Members:
Amgen, Inc.
AstraZeneca
Bayer CropScience
Bristol-Myers Squibb Company
Dow Chemical Company
E.I. du Pont de Nemours and Company
Endo Pharmaceuticals
GlaxoSmithKline Inc.
Hoffmann-La Roche, Inc.
Merck Research Laboratories
Novartis Pharmaceuticals Corporation
Pfizer, Inc.
The Procter & Gamble Company
Purdue Pharma, L.P.
sanofi-aventis
Public Sector Participation:
European Agency for the Evaluation of Medicinal Products
Georgetown University
Johns Hopkins University
Medical University of South Carolina
State University of New York
U.S. Environmental Protection Agency
U.S. Food and Drug Administration
U.S. Food and Drug Administration, National Center for Toxicological Research
U.S. National Institute of Environmental Health Sciences
University of Arizona
University of California – Davis
University of Maryland
University of Nebraska
Wake Forest University
The Weinberg Group
Project: Role of Juvenile Animal Studies in Assessments of Pediatric Safety
It has long been recognized that important stages of development continue postnatally in both humans and animals. Recent attention to children’s health has driven the need to improve safety assessments for pediatric populations. Compliance with the FDA Pediatric Rule and current EPA regulations has led to a rapidly increasing demand for juvenile animal studies. However, it is increasingly recognized that there are many challenges to the determination of when juvenile animal studies are needed to provide assessments of safety and further, the necessary scientific basis to design reasonable studies may not exist. This project was undertaken to provide information that will become the foundation for design and interpretation of juvenile animal studies.
Project Objectives:
Conduct a literature review focused on clinically relevant endpoints of comparative postnatal development. Target systems include male and female reproduction, CNS, bone, kidney, immune, and cardiovascular.
Review clinical experience for pediatric toxicity.
Define decision process to determine when juvenile animal studies are needed to provide safety assessments.
Propose effective study designs and testing strategies.
Address the questions of need and/or utility of pharmacokinetics in juvenile animals.
In 2004:
- Proceedings published from November 2003, “Workshop on Juvenile Animal Studies: Testing Strategies and Design” in Birth Defects Research – Part B. Some 120 scientists from the regulatory community, academia, and industry in North America and Europe met to identify testing strategies for juvenile animal studies, and agreed that case-by-case determinations should be made as to when juvenile animal studies are needed. Key considerations for each case should include the patient population, the relevant adult organ toxicity, the mechanism(s) of action, and class effects. They further agreed that one species is sufficient for each study, and the preferred species is generally the rat. Toxicokinetics or pharmacokinetics should be part of the study.
- Adding to the reviews of post-natal development of a range of organ systems already published as part of this project, reviews of the gastro-intestinal system and postnatal anatomic development of the central nervous systems are anticipated shortly.
- A review of common clinical manifestations of pediatric toxicity and their relationship to juvenile animal testing is also under way
Project Chair: Mark Hurtt, Ph.D., Pfizer
Project: Neurobehavioral Assessment – Use and Value in Safety Assessment Studies
For many years, behavioral testing of F1 animals exposed to drugs in utero and/or neonatally has been a routine component of new drug and chemical safety assessment/toxicology programs. Thus, a large amount of data and experience exists on the use and interpretation of behavioral testing paradigms. The primary objective of this project was to evaluate the contribution of such behavioral testing, with regards to hazard identification and characterization, to safety assessment studies.
In 2003, DART published a report in the journal Toxicological Sciences, with the results of its project to address behavioral testing. Data were analyzed from a survey of tests results of pharmaceutical, agricultural and industrial compounds from industrial laboratories in the United States, Europe, and Japan. The analysis showed that, although affected by agents less often than general toxicology parameters, F1 behavioral parameters along with other parameters defined the no effect level (NOEL) in 17/113 (15%) studies, and solely defined the NOEL in 3/113 (2.6%) studies, and thus sometimes improved on the standard toxicological measures of hazard identification. Results noted in the report were presented in a roundtable discussion at the 2004 Annual Meeting of the Society of Toxicology.
A follow-up activity to the project has begun, and is anticipated to result in an opinion paper on the specific value of these types of tests, and on possible triggers for the tests. DART is exploring the conduct a workshop on the issue in late 2005 or early 2006.
Project: Interpretation of Skeletal Variations for Human Health Risk Assessment
Project Objective: To assess the relevance of skeletal variations in predicting adverse developmental outcomes:
- Are skeletal variants mechanistically related to malformations?
- Relationship between skeletal variants in experimental animals and abnormal human development
- Molecular control of skeletal development, including growth factors, hormones, specific genes
- Mode of chemical action to induce skeletal variations
- Implications for current risk assessment practices.
Project Deliverables and Potential Impact:
- Series of papers being finalized for submission to Birth Defects Research – Part B
- Guidance to regulatory agencies and industry on how to evaluate skeletal variations for human risk assessment
- Possible precedent for use of molecular level data in risk assessment
- Will foster more consistent approach to evaluations
- Precedent for evaluation of fetal data from other organ systems.
- Publication anticipated in Spring 2005.
Chairs: George Daston, Ph.D. (Procter & Gamble); Jennifer Seed, Ph.D. (U.S. EPA)
Project: Definitive Histopathology Text of Female Reproductive Physiology
The DART committee has acknowledged the need for a publication that clearly correlates circulating female hormones with the vaginal smears and histology of the ovary, uterus, vagina and mammary gland in rodents, canines, and primates. This is a need that many pathologists feel most acutely: they have no good source to turn to for a clear description of what the normal process is, what the normal interactions are, and what the characteristics of one tissue’s appearance means to the appearance of another part of the system, and how one can use these tissues interdependently to understand what’s going on. A team of authors has been identified to assemble this definitive text. The book will contain case studies illuminating how to go about unraveling a problem in female reproductive toxicology - identifying the key experimental drivers, experiment sequencing and construction, etc. Publication is anticipated in Spring 2005.
Book chapters and cases include:
- Development, Growth, and Evaluation of the Rodent Mammary Gland
- Assessing the Mammary Gland of Nonhuman Primate
- Female Rodent Vaginal Cytology and Interpretation
- Basics of Ovarian Histomorphology with respect to Toxicologic Histopathology
- Spontaneous Lesions in the Reproductive Tract of Female non-Human Primates
- Rodent Vaginal and Uterine Morphology during the Estrous Cycle
- Estrous Cycle-Dependent Histology and Review of Sex Steroid Receptor Expressions in Dog Reproductive Tissues and Mammary Gland
- Estrous Cycle of the Dog: Physiology and Histology
- Spontaneous Pathology of the Rodent Reproductive Tract
- Primate Endometrium: Histomorphology and Physiology
- Physiology and Endocrinology of the Primate Ovarian Cycle
Case Studies:
- Tibulone: Qualitative & Quantitative Assessments of the Mammary Gland
- Atrazine
- Problem-solving Ovarian-specific Reproductive Toxicants
- Development of Animal Model for Ovatoxicity using 4-vinylcyclohexane
- Histologic Changes in Ovary, Uterus, Vagina, and Mammary Gland of Mature Beagle Dogs Treated with SERM Idoxifene
- Identification of Drug-Induced Hypo/Hyperprolactinemia in the Female Rat
- Dietary Effects on Mammary Tissue: Exploiting Individual Variations in Responses
Editors: Robert Chapin, Ph.D. (Pfizer), Barbara Davis, Ph.D. (National Institute of Environmental Health Sciences)
Project: An Evaluation and Interpretation of Reproductive Endpoints for Human Health Risk Assessment
One of the DART Committee’s initial efforts focused on scientific issues related to the evaluation and interpretation of nontraditional reproductive endpoints. The goal of this project was to assess and build consensus among the various sectors of the scientific community (academic, industry, and government) regarding the value, application, and interpretation of both commonly measured and nontraditional reproductive endpoints for the purposes of characterizing the potential reproductive toxicity to humans of various chemical agents. The project was completed in four phases:
- A literature review to determine what is known about the measurement and interpretation of data on nontraditional reproductive endpoints. The endpoints included oocyte quantitation and ovarian histology, sperm parameters and testis histology, vaginal cytology, circulating hormones, reproductive performance, and endpoints of reproductive system development.
- A group of experts from government, industry, and academia was convened to draft and review a series of working papers on each endpoint.
- The committee sponsored a workshop on the “Evaluation and Interpretation of Reproductive Endpoints for Human Health Risk Assessment” on November 12-14, 1997, in Washington, D.C. All participants, including observers, reviewed and submitted comments on the “working papers” on the six reproductive endpoints in advance of the workshop. The goals of the workshop were to review the working papers and determine where consensus exists and where there are gaps in the knowledge base.
- A consensus report was produced from the draft endpoint papers, the written comments and the proceedings of the workshop, and was made available for distribution in December 1998.
- The committee determined that a re-review of the state of the knowledge should be conducted in five years.
DART is now conducting a broad-based re-evaluation of these endpoints. Included in the effort are a data call-in (completed in 2004), collation, and analysis, involving a statistician and blinded data. These data have been contributed by ~35 laboratories, companies and agencies that have conducted EPA guideline studies. Once the collation and analysis of the data are completed, the project committee will develop provisional conclusions. A public workshop will be held in the fall of 2005, to share the preliminary conclusions and reach consensus on the value of the endpoints. Implementing the recommendations from this workshop should result in the best balance of resource use and complexity vs. ability to identify toxicities.
Project committee: Robert Chapin, Ph.D. (Pfizer); Ralph Cooper, Ph.D. (U.S. EPA); George Daston, Ph.D. (Procter & Gamble); Jodi Flaws, Ph.D. (University of Maryland); Paul Foster, Ph.D. (National Institute of Environmental Health Sciences); Susan Makris, Ph.D. (U.S. EPA); M. Sue Marty, Ph.D. (Dow Chemical Company); John O’Connor, Ph.D. (DuPont); J. David Sandler (HESI); Shelly Tyl, Ph.D. (Research Triangle Institute)
Consultant: Bruce Allen, Ph.D. (Environ)