Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies

• Published in: Regulatory toxicology and pharmacology Vol. 148; p. 105585
• Main Authors: Lewis, R.W., Andrus, A.K., Arroyo, J., Brescia, S., Botham, P.A., Corvaro, M., Daston, G.P., Hofmann, T., Rodriguez, C., Sewell, F., van Ravenzwaay, B., Wiench, K., Marty, S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.03.2024
• Subjects: 3Rs; Animal welfare; Animals; Body Weight; Dose selection; Ecotoxicology; Humans; Maximum tolerated dose; Regulatory guideline studies; Reproduction; Reproductive and development toxicity; Toxicity Tests; Weight Gain; Regulatory guideline studies; Maximum tolerated dose; Animal welfare; Reproductive and development toxicity; 3Rs; Dose selection
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2024.105585

In 2022, the European Chemicals Agency issued advice on the selection of high dose levels for developmental and reproductive toxicity (DART) studies indicating that the highest dose tested should aim to induce clear evidence of reproductive toxicity without excessive toxicity and severe suffering in parental animals. In addition, a recent publication advocated that a 10% decrease in body weight gain should be replaced with a 10% decrease in bodyweight as a criterion for dose adequacy. Experts from the European Centre for Ecotoxicology and Toxicology of Chemicals evaluated these recent developments and their potential impact on study outcomes and interpretation and identified that the advice was not aligned with OECD test guidelines or with humane endpoints guidance. Furthermore, data analysis from DART studies indicated that a 10% decrease in maternal body weight during gestation equates to a 25% decrease in body weight gain, which differs from the consensus of experts at a 2010 ILSI/HESI workshop. Dose selection should be based on a biological approach that considers a range of other factors. Excessive dose levels that cause frank toxicity and overwhelm homeostasis should be avoided as they can give rise to effects that are not relevant to human health assessments. •ECHA's advice to increase dose levels in reproductive (DART) studies is evaluated.•Recommended high dose criteria contrary to OECD guidelines and DART experts' opinion.•Excessive dose levels may cause irrelevant secondary effects on reproduction.•Dose selection should consider the complexity of the maternal-placental-fetal model.