Letter to the editor regarding "Bichlmaier, I. Differences in endocrine and reproductive responses to substance exposure across generations: highlighting the importance of complementary findings. Arch Toxicol 98, 3215-3230 (2024)".

In the paper of Bichlmaier (Arch Toxicol 98:3215-3230, 2024), the author conducted an overall statistical assessment of the endocrine and reproductive responses across the two (F0 and F1) or three (F0, F1 and F2) generations in a total number of 112 Extended-One-Generation-Reproductive-Toxicity (EOGRT) studies (OECD TG 443). The author's conclusion is that "….confirmation of treatment-related reproductive and endocrine effects across different generations and life stages within the same study is relatively infrequent. It is much more common for animals of different generations and life stages to exhibit varied endocrine and reproductive responses" and "positive findings observed exclusively in one generation and/or life stage and not in others should not be dismissed due to the absence of continuity". Our key concerns/issues about this analysis are that 'a positive finding', 'treatment-relationship' and 'adversity' in each of the studies cannot be verified from this paper; any 'endocrine or reproductive response' may have been the conclusion from the author alone. Moreover, a conclusion about positive findings in each of the reviewed studies may have been based on statistical significance only, not on biological relevance and plausibility. In addition, in the investigation all data were binarized; however, the question remains whether biological endpoints such as reproductive toxicity data can be binarized to arrive at realistic and relevant conclusions. In the next sections, these issues are further elucidated.