Implications for the Use of Thyroid Endpoints from Rat Reproductive/Developmental Toxicity Studies in Human Health Risk Assessment. M. K. Peterson, G. M. Bruce, and R. C. Pleus, Intertox Inc.
U.S. EPA guidelines for reproductive and developmental toxicity risk assessment of environmental chemicals recommend assuming that an agent that produces adverse reproductive effects in experimental animals (e.g., in the rat) poses a potential threat to humans. Often rat studies are the primary data available for human health risk assessment; however, application of these data in determining if and under what conditions an agent causes reproductive toxicity can be confounded by the numerous physiological and pharmacokinetic differences between animals and humans. We discuss the risk assessment implications of some of these interspecies differences between rats and humans with regard to xenobiotics whose critical effect is on the thyroid system. Data on normal levels of thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) in maternal and prenatal rats and humans during gestation, as reported in experimental controls, were collected to determine the relevance of thyroid hormone perturbations in rats to predicting effects in humans. In prenatal humans, concentrations of these three hormones increase through gestation; trends in the prenatal rat are similar. However, trends in concentrations of the hormones in maternal rats and humans were distinctly different. These differences reflect the distinct variation between the thyroid endocrinology of the rat and human are during gestation, and raise questions regarding the applicability of changes in thyroid hormones in rat reproductive toxicity studies as the basis for human health risk assessment.
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