A Practical Approach, Second Edition=Ronald D. Ho.pdf

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 361From the data presented in Table 9.16 and Table 9.17, the sensitivity and specificity limitationsintrinsic to the referenced screens are apparent. Strong conclusions regarding developmental andreproductive hazards can be drawn only from definitive studies containing adequate sample sizes,multiple endpoints, appropriate treatment duration, and ideally, some assessment of internal exposure(TK).The screening studies examined above are short-term experiments used to select and/or sort aseries of molecules on the basis of developmental and reproductive toxicity potential. These studiesmay be used to predict potential hazard, but the results generally cannot be used for risk assessment.Heuristically, two axioms have arisen: (1) if the primary intent of the screen is to reduce the numberof animals used, careful consideration must be given to the possible necessitation of subsequentstudies because of poor characterization of the dose-response curve, and (2) if the intent of thescreen is to reduce resource consumption, an analogy to the first point exists with the exception ofthe application to agents not developed for biologic activity, with limited human exposure andeconomic significance.C. Converging DesignsDose range-characterization studies can converge with screening studies for selected purposes. Thisconvergence often occurs in development of drugs in particular pharmacologic classes. An examplein the authors’ laboratory is a hybridized dose range–characterization and definitive embryo andfetal development study that was employed to screen retinoic acid analogs for teratogenic potency.The hybridized design utilized more animals than are typically employed for dose range-characterizationbut fewer than would be necessary for a definitive study. Generally, several candidateanalogs were evaluated concomitantly at high dose levels with one concurrent control group andone comparator group treated with a known potent analog (all-trans-retinoic acid). Teratogenicpotency was determined through a postmortem examination of greater scope than is regularlyemployed for a dose range-characterization study, as it consisted of both visceral and skeletalcomponents. Those analogs with the least expression of the classic terata were identified as potentialcandidates for further development. This type of specialized screening study can be adapted forother pharmacologic classes possessing known teratogenic potential. This, however, is only possiblewhen the investigator is able to correlate the selected study endpoints with a known overall patternof developmental effects. Furthermore, since teratogenic responses to certain classes of compoundsare well known and expected, an abbreviated treatment regimen could be employed, targeting acritical, susceptible period of organogenesis.V. DEVELOPMENTAL TOXICITY STUDIESThis section begins with a presentation of the key differences between various regulatory guidelinerequirements for developmental toxicity studies, including a brief discussion on the importance ofanimal models as well as the timing and duration of treatment. The interrelatedness of endpointsis discussed relative to both development (or delay thereof) and to the complexities of unravelingany interaction between developmental and maternal toxicity. A discussion of specific endpointsfrom these studies, within the context of the various interrelationships that may occur, is presentedwith historical control data to aid in determining toxicologic relevance. An in-depth evaluation ofthe challenges inherent in interpretation of fetal morphology data, including an exposition ofexperimental considerations relative to these critical examinations, is then presented. The sectionconcludes with case studies from the authors’ laboratory, illustrating the difficulties inherent ininterpreting the significance of several fetal developmental variations.© 2006 by Taylor & Francis Group, LLC