Consideration for dose level selection for DART studies...

Considerations for dose level selection for developmental and reproductive toxicity studies: 3Rs and scientific perspectives

Following advice on dose selection issued by the European Chemicals Agency (ECHA) in 2022 for reproductive toxicity studies conducted under REACH, this presentation will cover the implications for, and impact on, study outcomes and interpretation for different chemicals and sectors. The ECHA advice followed an evaluation of existing extended one-generation reproductive toxicity (EOGRT) studies with respect to design, conduct and toxicological findings, and concerns that potential hazardous effects could be missed due to inadequate dosing. The resulting advice specified that the highest dose tested should “demonstrate an aim to induce clear evidence of reproductive toxicity without excessive other toxicity and severe suffering in parental animals (e.g. prostration, severe inappetence (lack of appetite), excessive mortality as signs of severe suffering) that would compromise the interpretation of co-occurring reproductive effects.” This poses several challenges in terms of animal welfare and human safety goals. The recommendations have been evaluated by several expert groups, including the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), in relation to advice in existing Organisation for Economic Cooperation and Development (OECD) test guidelines and guidance document, such as humane endpoints and the maximum tolerated dose, and also discussed at recent scientific meetings, including EUROTOX and SOT. The results of these discussions will be summarised. Whilst there is a shared goal of ensuring a high level of human health protection, this must be balanced with scientific pragmatism to minimize impact on animal welfare. Therefore, it is recommended that dose selection should be based on a biological approach that considers factors such as maternal clinical signs of toxicity, food consumption/nutritional intake, clinical chemistry parameters, circulatory/cardiovascular changes, target organ toxicity, maternal stress and toxicokinetics. 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.