Use of the kinetically-derived maximum dose concept in selection of top doses for toxicity studies hampers proper hazard assessment and risk management

Heringa, Minne B.; Cnubben, N.H.P.; Slob, Wout; Pronk, Marja E.J.; Müller, André; Woutersen, Marjolijn; Hakkert, Betty C.

doi:10.1016/j.yrtph.2020.104659

Cited by 19 publications

(13 citation statements)

References 16 publications

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“…An understanding of the MOA of a test substance can facilitate the selection of dose levels much higher than those expected to be experienced by humans, but not beyond a dose level at which pathology becomes an experimental artefact of the high-dose level. As noted by Heringa et al, 1 under-classification of substance hazard is highly undesirable. However, over-classification of hazard can also be problematic as replacing an important chemical based on artefactual rodent results with another chemical could be disadvantageous economically and also from a human and environmental health perspective.…”

Section: Discussionmentioning

confidence: 98%

“…The use of the maximum tolerated dose (MTD), especially in animal carcinogenicity studies, remains controversial today despite its long history. 1,2 The development of the MTD occurred in evolutionary steps over a period of years. 3 By the 1950s, rodents were in wide use in comparatively short-term studies wherein exposures much higher than those expected in exposed humans were employed.…”

Section: History Of the Maximum Tolerated Dosementioning

confidence: 99%

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High-dose exposure to synthetic chemicals, hormones, or homeostatic substances in experimental animals or humans can induce artefactual pathology

Smith

Perfetti²

2020

Toxicology Research and Application

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The maximum tolerated dose (MTD) provides the highest probability of a positive result in a toxicology bioassay. The assumption underlying the MTD in animal bioassays is that adverse effects at very high doses are qualitatively the same as those occurring at low doses. In contrast with the MTD, the optimal top dose in a toxicology animal study is the highest dose that does not produce a pathological end point that presents no risk at lower doses, for example, the dose below which cytotoxicity induces tumors in the absence of genotoxicity or other carcinogenic mechanisms. Normal concentrations or biological activity levels of many substances necessary for normal physiological function induce pathology when found at high levels. For example, the demonstration that ingestion of abnormally high levels of certain dietary fats can cause or exacerbate atherosclerosis in relevant animal models like rhesus macaques does not demonstrate that normal levels of these fats should be considered as toxic. Excessive estrogenic stimulation is associated with breast, ovarian, and endometrial cancers. This does not imply that normal age-appropriate levels of estrogen are toxic. Normal wound healing is associated with transforming growth factors beta 1 and 2. Excessive stimulation of fibroblasts by these growth factors results in hypertrophic scarring and keloid formation. An understanding of the mode of action of a test substance can facilitate the selection of dose levels much higher than those expected to be experienced by humans, but not beyond a dose level at which pathology is an experimental artefact of the high-dose level.

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Section: Discussionmentioning

confidence: 98%

Section: History Of the Maximum Tolerated Dosementioning

confidence: 99%

High-dose exposure to synthetic chemicals, hormones, or homeostatic substances in experimental animals or humans can induce artefactual pathology

Smith

Perfetti²

2020

Toxicology Research and Application

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“…Arguments have been made that a variety of scenarios may result in human exposures higher than currently occur, and, therefore, that dose selection for toxicology studies based on the KMD, and even the MTD, would be too low to identify relevant human health effects. Those scenarios are said to include future chemical uses that produce human exposures higher than currently occur, as well as the possibility of personal protective equipment failure in the workplace, accidental chemicals releases, and intentional or unintentional overexposures from product misuse (Heringa et al 2020a ; Woutersen et al 2020 ). This argument is not compelling for several reasons.…”

Section: Principles and Conceptsmentioning

confidence: 99%

“…In fact, MTD-based testing would provide misinformation because the hazards and risks associated with a sub-KMD-based dosing strategy consistent with realistic occupational and general environmental exposures are well-separated from intentional high-dose chronic drinking scenarios and their consequent kinetic differences. Importantly, the Heringa et al ( 2020a) , Slob et al ( 2020 ) and Woutersen et al ( 2020 ) series of papers would incorrectly imply that toxicity and hazard associated with very high-dose ethanol consumption informs hazard, toxicity and risk from much lower consumption levels; it certainly does not, even though MTD studies will inform toxicity and hazards of chronic ethanol abuse scenarios.…”

Section: Principles and Conceptsmentioning

confidence: 99%

“…In asserting that saturation is a continuous process rather than a threshold condition, much argumentation has been made based on the presumption that a threshold event would produce an unambiguous inflection point in the administered-dose/blood-concentration relationship (Heringa et al 2020a , b , c ; Slob et al 2020 ; Woutersen et al 2020 ). Although the empirical basis of Heringa et al’s claim that “ a sharp inflection point is not observable in most instances ” has been challenged (Sewell et al 2020 ; Smith and Perfetti 2020 ; Terry et al 2020 ), a challenge to which the authors partially responded (Heringa et al 2020b , c ), our focus is on their conclusion that imprecision in the location of an inflection point means that saturation of metabolism must be a non-threshold, continuous process.…”

Section: Kmd Versus Mtdmentioning

confidence: 99%

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

Borgert

Fuentes

Burgoon³

2021

Arch Toxicol

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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.

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A novel approach to calculating the kinetically derived maximum dose

Burgoon¹,

Fuentes

Borgert

2022

Arch Toxicol

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The kinetically derived maximal dose (KMD) provides a toxicologically relevant upper range for the determination of chemical safety. Here, we describe a new way of calculating the KMD that is based on sound Bayesian, theoretical, biochemical, and toxicokinetic principles, that avoids the problems of relying upon the area under the curve (AUC) approach that has often been used. Our new, mathematically rigorous approach is based on converting toxicokinetic data to the overall, or system-wide, Michaelis–Menten curve (which is the slope function for the toxicokinetic data) using Bayesian methods and using the “kneedle” algorithm to find the “knee” or “elbow”—the point at which there is diminishing returns in the velocity of the Michaelis–Menten curve (or acceleration of the toxicokinetic curve). Our work fundamentally reshapes the KMD methodology, placing it within the well-established Michaelis–Menten theoretical framework by defining the KMD as the point where the kinetic rate approximates the Michaelis–Menten asymptote at higher concentrations. By putting the KMD within the Michaelis–Menten framework, we leverage existing biochemical and pharmacological concepts such as “saturation” to establish the region where the KMD is likely to exist. The advantage of defining KMD as a region, rather than as an inflection point along the curve, is that a region reflects uncertainty and clarifies that there is no single point where the curve is expected to “break;” rather, there is a region where the curve begins to taper off as it approaches the asymptote (Vmax in the Michaelis–Menten equation).

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Use of the kinetically-derived maximum dose concept in selection of top doses for toxicity studies hampers proper hazard assessment and risk management

Cited by 19 publications

References 16 publications

High-dose exposure to synthetic chemicals, hormones, or homeostatic substances in experimental animals or humans can induce artefactual pathology

High-dose exposure to synthetic chemicals, hormones, or homeostatic substances in experimental animals or humans can induce artefactual pathology

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

A novel approach to calculating the kinetically derived maximum dose

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