Thresholds for DNA-Reactive (Genotoxic) Organic Carcinogens

Williams, Gary M.; Iatropoulos, Michael J.; Jeffrey, Alan M.

doi:10.1293/tox.18.69

Cited by 26 publications

(10 citation statements)

References 75 publications

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“…40,41 Several factors could account for a NOAEL for adducts. Accordingly we suggest that this low level CD is a threshold for DNA adduct formation and hence carcinogenicity, as previously discussed.…”

Section: Discussionmentioning

confidence: 99%

A no observed adverse effect level for DNA adduct formation in rat liver with prolonged dosing of the hepatocarcinogen 2-acetylaminofluorene

et al. 2015

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We have previously reported that the DNA-reactive hepatocarcinogen 2-acetylaminofluorene (AAF) produced in rat liver several key effects that were less than linear over a range of repeat doses, and that at low cumulative doses, no-adverse-effect-levels (NOAEL) were observed for several effects including hepatocellular cytotoxicity, enhanced cell proliferation, induction of preneoplastic foci and promotable liver neoplasms, although DNA adducts were still formed at dosages below the lowest NOAEL of 28 mg kg −1 cumulative dose for these other effects. This report details two further dose-effect studies at lower repeat doses than those previously used as well as identification of the specific types of DNA adducts formed.AAF was administered orally to male F344 rats by gavage at repeat dosages which in one experiment (A) ranged from 0.01 to 2.24 mg kg −1 bw per day, 7 days per week for 12 weeks followed by recovery for 4 weeks, and in a second (B) at lower dosages of 0.0026 or 0.026 mg kg −1 bw per day 3 days per week for 16 weeks. Initially the nonacetylated guanine adduct, N-(deoxyguanosine-8-yl)-aminofluorene, predominated. With continued dosing, the pattern of adducts changed such that by 4 weeks more acetylated, N-(deoxyguanosine-N 2 -yl)-AAF and N-(deoxyguanosine-8-yl)-AAF, adducts were present. In experiment A, total adducts reached a maximum by 12 weeks with levels of 6.0 adducts per 10 8 nucleotides at the lowest dosage. In experiment B, the total DNA adducts at the lowest dosage was below the limit of detection at 12 weeks, and at 0.6 in 10 8 nucleotides at 16 weeks, levels within the background range of 1.0-3.1 per 10 8 nucleotides. Thus, the cumulative dose of 0.125 mg kg −1 bw over 16 weeks was a NOAEL for adducts and hence would be predicted to be a threshold for hepatocarcinogenicity. Fig. 7 Dose-response curve for CD1B/CD2B dose levels. Experiment B; values of the DNA adducts level in the control group over time are presented as an average. Paper Toxicology Research 238 | Toxicol. Res., 2015, 4, 233-240This journal is

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Section: Discussionmentioning

confidence: 99%

A no observed adverse effect level for DNA adduct formation in rat liver with prolonged dosing of the hepatocarcinogen 2-acetylaminofluorene

et al. 2015

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“…Quantification of these effects and the extent to which they interact with background effects is difficult, though a quantitative estimate has been made by Williams et al 49 Considering that the spontaneous DNA modifications of a mammalian cell is about one lesion per 10 6 bases, the lowest DNA adduct levels of three genotoxic carcinogens was determined to be one adduct per 10 8 nucleotides, which is far below the spontaneous DNA modifications and considered unlikely to be of biological significance.…”

Section: Discussionmentioning

confidence: 99%

“…15 Beyond considering species and individual differences in the capacity of metabolic activation and inactivation several aspects in DNA binding, DNA repair and mutations are discussed.…”

Section: Introductionmentioning

confidence: 99%

Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens

Greim¹,

Albertini²

2012

Issues in Toxicology

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“…The LNT model predicted that a single alteration of DNA could initiate the process of carcinogenesis, and that once initiated, this process was irreversible. However, this assumption has been consistently shown to be false (77). In one such study Driver et al (78) demonstrated that a single administration of the mutagen/carcinogen dimethylnitrosamine (DMN) induced a linear dose response for renal mesenchymal DNA adducts (early cancer process stage), as well as for mesenchymal foci (later cancer process stage), observations consistent with the LNT model.…”

Section: Mechanistic Challenges To Lnt-hit Modelmentioning

confidence: 93%

Estimating Risk of Low Radiation Doses – A Critical Review of the BEIR VII Report and its Use of the Linear No-Threshold (LNT) Hypothesis

Calabrese

O’Connor

2014

Radiation Research

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This article explores the origin of the linear no-threshold (LNT) dose-response model and how it came to be used in cancer risk assessment worldwide. Following this historical appraisal is an evaluation of the LNT model, within the framework of the BEIR VII report of the National Academy of Sciences, on the health effects of ionizing radiation. The final section of this article provides an assessment of the LNT model's capacity to make accurate predictions of risk in the low-dose zone based on recent molecular mechanistic findings and epidemiological methods, with particular emphasis on the limitations of epidemiological studies to estimate risks in the low-dose zone.

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Thresholds for DNA-Reactive (Genotoxic) Organic Carcinogens

Abstract: This paper reviews the evidence for thresholds for DNA-reactive carcinogens and presents dose response data for effects in rat liver of two DNA-reactive hepatocarcinogens, diethylnitrosamine and 2-acetylaminofluorene, which is consistent with thresholds. (J Toxicol Pathol 2005; 18: 69-77)

Cited by 26 publications

References 75 publications

A no observed adverse effect level for DNA adduct formation in rat liver with prolonged dosing of the hepatocarcinogen 2-acetylaminofluorene

A no observed adverse effect level for DNA adduct formation in rat liver with prolonged dosing of the hepatocarcinogen 2-acetylaminofluorene

Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens

Estimating Risk of Low Radiation Doses – A Critical Review of the BEIR VII Report and its Use of the Linear No-Threshold (LNT) Hypothesis

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