Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide

Huo

et al. 2022

Environ Sci Pollut Res

The main goal of the study was to investigate the genotoxic response of N-ethyl-N-nitrosourea (ENU) and ethyl methanesulfonate (EMS) at low doses in a multi-endpoint genotoxicity assessment platform in rats and to derive potential thresholds and related metrics. Male Sprague–Dawley rats were treated by daily oral gavage for 28 consecutive days with ENU (0.25 ~ 8 mg/kg bw) and EMS (5 ~ 160 mg/kg bw), both with six closely spaced dose levels. Pig-a gene mutation assay, micronucleus test, and comet assay were performed in several timepoints. Then, the dose–response relationships were analyzed for possible points of departure (PoD) using the no observed genotoxic effect level and benchmark dose (BMD) protocols with different critical effect sizes (CES, 0.05, 0.1, 0.5, and 1SD). Overall, dose-dependent increases in all investigated endpoints were found for ENU and EMS. PoDs varied across genetic endpoints, timepoints, and statistical methods, and selecting an appropriate lower 95% confidence limit of BMD needs a comprehensive consideration of the mode of action of chemicals, the characteristics of tests, and the model fitting methods. Under the experimental conditions, the PoDs of ENU and EMS were 0.0036 mg/kg bw and 1.7 mg/kg bw, respectively.

Section: Discussionmentioning

confidence: 99%

Determination of potential thresholds for N-ethyl-N-nitrosourea and ethyl methanesulfonate based on a multi-endpoint genotoxicity assessment platform in rats

Huo

et al. 2022

Environ Sci Pollut Res

“…Apart from MOE calculations, some authors suggested to consider genotoxicity data also for the derivation of HBGVs (Dearfield et al 2017 ; Gollapudi et al 2020 ; Heflich et al 2020 ; Johnson et al 2014 ; White et al 2020 ). As already mentioned, a HBGV represents a range of exposures that are not expected to result in an appreciable health risk.…”

Section: Discussed Opportunities Involving Quantitative Interpretatio...mentioning

confidence: 99%

“…Nevertheless, comparisons of BMD estimates obtained from different dose–response data sets for a given substance can at least provide a rough idea of the variability in sensitivity that occurs within the existing experimental boundaries. The available literature already provides several dose–response assessments of in vivo genotoxicity data that allow for comparisons of BMD estimates across different endpoints, target tissues and experimental settings (Cao et al 2014 ; Chen et al 2021 ; Gollapudi et al 2013 , 2020 ; Guerard et al 2017 ; Johnson et al 2014 ; Long et al 2018 ; Marchetti et al 2021 ; Mittelstaedt et al 2021 ; White et al 2020 ). As part of this review, we have compiled 104 BMD estimates for 10 substances from this body of literature (Supplementary Table 1).…”

Section: Challenges Arising From a Quantitative Interpretation Of Gen...mentioning

confidence: 99%

Genotoxicity assessment: opportunities, challenges and perspectives for quantitative evaluations of dose–response data

et al. 2023

Genotoxicity data are mainly interpreted in a qualitative way, which typically results in a binary classification of chemical entities. For more than a decade, there has been a discussion about the need for a paradigm shift in this regard. Here, we review current opportunities, challenges and perspectives for a more quantitative approach to genotoxicity assessment. Currently discussed opportunities mainly include the determination of a reference point (e.g., a benchmark dose) from genetic toxicity dose–response data, followed by calculation of a margin of exposure (MOE) or derivation of a health-based guidance value (HBGV). In addition to new opportunities, major challenges emerge with the quantitative interpretation of genotoxicity data. These are mainly rooted in the limited capability of standard in vivo genotoxicity testing methods to detect different types of genetic damage in multiple target tissues and the unknown quantitative relationships between measurable genotoxic effects and the probability of experiencing an adverse health outcome. In addition, with respect to DNA-reactive mutagens, the question arises whether the widely accepted assumption of a non-threshold dose–response relationship is at all compatible with the derivation of a HBGV. Therefore, at present, any quantitative genotoxicity assessment approach remains to be evaluated case-by-case. The quantitative interpretation of in vivo genotoxicity data for prioritization purposes, e.g., in connection with the MOE approach, could be seen as a promising opportunity for routine application. However, additional research is needed to assess whether it is possible to define a genotoxicity-derived MOE that can be considered indicative of a low level of concern. To further advance quantitative genotoxicity assessment, priority should be given to the development of new experimental methods to provide a deeper mechanistic understanding and a more comprehensive basis for the analysis of dose–response relationships.

“…Due to high repair rate of DNA adducts formed by alkylating agents, existence of thresholds for EtO genotoxicity it plausible [ 489 , 507 ]. Several studies also attempted to use dose–response data for genotoxicity endpoints to estimate safe exposure levels to EtO [ 508 , 509 ].…”

Section: Dna-reactive Carcinogens and Related Chemicals Present In Foodmentioning

confidence: 99%

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

Kobets

Smith

Williams

2022

Foods

Commonly consumed foods and beverages can contain chemicals with reported carcinogenic activity in rodent models. Moreover, exposures to some of these substances have been associated with increased cancer risks in humans. Food-borne carcinogens span a range of chemical classes and can arise from natural or anthropogenic sources, as well as form endogenously. Important considerations include the mechanism(s) of action (MoA), their relevance to human biology, and the level of exposure in diet. The MoAs of carcinogens have been classified as either DNA-reactive (genotoxic), involving covalent reaction with nuclear DNA, or epigenetic, involving molecular and cellular effects other than DNA reactivity. Carcinogens are generally present in food at low levels, resulting in low daily intakes, although there are some exceptions. Carcinogens of the DNA-reactive type produce effects at lower dosages than epigenetic carcinogens. Several food-related DNA-reactive carcinogens, including aflatoxins, aristolochic acid, benzene, benzo[a]pyrene and ethylene oxide, are recognized by the International Agency for Research on Cancer (IARC) as causes of human cancer. Of the epigenetic type, the only carcinogen considered to be associated with increased cancer in humans, although not from low-level food exposure, is dioxin (TCDD). Thus, DNA-reactive carcinogens in food represent a much greater risk than epigenetic carcinogens.