Chairperson(s): John M. DeSesso, Exponent, Alexandria, VA; and Anthony R. Scialli, Scialli Consulting LLC, Arlington, VA.
Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section
Reproductive and Developmental Toxicology Specialty Section
Mammalian embryo-fetal development comprises a complex and carefully orchestrated set of activities that can be perturbed by maternal and environmental factors. Perturbations of developing offspring can result in no discernible effect, reduced fetal weights at term, increased prevalence of anatomical variations, congenital defects, and/or the demise of the offspring. This course will focus on preclinical species and will begin by providing an overview of mammalian development, including important gestational milestones, comparative interspecies timelines, and definitions of critical periods in development. Next we will discuss how this information has factored into the design of traditional preclinical studies. The presentation will conclude with a brief introduction to normal variability in some organ systems. This variability is the source of considerable controversy when interpreting traditional developmental toxicity safety
tests. Succeeding presentations will discuss two organ systems that are the center of debate among scientists charged with extrapolating results found in safety assessments to potential human risk. The normal embryological development of the first organ system to function, the cardiovascular system, will be described with consideration of normal anatomical variations and nonadverse structural changes. The second organ system to be described is the skeletal system. Particular attention will be paid to its state of maturity at term in various species, the potential influence of maternal toxicity on skeletal maturation, and postnatal development of the skeleton throughout the lactation period. The final presentation will address the development of new testing methods that might be used to prioritize substances for testing or even to replace whole animal testing for developmental toxicity. The presentation will describe basic methods for whole embryo culture, embryonic stem cell test, and a Zebrafish assay, along with various proposed improvements in each. It will finish with some thoughts about integrating the results from multiple assays, and a survey of the regulatory landscape for these emerging methods. Information from the preceding presentations will provide the audience with an understanding of how the biological basis
of prenatal developmental toxicity testing and the results of such tests should impact risk assessment and ultimately, the rationale for the design and use of drugs and chemicals that minimizes environmental impact and ensures human health.