On April 22, 2020, researchers from the Dutch National Institute for Public Health and the Environment (RIVM) published two studies in the peer-reviewed journal Regulatory Toxicology and Pharmacology investigating the dosing used for regulatory toxicity studies of chemicals. The first study led by Marjolijn Woutersen found that in recent years toxicity testing has increasingly used doses that are too low, which has resulted in “severe consequences” on regulatory issues such as “classification and labeling, identification of endocrine disruptors, health impact assessment, and incident management.” A second study published by Minne Heringa and co-authors focused on specifically reviewing and criticizing the kinetically-derived maximum dose (KMD) concept, which they describe as inappropriate to use in the selection of top doses for toxicity studies.
Doses used in toxicity studies are important in determining regulatory decisions applied to chemicals, and guidelines exist such as those from the Organisation for Economic Co-operation and Development (OECD). As Chemical Watch reported, the OECD generally defines a maximum dose of 1,000 mg per kg body weight per day be used for toxicity studies unless clear evidence exists of effects occurring at lower doses. The RIVM studies, however, found that more and more published toxicity studies are presenting results with no or very minor adverse effects while still choosing to use maximum doses significantly below this recommended level. The authors write that this could be due to a discrepancy between classification criteria used in the EU classification, labeling, and packaging (CLP) regulation and the top dose requirements set within OECD test guidelines. The welfare of animals used in testing is also discussed as a relevant argument from both perspectives for and against using this recommended top dose. On one side, testing below the recommended top dose could reduce the suffering experienced by test animals, however, using low doses may then require an increased number of test animals in the end.
In their paper, Woutersen and co-authors “stress the importance of the use of sufficiently high dosing in toxicity studies” and recommend that descriptions in current OECD test guidelines and guideline documents are revised to ensure requirements for dose level setting is explicit and unambiguous.
Andrew Turley (April 30, 2020). “Dutch scientists identify low dose problem with regulatory testing.” Chemical Watch
Woutersen, M. et al. (April 22, 2020). “Regulating human safety: How dose selection in toxicity studies impacts human health hazard assessment and subsequent risk management options.” Regulatory Toxicology and Pharmacology
Heringa, B. et al. (April 22, 2020). “Use of the kinetically-derived maximum dose concept in selection of top doses for toxicity studies hampers proper hazard assessment and risk management.” Regulatory Toxicology and Pharmacology