good Laboratory Practice compliant, clinical pathology reference laboratory
performing hematology, chemistry, urinalysis, coagulation, immunoassays, hormone analysis, and esoteric tests. Antech now
offers veterinary clinical trial testing and non-GLP studies.
108 109 th
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Annual Meeting
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Exhibitor Directory
BASi (Bioanalytical Systems, Inc.)
2701 Kent Avenue
West Lafayette, IN 47906
Contact: Philip Downing
310
Tel: 765.463.4527
Email: pdowning@basinc.com
Website: www.basinc.com
BASi provides world-class research to the pharmaceutical industry. We offer an extensive array of contract research services and
manufacture specialty scientific instrumentation. Our non-clinical/GLP toxicology services include IND-enabling studies, non-clinical
animal studies, and pathology services.
Battelle401
505 King Avenue
Columbus, OH 43201
Contact: Philip Downing
Tel: 800.201.2011
Email: solutions@battelle.org
Website: www.battelle.org
Battelle provides GLP compliant, nonclinical services to the pharmaceutical industry and government agencies. Our capabilities
include safety and efficacy testing; GLP toxicology, pharmacology; pathology; analytical/bioanalytical chemistry; biomarker
discovery, method/assay development & validation. Battelle is the world’s largest independent nonprofit research organization,
specializing in Life Sciences Research.
Bio Medic Data Systems, Inc.
EXHIBIT INFO
1 Silas Road
Seaford, DE 19973
Contact: Geoff Hunt
317
Tel: 302.628.4100
Fax: 302.628.4110
Email: ghunt@bmds.com
Website: www.bmds.com
Bio Medic Data Systems offers an electronic RFID solution for accurate animal identification. Our injectable transponders can display
ID and body temperature. They can be paired with our advanced reader systems to display animal IDs as well as collect data from
other connected devices; calipers and scales. The readers can work as independent cordless devices or connected to a computer for
real time transfer. We are available in the USA, Europe and Asia to provide support and expert advice.
Bioo Scientific
7050 Burleson Road
Austin, TX 78744
Contact: Dawn Obermoeller
506
Tel: 512.707.8993
Email: jkrebs@biooscientific.com
Website: www.biooscientific.com
Bioo Scientific, an Austin, TX based biotechnology company, offers a complete line of kits for preclinical analysis including highthroughput, innovative assays for in vivo toxicity testing. These assays are ideal for assessing damage to liver, heart, kidneys and
other organs. Bioo Scientific also offers preclinical services designed to meet your specific needs.
BioReliance Corporation
14920 Broschart Road
Rockville, MD 20850
Contact: Scott Hickman
300
Tel: 301.738.1000
Email: scott.hickman@bioreliance.com
Website: www.bioreliance.com
BioReliance is a leading contract services company in the area of product safety. We specialize in genetic toxicology screening and
GLP assays, as well as transgenic mouse carcinogenicity testing. BioReliance has all the experience and expertise needed to design
and execute a toxicology testing program to meet your needs.
110 Leading Journals
from SAGE
JOURNAL OF
VETERINARY
DIAGNOSTIC
INVESTIGATION
vet.sagepub.com
ISSN: 0300-9858
Veterinary Pathology
OFFICIAL PUBLICATION OF THE AMERICAN ASSOCIATION
OF VETERINARY LABORATORY DIAGNOSTICIANS, INC.
jvdi.sagepub.coMsISSN: 1040-6387
Toxicologic
Pathology
ISSN:
IISSN
ISS
SSN
SN:
N: 0748-2337
07
0748
Mouse: Glomerular
m
Amyloidosis
JCVP
TOXICOLOGY
and the British Society of Toxicological Pathology
ISSN: 0192-6233
ECVP
INTERNATIONAL JOURNAL OF
The Official Publication of the Society of Toxicologic Pathology
www.toxpath.org
ACVP
OfÄcial Journal of the American College of Toxicology
Hepatocellular
ular intra
intracytoplasmic
racyto
oplasmic inclusions
Journal of Feline
Medicine and Surgery
Official Journal of the International Society of Feline Medicine
and the American Association of Feline Practitioners
Clinical Practice
http://jfms.com
www.sagepub.com
1148231
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Exhibitor Directory
BTS Research
PO Box 910418
San Diego, CA 92191
Contact: Sami Abunadi
103
Tel: 858.605.5882
Fax: 858.605.5916
Email: sabunadi@btsresearch.com
Website: www.btsresearch.com
BTS Research, previously BioTex Sciences and it's subsidiary Bio-Quant, Inc., is your premiere In Vitro & In Vivo preclinical CRO offering
research & development services from discovery to IND in small and large molecules in areas of oncology, inflammation, metabolic
diseases in rodents, guinea pigs, rabbits, dogs, pigs & NHP's.
Calvert Laboratories
130 Discovery Drive
Scott Township, PA 18477
Contact: Leslie Maas
312
Tel: 570.586.2411
Fax: 570.586.3450
Email: leslie.maas@calvertlabs.com
Website: www.calvertlabs.com
Calvert is a highly respected and experienced CRO providing a complete spectrum of nonclinical safety studies since 1969 to the
pharmaceutical, biotechnology and chemical industries. Services include Acute to Chronic Toxicology, DART studies, General and
Safety Pharmacology, Telemetry, Immunology, Immunotoxicology and Pharmacokinetic/ADME. If you are looking for a highly
personalized level of flexible, highly-communicative and responsive service, then Calvert is your laboratory of choice.
ChanTest Corporation
14656 Neo Parkway
Cleveland, OH 44128
Contact: Alissa Mague
215
Tel: 240.453.6331
Email: amague@chantest.com
Website: www.chantest.com
EXHIBIT INFO
ChanTest provides GLP/non-GLP preclinical safety testing for hERG and other cardiac ion channels, APD testing on stem cellderived cardiomyocytes, and in vitro and in vivo QT Prolongation Assays. The company offers the largest panel of ion channel
targets and has been recognized as “the most trusted services company” in independent surveys.
Charles River
251 Ballardvale Street
Wilmington, MA 01887
Contact: Jessica Janiak
301
Tel: 781.222.6548
Email: jessica.janiak@crl.com
Website: www.criver.com
Charles River provides essential products and services to accelerate research and drug development efforts. With flexible
solutions, accelerated timelines and customized approaches, we provide clients with exactly what they need to improve and
expedite the discovery, early-stage development and safe manufacture of new therapies every step of the way.
CiToxLAB101
445 Armand-Frappier Boulevard
Laval QC H7V 4B3 Canada
Contact: Francois Duguay
Tel: 450.973.2240
Email: duguayf@ca.citoxlab.com
Website: www.citoxlab.com
CiToxLAB (sites in France, Canada, Denmark, and Hungary) offers a wide range of GLP-nonclinical and specialty safety services
in large and small molecules. CiToxLAB provides expertise in toxicology (general, infusion, inhalation, ocular, dermal, DART,
immunotoxicology, carcinogenicity, transgenic, genetic, in vitro, chemical, agrochemical) and in specialty areas (genomics, safety
pharmacology, radiation, DMPK).
CorDynamics, Inc.
2242 W. Harrison St
Chicago, IL 60612
Contact: Peter Senese
200
Tel: 312.421.8876
Email: pbs@cordynamics.com
Website: www.cordynamics.com
CorDynamics is a preclinical contract research laboratory and consulting group focused on examining the cardiovascular effects
of emerging drug candidates with an emphasis on quality, affordability, flexibility, and reliability.
112 113 th
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Annual Meeting
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Exhibitor Directory
CRC Press - Taylor & Francis Group LLC
315
6000 Broken Sound Parkway NW, Suite 300 Tel: 561.994.0555
Boca Raton, FL 33487
Contact: Charmaine Lowe
Email: marie.horace@taylorandfrancis.com
Website: www.crcpress.com
CRC Press – Taylor & Francis Group is a global publisher of print and electronic books for medical, scientific and technical
communities. Visit our booth #315 to browse our new and bestselling publications in toxicology and take advantage of
convention discounts. Register for email alerts at www.crcpress.com.
CXR Biosciences Ltd.
2 James Lindsay Place
Dundee Scotland DD15JJ
United Kingdom
Contact: John McManus
212
Tel: +44 1382 432163
Fax: +44 1382 432153
Email: johnmcmanus@cxrbiosciences.com
Website: www.cxrbiosciences.com
CXR Biosciences is a unique CRO combining innovative and standard mechanism-based approached to improve compound
development or resolve toxicity issues. We are experts in mechanistic and investigative toxicology and ADME with emphasis on
the prediction of animal to human data. Our portfolio includes: toxicogenomics, screening, and mechanistic toxicology protocols.
Cyprotex216
313 Pleasant St.
Watertown, MA 02472
Contact: Sam Verla
Tel: 617.600.4300
Fax: 617.812.0712
Email: marketing@cyprotex.com
Website: www.cyprotex.com
EXHIBIT INFO
Cyprotex is an AIM-listed company (CRX) with headquarters in Macclesfield, UK and laboratories in Watertown, MA, USA
(Apredica). The combined company is the leader in predictive toxicology and ADME research, offers several proprietary
technologies (CellCiphr, CloePK, gADMETM) and prides itself on custom assay development and fast turnaround times.
Data Sciences International (DSI)
119 14th Street NW
St. Paul, MN 55112
Contact: Jennifer Seidl
400
Tel: 651.481.7400
Email: jseidl@datasci.com
Website: www.datasci.com
DSI offers preclinical physiological monitoring solutions for respiratory, CV, and CNS applications involving acute or chronic
studies. Products include data collection and analysis systems, hardwired amplifiers, implantable telemetry, infusion pumps, JET
external telemetry, glucose monitoring and respiratory chambers. New offerings include Validation, Surgical and Data Analysis
Services. Offices throughout Europe, USA, and Asia provide support and expertise.
DRIK107
865 Research Parkway, Suite 415
Oklahoma City, OK 73104
Contact: Kumar Sripathirathan
Tel: 405.384.8580
Email: kumar@atdrik.com
Website: www.atdrik.com
DRIK, as the name implies shines light on your discovery advancing your innovation. Our focus is on pharmacology and
toxicology services for both small and large molecules. DRIK facilitates DMPK studies, both in vivo and in vitro, by conducting
early ADME studies to identify lead candidates and their bio-distribution for IND filings. We specialize in 3D slice culture. We also
provide PK/PD experiments supporting discovery, pharmacology, and toxicology and compound development strategy. We
assess drug safety needs and save our clients' time and money to make safer drugs.
114 Vet Path Services, Inc.
Vision • Pride • Service
Fully Compliant with GLP’s
Histology Laboratory (Paraffin & Plastic)
Nine (9) Board-Certified (ACVP) Pathologists
Histopathology Evaluation & Reporting
Pathology Expert Reports and White Papers
Pathology Peer Review
Pathology Working Groups
Clinical Pathology Interpretation
Archiving
Vet Path Services, Inc.
6450 Castle Drive
Mason, OH 45040
info@vetpathservicesinc.com
www.vetpathservicesinc.com
Over 20 years in business with 35+ years combined
experience in toxicology consulting.
Consulting
•
Drug
•
Device
•
Combination products
•
Study Placement
•
Regulatory guidance, writing & filing
•
Risk Assessment for drugs & medical devices
including product contamination, impurities and
degradants, leachables and extractables & (Q)SAR
Training
•
(Q)SAR
•
Drug and Device Development
•
Combination products
•
Application of Guidance
•
Customizable
Audits
•
GLP analytical & preclinical
•
cGMP
No project is too small, able to accommodate urgent requests
learn more and meet our team @ www.gadconsulting.com
115 th
35
American
Annual Meeting
2014
Exhibitor Directory
emka TECHNOLOGIES, Inc.
307 Annandale Road, Suite 203
Falls Church, VA 22042
Contact: Virginie Brechet
407
Tel: 703.237.9001
Fax: 703.237.9006
Email: vb@emkatech.com
Website: www.emkatech.com
emka TECHNOLOGIES specializes in software and hardware products for preclinical research. We offer a complete range of
products for CNS, CV, Pulmonary research, and dedicated services for data analysis and system validation. New and featured
products include: - easyMATRIX V2, a direct hardware bridge to implantable telemetry systems.- emkaPACK 4G, a smaller yet more
capable version of our renowned non-invasive telemetry. - flexiVENT, precision laboratory instruments for pulmonary research,
by SCIREQ.
EPL Archives
45610 Terminal Drive
Sterling, VA 20166
Contact: Allison Tyler
413
Tel: 703.435.8780
Fax: 703.435.1330
Email: contact@eplarchives.com
Website: www.eplarchives.com
EPL Archives, a globally recognized leader in the research archiving and biorepository field, provides secure GLP, cGCP and cGMP
storage for research materials.
EPL, Inc.
EXHIBIT INFO
PO Box 169
Sterling, VA 20167
Contact: Paul Sanders
306
Tel: 703.471.7060
Fax: 703.471.8447
Email: psanders@epl-inc.com
Website: www.epl-inc.com
Experimental Pathology Laboratories, Inc. (EPL) is the world’s largest independent provider of GLP-compliant toxicologic
pathology services. Since 1971, EPL has provided necropsy and histology support, pathology evaluation and consultation
including pathology peer review and organizing Pathology Working Groups (PWG) for industry and government clients. We are
able to customize our services to meet our clients’ specific scientific, regulatory, and management objectives.
Experimur211
4045 S. Morgan Street
Chicago, IL 60609
Contact: Farah Denahan
Tel: 773.254.2700 (Ext. 232)
Fax: 773.254.2723
Email: fdenahan@experimur.com
Website: www.experimur.com
Experimur is a full-service CRO with extensive capabilities in the conduct of preclinical toxicology studies. Place your programs
with Experimur and experience the superiority of a team skilled with decades of expertise, top quality and unmatched service. We
invite you to visit our spectacular, custom-built, AAALAC-accredited, 54,000 sq ft, state-of-the-art facility and vivarium, including
extensive in-house support services for histology, diagnostic pathology, clinical pathology, and analytical chemistry.
Gentronix Limited
BioHub at Alderley Park
Alderley Edge, Cheshire SK10 4TG
United Kingdom
Contact: Steve Beasley
512
Tel: +44 0 1625 238 700
Fax: +44 (0) 1625 238 701
Email: steve.beasley@gentronix.co.uk
Website: www.gentronix.co.uk
Gentronix is a specialist genetic toxicology company providing services and products worldwide. We work to tight deadlines to
deliver quality results with expert follow up from product discovery and early screening through to GLP compliant OECD in vitro
genetic test battery studies. You can find details of all of our products and services on our website: www.gentronix.co.uk or email
us at info@gentronix.co.uk or come talk to us at Booth #512.
116 NO TWO ARE EVER THE SAME.
At Covance, we understand that every biologic molecule is uniquely
developed. So we’ve created dedicated biologics teams to expertly
partner with you. Together, we’ll address the complexities of your
molecule to transform data into insight that expedites your molecule’s
development. Over the last few years we’ve proudly completed
thousands of biologics studies and more than 40 biologics IND/CTA
packages. Discover how we can help transform your biologic with
Solutions Made Real™.
TO LEARN MORE CALL
The Americas +1.888.COVANCE | Europe/Africa +00.800.2682.2682
Asia/Pacific +800.6568.3000 | Or go to Covance.com/biologics
COVANCE is an independent, publicly held company with headquarters in Princeton, New Jersey, USA.
COVANCE is the marketing name for Covance Inc. and its subsidiaries around the world.
© Copyright 2014. Covance Inc.
117 th
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Annual Meeting
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Exhibitor Directory
Histo-Scientific Research Laboratories (HSRL)
5930 Main Street
Mt. Jackson, VA 22842
Contact: Patty Schwartz
Tel: 540.477.4440
313
Email: pschwartz@hsrl.org
Website: www.hsrl.org
HSRL’s necropsy, histology, pathology, and archiving services are known for expertise, quality and efficiency. We support GLP
studies in a responsive and cost-effective manner. Necropsy services are provided at your facility. Our board-certified pathologists
have extensive experience. HSRL Archives offers ambient, refrigerated and frozen storage.
HistoTox Labs, Inc.
5541 Central Avenue, Suite 150
Boulder, CO 80301
Contact: Jon Bishop
207
Tel: 303.633.5401
Fax: 303.565.3764
Email: jbishop@histotoxlabs.com
Website: www.histotoxlabs.com
HistoTox Labs is a GLP-compliant contract laboratory performing routine and specialized Histology, Immunohistochemistry and
Pathology services for toxicity, arthritis, cancer and inflammation related studies. Additional services include decalcified bone
techniques, antibody optimization, full slide scanning, digital image analysis, special stains and frozen techniques.
Huntingdon Life Sciences/ Harlan
P. O. Box 2360, Mettlers Road
East Millstone, NJ 08875
Contact: Melissa Zeier
416
Tel: 732.873.2550
Fax: 732.873.8899
Email: zeierm@princeton.huntingdon.com
Website: www.huntingdon.com
EXHIBIT INFO
Huntingdon Life Sciences provides complete preclinical drug development services for large and small molecules. With sixty
years experience, we are committed to our customers' needs through quality service and scientific expertise. Our services:
Toxicology, DART, safety pharmacology, DMPK, genetic tox, immunoassay, bioanalytical CMC, cell-based assays, flow cytometry,
environmental risk assessment.
IDEXX BioResearch
One IDEXX Drive
Westbrook, ME 04092
Contact: Melissa Terrano
302
Tel: 207.556.8628
Fax: 207.556.2005
Email: melissa-terrano@idexx.com
Website: www.idexxbioresearch.com
IDEXX BioResearch delivers research analyzers and analytical testing services for laboratory animals to the global biomedical
research community. Our animal health monitoring, genetic testing, preclinical research services and cell-line quality assurance
simplify your ability to conduct quality research.
IIT Research Institute (IITRI)
10 W 35th Street
Chicago, IL 60616
Contact: Jennifer Van Dinther
405
Tel: 312.567.4911
Fax: 312.567.4924
Email: jvandinther@iitri.org
Website: www.iitri.org
IIT Research Institute (IITRI) brings together the best of both worlds with the comprehensive, service offering of a large CRO
and the personalized collaborations of a small CRO. Specialties include GLP toxicology and safety testing to support IND
submissions, cancer drug discovery and development, inhalation toxicology, and efficacy and safety testing of vaccines and antiinfective drugs.
118 Patricia Frank & Associates, Inc.
Assisting the Pharmaceutical Industry since 1993
Congratulations to the ACT on
another successful Annual Meeting
patfrank@att.net
847.864.6528
Are you looking for a Toxicology Consultant?
Search through our comprehensive database of
Toxicologists around the country.
RTC is the oldest and largest consortium of independently practicing toxicologists dedicated to solving the problems of clients on the basis of good science
and the expertise gained through many years of industry, government and/or academic experience. Collectively, we work in the following industries:
•Pharmaceuticals (drugs)
•Chemical
•Foods
•Consumer Products
•Medical Devices
•Legal – Expert Witnesses
•Environmental Technology / Pesticides
•Occupational Exposure / Safety
http://www.toxconsultants.com/
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119 th
35
American
Annual Meeting
2014
Exhibitor Directory
ImmunoTox, a Division of AIBioTech, LLC
601 Biotech Drive
Richmond, VA 23235
Contact: John Stradling
Tel: 804.648.3820
204
Email: info@aibiotech.com
Website: www.immunotox.com
ImmunoTox, Inc. specializes in studys evaluating the effects of drugs, chemicals, and physical agents on the immune system. In
Vivo and In Vitro studys are carried out in well-equipped laboratories specifically designed for immunotoxicological studies.
Indigo Biosystems
7820 Innovation Blvd. Suite 250
Indianapolis, IN 46278
Contact: Sasha Bannister
415
Tel: 317.493.2400
Email: sbannister@indigobio.com
Website: www.indigobio.com
Indigo’s ASCENT software supports that scientist by applying sophisticated software automation to the processing, reviewing and
reporting of quantitative mass spectrometry applications. ASCENT dramatically accelerates the overall workflow by highlighting
problematic results and outliers for expert review. A rigorous peak processing algorithm reveals the true chromatographic data
in complex samples, and a system of automated quality assurance checks provides an overarching and unified quality standard
across the lab. The ASCENT system can operate with a wide variety of manufacturer instrumentation, through a web browser,
providing a comprehensive data automation suite in which quantified results are available anywhere, and delivered quickly,
consistently and reliably.
ITR Laboratories Canada Inc.
EXHIBIT INFO
19601 Clark Graham Boulevard
Baie D Urfe (Montreal) QC H9X 3T1
Canada
Contact: Vittoria Badalone
411
Tel: 514.457.7400
Email: VBadalone@itrlab.com
Website: www.itrlab.com
ITR Laboratories, a midsized global CRO, provides a comprehensive array of nonclinical services for the biopharmaceutical
industry in support of IND and later-stage regulatory submissions. ITR offers GLP and non-GLP studies in general, inhalation,
infusion, genetic and reproductive toxicology, carcinogenicity, and safety pharmacology that are compliant with current
international guidelines.
KCAS Bioanalytical Services
12400 Shawnee Mission Parkway
Shawnee, KS 66216
Contact: Terry Osborn
402
Tel: 847.778.0522
Email: terry.osborn@kcasbio.com
Website: www.kcasbio.com
KCAS, they know bioanalysis. Their strength is their ability to support your drug development program from non-GLP research
through NDA. For more than 30 years their boutique lab has provided a full-spectrum of bioanalytical services, including small
molecule analysis, large molecule PK and immunogenicity analysis and predictive toxicology biomarker analysis. Learn more
about KCAS and how they can support your toxicology program by visiting the KCAS website.
120 Be part of a scientific community
working to advance systems toxicology
Network Verification Challenge 2 is now open.
sbv IMPROVER stands for Systems Biology Verification combined with Industrial Methodology for PROcess VERification in
Research. It is a robust methodology that verifies systems biology approaches using double-blind performance assessment
and applies the wisdom of crowds to solve scientific challenges.
Call for Action
Classical peer review system
Are the conclusions supported by
the results shown in the publication?
SCIENTIFIC
QUESTION
PUBLICATION
DATA
ANALYSIS
PEER
REVIEW
CONCLUSIONS
& CLAIMS
REPRODUCIBILITY
ISSUES
DATA
GENERATION
ALL DATA
MADE
AVAILABLE
Are the conclusions supported
by the data?
INDEPENDENT
DATA ANALYSIS
DISCUSSION
OF RESULTS
ROBUST/
TRUSTED/
REPRODUCIBLE
CONCLUSIONS
sbv IMPROVER
• Join the sbv IMPROVER community and expand your network
• Participate in the ongoing Network Verification Challenge 2 (February
2014 - April 2015)
• Explore the networks at https://bionet.sbvimprover.com
• Watch our online training videos and attend the free tutorials
https://sbvimprover.com/challenge-3/videos
https://sbvimprover.com/challenge-3/tutorials
• Gain early access to high-quality, well-curated networks
• Become a contributor in network biology for toxicology and drug and
biomarker discovery
www.sbvimprover.com
Use smarter solutions to complement peer
review with collaborative crowd-sourcing
Network Verification Challenge at a Glance
sbv IMPROVER
Network Model
Construction
Boundary
Definition
+
Nature
YOU
sbv IMPROVER
YOU
SCIENTIFIC COMMUNITY
Online Crowd-Verification
Jamboree
Preparation
Network
Jamboree
Network Dissemination
Continuous Improvement
Web-based
platform
Reputation
System
Scientific
Seminars
Further
Enhancements
Science
JBC
PNAS
Publications
Face
to face
meeting
Best Contributors
Academia
Lung Disease Community
Experts
Pharma
Team
Network Building
Systems Biologists
University Students
Biologists
Feb 2014
Public Use of
Scientifically
Accepted
Networks
Publications
Web-based
platform
Graduate Students
Postdocs
Evidence
Summary
Online
Forum
Moderation
by experts
Analysis
Prioritization
Webinars,
Training
=
CausalBioNet
Early
Access to
Networks
BEL
editor
+
General
Access to
Networks
Scoring
Leaderboard
+
April 2015
Researchers Students
Teachers
Pharma
Toxicologists
The sbv IMPROVER Network Verification
Challenge (NVC) aims to verify and
enhance existing biological network
models. The NVC is expected to increase
the networks’ value and promote their
use in research applications such as drug
discovery, personalized medicine and
toxicological risk assessment.
CONSENSUS
May 2015
Mid 2015
Be part of a scientific community working to advance systems toxicology
www.sbvimprover.com
The sbv IMPROVER project, the website and the Symposia are part of a collaborative project designed to enable scientists
to learn about and contribute to the development of a new crowd sourcing method for verification of scientific data and
results. The current challenges, website and biological network models were developed and are maintained as part of a
collaboration among Selventa, OrangeBus and ADS. The project is led and funded by Philip Morris International. For more
information on the focus of Philip Morris International’s research, please visit www.pmi.com.
121 TM
th
35
American
Annual Meeting
2014
Exhibitor Directory
Leadscope, Inc.
1393 Dublin Rd.
Columbus, OH 43215
Contact: Michael Conley
208
Tel: 614.675.3768
Fax: 614.675.3732
Email: mconley@leadscope.com
Website: www.leadscope.com
Leadscope produces high quality QSAR models and databases. Our Model Applier meets all the requirements of the ICH M7
Guidance on testing for impurities. In addition, our Model Applier produces an ICH M7 consensus prediction as used by the U.S.
FDA. Our consensus prediction incorporates the statistical QSAR models; expert alerts results and experimental data.
Lhasa Limited
Granary Wharf House, 2 Canal Wharf
Leeds, LS11 5PS
United Kingdom
Contact: Lorraine Bowe
417
Tel: +44 (0)113 394 6020
Fax: +44 (0)113 394 6099
Email: lorraine.bowe@lhasalimited.org
Website: www.lhasalimited.org
Lhasa Limited is an educational charity and leading supplier of expert knowledge based and statistical software and databases
including; Derek Nexus: For predicting toxicity, Meteor Nexus: For predicting metabolic fate, Sarah Nexus: For predicting toxicity,
Vitic Nexus: Toxicity database and management system, Zeneth: For predicting chemical degradation pathways. Lhasa Limited
is an active research organisation with an enviable reputation for collaborative work and data sharing. We work closely with our
members in the R&D of software for the chemical and bio-molecular sciences. Members include the world’s top 20 pharmaceutical
companies, leading consumer products manufacturers, academics, regulatory bodies and government organisations.
Lovelace Respiratory Research Institute (LRRI)
EXHIBIT INFO
2425 Ridgecrest Drive SE
Albuquerque, NM 87108
Contact: William Bechtold
Tel: 505.348.9456
403
Email: wbrechtol@lrri.org
Website: www.lrri.org
The Lovelace Respiratory Research Institute is a private nonprofit biomedical research organization. LRRI offers internationallyrecognized expertise in aerosol science, inhalation exposure technology, respiratory animal models, inhalation toxicology,
pharmacokinetics, and clinical trials. Respiratory tract dosimetry is measured using both in vivo and in vitro techniques. Studies
routinely performed under GLP standards.
Marshall BioResources
5800 Lake Bluff Road
North Rose, NY 14516
Contact: Nicole Navratil
318
Tel: 315.587.2295
Fax: 315.587.2109
Email: nnavratil@marshallbio.com
Website: www.marshallbio.com
Marshall BioResources provides quality, purpose-bred animals for biomedical research. We supply Marshall Beagles, ferrets, and
mixed-breed mongrels and hounds globally. We are also the exclusive North American source of Göttingen Minipigs. Please visit
us to discuss your nonrodent animal needs.
Millar Inc.
6001-A Gulf Freeway
Houston, TX 77023
Contact: Michelle Sanders
206
Tel: 832.667.7000
Fax: 713.714.8497
Email: msanders@millar.com
Website: www.millar.com
The Millar Telemetry System provides high-resolution, physiologically accurate, long-term recordings for superior data
measurements in real time. Unequaled signal quality allows for results in a shorter time frame. The device is fully implantable and
recharges wirelessly. Measurable parameters include pressure, temperature, SNA, BP and tissue oxygen.
122 Toxicologic Pathology:
Know What to Look for?
Functions truly INDEPENDENTLY — unrestricted by Wall Street influences or large
corporate bureaucracy, assuring objective, quality toxicologic pathology evaluation and
consultation.
High degree of sophistication and quality throughout, so every function is performed
EXPERTLY — from highly trained and experienced pathologists and technicians to
outstanding IT systems, state-of-the-art laboratories, and innovative quality procedures.
Extraordinary RESPONSIVENESS to client needs — such as availability of client-site or
in-house services, routine or highly specialized procedures, and expedited completion of
projects.
Large enough to meet your needs…….small enough to care.
P.O. Box 169
Sterling, VA 20167-0169
Tel: 703.471.7060
Fax: 703.471.8447
www.epl-inc.com
Independent. Expert. Responsive.
123 th
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Annual Meeting
2014
Exhibitor Directory
Moltox414
PO Box 1189, 157 Industrial Park Drive
Boone, NC 28607
Contact: Ray Cameron
Tel: 828.264.9099
Fax: 828.264.0103
Email: rcameron@moltox.com
Website: www.moltox.com
Since 1986, Moltox has been providing CRO’s, QC departments and drug discovery scientists with reagents, bacterial strains,
metabolic activation products and bacteriological media. As the leading manufacturer of products for use in the Ames Assay,
Moltox distributes culture media, tester strains, S9 and positive controls through our partners worldwide.
MPI Research
54943 N. Main Street
Mattawan, MI 49071-9399
Contact: Katie Kridler
201
Tel: 269.668.3336
Fax: 269.668.4151
Email: katie.elster@mpiresearch.com
Website: www.mpiresearch.com
MPI Research is a preclinical and early clinical CRO that provides discovery, surgery, safety evaluation, bioanalytical, and analytical
services. We exceed expectations through consistency and quality, with a commitment to communication and innovation,
delivering benefits throughout all phases of development. Learn how we can go beyond for you at http://www.mpiresearch.com
MultiCASE Inc.
23811 Chagrin Boulevard, Suite 305
Beachwood, OH 44122
Contact: Roustem Saiakhov
510
Tel: 216.831.3740
Fax: 216.831.3742
Email: saiakhov@multicase.com
Website: www.multicase.com
EXHIBIT INFO
MultiCASE provides powerful software and QSAR models developed through Research Collaboration (RCA) with the US FDA.
Our software/models packages help scientists to assess the potential toxicity of pharmaceuticals, impurities, degradants and
metabolites, complying with the ICH M7 Step 2 guideline on testing of impurities using statistical-based QSAR methodology.
National Jewish Health
1400 Jackson Street
Denver, CO 80228
Contact: David Trollinger
214
Tel: 303.398.1669
Fax: 303.270.2175
Email: trollingerd@njhealth.org
Website: www.njlabs.com
The National Jewish Health Advanced Diagnostic Laboratories offer pre-clinical and clinical testing services under CAP/CLIA/
ISO15189 and FDA GLP. The Complement Laboratory offers the most comprehensive specialized test menu. Offering study
design and data analysis based on a proven track record assessing complement with a variety of test systems and test articles.
Our experience includes complement activation, cytokines assessment, ADA and immune complex formation for biologics,
vaccines, particulars, devices, antibodies, nanoparticles and oligonucleotides.
Optivia Biotechnology Inc.
115 Constitution Drive #7
Menlo Park, CA 94025
Contact: David Lustig
314
Tel: 650.324.3177
Email: sales@optiviabio.com
Website: www.optiviabio.com
Optivia Biotechnology offers a suite of in vitro transporter assay services to assist drug development companies discover
and design better drugs with improved therapeutic responses and safety profiles. Our clients and collaborators include
pharmaceutical and biotechnology companies, research institutions and government agencies.
124 dedicated to innovation
exceptionalscience
nc
ie
sc
gh
ro
u
th
s
tie
ili
po
WIL Research is dedicated to listening to your
specific study requirements. Stop by booth
309 and together we’ll discuss the right
approach for you.
ib
So tell us about your CRO needs.
MedImmune leads a movement
that demands more out of
medicine. With one of the
largest and most robust
pipelines in the industry,
we pioneer the future of
science — creating
advancements in
biotechnology that have
a true impact on health.
ss
TO YOUR
EVERY WORD
e.
We’re hanging on
tin
g
ne
w
Be sure to attend this continuing education
course sponsored by WIL Research.
cr
ea
Toxicology and Pathology of the
Respiratory System
Sunday, November 9
1:00 p.m. – 4:30 p.m.
Let’s start the conversation at booth 309.
We have listening down to a science.
www.wilresearch.com
www.medimmune.com
© 2013 MedImmune. All rights reserved.
125 th
35
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Annual Meeting
2014
Exhibitor Directory
OtoScience Labs
401 Timbercreek Drive
Jacksonville, IL 62650
Contact: Jeremy Turner
217
Tel: 217.883.1533
Email: jturner@otosciencelabs.com
Website: www.otosciencelabs.com
OtoScience Labs specializes in providing comprehensive preclinical contract research and consulting services related to
ototoxicity. Our patented OtoCentrix technology helps streamline drug development and safety assessment by rapidly screening
rodent models for hearing loss and tinnitus, helping to more efficiently identify toxicity by using the ear as a sentinel system.
PDS Preclinical Data Systems, Inc.
100 Valley Road, Suite 204
Mt. Arlington, NJ 07856
Contact: Maro Schuster
307
Tel: 973.398.2800 (Ext. 19)
Fax: 815.301.3115
Email: maro.schuster@pds-america.com
Website: www.pds-europe.com
PDS, Inc, has been helping accelerate drug development efforts with global clients in Pharma, CRO, Biotech, Academia and
Regulatory fields for over 34 years. Our Ascentos™ Preclinical Suite of solutions and TranSEND™will enable your laboratory to
complete your studies and prepare your data in SEND format. Stop by for a discussion and demonstration of our Ascentos and
TranSend Solutions.
Perceptive Instruments Ltd
EXHIBIT INFO
St. Francis House, Olding Road
Bury St Edmunds IP33 3TA
United Kingdom
Contact: Frances Hall
419
Tel: +44 (0)1284 765566
Email: sales@perceptive.co.uk
Website: www.perceptive.co.uk
Perceptive Instruments supplies image analysis and study management systems which integrate data acquisition, auditing and
reporting for genetic toxicology assays. Our flagship products include Comet Assay IV, Sorcerer Colony Counter, Ames Study
Manager and Cyto Study Manager. With over 20 years experience, we have a global reputation for delivering highly effective GLPcompliant solutions along with excellent customer service.
PointCross Life Sciences, Inc.
1291 E. Hillsdale Blvd, Suite 304
Foster City, CA 94404
Contact: Ana Belo
119
Tel: 650.350.1900
Fax: 650.350.1903
Email: ana@pointcross.com
Website: www.pointcrosslifesciences.com
PointCross Life Sciences offers solutions to standardize, visualize and analyze nonclinical study data. Our DSIMS™ solution is
used to review nonclinical studies and package data to comply with the FDA’s implementation of the CDISC SEND standard. It is
installed as NIMS at the FDA for regulatory review of NDA and IND study data. We provide data standardization services to the
FDA for sponsor submissions to help jump start the regulatory review process. This service is offered to global commercial clients.
Companies use SDIS™, our cross-study analytics solution, for R&D purposes.
PreClinical Research Services, Inc.
1512 Webster Court
Fort Collins, CO 80524
Contact: Patti Waters
500
Tel: 970.232.1122
Fax: 970.232.1126
Email: patti.waters@
preclinicalresearch.com
Website: www.preclinicalresearch.com
PCRS offers GLP and non-GLP services to support pharmacokinetics, pharmacology, and toxicology studies in addition to
osteoarthritis, vascular, and surgical models. Our expertise with purpose-bred small and large animal species allows us to
efficiently support drug and medical device development. We provide rapid startup times and turnaround to manage our
clients’ needs.
126 127 th
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Annual Meeting
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Exhibitor Directory
Product Safety Labs
2394 Highway 130, #E
Dayton, NJ 08810
Contact: Genevieve Hutchins-Booker
305
Tel: 732.438.5100 (Ext. 262)
Email: genahutchinsbooker@
productsafetylabs.com
Website: www.productsafetylabs.com
For over 40 years PSL has provided Toxicological Research, Analytical Chemistry and other testing services. PSL is able to
assist their clients by providing data to support a variety of needs, including custom designed studies, product and discovery
development, preclinical safety evaluations, product stewardship, regulatory compliances and risk assessment. PSL prides itself on
its commitment to quality, offering competitive pricing and on-time reports delivered through a team of expert, professional staff.
Quidel105
12544 High Bluff Drive, #200
San Diego, CA 92130
Contact: Kim Wilson
Tel: 858.552.1100
Fax: 858.882.4131
Email: kwilson@quidel.com
Website: www.quidel.com
Quidel® MicroVue® products are focused on delivering innovative research and diagnostic tools for identification, development,
marketing and sale of biochemical bone markers, immune system monitoring and assays for the assessment of Complement
activation. Many of these products are unique in nature and provide researchers and clinicians valuable scientific and diagnostic
information. Looking to expand the methodical arsenal of Complement analysis in animals, Quidel marketed the Pan-Specific C3
Reagent kit (RUO product). Microwell kits, related products and core technologies are currently marketed directly and through
distribution worldwide under the Quidel® and MicroVue® brands.
Quintiles109
EXHIBIT INFO
4820 Emperor Boulevard
Durham, NC 27703
Contact: Dominque Talbert
Tel: 866.267.4479
Email: clinical@quintiles.com
Website: www.quintiles.com
Quintiles (NYSE: Q), a Fortune 500 company, is the world’s largest provider of biopharmaceutical development and commercial
outsourcing services. With a network of more than 30,000 employees conducting business in ~100 countries, we helped develop
or commercialize all of 2013’s top-100 best-selling drugs on the market. Quintiles’ CardioCheck consists of a panel of in vitro assays
that provide rapid insight into the cardiotoxic potential of drugs in pre- and early clinical stages of development.
SAGE304
2455 Teller Road
Thousand Oaks, CA 91320
Contact: Lisa Lamont
Tel: 805.410.7239
Fax: 805.499.0871
Email: lisa.lamont@sagepub.com
Website: www.sagepub.com
SAGE is a leading international publisher of journals, books, and electronic media for academic, educational, and professional
markets. Since 1965, SAGE has helped educate a global community spanning a wide range of subject areas including business,
humanities, social sciences, and science, technology, and medicine.
SAI Infusion Technologies
276 Park Ave.
Lake Villa, IL 60046
Contact: Steve Denault
412
Tel: 847.356.0321
Fax: 847.356.0382
Email: info@sai-infusion.com
Website: www.sai-infusion.com
SAI Infusion Technologies designs and manufactures systems and components for preclinical infusion and sampling. SAI surgeons
and scientists provide on-site comprehensive training for all of our systems including: Wireless-infusion management software
(Axios), pumps, harnesses, access ports, jackets, swivels, catheters, and virtually everything else used in research involving infusion
or sampling.
128 SOLVING WHAT MATTERS
MOST IN TOXICOLOGY
For more than 30 years, industries and government agencies
alike have trusted Battelle to solve their most complex
toxicology challenges.
With expertise spanning dozens of interrelated scientific disciplines, premier
test facilities, and objectivity as the world’s largest independent R&D organization,
Battelle provides comprehensive toxicology solutions for pharmaceutical,
biotechnology, medical device, agrochemical industries and government clients.
To solve your most pressing challenges, Think Battelle first.
800.201.2011 ú solutions@battelle.org ú www.battelle.org
129 th
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Annual Meeting
2014
Exhibitor Directory
sbv IMPROVER
113
Email: Sbvimprover.RD@pmi.com
Website: www.sbvimprover.com
The sbv IMPROVER project demonstrated that crowd sourcing is a viable strategy to verify scientific methods and concepts in
an industrial context. sbv IMPROVER stands for Systems Biology Verification combined with Industrial Methodology for Process
Verification in Research. This approach aims to provide a measure of quality control of industrial research and development by
verifying the methods used. It is different from other scientific crowdsourcing approaches as it focuses on the verification of
processes in an industrial context, and not just on basic questions regarding science. Visit us at booth #113 to learn more about
the challenges.
Seventh Wave
743 Spirit 40 Park Drive, Suite 209
Chesterfield, MO 63005
Contact: Jody DeBold
203
Tel: 636.519.4885
Fax: 636.519.4886
Email: jdebold@7thwavelabs.com
Website: www.7thwavelabs.com
Seventh Wave is a laboratory with the strength and flexibility to maximize your lead development initiatives. We are uniquely
qualified to provide you with the scientific expertise you demand and the advice and counsel your project deserves. Our highly
collaborative approach means a close working relationship with you, and a measure of flexibility and responsiveness not found
with other CRO’s.
Simulations Plus, Inc.
EXHIBIT INFO
42505 10th Street West
Lancaster, CA 93534
Contact: Renee Bouche
408
Tel: 661.723.7723
Fax: 661.723.5524
Email: renee@simulations-plus.com
Website: www.simulations-plus.com
GastroPlus™ sets the standard for PBPK/PD modeling for different administration routes in humans and animals, plus population
simulations and DDI capabilities. The ADMET Design Suite™ mines compound libraries, designs new molecules, and virtually
screens structures for ADMET properties. DDDPlus™ and MembranePlus™ offer simulations of in vitro dissolution and permeability
experiments.
Sinclair Research Center, LLC
P.O. Box 658
Columbia, MO 65205
Contact: Carrie Horton
219
Tel: 573.387.4400
Fax: 573.387.4404
Email: chorton@sinclairresearch.com
Website: www.sinclairresearch.com
Toxicology, DMPK, and Efficacy studies in 16 species including NHP, acute-chronic, IND enabling studies. TK/PK/ADME with
nonradiolabeled compounds. Specialists in dermal, wound healing, ocular, and juvenile toxicology studies. Surgical Services:
orthopedic, wound healing, vascular/GI access cannulas in large animals, and many pharmacology models. Animal Models: Type I/
II diabetes, inflammation, ocular, dyslipidemia, obesity, osteoporosis, transdermal delivery, melanoma, cardiovascular.
Smithers Avanza
11 Firstfield Rd.
Gaithersburg, MD 20878
Contact: Hope Aubin
202
Tel: 240.364.6360
Email: haubin@smithers.com
Website: www.smithersavanza.com
Smithers Avanza Toxicology Services is a GLP-compliant, AAALAC-accredited, USDA-registered, OLAW-assured, DEA-licensed
facility located in Gaithersburg, Maryland. Our team plans and conducts safety assessment studies for pharmaceuticals (small
molecules and biologics), nutraceuticals, vaccines, and agro and industrial chemicals. Our studies are conducted to the highest
scientific standards and in compliance with regulatory requirements.We offer a proven track record of on time delivery of results
and reports.
130 GO
BEYOND
Discovery. Surgery. Imaging. Progress.
PreClinical Research Services, Inc.
offers GLP and Non-GLP pre-clinical
testing for the pharmaceutical and
medical-device industries.
Experimental Surgery
Medical devices
Proof of Concept
Device V&V Labs
Cardiovascular Devices
GI/Orthopedic/Thoracic
Osteoarthritis
Medical imaging
Fluoroscopy
Angiography
MPI Research is dedicated to bringing safer,
more effective treatments to the world. With
diverse routes of administration, advanced
electronic data support, and experience with
a wide variety of compounds, our Drug Safety
experts go beyond to move your program
through the development pathway.
Ultrasound/Echo
Toxicology
Pilot/Acute/MTD/Subacute/Chronic
Multiple species and administration routes
Go beyond with us in booth 201 and receive
a unique gift.
Pharmacokinetics
(PK/PD/TK)
www.PreClinicalResearch.com
131 th
35
American
Annual Meeting
2014
Exhibitor Directory
SNBL USA, Ltd.
6605 Merrill Creek Parkway
Everett, WA 98203
Contact: Shelby Wilcox
406
Tel: 425.322.2420
Fax: 425.407.8601
Email: swilcox@snblusa.com
Website: www.snbl.com
SNBL USA offers a unique range of safety assessment services to fulfill its commitment to help free patients from suffering.
Managed and operated by a team world renowned for its wide-ranging NHP expertise, SNBL USA offers programs ranging from
regulatory tox to customized study designs in multiple drug classes (biologics, small molecules, oligonucleotides, vaccines).
Specialized capabilities include DART, radiation, apheresis, TBI, immunotoxicology and carcinogenicity.
Southern Research Institute
2000 Ninth Avenue South
Birmingham, AL 35205
Contact: Freida Lindsey
213
Tel: 205.581.2000
Fax: 205.581.2044
Email: lindsey@southernresearch.org
Website: www.southernresearch.org
Southern Research Institute is a preclinical contract research organization with over 50 years experience. Services include efficacy
testing with special expertise in the areas of oncology and infectious diseases, supported by a complete range of in-house
bioanalytical, PCR, immunology, clinical pathology and anatomic pathology facilities.
Taconic Biosciences
EXHIBIT INFO
One Hudson City Center
Hudson, NY 12534
Contact: Holly Jordan
514
Tel: 518.697.3900
Email: holly.jordan@taconic.com
Website: www.taconic.com
Taconic Biosciences is a global provider of genetically modified mouse and rat models and services. As a full-service industry
leader, founded in 1952, Taconic helps clients acquire, test, develop, breed, cryopreserve, prepare, and distribute highly
relevant research lines worldwide. Whether you require custom genetically engineered, humanized or research-ready models,
Taconic's scientists will partner with you to rapidly and efficiently obtain the high quality models needed for your discovery or
preclinical programs.
TSE Systems Inc.
186 Chesterfield Industrial Blvd.
Chesterfield, MO 63005
Contact: Jens-Uwe Engler
404
Tel: 636.346.0144
Email: info@tse-systems.com
Website: www.tse-systems.com
TSE Systems develops, manufactures and markets sophisticated life science research instrumentation for preclinical
cardiovascular, behavioral, metabolic, physiological and toxicological research since 1886. Featured product: STELLAR TELEMETRY
next generation implantable telemetry (Pressure, Biopotentials (ECG/EEG/EMG/EOG), Activity, Temperature). NO receiver
platforms needed. Unlimited options in research protocol setups with single/group housed animals monitored with only one
receiver.
Vet Path Services, Inc. (VPS)
6450 Castle Drive
Mason, OH 45040
Contact: Chris Johnson
205
Tel: 513.469.0777
Fax: 513.469.2474
VetPath Services, Inc. is a contract histopathology lab.
132 Email: booth@vetpathservicesinc.com
Website: www.vetpathservicesinc.com
Build your career and capabilities while transforming
patients’ lives around the world for the better. When you
embark on a journey to cure at Cubist, innovation is
instinctive, collaboration is imperative and your
opportunities are endless.
Be the diﬀerence.
See where you can go
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@CubistCareers
cubist-pharmaceuticals
www.cubist.jobs
133 th
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Annual Meeting
2014
Exhibitor Directory
VivoPharm518
1214 Research Boulevard, Suite 1050
Hummelstown, PA 17036
Contact: Ralf Brandt
Tel: 717.798.9990
Fax: 717.724.5399
Email: ralf.brandt@vivopharm.com
Website: www.vivopharm.com
VivoPharm is a successful and fast-growing contract research organization that provides integrated preclinical services in various
disease areas to the biotechnology amd pharmaceutical sectors worldwide. We specialize in planning and conducting tailoried
studies to guide with our experience your drug development program, starting from early compound selections and ending with
a comprehensive set of in vitro and in vivo data reports, as needed for IND filings.
WIL Research
1407 George Road
Ashland, OH 44805
Contact: Katie Geitgey
309
Tel: 419.289.8700
Fax: 419.289.3650
Email: katie.geitgey@wilresearch.com
Website: www.wilresearch.com
WIL Research is a global CRO dedicated to listening to customer needs. They custom design product safety toxicological research,
bioanalytical, and formulation services for pharmaceutical, biotechnology, chemical, agrochemical, and food companies. With
approximately 1,200 scientific, technical, and support personnel located throughout the world, WIL Research offers technological
expertise, flexible study design, and quality results.
Worldwide Primates, Inc.
EXHIBIT INFO
P.O. Box 971279
Miami, FL 33197
Contact: John Resuta
502
Tel: 305.378.9585
Fax: 305.232.3838
Email: sales@wwprimates.com
Website: www.wwprimates.com
An importer, distributor and breeder of premium quality nonhuman primate models as well as nonhuman primate bio-products.
We offer cynomolgus from multiple country origins, rhesus, Caribbean Green monkeys, marmosets, squirrel monkeys, and
baboons. We have two facilities in the US, both CDC approved quarantine centers. We provide logistical support for transport,
consulting, and delivery to clients. Please contact us for more information on our NHP models.
WuXi AppTec
2540 Executive Drive
St. Paul, MN 55120
Contact: Mary Trelstad
316
Tel: 651.675.2801
Fax: 651.675.2005
Email: mary.trelstad@wuxiapptec.com
Website: www.wuxiapptec.com
WuXi AppTec partners with our customers to provide a wide range of IND/NDA enabling toxicology and laboratory services that
meet global regulatory standards. As part of our integrated portfolio offering, our preclinical services are designed to shorten the
time and lower the cost of drug and medical device R&D.
Xenometrics LLC
17745 Metcalf Avenue
Stilwell, KS 66085
Contact: Sara Quade
303
Tel: 913.850.5073
Fax: 913.850.5100
Email: squade@xenometricsllc.com
Website: www.xenometricsllc.com
Xenometrics, LLC, of Stilwell, Kansas, is a GLP compliant, USDA registered, AAALAC-accredited contract research organization,
providing services to the pharmaceutical, biotech, companion animal health, and industrial- and agro-chemical industries.
Xenometrics’ research species includes rodents, rabbits, minipigs, dogs, cats, nonhuman primates, and other research species.
Xenometrics’ study services include: General Toxicology, and DART, Safety Pharmacology and DMPK.
134 Can Scientists
Bridge the Gap
Between Preclinical &
Clinical Test Results?
They’re getting closer
with Taconic’s help.
is a unique and evolving portfolio of
translational mouse models and in vitro tools &
services that improve the predictability of
preclinical ADME and Toxicity studies.
Find out more at www.taconic.com/tadmet
SPONSORED SYMPOSIUM
Join Us on Monday, November 10th, for the
“Use of Humanized Mouse Models In DMPK and
Safety Testing of Compounds” symposium.
135 th
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Annual Meeting
Exhibitor
Exhibit Hall
Directory
Map
EXHIBIT INFO
136 2014
th
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Annual Meeting
2014
Exhibitor-Hosted
Exhibitor Directory
Programs
Exhibitor-Hosted Programs are commercially supported educational sessions held in conjunction with the ACT Annual Meeting.
Programs are open to all meeting attendees.
toxicology research as the need for higher throughput toxicity
screens has grown. This presentation will focus on the ways in
which zebrafish research is changing the field of toxicology.
Submitting Standardized SEND to the FDA:
Data Fitment and Review Considerations
Sunday, November 9
12:00 Noon–12:55 PM
Regency Hall #4
Presented by: PointCross Life Sciences, Inc.
An overview of the FDA’s e-data submission and JumpStart
initiatives for nonclinical studies will be provided. Data fitment
requirements, analytics and viewers for reviewing e-data and
lessons learned from industry and FDA implementations will
be presented. Benefits of standardizing NDA submissions for
early engagement with the FDA will be discussed.
Maintaining Quality and Regulatory Compliance
in a Global Setting
7:00 AM–7:55 AM
Grand Cypress Ballroom H
Presented by: WuXi AppTec
Practicalities of Dermal Administration
7:00 AM–7:55 AM
Grand Cypress Ballroom G
Presented by: Huntingdon Life Sciences
Dermal administration for preclinical evaluations presents
logistical challenges. The goal is to mimic as closely as possible
the clinical (human) situation using an animal model which
may have skin similar to a human's but may be anatomically
and behaviorally different from a human. This session will
discuss techniques and materials that have been developed to
assure that test articles applies to animals (primarily rats and
minipigs) remain in place and provide appropriate exposure
in preclinical studies.
Zebrafish: Reshaping Toxicity Testing
7:00 AM–7:55 AM
Grand Cypress Ballroom I
Presented by: Charles River
Over the past two decades, the zebrafish has transformed
from an alternative model to a firmly established workhorse in
12:00 Noon–12:55 PM
Grand Cypress Ballroom H
Presented by: Leadscope Inc.
ICH M7 guidelines require the use of an expert alert-based
and a statistical-based QSAR methodology. This seminar will
demonstrate the new Leadscope Model Applier – Genetic
Toxicity Expert Alerts system. Additionally, we will review
our “consensus prediction” using integrated results from
our new Genetox Expert Alerts system and statistical-based
Genetox QSAR models.
Evaluation of Electronic Cigarettes in Testing
Tobacco-Related Products
12:00 Noon–12:55 PM
Grand Cypress Ballroom G
Presented by: Battelle
E-cigarettes are regarded as less hazardous than traditional
combustible tobacco products. However, the health effects
from e-cigarettes are not clearly understood. We will present
results from the characterization of exposure atmospheres
from e-cigarettes and discuss our perspective on how
tobacco-related products may be evaluated to comply with
the regulations established by the CTP.
Seizure Liability, qEEG and Sleep Quantification
in Nonclinical Drug Development: Regulatory
and Scientific Considerations
12:00 Noon–12:55 PM
Grand Cypress Ballroom I
Presented by: CiToxLAB
Current topics in Neurotoxicology:
• EEG strategies to investigate seizure liabilities at early and
late stages of drug development.
• Regulatory considerations that impact study design, species
selection and EEG experimental endpoints.
• qEEG: a sensitive tool in drug development?
• Quantification of drug effects on sleep patterns.
137 EXHIBIT INFO
With the need now to reach larger patient populations faster
and quicker, global submissions are an attractive proposition
to drug companies. By doing a single program designed to be
globally compliant, companies can save time and money as
well as reducing the need for repeating studies and thereby
reducing animal use.
Demonstration of New Expert Alert System for
In Silico Assessment of Impurities under ICH M7
Guidelines
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35
American
Annual Meeting
2014
Council Listing
2013–2014 Council
President
• Drew A. Badger, PhD, DABT
Amgen Inc.
One Amgen Center Drive
Tel: 805.447.5875
Email: dbadger@amgen.com
Councilors
• Nancy R. Bordelon, PhD, DABT (2013–2016)
Covance Laboratories
671 South Meridian Road
Greenfield, IN 46140
Tel: 317.467.2736
Email: nancy.bordelon@covance.com
President-Elect
• Alan P. Brown, PhD, DABT (2013–2014)
Novartis Institutes for Biomedical Research
100 Technology Square
607-951P
Cambridge, MA 02139
Tel: 617.871.3263
Email: alan_p.brown@novartis.com
• Mary Ellen Cosenza, PhD, DABT, RAC
Amgen Inc.
Mail Stop 17-2-A
Thousand Oaks, CA 91320-1789
Tel: 805.447.6318
Email: mcosenza@amgen.com
• David R. Compton, PhD, DABT (2013–2016)
Sanofi US
55 Corporate Drive, PO Box 5925
MC: 55B-425A / B-4-4421
Bridgewater, NJ 08807-5925
Tel: 908.981.3272
Email: david.compton@sanofi.com
Vice President
• Hanan N. Ghantous, PhD, DABT
US FDA
CDER/OAP/DAVP
10903 New Hampshire Avenue
Silver Spring, MD 20993
Tel: 410.458.2930
Email: hanan.ghantous@fda.hhs.gov
Secretary
REFERENCE
Treasurer
• Jerry F. Hardisty, DVM (2011–2014)
Experimental Pathology Laboratories, Inc.
PO Box 12766
Research Triangle Park, NC 27709
Tel: 919.423.1148
Email: jhardisty@epl-inc.com
• Grace M. Furman, PhD, DABT
Paracelsus, Inc.
128 Daphne Street
Leucadia, CA 92024
Tel: 760.271.2858
Email: paracelsus.inc@cox.net
• Anthony L. Kiorpes, PhD, DVM, DABT (2012–2015)
River Bluff Associates LLC
2470 Skyline Drive
Bloomington, MN 55425-2188
Tel: 952.854.9060
Email: andy@kiorpes.net
• Alan M. Hoberman, PhD, DABT, ATS
Charles River Laboratories
Global Development
905 Sheehy Drive
Horsham, PA 19044
Tel: 215.443.8710
Email: alan.hoberman@crl.com
• Timothy J. McGovern, PhD (2011–2014)
US FDA
CDER/Office of New Drugs
WO22
Tel: 240.402.0477
Email: timothy.mcgovern@fda.hhs.gov
Past President
• Robin C. Guy, MS, DABT, RQAP-GLP
Robin Guy Consulting, LLC
PO Box 830
Preclinical Toxicology & GLP Training
Lake Forest, IL 60045-0830
Tel: 847.295.9250
Email: robinguy@robinguy.com
138 th
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Council Listing
2013–2014 Council (continued)
Councilors (continued)
Editor-In-Chief
• Sandra L. Morseth, PhD (2012–2015)
Morseth Consulting, LLC
4804 Old Middletown Road
Jefferson, MD 21755
Tel: 240.422.7699
Email: smorseth@comcast.net
• Mary Beth Genter, PhD, DABT
University of Cincinnati
160 Panzeca Way
Kettering Lab, Room #129
Cincinnati, OH 45267
Tel: 513.558.6266
Email: marybeth.genter@uc.edu
• Melissa C. Rhodes, PhD, DABT (2013–2016)
GlaxoSmithKline
5 Moore Drive
Tel: 919.483.6908
Email: melissa.c.rhodes@gsk.com
Executive Director
• Nancy Rollman
1821 Michael Faraday Drive, Suite 300
Reston, VA 20190
Tel: 703.547.0875
Email: nrollman@actox.org
• Patricia C. Ryan, PhD (2012–2015)
MedImmune, LLC
One MedImmune Way
Tel: 301.398.4387
Email: ryanp@medimmune.com
2014–2015 Incoming Council
President
Secretary
President-Elect
Past President
Amgen Inc.
Mail Stop 17-2-A
Tel: 805.447.6318
US FDA
CDER/OAP/DAVP
Tel: 410.458.2930
• Timothy J. McGovern, PhD
US FDA
CDER/Office of New Drugs
10903 New Hampshire Avenue WO22
Tel: 240.402.0477
• Drew A. Badger, PhD, DABT
Amgen Inc.
Tel: 805.447.5875
Vice President
139 • Holly D. Dursema, MS, DABT
Boehringer Ingelheim
R9-5900 Ridgebury Rd., Box 368
Ridgefield, CT 06877-0368
Tel: 203.798.5694
Email: holly.dursema@boehringeringelheim.com
• Kenneth J. Olivier Jr, PhD, BS
Merrimack Pharmaceuticals
One Kendall Square
Suite B7201
Cambridge, MA 02139
Tel: 774.219.3130
Email: kolivier@merrimackpharma.com
• Michael S. Orr, PhD
US FDA
Silver Spring , MD 20993-002
Tel: 301.796.1604
Email: michael.orr@fda.hhs.gov
REFERENCE
• Tracey Zoetis, MS
SciLucent, LLC
585 Grove Street
Suite 300
Herndon, VA 20170
Tel: 703.342.8747
Email: tzoetis@scilucent.com
Councilors (2014–2017)
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35
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Annual Meeting
2014
Committee Listings
2013–2014 Committees
Awards Committee
• Chair, Hanan N. Ghantous, PhD, DABT
US FDA
Tel: 410.458.2930
• William J. Brock, PhD, DABT, ATS
Brock Scientific Consulting, LLC
19909 Hamil Circle
Montgomery Village, MD 20886
Tel: 301.519.3666
Email: billbrock@comcast.net
• Stephen B. Harris, PhD, FATS, FSB
Stephen B. Harris Group
6109 Madra Avenue
San Diego, CA 92120
Tel: 619.469.7886
Email: steve@sbhgrp.com
• A. Wallace Hayes, PhD, DABFE, DABT,
FATS, FIBiol, ERT
Harvard University
School of Public Health
298 South Main Street
Andover, MA 01810
Tel: 978.749.3085
Email: awallacehayes@comcast.net
• Ex Officio, Drew A. Badger, PhD, DABT
Amgen Inc.
Tel: 805.447.5875
• Lisa B. Biegel, PhD
Covance Laboratories, Inc.
3301 Kinsman Blvd.–15
Madison, WI 53704
Tel: 608.245.7093
Email: lisa.biegel@covance.com
• Holly D. Dursema, MS, DABT
900 Ridgebury Rd., Box 368
Ridgefield, CT 06877-0368
Tel: 203.798.5694
Email: holly.dursema@boehringeringelheim.com
• Kate E. Lane, PhD, DABT
Cubist Pharmaceuticals Inc.
65 Hayden Ave
Lexington, MA 02421
Tel: 781.860.1026
Email: kate.lane@cubist.com
• Melissa C. Rhodes, PhD, DABT
GlaxoSmithKline
5 Moore Drive
Tel: 919.483.6908
Email: melissa.c.rhodes@gsk.com
Amgen Inc.
Tel: 805.447.5875
Education Committee
• Chair, Jerry F. Hardisty, DVM
EPL, Inc.
PO Box 12766
Tel: 919.423.1148
• Co-Chair, Patricia Ryan, PhD
MedImmune, LLC
One MedImmune Way
Tel: 301.398.4387
Email: ryanp@medimmune.com
• Ilona Bebenek, PhD
US FDA
10903 New Hampshire Ave. Bldg 22
Room 6237
Tel: 240.402.3843
Email: igbebenek@gmail.com
REFERENCE
Education Committee: Webinar Subcommittee
• Chair, Ilona G. Bebenek, PhD
US FDA
10903 New Hampshire Ave.
Bldg 22, Room 6237
Tel: 240.402.3843
Email: igbebenek@gmail.com
• Lisa D. Beilke, MSPH, PhD, DABT
Toxicology Solutions, Inc.
7015 Schilling Ave
San Diego, CA 92126
Tel: 650.504.2547
Email: lisa@toxsolutions.biz
• Nancy R. Bordelon, PhD, DABT
Tel: 317.467.2736
• Angélique Braen, PhD, DABT
Ikaria, Inc.
53 Frontage Road, POB 9001
Hampton, NJ 08827
Tel: 908.238.6471
Email: angelique.braen@ikaria.com
140 • Hanan N. Ghantous, PhD, DABT
US FDA
Tel: 410.458.2930
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Annual Meeting
2014
Committee Listings
2013–2014 Committees (continued)
Education Committee: Webinar Subcommittee (continued)
• Anthony Ndifor, PhD
Janssen R&D
3210 Merryfield Row
San Diego, CA 92121
Tel: 858.784.3260
Email: andifor@its.jnj.com
• Kenneth Olivier Jr., PhD, BS
One Kendall Square
Suite B7201
Cambridge, MA 02139
Tel: 774.219.3130
• Adam Woolley, DABT, MS, FRCPath, ERT,
ATS
ForthTox Ltd.
PO Box 13550
Linlithgow, West Lothian, EH49 7YU
Tel: 44 1506 844036
Email: adam@forthtox.com
Amgen Inc.
Tel: 805.447.5875
US FDA
Tel: 410.458.2930
• Michael P. Holsapple, PhD, ATS
Covance Laboratories Inc.
3301 Kinsman Blvd
Madison, WI 53704-2523
Tel: 608.218.0299
Email: michael.holsapple@covance.com
• Theresa Sweeney, PhD, DABT
Nektar Therapeutics
455 Mission Bay Blvd, South
San Francisco, CA 94158
Tel: 415.482.5681
Email: tsweeney@nektar.com
Amgen Inc.
Tel: 805.447.5875
• Anthony L. Kiorpes, PhD, DVM, DABT
River Bluff Associates LLC
2470 Skyline Drive
Bloomington, MN 55425-2188
Tel: 952.854.9060
Email: andy@kiorpes.net
• Dennis J. Naas, BS, PMP
ProDev Consulting Services, Ltd.
14244 Silver Ridge Road
Poway, CA 92064
Tel: 858.883.2992
Email: dennisnaas@cox.net
• Deborah L. Novicki, PhD, DABT
Novartis Vaccines
350 Massachusetts Avenue
45 SS 5103C
Cambridge, MA 02139
Tel: 510.703.2713
Email: deborah.novicki@novartis.com
Amgen Inc.
Tel: 805.447.5875
Finance Committee
• Chair, Alan M. Hoberman, PhD, DABT, ATS
Charles River
905 Sheehy Drive
Horsham, PA 19044
Tel: 215.443.8710
• Lisa D. Beilke, MSPH, PhD, DABT
Toxicology Solutions, Inc.
7015 Schilling Ave
San Diego, CA 92126
Tel: 650.504.2547
Email: lisa@toxsolutions.biz
Membership Committee
141 REFERENCE
• Chair, Timothy J. McGovern, PhD
US FDA
10903 New Hampshire Ave
WO22
Tel: 240.402.0477
Tel: 317.467.2736
• Anne H. Chappelle, PhD, DABT
Chappelle Toxicology Services, LLC
3850 Rotherfield Lane
Chadds Ford, PA 19317
Tel: 484.844.7662
Email: ahchappelle@gmail.com
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35
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Annual Meeting
2014
Committee Listings
Nominating Committee
• Chair, Robin C. Guy, MS, DABT, RQAP-GLP
PO Box 830
Tel: 847.295.9250
• Carol S. Auletta, MBA, DABT, RAC
PO Box 2360
Mettlers Road
East Millstone, NJ 08875-2360
Tel: 732.873.2550 (2960)
Email: aulettac@princeton.huntingdon.com
• Tracey L. Spriggs, PhD, DABT
GlaxoSmithKline Consumer Healthcare
1500 Littleton Road
Parsippany, NJ 07054-3884
Tel: 973.889.2503
Email: tracey.l.spriggs@gsk.com
Amgen Inc.
Tel: 805.447.5875
• Kenneth Olivier Jr., PhD, BS
One Kendall Square
Suite B7201
Cambridge, MA 02139
Tel: 774.219.3130
• Tracy Williams, PhD, DABT
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, IN 46285
Tel: 317.277.4197
Email: tracy.williams@lilly.com
Amgen Inc.
Tel: 805.447.5875
• Florence Burleson, PhD
Burleson Research Technologies, Inc.
(BRT)
120 First Flight Lane
Tel: 919.719.2500
Email: fburleson@brt-labs.com
US FDA
Tel: 410.458.2930
• Jerry F. Hardisty, DVM
EPL, Inc.
PO Box 12766
Tel: 919.423.1148
• Wafa A. Harrouk, PhD-DABT/D
US FDA
Tel: 301.796.0908
Email: wafa.harrouk@fda.hhs.gov
• David Hobson, PhD, DABT
LoneStar PharmTox LLC
613 Pleasant Valley Drive N.
Boerne, TX 78006
Tel: 210.269.6169
Email: dave@lonestarpharmtox.com
• Norman Kim, MS, DABT
Biogen Idec Inc.
14 Cambridge Center
Cambridge, MA 02142
Tel: 617.679.4995
Email: norman.kim@biogenidec.com
• Patrick D. Lilly, DABT
ALCS
601 East Jackson St
Richmond, VA 23219
Tel: 804.335.2670
Email: patrick.d.lilly@altria.com
• Michael Moore, PhD
AZ–Pharma Consulting LLC
16419 S 16th Ave
Phoenix, AZ 85045-1721
Tel: 301.943.3325
Email: moore4mike@msn.com
Outreach Committee
• Chair, Robin C. Guy, MS, DABT, RQAP-GLP
PO Box 830
Tel: 847.295.9250
• Florence Burleson, PhD
Burleson Research Technologies, Inc.
(BRT)
120 First Flight Lane
Tel: 919.719.2500
Email: fburleson@brt-labs.com
REFERENCE
Program Committee
• Chair, Mary Ellen Cosenza, PhD, DABT, RAC
Amgen Inc.
1 Amgen Center Drive
Mail Stop 17-2-A
Tel: 805.447.6318
Tel: 317.467.2736
• Angélique Braen, PhD, DABT
Ikaria, Inc.
53 Frontage Road, POB 9001
Hampton, NJ 08827
Tel: 908.238.6471
Email: angelique.braen@ikaria.com
142 th
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Annual Meeting
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Committee Listings
Program Committee (continued)
• Sandra Morseth, PhD
4804 Old Middletown Rd
Jefferson, MD 21755
Tel: 301.473.4730
Email: smorseth@morsethconsulting.com
• Deborah L. Novicki, PhD, DABT
Novartis Vaccines
350 Massachusetts Avenue
45 SS 5103C
Cambridge, MA 02139
Tel: 510.703.2713
Email: deborah.novicki@novartis.com
• Thulasi Ramani, PhD
100 Mettlers Road
Somerset, NJ 08873
Tel: 732.873.2550 (4329)
Email: ramanit@princeton.huntingdon.
com
• David Serota, PhD, DABT
MPI Research
Mattawan, MI 49071
Tel: 269.668.3336 (1338)
Email: dave.serota@mpiresearch.com
• Suzanne Wolford, PhD, DABT
Covance, Inc.
3301 Kinsman Blvd
Madison, WI 53704
Tel: 608.242.2721
Email: suzanne.wolford@covance.com
SciLucent, LLC
585 Grove Street
Suite 300
Herndon, VA 20170
Tel: 703.342.8747
Amgen Inc.
Tel: 805.447.5875
• Shayne C. Gad, PhD, DABT
Gad Consulting Services
102 Woodtrail Lane
Cary, NC 27518
Tel: 919.233.2926
Email: scgad@ix.netcom.com
• Kenneth L. Hastings, DrPH, DABT, ATS
Hastings Toxicology Consulting, LLC
3860 Turf Court South
Mount Airy, MD 21771
Tel: 301.829.5663
Email: kennethhastingus@gmail.com
• Alan Hoberman, PhD, DABT, ATS
Charles River
905 Sheehy Drive
Horsham, PA 19044
Tel: 215.443.8710
Boerne, TX 78006
Tel: 210.269.6169
SciLucent, LLC
585 Grove Street
Suite 300
Herndon, VA 20170
Tel: 703.342.8747
Amgen Inc.
Tel: 805.447.5875
• Patricia Frank, PhD
Patricia Frank & Associates, Inc.
417 Dewey Avenue
Evanston, IL 60202
Tel: 847.864.6535
Email: patfrank@att.net
• Robin C. Guy, MS, DABT, RQAP-GLP
PO Box 830
Tel: 847.295.9250
• Kenneth Hastings, DrPH, DABT, ATS
3860 Turf Court South
Mount Airy, MD 21771
Tel: 301.829.5663
Email: kennethhastingus@gmail.com
Publications Committee
• Editor-In-Chief, Mary Beth Genter, PhD,
DABT, ATS
University of Cincinnati
160 Panzeca Way
Kettering Lab, Room #129
Cincinnati, OH 45267
Tel: 513.558.6266
Email: marybeth.genter@uc.edu
Amgen Inc. 1 Amgen Center Drive
Mail Stop 17-2-A
Tel: 805.447.6318
• Grace Furman, PhD, DABT
Paracelsus, Inc.
128 Daphne Street
Leucadia, CA 92024
Tel: 760.271.2858
Resource Committee
143 REFERENCE
• Chair, David Serota, PhD, DABT
MPI Research
Mattawan, MI 49071
Tel: 269.668.3336 (1338)
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35
American
Annual Meeting
2014
Committee Listings
Resource Committee (continued)
Boerne, TX 78006
Tel: 210.269.6169
• Robert Osterberg, PhD, ATS
Osterberg Pharm-Tox Consulting LLC
4617 Morgan Drive
Chevy Chase, MD 20815
Tel: 301.951.0338
Email: pharmdrugs@comcast.net
Amgen Inc.
Tel: 805.447.5875
• Ex Officio, Alan Hoberman, PhD, DABT, ATS
Charles River
905 Sheehy Drive
Horsham, PA 19044
Tel: 215.443.8710
Website Committee
• Chair, David Compton, PhD, DABT
Sanofi US
55 Corporate Drive, PO Box 5925
MC: 55B-425A, B-4-4421
Bridgewater, NJ 08807-5925
Tel: 908.981.3272
Email: david.compton@sanofi.com
• Grace Furman, PhD, DABT
Paracelsus, Inc.
128 Daphne Street
Leucadia, CA 92024
Tel: 760.271.2858
• William Mattes, PhD, DABT
US Food and Drug Administration
National Center for Toxicological Research
Room 50-333
Jefferson, AR 72079
Tel: 870.543.7681
Email: william.mattes@fda.hhs.gov
• Tracey Spriggs, PhD, DABT
GlaxoSmithKline Consumer Healthcare
1500 Littleton Road
Parsippany, NJ 07054-3884
Tel: 973.889.2503
Email: tracey.l.spriggs@gsk.com
• Ric Stanulis, PhD, DABT
Acorda Therapeutics Inc
420 Saw Mill River Road
Ardsley, NY 10502
Tel: 914.326.5376
Email: rstanulis@acorda.com
• Alan Stokes, PhD, DABT
GlaxoSmithKline
RD9-2015
Five Moore Drive
Res Triangle Pk, NC 27709-3398
Tel: 919.315.2598
Email: alan.h.stokes@gsk.com
Amgen Inc.
Tel: 805.447.5875
2014–2015 Incoming Committee Members
REFERENCE
Awards Committee
• Elaine V. Knight, PhD
National Cancer Institute, NIH
Toxicology and Pharma Branch
9609 Medical Center Drive
RM 4-W108, MSC 9734
Bethesda, MD 20892
Tel: 240.276.5939
Email: knightev2@mail.nih.gov
Education Committee
• Pam Marone, PhD
1804 Keelingwood Lane
Virginia Beach, VA 23454
Tel: 757.450.7191
Email: pamarone@verizon.net
• Laine Peyton Myers, PhD
US FDA
CDER / Div of Antiviral Products
10903 New Hampshire Ave
Tel: 301.796.2217
Email: laine.myers@fda.hhs.gov
144 Finance Committee
• Jeff Tepper, PhD, DABT
Tepper Nonclinical Consulting
197 Glasgow Lane
San Carlos, CA 94070
Tel: 510.717.1413
Email: teppertox@gmail.com
Membership Committee
• Elliot B. Gordon, PhD, DABT
Elliot Gordon Consulting, LLC
55 Lillie Street
Princeton Junction, NJ 0855
Tel: 609.936.1977
Email: SoundScience@comcast.net
th
35
American
Annual Meeting
Nominating Committee
• David Serota, PhD, DABT
MPI Research
Mattawan, MI 49071
Tel: 269.668.3336 (1338)
• Jerry F. Hardisty, DVM
EPL, Inc.
PO Box 12766
Tel: 919.423.1148
2014
Outreach Committee
• Harry M. Olson, PhD, DVM
STA Preclinical Services LLC
720 Dartmouth Avenue
Tel: 860.304.5114
Email: hmolson.sta@outlook.com
ACT Headquarters
Tel: 703.547.0875 • Fax: 703.438.3113
Email: acthq@actox.org • Website: www.actox.org
Executive Director
Meetings Manager
Nancy Rollman
Email: nrollman@actox.org
Ext. 1404
Elsa Cannon
Email: ecannon@actox.org
Ext. 1890
Program Manager
Program Coordinator
Elisa Turner
Email: eturner@actox.org
Ext. 1650
Jordan Ballance
Email: jballance@actox.org
Ext. 1425
REFERENCE
145 th
35
American
Annual Meeting
2014
ACT Presidents
1979–1980 M. Selikoff*
1997–1998 Christopher P. Chengelis, PhD
1980–1981 Myron Mehlman, PhD
1998–1999 David W. Hobson, PhD, DABT
1981–1982 Yula Bingham, PhD
1999–2000 Merrill R. Osheroff, PhD, DABT
1982–1983 Arthur Furst, PhD, ScD*
2000–2001 Suzanne C. Fitzpatrick, PhD, DABT
1983–1984 Gary Flamm, PhD
2001–2002 Robert E. Osterberg, PhD
1984–1985 Ronald W. Hart, PhD
2002–2003 John E. Atkinson, PhD, DABT
1985–1986 Marshall Steinberg, PhD*
2003–2004 Robert Snyder, PhD, ATS
1986–1987 Gordon W. Newell, PhD
2004–2005 Patricia Frank, PhD
1987–1988 Robert M. Diener, DVM
2005–2006 Leigh Ann Burns Naas, PhD, DABT
1988–1989 Richard M. Hoar, PhD
2006–2007 Stephen B. Harris, PhD, FATS, FSB
1989–1990 Carol M. Henry, PhD, DABT
2007–2008 A. Wallace Hayes, PhD, DABT, FATS
1990–1991 Shayne C. Gad, PhD, DABT
2008–2009 Kenneth L. Hastings, DrPH, DABT, ATS
1991–1992 Mildred S. Christian, PhD, ATS*
2009–2010 Carol S. Auletta, MBA, DABT
1992–1993 Karen M. MacKenzie, PhD, DABT
2010–2011 Russette M. Lyons, PhD
1993–1994 Richard D. Thomas, PhD, DABT
2011–2012 David G. Serota, PhD, DABT
1994–1995 Sharon J. Northup, PhD
2012–2013 Robin C. Guy, DABT, MS, RQAP–GLP
1995–1996 Sidney Green, PhD
2013–2014
1996–1997 John A. Thomas, PhD
REFERENCE
*Deceased
146 th
35
American
Annual Meeting
2014
ACT Award Recipients
Distinguished Scientist Award
ACT Service Award
2013 Albert E. Munson
2013 John A. Thomas
2012 A. Wallace Hayes
2012 Mary Ellen Cosenza
2011 Glenn Sipes
2011 David Hobson
2010 Elizabeth Weisburger
2010 Jerry F. Hardisty
2009 John Casida
2009 Patricia Frank
2008 Ron Estabrook
2008 Shayne Gad
2007 Gerald Wogan
2007 Harihara Mehendale
2006 Joseph Rodricks
2006 Robert Diener
2005 Bernard Goldstein
2004 Mildred Christian
2004 Peter Guengerich
2001 Arthur Furst
2003 Jack Dean
ACT Student Travel Awards
2002 Carol Henry
2001 Curtis Klaassen
2000 Bernard Schwetz
1999 John Thomas
1998 Robert Scala
1997 Joe Borzelleca
1996 John Doull
1995 Kenneth Olden
(formerly Distinguished Service Award)
2014 Anthony D. Dayan
(formerly Lifetime Contribution Award)
2014 Norman N. Kim
2013 Shailender Singh Chauhan
Chand Basha Davuljigari
Heidi Hsieh
Chitrada Kaweeteerawat
ACT Young Professional Award
2014 Ilona G. Bebenek
2013 Lisa D. Beilke
2012 Kenneth J. Olivier Jr.
2011 Melissa C. Rhodes
2010 Nancy Bordelon
ACT Unsung Hero Award
2014 Kok-Wah Hew
2013 Eve Kagan
2012 Carol C. Lemire
REFERENCE
147 th
35
American
Annual Meeting
2014
Corporate Members
Alcon Research, Ltd.
Gilead Sciences, Inc.
Fort Worth, Texas
Foster City, California
Allergan, Inc.
GlaxoSmithKline
Irvine, California
Research Triangle Park, North Carolina
Amgen Inc.
Huntingdon Life Sciences, PRC
Astellas Pharma US, Inc.
Janssen R&D (Johnson & Johnson)
Thousand Oaks, California
East Millstone, New Jersey
Northbrook, Illinois
Spring House, Pennsylvania
BASi
MPI Research
West Lafayette, Indiana
Mattawan, Michigan
Biogen Idec Inc.
Pfizer Inc.
Cambridge, Massachusetts
Andover, Massachusetts
BioReliance Corporation
Philip Morris International R&D
Purdue Pharma, LP
Rockville, Maryland
Neuchâtel, Switzerland
Ridgefield, Connecticut
Cranbury, New Jersey
Bristol-Myers Squibb Company
R. J. Reynolds Tobacco Co
Princeton, New Jersey
Winston-Salem, North Carolina
Charles River
Sanofi US
Wilmington, Massachusetts
Bridgewater, New Jersey
Covance Laboratories, Inc.
Takeda Global R&D
Eli Lilly and Company
Vertex Pharmaceuticals Inc.
Experimental Pathology Laboratories, Inc.
WIL Research
Madison, Wisconsin
Deerfield, Illinois
Indianapolis, Indiana
Cambridge, Massachusetts
Sterling, Virginia
Ashland, Ohio
REFERENCE
Genentech, Inc.
South San Francisco, California
148 th
35
American
Annual Meeting
2014
Welcome New Members
Melanie Abongwa
Anna Adamou
Chidozie Amuzie
Mark Bauter
Conney Berger
Terri Blake
Christopher Brynczka
Steven Bulera
Julie Castaneda
Hao Chen
Paul Ciaccio
David Clarke
Roger Clemens
Frances Crofts
Alison Easter
Ikram Elayan
Peter Emau
Marc Fariss
James Fishback
Marie Fortin
Clay Frederick
Brenda Gannon
Ronald Gerson
Shubham Goyal
Arielle Hinds
Heidi Hsieh
Mohd Jaafar
William Jo
Laura Kaufman
Chitrada Kaweeteerawat
Noreen Khan-Mayberry
Yumee Kim
Andrea Kim
Sheri Klas
Mark Kleven
Seva Kostrubsky
Dan Krietlow
Raluca Kubaszky
Theresa Lansdell
Jinyoung Lee
Betina Lew
Patrick Lilly
Zhiwei Liu
Norbert Makori
Andrea Mason
Dani Matsushima
Ray Matulka
Tanya McDonnell
Carrie McMahon
Tiffany Messerli
Mark Miller
David Miller
Lance Molnar
Paramita Mookherjee
Nadia Moore
Brian Mulhern
Stefan Nechev
Louise Neilson
Tin Ngo
Wei Niu
Michael Orr
Gopinath Palanisamy
Chris Papagiannis
David Peters
Jessica Phillips
Jason Pinkstaff
Kara Polhamus
Bindu Prabhakar
Priti Prasad
Larry Rodman
Shakil Saghir
Natalie Scholpa
David Scoville
Flemming Simonsen
Phillip Smiraldo
Graeme Smith
Chelsea Snyder
Robert Spaet
Donald Stump
Timothy Teague
Michael Templin
Donald Thompson
Alessandro Venosa
W. Mark Vogel
Lorraine Webster
John Wise
David Woolley
M. Keith Wyatt
Li Yang
ACT Charter Members
(ACT Founded in 1977)
Ed Kerfoot
Sandra Reiss
Bruce Bernard
Mearl Kilmore
Harry Salem
Morris Cranmor
Perry Kurtz
Ceinwen Schreiner
Mike Farrow
Walter Melvin
Van Seabaugh
William George
Robert Osterberg
D.P. Sinha
Robert Hinderer
Matthew Palazzolo
Robert Szot
Edward Jackson
Richard Parent
William Watt
John Johnnidis
John Pollock
ACT Distinguished Fellows
A. Wallace Hayes (2013)
Harry Salem (1998)
Myron Mehlman (1989)
Joe Borzelleca (2012)
Gary Flamm (1989)
Joseph Arcos (1985)
John Thomas (2003)
Art Furst (1989)
149 REFERENCE
Mohamed Abou-Donia
American College of Toxicology
www.actox.org
36thth ANNUAL
ANNUAL MEETING
MEETING
Red Rock Resort • ummerlin, Nevada
s
Call for Proposals
Do you or a colleague have an idea for a scientific Symposium
Session, a speaker, or a Continuing Education course?
If so, consider submitting a 2015 Session Proposal for the
36th Annual Meeting to be held in Summerlin, Nevada.
Your ideas are invaluable to the College and
the success of the Annual Meeting.
The deadline for submission is Friday, February 20, 2015.
Visit ACT’s website to obtain 2015 Session Proposal information.
www.actox.org
150 Reserve Your
Exhibit Booth Today
for 2015!
To reserve your 2015 booth
visit the ACT Registration Desk
or contact exhibits@actox.org
Tel: 703.547.0875
American College of Toxicology
36th Annual Meeting
Red Rock Resort, Summerlin, Nevada
www.actox.org
151 American College
of Toxicology
36
th
th
ANNUAL
ANNUAL MEETING
MEETING
Red Rock Resort
summerlin, Nevada
www.actox.org
152 The American College of Toxicology
would like to thank these meeting sponsors.
Silver $2,500–$4,999
BASi Patricia Frank &
Associates, Inc.
Vet Path Services, Inc.
MPI Research
PreClinical Research
Services, Inc.
WIL Research
Bronze $1,000–$2,499
Calvert Laboratories
CiToxLAB
Eisai, Inc.
Gilead Sciences, Inc.
Lovelace Respiratory
Research Institute
Quidel Corporation
Seventh Wave Laboratories
Society of Toxicology
Southern Research
Tox Path Specialists (TPS), LLC
Shire
Consultant Sponsors
Bill Brock
Brock Scientific Consulting
Chris Chengelis
Chengelis Scientific Consulting Services
Charles Lindamood
CLIII Consulting, LLC
Stephen Montgomery
Sandra Morseth
Michael J. Taylor
NonClinical Safety Assessment
Grace Furman
Stephen Harris
Stephen B. Harris Group
Robert Susick
Paracelsus, Inc.
Susick Consulting, LLC
John Budny
Marian Glynn
Consultant in Nonclinical
Safety Assessment
PharmaCal, Ltd.
Adam Woolley
ProDev Consulting Services, Ltd.
ForthTox Limited
Robin Guy
Robin Guy Consulting
Dennis Naas
Anthony Kiorpes
River Bluff Associates
Tox Clarity
Alan Katz
ToXcel, LLC
The American College of Toxicology
would like to thank these meeting sponsors.
Platinum $10,000+
Gold $5,000–$9,999
Altria

35th Annual Meeting Program - American College of Toxicology

Transcription

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