The Henry Stewart Annual Briefing
on

Current Thinking, Problems
and Solutions
in
Reproductive, Developmental and Endocrine Toxicity Studies

Chair:
Paul M.D. Foster
Senior Fellow
National Institute of Environmental Health Sciences

Speakers:
Robert E. Chapin
Research Advisor
Groton Laboratories, Pfizer

Ralph L. Cooper
Chief, Endocrinology Branch,
MD-72
RTD, NHEERL, U.S. Environmental Protection Agency

John DeSesso
Senior Fellow and Director
Mitretek Systems

Ben Fisher
Study Director, Manager in DART
Mammalian Toxicology
Covance

Joseph F. Holson
President, Director
WIL Research Laboratories, Inc.

Thomas B. Knudsen
Professor
University of Louisville, Birth Defects Center

Christopher Lau
Pharmacologist
Developmental Biology Branch
Reproductive Toxicology Division
National Health and Environmental Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency

Donald R. Mattison
CAPT, US Public Health Service
Senior Advisor to the Directors of NICHD and CRMC
National Institutes of Health, HHS

William Slikker, Jr.
Director, Division of Neurotoxicology
National Center for Toxicological Research/FDA

Steve Teo
Associate Director
Nonclinical Development and Experimental Medicine
Celgene Corporation

Rochelle W. Tyl
Research Director
Life Sciences and Toxicology
RTI International

 

Satisfying the Regulators
• What do the regulators want?
- the FDA
- the EPA
- other regulatory agencies
• What do the current regulatory guidelines require us to do and when?
- pharmaceuticals versus other chemicals
• Animal : human concordance studies for prenatal toxicity
• Examining the relationship between maternal toxicity and fetal outcome in humans
• What are the answers to the twelve “key questions” that will be asked by regulators?
Joseph F. Holson
President, Director
WIL Research Laboratories, Inc.

Male Reproductive Toxicants: From the Fetus to the Adult
• Current investigations which explore the action of chemicals and pharmaceuticals on the development of the male reproductive system
• Adequacy of our current testing protocols to characterize these changes
• Targets for the action of chemicals on the male reproductive system
• Testicular histopathology
• Sperm parameters and the correlation to reproductive performance
• Significance of changes in sexually dimorphic end points e.g. anogenital distance, retention of nipples
• Malformations of the male reproductive tract
• Consequences of in utero changes to the adult
• New molecular approaches to aid the understanding of the mode of action of these agents
Paul M.D. Foster
Senior Fellow
National Institute of Environmental Health Sciences

Female Reproductive Toxicology
• Current tests
- how to determine the female endpoints
- enhanced multigenerational protocol
• Update on EPA’s endocrine disruptor screening and testing protocols
• Special studies
- harmonizing cancer and non-cancer effects
o what endpoints?
o what do endocrine measures tell us?
Ralph L. Cooper
Chief, Endocrinology Branch, MD-72
RTD, NHEERL, U.S. Environmental Protection Agency

Design and Evaluation of Developmental Toxicology Studies
• Events in the female reproductive tract from copulation through implantation
• Dose-response patterns for developmental toxicity endpoints
• Interactions among developmental toxicity endpoints
• Gestational stage and developmental susceptibility as they relate to exposure periods
• Interspecies differences: those that matter and those that don’t
• Maternal toxicity and its impact on interpretation
• Appropriate use of concurrent and historical data
• Considerations when attempting to resolve a putative positive developmentally toxic effect
John DeSesso
Senior Fellow and Director
Mitretek Systems

Reproductive Toxicology of Thalidomide
• The road to thalidomide approval in the US
• Regulatory issues in teratology
• Post-approval studies
- fertility and general reproductive toxicity in rabbit
- developmental, peri and postnatal toxicity in rabbit
• Controlling and monitoring access to thalidomide: the STEPS® program
• Future of the thalidomide/IMiD® class of compounds
Steve Teo
Associate Director
Nonclinical Development and Experimental Medicine
Celgene Corporation

Living with New Endocrine-Relevant Testing Guidelines and Endpoints
Since the 1996 Congressional mandate to identify endocrine disruptors, the U.S. EPA OPPTS, FDA, OECD, etc., have established new or enhanced testing guidelines with new endocrine-relevant endpoints. Many laboratories have performed studies under these new testing guidelines (as well as studies not [yet] included in testing guidelines) with the new endpoints.
Dr. Tyl will describe the new study designs and the new endpoints, with examples of data collection and interpretation, strengths and weaknesses (e.g., anogenital distance, vaginal patency, preputial separation, ovarian primordial follicle counts, andrology, histopathology, circulating hormones), and provide suggestions for the next iteration of these testing guidelines.
Rochelle W. Tyl
Research Director
Life Sciences and Toxicology
RTI International

Embryonic and Fetal Origins of Adult Physiological Disorders
The “Barker hypothesis” postulates that a number of organ structures and functions undergo programming during embryonic and fetal development, which in turn determines the set points of physiological and metabolic responses in adult life. Alterations of these set points and/or changes in the adult environment will therefore predispose an individual to disease states. Results derived primarily from epidemiological data have discovered strong inverse correlations between birth weights and the risk of coronary heart disease, hypertension and type 2-diabetes. The speaker will examine the basis of the “Barker hypothesis”, highlight corresponding animal models that may provide clues for the underlying mechanism and its implications for developmental toxicology.
Christopher Lau
Pharmacologist
Developmental Biology Branch
Reproductive Toxicology Division
National Health and Environmental Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency

Is that all there is?! - Sharpening our Tools
• Hormones are critically important yet impossible to quantify. What approaches are being explored to bring some certainty to measuring hormone levels, what are the prospects for some real advances in this area?
• Biomarkers for seminiferous tubule damage, their reliability and their performance
• Risk assessment questions that you should ask as you go forward into the clinic with a compound which has some male reproductive signals
Robert E. Chapin
Research Advisor
Groton Laboratories, Pfizer

Assessment of Developmental Toxicity and the Safety/Efficacy of Pharmaceuticals - The Role of Development
• Developmental trajectories
• Drug development in the context of developmental trajectories
• Implementation of the “Best Pharmaceuticals for Children Act”
Donald R. Mattison
CAPT, US Public Health Service
Senior Advisor to the Directors of NICHD and CRMC
National Institutes of Health, HHS

Post Natal Toxicity Assessment
• Susceptibility of the Neonate
• Continuous development - drugs can’t alter development, but development can alter drugs
• ICH Tripartite Guideline 4.1.2 versus The Pediatric Rule
- historical perspective
- guideline stringency
• Pre- and post natal studies
- rationale, "appropriate endpoints", limitations
• Pediatric/juvenile studies
- what is the appropriate design (species, dosing window, endpoints)?
• What are the benefits?
Ben Fisher
Study Director, Manager in DART
Mammalian Toxicology
Covance

Developmental Neurotoxicology: Approaches for Risk Assessment
• Assessment tools: neurobiology, physiology, pathology and behavior
• Tiered approaches
• Systems biology approaches
• Quantitative risk assessment approaches
William Slikker, Jr.
Director, Division of Neurotoxicology
National Center for Toxicological Research/FDA

Synthesis of Experimental and Computational Approaches for Developmental Toxicity
High throughput data acquisition and the open database movement have enabled predictive model building in simple organisms and study systems. But, it is only when high-throughput data streams are properly aligned with inferential entailment and plausible biological hypotheses that we can ever hope to tap the substantial predictive power of toxicogenomics. This presentation will review the current research and technology pipeline for biological inference and plausibility in developmental toxicity. Of specific interest is the computational analysis of developing systems and responses to drug and chemical exposure.
• Linking differential gene expression with developmental origins of disease
• Meta-analysis tools and resources to find common pathways in drug/chemical injury
• Communication and control systems (biological regulatory networks)
• Applications to safety assessment
Thomas B. Knudsen
Professor
University of Louisville, Birth Defects Center