Regulating human safety: How dose selection in toxicity studies impacts human health hazard assessment and subsequent risk management options

Woutersen, Marjolijn; Müller, André; Pronk, Marja E.J.; Cnubben, N.H.P.; Hakkert, Betty C.

doi:10.1016/j.yrtph.2020.104660

Cited by 18 publications

(14 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An alternative method for identifying the KMD based on changes in slope and maximum curvature of the administered dose/blood concentration relations is the topic of a companion paper (Burgoon et al 2021). This method obviates recent criticisms of the KMD approach (Heringa et al 2020a, b, c;Slob et al 2020;Woutersen et al 2020) and offers advantages that will increase confidence regarding the safe dose range and reduce unnecessary use of animals in regulatory toxicity testing.…”

Section: Discussionmentioning

confidence: 98%

“…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).…”

Section: Inflection Points Are Irrelevantmentioning

confidence: 99%

“…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%

See 3 more Smart Citations

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

Borgert

Fuentes

Burgoon³

2021

Arch Toxicol

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Inflection Points Are Irrelevantmentioning

confidence: 99%

Section: Principles and Conceptsmentioning

confidence: 99%

Section: Principles and Conceptsmentioning

confidence: 99%

See 2 more Smart Citations

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

Borgert

Fuentes

Burgoon³

2021

Arch Toxicol

View full text Add to dashboard Cite

show abstract

“…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%

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

View full text Add to dashboard Cite

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.

show abstract

In vitro evaluation of the inhalation toxicity of the cosmetic ingredient aluminum chlorohydrate

Thá

Gagosian

Canavez

et al. 2022

J of Applied Toxicology

View full text Add to dashboard Cite

Aluminum chlorohydrate (ACH) is a major aerosol component frequently used as the active ingredient in antiperspirants, and in vivo studies have raised a concern about its inhalation toxicity. Still, few studies have addressed its effects on the human respiratory tract. Therefore, we developed a study on ACH inhalation toxicity using an in vitro human alveolar cell model (A549 cells) with molecular and cellular markers of oxidative stress, immunotoxicity, and epigenetic changes. The chemical characterization of ACH suspensions indicated particle instability and aggregation; however, side-scatter analysis demonstrated significant particle uptake in cells exposed to ACH. Exposure of A549 cells to non-cytotoxic concentrations of ACH (0.25, 0.5, and 1 mg/ml) showed that ACH induced reactive oxygen species. Moreover, ACH upregulated TNF, IL6, IL8, and IL1A genes, but not the lncRNAs NEAT1 and MALAT1.Finally, no alterations on the global DNA methylation pattern (5-methylcytosine and 5-hydroxymethylcytosine) or the phosphorylation of histone H2AX (γ-H2AX) were observed. Our data suggest that ACH may induce oxidative stress and inflammation on alveolar cells, and A549 cells may be useful to identify cellular and molecular events that may be associated with adverse effects on the lungs. Still, further research is needed to ensure the inhalation safety of ACH.

show abstract

Regulating human safety: How dose selection in toxicity studies impacts human health hazard assessment and subsequent risk management options

Cited by 18 publications

References 3 publications

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

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

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

In vitro evaluation of the inhalation toxicity of the cosmetic ingredient aluminum chlorohydrate

Contact Info

Product

Resources

About