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

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.

Automated summary

To justify the inclusion of learning and memory (L & M) tests in extended one-generation reproductive toxicity studies (EOGRTS) for chemical registration under REACH, the European Chemicals Agency referred to three publications suggesting that perturbation of thyroid hormone signaling in offspring affects spatial cognitive abilities. However, this paper challenges the validity of including these tests, questions the reliability of the publications relied upon, and argues that they cannot be used to substantiate the claim that decreased blood thyroid hormone levels alone result in impaired L & M in rats.