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

Autor: Heringa MB; National Institute for Public Health and the Environment (RIVM), Centre for Safety of Substances and Products (VSP), Bilthoven, the Netherlands., Cnubben NHP; National Institute for Public Health and the Environment (RIVM), Centre for Safety of Substances and Products (VSP), Bilthoven, the Netherlands., Slob W; National Institute for Public Health and the Environment (RIVM), Centre for Safety of Substances and Products (VSP), Bilthoven, the Netherlands., Pronk MEJ; National Institute for Public Health and the Environment (RIVM), Centre for Safety of Substances and Products (VSP), Bilthoven, the Netherlands., Muller A; National Institute for Public Health and the Environment (RIVM), Centre for Safety of Substances and Products (VSP), Bilthoven, the Netherlands., Woutersen M; National Institute for Public Health and the Environment (RIVM), Centre for Safety of Substances and Products (VSP), Bilthoven, the Netherlands. Electronic address: Marjolijn.woutersen@rivm.nl., Hakkert BC; National Institute for Public Health and the Environment (RIVM), Centre for Safety of Substances and Products (VSP), Bilthoven, the Netherlands.
Jazyk: angličtina
Zdroj: Regulatory toxicology and pharmacology : RTP [Regul Toxicol Pharmacol] 2020 Jul; Vol. 114, pp. 104659. Date of Electronic Publication: 2020 Apr 22.
DOI: 10.1016/j.yrtph.2020.104659
Abstrakt: The KMD (kinetically-derived maximum dose) is an increasingly advocated concept that uses toxicokinetic data in the top dose selection for toxicity testing. Application of this concept may have serious regulatory implications though, especially in the European Union. The basic assumption is that the relationship between internal and external dose (IED) shows an inflection point where linearity transits into non-linearity due to saturation of underlying processes; top doses in toxicity tests should not be above the inflection point, provided human exposures are well below this point. A critical analysis of the KMD concept and its underlying assumptions shows, however, that the IED relationship is non-linear over the whole dose range, without any point of inflection. The KMD concept thus aims to estimate a non-existing point, rendering it invalid for use in toxicity testing. Moreover, the concept ignores the key question in toxicology: What kind of toxic effects occur at which doses? These and several other reservations against the KMD concept are discussed and illustrated with three existing applications of the KMD approach. Hence, we recommend to abolish the KMD concept for selecting top doses in toxicity testing. This requires the updating of regulations, guidance documents and OECD test guidelines.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020. Published by Elsevier Inc.)
Databáze: MEDLINE
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