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 toxicitymodifying 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 standardrisk-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.

Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety

“…Focusing on so-called "intrinsic hazards" rather than on safe doses ranges is illogical because hazards are not "intrinsic." All chemicals-natural or synthetic, endogenous or exogenous-exhibit toxicity (hazard), the manifestation of which is always dose-dependent (McCarty et al 2020). Unless it is imagined that some chemicals lack hazards, such a focus wastes time and effort because it simply confirms what is already known.…”

“…In vivo KMD data are necessary for interpreting the risk relevance of responses observed from in vitro and high-throughput studies, which carry limited, if any, relevance for human risk when the concentrations at which responses are observed exceed the blood/tissue concentrations produced at the KMD as identified by in vivo TK studies. Focusing on so-called “intrinsic hazards” rather than on safe doses ranges is illogical because hazards are not “intrinsic.” All chemicals—natural or synthetic, endogenous or exogenous—exhibit toxicity (hazard), the manifestation of which is always dose-dependent (McCarty et al 2020 ). Unless it is imagined that some chemicals lack hazards, such a focus wastes time and effort because it simply confirms what is already known.…”

“…In the vernacular of chemistry, toxicity is not an “intensive” property of a chemical. To the contrary, toxicity and hazard are “extensive” properties, meaning that in addition to a chemical’s structure and physical nature, toxicity and hazard depend upon the quantity of the chemical encountered, the route of exposure and the conditions under which a chemical is encountered, and other factors such as the species, age, sex, behavior, and other characteristics of the organism exposed to the chemical (McCarty et al 2020 ). Thus, the dose range and conditions under which a chemical produces toxicity may provide little useful information about the dose range and conditions necessary to assure a lack of relevant hazard or adverse effects.…”

A novel approach to calculating the kinetically derived maximum dose

“…Regulatory toxicology studies are conducted to help society avoid hazards and unacceptable risks that might be posed by exposure to chemicals. Since toxicity, and thus, hazards, are not intrinsic to the chemical itself but also depend upon the dose and the conditions under which consumers, workers, plants, and animals encounter chemicals (McCarty et al 2020 ), avoiding hazards and unacceptable risks requires identifying doses of chemicals that produce no adverse effects; see explanation in our companion paper, Borgert et al ( 2021 ). The goal is to ensure safety by providing regulatory agencies with information about the safe dose range, so they can set safe exposure levels.…”

In Silico Evaluation of the Physicochemical, Pharmacokinetics, and Toxicity Profiles of Sesquiterpene Lactones of South African Leaf (Vernonia amygdalina Delile)

“…Toxicity testing of material is specific or alternative to determine risk factors. 2 The process of introducing new drugs to the market is very complex, including preclinical trials and clinical trials to prove safety, efficacy, and quality. 3 The safety of a developed drug compound must be verified by its low toxicity during preclinical and clinical trials.…”