Extrapolation Models in Teratogenesis

摘要

The teratology literature (over 500 articles) contained in the Environmental Teratology Information Center, Toxline, Medline and selected major journals (Teratology, 1968-1979 and Toxicology and Applied Pharmacology, 1959-1979) was screened for dose-response studies and 53 were found which met the following criteria: (1) used approximately 3 doses, (2) employed approximately 10 animals/dose, (3) dose-dependent effects were found, and (4) a complete and interpretable presentation of data allowed retrospective analyses. Utilizing this literature survey, several factors influencing the dose-response curve for the extrapolation model were examined. Special attention was directed to pharmacokinetics and the use of computer modeling to enhance understanding of linear/nonlinear dose-response relationships, in addition to the specific 'window' or period of teratogenic sensitivity. Six factors influenced the slope of the dose-response and the discernibility of teratogenic thresholds: (1) experimental design of the study, (2) potency of the teratogen, (3) type and combinations of endpoints examined, (4) developmental periods of sensitivity and repair, (5) placental transfer of the agent, and (6) maternal homeostasis and pharmacokinetics.