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

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 337Table 9.7 Relationship between maternal and fetal toxicityfor established human developmental toxicantsEmbryo and fetal toxicity produced at or near exposure levels that elicitovert maternal toxicity:• Aminopterin• Methylmercury• Polychlorinated biphenylsEmbryo and fetal toxicity produced at exposure levels that cause maternalphysiologic changes or stress:• Cigarette smoking• Steroidal hormones• Ethanol consumptionEmbryo and fetal toxicity produced at exposure levels that do not producesignificant maternal effects during pregnancy:• Ionizing radiation• Diethylstilbestrol• ThalidomideSource: Adapted from Holson, J. F., Estimation and extrapolation of teratologicrisk, in Proceedings of NATO Conference on in vitro Toxicity Testingof Environmental Agents: Current and Future Possibilities, NATO, MonteCarlo, Monaco, 1980.area, corporate representatives, animal rights activists, and lay people are often confused or misguidedby inconsistencies in technical reports or lay publications that allege differences betweenhuman experience and animal studies. Such allegations present a problem for the future of thediscipline because they have contributed to past catastrophes. In Table 9.9, an attempt has beenmade to summarize the reasons for the high frequency of such misrepresentations. These reasonsare self-explanatory, with the exception of the last entry, which the authors have included out ofnecessity because none can predict all possibilities for the future. No established or generallyaccepted example of an agent that has adversely affected human development but has not inducedadverse developmental effects in an animal model currently exists. The reader is referred to theoriginal assumptions made in the NCTR study to better reconcile the reasons for apparent discrepancieslisted in Table 9.9.Developmental toxicity studies in laboratory animals provide the only controlled and ethicalmeans of identifying the potential risks of a large array of drugs, chemicals, and other agents tothe developing human embryo and fetus. However, they cannot replace direct human evidence orexperience. Often, the findings from the animal models will be supplemented by confirmation inpregnancy registries. These registries involve collection of information from human pregnanciesthrough use of questionnaires and may be conducted after product approval and/or marketing.However, pregnancy registries are variably sensitive, and rarely serve as early predictors of developmentalhazard. Therefore, the design and interpretation of results from animal developmentaltoxicity studies are critical to the hazard identification phase of risk assessment, and in the case ofequivocal findings, such studies will guide the use of postmarketing registry analyses.B. Animal-to-Human Concordance for Reproductive ToxicityReproductive toxicology is also a complex field of science, as many authors of textbooks and reviewarticles have declared in their opening paragraphs. The reason for this complexity is that sexualreproduction involves the union of gametes from two genders, resulting in progeny that in turnexperience development and maturation of the myriad processes that enable continuation of the“life cycle.” That cycle comprises several life stages, each having a unique biology and temporallyentrained acquisition of features. Reproductive physiology (and its dynamic anatomy) includes© 2006 by Taylor & Francis Group, LLC