Citation:

Browne, P., K. Friedman, K. Boekelheide, AND R. Thomas. Adverse effects in traditional and alternative toxicity tests. REGULATORY TOXICOLOGY AND PHARMACOLOGY. Elsevier Science Ltd, New York, NY, 148:105579, (2024). https://doi.org/10.1016/j.yrtph.2024.105579

Impact/Purpose:

Human health risk assessment has largely relied on information from studies that administer chemicals to laboratory animals and assume adverse effects observed in the animal models are potentially relevant to humans. The safety of most chemicals is assessed from a variety of in vivo animal toxicity tests, most of which were developed decades ago, to measure effects on the health and survival of organisms. Endpoints included in standardized test guidelines are measured in animals exposed to the test chemicals and compared to the same endpoints measured in control animals to provide information on chemical effects. Apical effects observed in the whole organism related to development, disease, survival, and reproduction are measured in various guideline tests CITATION Mendeley_I1xFk4FkjzSAw0bqMxk__ig \l 2057 (NAS, 2007). The lowest dose determined to cause changes considered adverse (i.e., the critical effect level) is used as the starting point for regulatory decisions regarding safe production, use, and potential exposure to the chemical. Health protection goals have expanded to include more subtle impairments of specific organ systems and their functions. As such, in vivo animal test guidelines have been developed to detect effects on endpoints indicative of chemical interactions with specific biological systems resulting in in a functional response in one or more organs (e.g., immune, neurological, reproductive functions; Organisation for Economic Co-Operation and Development [OECD] Test Guidelines[1] 443, 453, 413, 421, 426, 414). However, the elephant in the room is acknowledging that chemical responses in these specific studies may be a result of systemic or overt toxicity, and distinguishing positives in these complex studies based on the type of toxicity observed may impact characterization of chemicals as specific types of toxicants (e.g., developmental toxicants versus systemic toxicants) as well as development of reference chemical data to verify performance of alternative new approach methods. Acknowledging that the decades of accumulated animal reference data may be considered protective of adverse chemical effects rather than predictive of specific chemical effects permits development of new methods and approaches that do the same. Batteries of methods can be used in combination to detect dose thresholds for chemical-induced changes, and the performance of such approaches can be determined using these existing in vivo data.  Decisions made from a combination of in silico methods and broad profiling batteries of in vitro assays would be expected to be as protective as the in vivo data used to benchmark against general, non-specific adverse effects of chemicals, provided that enough biology is covered, and relevant test chemical metabolites are also considered by the new approach methods (NAMs). In addition, NAMs could be used to provide information on the >70% of chemicals used in commerce for which there are inadequate data to characterize hazard or exposure CITATION Mendeley_3tpwCL1GazuxqI0muziGHg \l 2057 (European Environment Agency, 2019). Generating animal test results for the data-poor chemical universe would take decades and millions of animals and is thus impractical and unethical to pursue. In addition, recent publications evaluating the value of information has determined that the cost associated with increased data generation and reduced uncertainty is less beneficial than taking less time to make less certain decisions that are protective of human health and the environment  CITATION Mendeley_t1mkL3n0IDqNNLTSPTqtkw \l 2057 (Hagiwara, et al., 2023). Increasing the implementation of NAMs would provide data and reduce time required

Description:

Chemical safety assessment begins with defining the lowest level of chemical that alters one or more measured endpoints. This critical effect level, along with factors to account for uncertainty, is used to derive limits for human exposure. In the absence of data regarding the specific mechanisms or biological pathways affected, non-specific endpoints such as body weight and non-target organ weight changes are used to set critical effect levels. Specific apical endpoints such as impaired reproductive function or altered neurodevelopment have also been used to set chemical safety limits; however, in test guidelines designed for specific apical effect(s), concurrently measured non-specific endpoints may be equally or more sensitive than specific endpoints. This means that rather than predicting a specific toxicological response, animal data are often used to develop protective critical effect levels, without assuming the same change would be observed in humans. This manuscript is intended to encourage a rethinking of how adverse chemical effects are interpreted: non-specific endpoints from in vivo toxicological studies data are often used to derive points of departure for use with safety assessment factors to create recommended exposure levels that are broadly protective but not necessarily target-specific.

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