Dose–response modeling of in vivo genotoxicity data for use in risk assessment: some approaches illustrated by an analysis of acrylamide

Allen, Bruce C.; Zeiger, Errol; Lawrence, Gregory A.; Friedman, Marvin A.; Shipp, Annette M.

doi:10.1016/j.yrtph.2004.09.006

Cited by 24 publications

(15 citation statements)

References 48 publications

(12 reference statements)

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“…In contrast, genotoxicity would seem to be a plausible key event for acrylamide carcinogenicity in the mouse, as BMD values for micronucleus induction and tumour development largely overlap. Although caution is necessary in extrapolating results of genotoxicity evaluation in the bone marrow compartment to other organs, the dissociation between DNA damaging/mutagenic concentrations of acrylamide and the carcinogenic response pattern (36), as well as the lack of correlation between organ distribution of DNA-glycidamide adducts and acrylamide induced tumours (60,62), is consistent with a role for alternate mechanisms of acrylamide tumorigenicity. Potential involvement of altered signal transduction pathways, cell proliferation, microtubule function, cellular thiol status and/or prolonged hormonal imbalance has been proposed (10,(63)(64)(65).…”

Section: Discussionmentioning

confidence: 95%

“…However, the situation is less clear for rats and humans, that produce less glycidamide than mice at equivalent exposure levels (33). In general, acrylamide genotoxic potential in mice as measured by DNA and chromosomal damage has been detected only at concentrations exceeding those found to be carcinogenic in the rodent cancer bioassays (20,21,(34)(35)(36). The recent development of the Pig-a (phosphatidylinositol glycan, Class A) gene mutation assay (37-41) now readily permits highly sensitive evaluation of the mutagenic potential of acrylamide at carcinogenic exposure levels using the same rodent strains tested in the cancer bioassays.…”

Section: Introductionmentioning

confidence: 99%

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Differential genotoxicity of acrylamide in the micronucleus andPig-a gene mutation assays in F344 rats and B6C3F1 mice

Hobbs¹,

Davis²,

Shepard³

et al. 2016

MUTAGE

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Acrylamide is used in many industrial processes and is present in a variety of fried and baked foods. In rodent carcinogenicity assays, acrylamide exposure leads to tumour formation at doses lower than those demonstrated to induce genotoxic damage. We evaluated the potential of acrylamide to induce structural DNA damage and gene mutations in rodents using highly sensitive flow cytometric analysis of micronucleus and Pig-a mutant frequencies, respectively. Male F344 rats and B6C3F1 mice were administered acrylamide in drinking water for 30 days at doses spanning and exceeding the range of acrylamide exposure tested in cancer bioassays-top dose of 12.0 and 24.0 mg/kg/day in mice and in rats, respectively. A positive control, N-ethyl-N-nitrosourea, was administered at the beginning and end of the study to meet the expression time for the two DNA damage phenotypes. The results of the micronucleus and Pig-a assays were negative and equivocal, respectively, for male rats exposed to acrylamide at the concentrations tested. In contrast, acrylamide induced a dose-dependent increase in micronucleus formation but tested negative in the Pig-a assay in mice. Higher plasma concentrations of glycidamide in mice than rats are hypothesized to explain, at least in part, the differences in the response. Benchmark dose modelling indicates that structural DNA damage as opposed to point mutations is most relevant to the genotoxic mode of action of acrylamide-induced carcinogenicity. Moreover, the lack of genotoxicity detected at <6.0 mg/kg/day is consistent with the notion that non-genotoxic mechanisms contribute to acrylamide-induced carcinogenicity in rodents.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Differential genotoxicity of acrylamide in the micronucleus andPig-a gene mutation assays in F344 rats and B6C3F1 mice

Hobbs¹,

Davis²,

Shepard³

et al. 2016

MUTAGE

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“…Successful applications with quantal data include adverse developmental endpoints (Krewski, Zhu, and Fung 1999; Zhu, Wang, and Jelsovsky 2007), genetic toxicity (Allen et al 2005), inhalation toxicity (Fowles, Alexeeff, and Dodge 1999; Gift et al 2008), and extensions to human epidemiological studies (Yeh, Lee, and Chen 2006). In all the cases, the risk-analytic context may change with the differing endpoint(s), but the fundamentals of the benchmark concept remain essentially unchanged.…”

Section: Traditional Benchmark Analysis With Quantal Datamentioning

confidence: 99%

Translational benchmark risk analysis

Piegorsch

2010

Journal of Risk Research

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Translational development – in the sense of translating a mature methodology from one area of application to another, evolving area – is discussed for the use of benchmark doses in quantitative risk assessment. Illustrations are presented with traditional applications of the benchmark paradigm in biology and toxicology, and also with risk endpoints that differ from traditional toxicological archetypes. It is seen that the benchmark approach can apply to a diverse spectrum of risk management settings. This suggests a promising future for this important risk-analytic tool. Extensions of the method to a wider variety of applications represent a significant opportunity for enhancing environmental, biomedical, industrial, and socio-economic risk assessments.

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“…Probabilistic methods are gaining attention in the Wrst two steps of risk assessment. Instead of the NOAEL approach, doseresponse modeling (the benchmark approach) is sometimes used to derive HLVs (Allen et al, 2005;Gaylor and Aylward, 2004;Stelljes and Wood, 2004). The benchmark approach is less sensitive to study design and experimental error, and therefore estimates the true noadverse-eVect-level (NAEL) more accurately.…”

Section: Introductionmentioning

confidence: 99%