This article discusses the interpretation of adverse chemical effects in traditional and alternative toxicity tests. It highlights the use of non-specific endpoints, such as body weight and non-target organ weight changes, to set critical effect levels in chemical safety assessments. These endpoints are often used to derive points of departure for safety assessments, even though they may not directly relate to the specific toxicological response being assessed. The article also discusses the potential for confusion between specific and non-specific effects in test guidelines designed for specific apical effects, and the implications for regulatory decisions. It emphasizes the importance of distinguishing between true positive responses and non-specific effects in complex studies, as well as the need for careful interpretation of data to avoid mischaracterization of chemicals. The article also discusses the use of New Approach Methods (NAMs) in toxicity testing, and the challenges in using in vivo data to benchmark these methods. It concludes that while NAMs may not always be predictive of specific toxic effects, they can be used in a protective manner to assess chemical safety. The article also highlights the importance of data curation and controlled vocabulary in ensuring that the details of endpoints affected are accessible for guideline studies. Overall, the article calls for a rethinking of how adverse chemical effects are interpreted in order to better protect human health.This article discusses the interpretation of adverse chemical effects in traditional and alternative toxicity tests. It highlights the use of non-specific endpoints, such as body weight and non-target organ weight changes, to set critical effect levels in chemical safety assessments. These endpoints are often used to derive points of departure for safety assessments, even though they may not directly relate to the specific toxicological response being assessed. The article also discusses the potential for confusion between specific and non-specific effects in test guidelines designed for specific apical effects, and the implications for regulatory decisions. It emphasizes the importance of distinguishing between true positive responses and non-specific effects in complex studies, as well as the need for careful interpretation of data to avoid mischaracterization of chemicals. The article also discusses the use of New Approach Methods (NAMs) in toxicity testing, and the challenges in using in vivo data to benchmark these methods. It concludes that while NAMs may not always be predictive of specific toxic effects, they can be used in a protective manner to assess chemical safety. The article also highlights the importance of data curation and controlled vocabulary in ensuring that the details of endpoints affected are accessible for guideline studies. Overall, the article calls for a rethinking of how adverse chemical effects are interpreted in order to better protect human health.