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

340 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITION30002500No. of Animals/Study2000150010005000Acute OralToxicitySubchronicToxicity2-Year CancerBioassayDevelopmentalToxicity2-GenerationReproductionFigure 9.2Comparison of the number of animals on study in various experimental designs.Changes in a specific reproductive process in which the mode of action is well understood andconserved among species are considered a clear threat to human health. Command of the issueswill afford the most enlightened use (or will prevent misuse) of the data for the intended purpose.Reproductive and developmental toxicity studies are large in scale and complex (Figure 9.2). Nomatter what systematic approach is applied to the data to formulate conclusions, the final interpretationmust consider interrelated endpoints collectively if the risk assessment process is to proceedefficiently and effectively.One potential problem related to extrapolation of reproductive hazard from animals to humansis embedded in the phenotypic diversity of humanity. Expansion of the human population overmany years has given rise to a heterogeneous gene pool. Animals that are purpose-bred forexperimental applications are genotypically more homogeneous than, and less predictive of, theoutlier responders in the diverse human population. The logical assumption is that humans are morelikely to be predisposed to idiosyncratic toxicologic responses. A second potential problem is thatwith reproductive toxicity, as compared to developmental toxicity, there are many more structuresand processes in the maternal and paternal animals that may be affected or manifest toxicity. Thisis in contrast to prenatal development, with its highly conserved embryo and fetus, which has amuch more limited phenotypic variety among species. While some phenotypic diversity may existin embryos and fetuses among species, it is certainly far less than in the adult life stage, in whichnumerous structures reside in either or both of the parental sexes. Hence, caution must be exercisedwhen extrapolating effects from animal models to humans for many aspects of reproductive toxicity.Nevertheless, the finding of reproductive toxicity in a well-conducted guideline study should beconsidered to constitute a strong signal, which currently could be negated only by appropriateinformation on mode of action or the existence of an adequate study in humans. The use ofepidemiology has become increasingly important in establishing cause and effect relationships. 19It is an essential scientific need that an organized and critical analysis of the primary literaturein reproductive toxicology be conducted to evaluate the concordance of regulatory reproductivetoxicity studies to human reproductive outcomes. Such a study would need to be modeled after theFDA-NCTR study discussed in the beginning of this chapter. Assumptions for inclusion andexclusion of papers, consideration of power, establishment of exposure parameters, and criteria forconcordance would need to be developed and used.Figure 9.3 is an idealized depiction of the relationship between progression of time in developmentand the degree of phenotypic variability, both on an ontogenic and species basis. The earlier© 2006 by Taylor & Francis Group, LLC