Teratogenicity Testing

Danielsson BR, Bengt R. Danielsson, Danielsson, Bengt R.

Although demonstration of some degree of maternal toxicity is required in regulatory developmental toxicology studies, marked maternal toxicity may be a confounding factor in data interpretation. Reduction in maternal body weight gain is the far most frequently used endpoint of toxicity, but alternative endpoints, like organ toxicity or exaggerated pharmacological response, can also be taken into consideration. The following conclusions are based on literature data and discussions at maternal toxicity workshops attended by representatives from regulatory agencies, academia, and industry: (1) Available results do not support that maternal toxicity (defined as clinical signs, decreased body weight gain or absolute body weight loss of up to 15% in rats or 7% in rabbits) can be used to explain the occurrence of major malformations. (2) There is clear evidence that substantial reductions in maternal weight gain (or absolute weight loss) are linked with other manifestations of developmental toxicity. Among these can be mentioned decreased fetal weight, and skeletal anomalies (e.g., wavy ribs) in rats and decreased fetal weights, post implantation loss, abortions, and some skeletal anomalies in rabbits. (3) There are several examples of misinterpretation among companies, where it was incorrectly expected that regulatory authorities would not label chemicals/drugs as "teratogens/developmental toxicants" because embryo fetal adverse effects were only observed at doses also causing signs of maternal toxicity. (4) Similarly, even if mechanistic studies indicate that a substance causes developmental toxicity via exaggerated pharmacological effects in the mother, such a mechanism does not automatically negate the observed fetal adverse effects.From a regulatory perspective, an observed developmental toxic finding is considered to be of potential human relevance (even if it is mediated via maternal pharmacological effects or occur at doses causing signs of maternal toxicity) unless the company can provide appropriate mechanistic and/or other convincing evidence to the contrary.