Investigations on learning and memory function in extended one-generation reproductive toxicity studies – when considered needed and based on what?

Abstract

To justify investigations on learning and memory (L&M) function in extended one-generation reproductive toxicity studies (EOGRTS; Organization for Economic Co-operation and Development (OECD) test guideline (TG) 443) for registration under Registration, Evaluation, Authorization, and Restriction of Chemical (REACH), the European Chemicals Agency has referred to three publications based on which the Agency concluded that “perturbation of thyroid hormone signaling in offspring affects spatial cognitive abilities (learning and memory)” and “Therefore, it is necessary to conduct spatial learning and memory tests for F1 animals”. In this paper, the inclusion of the requested L&M tests in an EOGRTS is challenged. In addition, next to the question on the validity of rodent models in general for testing thyroid hormone-dependent perturbations in brain development, the reliability of the publications specifically relied upon by the agency is questioned as these contain numerous fundamental errors in study methodology, design, and data reporting, provide contradicting results, lack crucial information to validate the results and exclude confounding factors, and finally show no causal relationship. Therefore, in our opinion, these publications cannot be used to substantiate, support, or conclude that decreases in blood thyroid (T4) hormone level on their own would result in impaired L&M in rats and are thus not adequate to use as fundament to ask for L&M testing as part of an EOGRTS.

Keywords:

• Cognitive testing
• spatial learning and memory
• Morris water maze
• radial arm maze
• EOGRTS
• reproductive toxicity
• rodents
• regulatory requirements
• REACH

Acknowledgements

The authors would like to thank Manon Beekhuijzen from Charles River in Den Bosch, the Netherlands for her valuable suggestions while drafting this article. The authors acknowledge the reviewers and the editor for their time and dedication in reviewing this work. The authors would also like to thank the Aromatics Producers Association (APA) Sector Group of Cefic and the Organic Peroxide Consortium for funding open access.

Declaration of interest

All authors of this manuscript are working in the chemical industry. This manuscript is important as a contribution to ongoing discussions on the validity and value of the inclusion and performance of learning and memory tests as part of an EOGRTS. The authors had sole responsibility for the manuscript. Opinions and conclusions expressed within this manuscript are those of the authors.