Cross-species extrapolations and the biologic basis for safety factor determinations in developmental toxicology

Designations of agents as teratogenic or nonteratogenic often are inaccurate, as adverse effects are more a reflection of the timing and severity of treatment during pregnancy than agent nature. Careful consideration of both the similarities and the differences between developmental effects in animals and humans and the extent and nature of the data available are essential for protection of the human conceptus. Animal surrogates prove reliable predictors of human developmental effect levels. When the data are evaluated consistent with contemporary concepts of developmental toxicity, for example, where the effect in the embryo is only seen at maternally toxic doses and exposure is below the adult toxic level, relatively modest safety factors are sufficient for safe cross-species extrapolation. Developmental toxicity safety factor magnitude is predicated on data quality and the fact that thresholds of effect exist in mammalian pregnancy. Safety of human concepti is achieved by considering both the developmental hazard index of the chemicals in question and the severity of exposure.