Hierarchization of animal teratology findings for improving the human riskevaluation of drugs

The risk assessment of drugs in pregnancy can be improved through better kn owledge and interpretation of significant experimental findings. Embryo-fet al effects can be considered as the endpoint of importance, after excluding that their occurrence is related to maternal toxicity. If embryo-fetal tox ic effects occur in the presence of maternal toxicity, the dam influence sh ould be clearly assessed, and can be taken into account in the determinatio n of a safety margin. A determination of the lowest developmental toxic dos e, if any, apart from any maternal toxicity, should be made. With positive animal developmental findings, interpretation should take into account vari ous parameters including the incidence and the severity of the embryo-fetal insult, interspecies reproducibility, the level of exposure, metabolic pat hways, and the results of possible mechanistic investigations. Hierarchizat ion of the experimental findings should take into account all these paramet ers together to provide support for the risk assessment in humans. (C) 2000 Elsevier Science Inc. All rights reserved.