Re: Gi et al. 2018, In vivo positive mutagenicity of 1,4-dioxane and quantitative analysis of its mutagenicity and carcinogenicity in rats, Archives of Toxicology 92:3207–3221

White, Paul A.; Zeller, Andreas; Pfuhler, Stefan; Johnson, George E.

doi:10.1007/s00204-018-2370-1

Cited by 5 publications

(1 citation statement)

References 6 publications

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“…Otherwise, data were modeled as continuous summary data (i.e., mean response and standard deviation or standard error with sample size). As a quality control measure, a BMC 100 or BMD 100 value was excluded if the corresponding BMCU/BMCL or BMDU/BMDL (upper and lower confidence interval ratio) was above 100 (White, Zeller, et al, 2019). This filter removes concentration-response or dose-response data where a response is not detected or the response is much lower than the benchmark response.…”

Section: Benchmark Concentration and Benchmark Dose Modelingmentioning

confidence: 99%

Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose

Beal

Audebert

Barton-Maclaren

et al. 2022

Environ and Mol Mutagen

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Genotoxicity assessment is a critical component in the development and evaluation of chemicals. Traditional genotoxicity assays (i.e., mutagenicity, clastogenicity, and aneugenicity) have been limited to dichotomous hazard classification, while other toxicity endpoints are assessed through quantitative determination of points-of-departures (PODs) for setting exposure limits. The more recent higher-throughput in vitro genotoxicity assays, many of which also provide mechanistic information, offer a powerful approach for determining defined PODs for potency ranking and risk assessment.

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Section: Benchmark Concentration and Benchmark Dose Modelingmentioning

confidence: 99%

Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose

Beal

Audebert

Barton-Maclaren

et al. 2022

Environ and Mol Mutagen

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Quantitative Interpretation of Genetic Toxicity Dose‐Response Data for Risk Assessment and Regulatory Decision‐Making: Current Status and Emerging Priorities

White

Long

Johnson

2019

Environ and Mol Mutagen

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The screen‐and‐bin approach for interpretation of genotoxicity data is predicated on three false assumptions: that genotoxicants are rare, that genotoxicity dose–response functions do not contain a low‐dose region mechanistically characterized by zero‐order kinetics, and that genotoxicity is not a bona fide toxicological endpoint. Consequently, there is a need to develop and implement quantitative methods to interpret genotoxicity dose–response data for risk assessment and regulatory decision‐making. Standardized methods to analyze dose–response data, and determine point‐of‐departure (PoD) metrics, have been established; the most robust PoD is the benchmark dose (BMD). However, there are no standards for regulatory interpretation of mutagenicity BMDs. Although 5–10% is often used as a critical effect size (CES) for BMD determination, values for genotoxicity endpoints have not been established. The use of BMDs to determine health‐based guidance values (HBGVs) requires assessment factors (AFs) to account for interspecies differences and variability in human sensitivity. Default AFs used for other endpoints may not be appropriate for interpretation of in vivo mutagenicity BMDs. Analyses of published dose–response data showing the effects of compensatory pathway deficiency indicate that AFs for sensitivity differences should be in the range of 2–20. Additional analyses indicate that the AF to compensate for short treatment durations should be in the range of 5–15. Future work should use available data to empirically determine endpoint‐specific CES values; similarly, to determine AF values for BMD adjustment. Future work should also evaluate the ability to use in vitro dose–response data for risk assessment, and the utility of probabilistic methods for determination of mutagenicity HBGVs. Environ. Mol. Mutagen. 61:66–83, 2020. © 2019 Her Majesty the Queen in Right of Canada

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

Zhu

Huo

Zhu

et al. 2022

Environ Sci Pollut Res

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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.

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Re: Gi et al. 2018, In vivo positive mutagenicity of 1,4-dioxane and quantitative analysis of its mutagenicity and carcinogenicity in rats, Archives of Toxicology 92:3207–3221

Cited by 5 publications

References 6 publications

Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose

Quantitative in vitro to in vivo extrapolation of genotoxicity data provides protective estimates of in vivo dose

Quantitative Interpretation of Genetic Toxicity Dose‐Response Data for Risk Assessment and Regulatory Decision‐Making: Current Status and Emerging Priorities

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

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