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

Abstract

Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals—i.e., the field of kinetics—often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

Kinetically-derived maximal dose (KMD) indicates lack of human carcinogenicity of ethylbenzene

“…Risk assessors should consider the KMD when evaluating the mode of action that underlies dose–response relationships (Borgert et al 2021 ; Burgoon et al 2022 ) because, as we and others have discussed (Andersen 1981 ; Bus 2017 ), toxicity and modes of action are likely to change once exposure nears the point of metabolic saturation and/or saturation of clearance mechanisms. This is a critical point in the case of ethylbenzene risk assessment.…”

“…Risk assessors are tasked with characterizing and quantifying risks and identifying chemical exposure levels that are safe for humans but in doing so, are required by regulatory agencies to consider data from animals exposed up to the maximum tolerated dose (MTD). Typically, the MTD not only exceeds anticipated human exposure levels but frequently exceeds dose levels that saturate drug and chemical metabolism and elimination pathways in the test species, leading to a host of toxic effects that are irrelevant to the effects expected from lower concentrations where kinetic processes 1 are not saturated (Borgert et al 2021 ; Burgoon et al 2022 ; Bus 2017 ; Andersen 1981 ). In addition, effects seen at high dose levels provide false information on the mechanism of action by which the compound is producing the toxic effect.…”

“…In addition, effects seen at high dose levels provide false information on the mechanism of action by which the compound is producing the toxic effect. Thus, we have argued that MTD testing is biologically irrelevant to human exposures and therefore an unethical waste of animals and resources (Borgert et al 2021 ). Instead, we contend that toxicity testing should be constrained to the kinetically-derived maximum dose (KMD).…”

“…We define the KMD as the maximal external dose where kinetics are unchanged relative to lower doses (Borgert et al 2021 ). In practice, we estimate the KMD as a range to represent our uncertainty about the precise location of the KMD (Burgoon et al 2022 ).…”

A new approach to the classification of carcinogenicity

“…Care should be taken not to use evidence from excessively high doses either in vitro or in vivo, which have little relation to human exposures or to internal concentrations derived from relevant exposures, as they may produce anomalous results (Bogert et al 2021 ). Examples of the evidence that can be used to assess MOA are explored in section 6 of this paper, “ Examples of using the new approach carcinogenicity classification scheme ”.…”