Evaluation of the Inherent Toxicity Concept in Environmental Toxicology and Risk Assessment.

Abstract

Intrinsic/inherent chemical properties are characteristic, irrespective of the number of molecules present. However, toxicity is an extensive/extrinsic biochemical property that depends on the number of molecules. Paracelsus, often considered the father of toxicology, noted that all things are poisonous. Because dose magnitude (i.e., number of molecules) determines the occurrence of poisonous effects, toxicity cannot be an intrinsic/inherent biochemical property. Thus, toxicology's task is to determine case‐specific risks resulting in adverse effects produced by the interaction of toxic doses/exposures, toxic mechanisms, and case‐specific influencing factors. Experimental testing results are known to vary within and between chemicals, test organisms, and experimental conditions and repetitions; however, hazard‐based approaches treat toxicity as a fixed and constant property. A logical alternative is the standard‐risk, case‐specific risk model. In this approach, testing data are defined as standard risks where the nature, magnitude, and toxicity effect is standardized to the organism, chemical, and test conditions. Interpolation/extrapolation of standard risks to site‐specific conditions (i.e., case‐specific risks) is challenging, requiring understanding of the influences of the complex interactions within and between differing species, conditions, and toxicity‐modifying factors. Therefore, Paracelsus's paradigm is perhaps better abbreviated as “dose–causality–response”, because a key interpretive requirement is establishing toxicity causality by separating mode/mechanism of toxic action from modifying factor influences in overall toxicity responses. Unfortunately, the current knowledge base is inadequate. Moving to a standard‐risk–specific‐risk paradigm would highlight the importance of improving the toxicity causality knowledge base. Thereby, a rationale would be provided for enhancing the design and interpretation of toxicity testing that is necessary for achieving advances in routine translation of standard‐risk to specific‐risk estimates—the raison d'être of regulatory risk decision making. Environ Toxicol Chem 2020;39:2351–2360. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.