ABSTRACT
Basis of the Chapter In the second edition of this book, the authors’ goal was to produce the first in-depth publication on the interpretation of guideline developmental and reproductive toxicity study findings. During the past two decades, increasing numbers of individuals without training in either of these disciplines have begun working in areas requiring the oversight, execution, and interpretation of these types of toxicity studies. For this reason, the authors have supplemented the data interpretation theme with information concerning the significance and reliability of the studies. While recognizing that developmental toxicology is a
subdiscipline of reproductive toxicology, the authors have separated them for reasons of convenience when examining these complex topics. However, regulatory protocol designs may entail exposure during and evaluation of both reproduction and development. The “significance” aspect of this chapter is presented initially
to demonstrate the scientific basis for viewing these studies as strong signals of potential human hazard. The “reliability” components of this chapter are interspersed, as they are associated with the particular measures or procedures of import. The sections on interpretation constitute the remainder of the chapter. The guidance provided in this chapter is in part based on the
extensive database at WIL Research Laboratories, LLC (WIL) and is augmented by selected reports from the open literature. For 25 years, WIL has been one of the contract research organizations conducting large numbers of reproductive and developmental toxicity studies for regulatory submission. The authors have been involved with the oversight, review and/or interpretation of more than 1500 such studies over a composite of 80 person-experience years. The experience gained at our laboratory is based on consistent management, staffing, and methodologies, with studies conducted primarily at a single facility maintaining best husbandry practices, training, and progressive approaches. In addition, many exploratory, investigative and mode-of-action studies have been designed and conducted to verify and/or clarify findings or elucidate modes of action for a wide array of products and chemistries, thus providing additional information concerning variability and validity of certain endpoints. Central themes of this chapter include the following:
(i) validity and concordance of experimental animal studies
to human outcome scenarios for both developmental and reproductive toxicity endpoints; (ii) analyses of selected aspects of the guidelines and their effects on reliability of the data; (iii) appropriate statistical paradigms, in simple language, with computational examples; (iv) critique and guidance relative to experimental techniques; (v) data for selected anatomic variants and other key measures common to these studies; (vi) guidance for interpretation of substatistical findings (including rare events); and (vii) the role of kinetic data in the interpretation of study outcomes. It is not possible to cover all contingencies or combinations
of findings in the limited space of this chapter. For example, in a single developmental toxicity study the possible number of permutations of the variables may exceed tens of thousands. The numerous values and trigger levels of various endpoints cited herein probably extrapolate to other laboratory venues, databases, and experimental scenarios. However, exceptions may occur because of the differences in levels of control of husbandry, training, and consistency of applying state-of-thescience standard operating procedures. In the final analysis, however, recognition of the interrelatedness of various endpoints is the basis for study interpretation.
