Exposure and dose selection

Better consideration of exposure within toxicological testing is necessary to ensure that the data generated are relevant to answer the scientific questions being asked. For example, measurement of internal test compound concentrations (toxicokinetics) can aid in dose setting for toxicology studies to ensure that doses causing overt toxicity are not used in test animals. Also, a greater understanding of exposure within new approach methodology test systems will support the translation of effects to in vivo situations - making these data more useful for decision-making purposes, and ultimately reducing the current reliance on data from animal tests.

The European Chemicals Agency (ECHA) issued new advice in 2022 on dose selection for Developmental and reproductive toxicity (DART) studies. Concern was raised that the advice did not align with existing OECD test guidelines and could potentially lead to testing at unnecessarily high doses in animals, impacting on study outcomes and leading to differences in interpretation. We are collaborating with industry and regulatory partners to clarify ECHA advice and make recommendations for the selection of appropriate dose levels in DART studies to collect relevant scientific information, protect human reproductive health and maintain high standards of animal welfare.

As part of the ECETOC Task Force on Dose Selection, we published a paper advocating for a scientific approach that considers a range of factors to avoid exposing animals to unnecessary high doses.

We held a satellite event to EUROTOX 2024, co-organised by the NC3Rs, ECETOC, Charles River Laboratories and ECHA, to bring together global stakeholders from a range of sectors to understand different perspectives on dose setting for DART studies. The workshop highlighted a lack of clarity and understanding about ECHA’s requirements, with agreement from ECHA that its advice would benefit from some further clarification.

We are organising symposium sessions at Society of Toxicology meeting in 2025 and EUROTOX 2025 to present the results from the workshop and provide a platform to resolve the discrepancies around the need for very high dose levels. ECHA are holding workshops in November 2024 to establish an open discussion between contract research organisations performing animal studies and ECHA’s regulatory scientists assessing those studies.

Bringing together experts in the fields of exposure science, efficacy and toxicology to increase the uptake of non-animal approaches.

Publication: The current status of exposure-driven approaches for chemical safety assessment: A cross-sector perspective

2017 workshop report: Applying exposure science to increase the utility of non-animal data in efficacy and safety testing (PDF).

You can read more about this project on our project page: Applying exposure science to increase the utility of non-animal data in efficacy and safety testing.

An industry collaboration to provide evidence to define the upper limit of body weight loss in rat, dog and non-human primate maximum tolerated dose (MTD) studies.

You can read more about this project on our project page: Refining MTD studies. 

Reducing the number of animals use in the prediction of human pharmacokinetics (PK).

Publication: Human clearance prediction: shifting the paradigm

Publication: Towards an integrated human clearance prediction strategy that minimizes animal use

You can read more about this project on our project page: Pharmacokinetics in candidate selection.

Increasing the use of toxicokinetics in the evaluation of non-pharmaceutical chemicals.

Publication: Application of toxicokinetics to improve chemical risk assessment: Implications for the use of animals

Publication: Use of toxicokinetics to support chemical evaluation: Informing high dose selection and study interpretation

You can read more about this project on our project page: Toxicokinetics in the chemicals industry.