Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens

Greim, Helmut; Albertini, Richard J.

doi:10.1039/9781849732925-00001

Cited by 3 publications

(4 citation statements)

References 35 publications

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“…When stem cells divide, they become exposed to unavoidable and carcinogen-mediated DNA alterations that increase their risk of malignant transformation . Second, repetitive and accumulated carcinogenic insult may result in carcinogenesis, whereas physiological homeostasis would be effective under conditions such as episodic alcohol exposure . Chronic exposure to acetaldehyde resulting from frequent drinking can lead to the formation of DNA adducts and induces chromosomal aberrations and sister chromatid exchanges in human lymphocytes .…”

Section: Discussionmentioning

confidence: 96%

Association of the Frequency and Quantity of Alcohol Consumption With Gastrointestinal Cancer

et al. 2021

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Key Points Question Which is the more important factor in the development of gastrointestinal (GI) cancer: frequency of drinking alcohol or quantity of alcohol consumed per occasion? Findings In this cohort study of 11 737 467 participants, the risk of GI cancer was significantly associated with drinking frequency. Compared with similar weekly alcohol consumption levels, the risk of GI cancer increased with a higher frequency of drinking but decreased with larger amounts per occasion. Meaning This study suggests that frequent drinking may be a more important risk factor for incident GI cancers than the amount of alcohol consumed per occasion, and patients should be careful with their drinking habits, including regular consumption of small amounts of alcohol.

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Section: Discussionmentioning

confidence: 96%

Association of the Frequency and Quantity of Alcohol Consumption With Gastrointestinal Cancer

et al. 2021

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“…Because of conservative assumptions that increase risk, such as low‐dose linearity and the assumption that animal carcinogens are likely to be human carcinogens, our risk calculations are upper‐bound hypothetical estimates. For example, the use of the LNT model is likely to overestimate the actual risks of MTBE because of MTBE's lack of genotoxicity (Greim & Albertini, 2012; Aschner et al., 2016) and because the positive cancer findings reported in animal bioassays with MTBE are either not reliable (e.g., LCTs, leukemias/lymphomas, and astrocytomas) or likely not relevant to humans (i.e., kidney tumors in male rats and liver cancer in female mice). Including these endpoints in our analysis results in a very conservative analysis that is likely to overstate risk.…”

Section: Discussionmentioning

confidence: 99%

“…We calculated the ED 10 values and LED 10 values using an LMS model in US EPA's Benchmark Dose Software (Version 2.6.0.1) (US EPA, 2016). The use of the LNT model is likely to overestimate the actual MTBE risks because of MTBE's lack of genotoxicity (Greim & Albertini, 2012; Aschner et al., 2016).…”

Section: Mos Analysismentioning

confidence: 99%

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

2020

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Methyl tert-butyl ether (MTBE) was added to gasoline in New Hampshire (NH) between 1995 and 2006 to comply with the oxygenate requirements of the 1990 Amendments to the Clean Air Act. Leaking tanks and spills released MTBE into groundwater, and as a result, MTBE has been detected in drinking water in NH. We conducted a comparative cancer risk assessment and a margin-of-safety (MOS) analysis for several constituents, including MTBE, detected in NH drinking water. Using standard risk assessment methods, we calculated cancer risks from exposure to 12 detected volatile organic compounds (VOCs), including MTBE, and to four naturally occurring compounds (i.e., arsenic, radium-226, radium-228, and radon-222) detected in NH public water supplies. We evaluated exposures to a hypothetical resident ingesting the water, dermally contacting the water while showering, and inhaling compounds volatilizing from water in the home. We then compared risk estimates for MTBE to those of the other 15 compounds. From our analysis, we concluded that the high-end cancer risk from exposure to MTBE in drinking water is lower than the risks from all the other VOCs evaluated and several thousand times lower than the risks from exposure to naturally occurring constituents, including arsenic, radium, and radon. We also conducted an MOS analysis in which we compared toxicological points of departure to the NH maximum contaminant level (MCL) of 13 µg/L. All of the MOSs were greater than or equal to 160,000, indicating a large margin of safety and demonstrating the health-protectiveness of the NH MCL for MTBE.

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“…As a consequence, replicative DNA polymerases readily bypass the HdU lesion, preferentially incorporating dAMP [2,7]. HdU found in double-helical DNA is potentially mutagenic [6,7,8] and not cytotoxic [9]. Interestingly, several enzymes from human cells capable of removing HdU lesions from DNA have been described [3].…”

Section: Introductionmentioning

confidence: 99%

Translesion DNA Synthesis Across Lesions Induced by Oxidative Products of Pyrimidines: An Insight into the Mechanism by Microscale Thermophoresis

Hrabina

Brabec

Nováková

2019

IJMS

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Oxidative stress in cells can lead to the accumulation of reactive oxygen species and oxidation of DNA precursors. Oxidized nucleotides such as 2’-deoxyribo-5-hydroxyuridin (HdU) and 2’-deoxyribo-5-hydroxymethyluridin (HMdU) can be inserted into DNA during replication and repair. HdU and HMdU have attracted particular interest because they have different effects on damaged-DNA processing enzymes that control the downstream effects of the lesions. Herein, we studied the chemically simulated translesion DNA synthesis (TLS) across the lesions formed by HdU or HMdU using microscale thermophoresis (MST). The thermodynamic changes associated with replication across HdU or HMdU show that the HdU paired with the mismatched deoxyribonucleoside triphosphates disturbs DNA duplexes considerably less than thymidine (dT) or HMdU. Moreover, we also demonstrate that TLS by DNA polymerases across the lesion derived from HdU was markedly less extensive and potentially more mutagenic than that across the lesion formed by HMdU. Thus, DNA polymerization by DNA polymerase η (polη), the exonuclease-deficient Klenow fragment of DNA polymerase I (KF–), and reverse transcriptase from human immunodeficiency virus type 1 (HIV-1 RT) across these pyrimidine lesions correlated with the different stabilization effects of the HdU and HMdU in DNA duplexes revealed by MST. The equilibrium thermodynamic data obtained by MST can explain the influence of the thermodynamic alterations on the ability of DNA polymerases to bypass lesions induced by oxidative products of pyrimidines. The results also highlighted the usefulness of MST in evaluating the impact of oxidative products of pyrimidines on the processing of these lesions by damaged DNA processing enzymes.

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Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens

Cited by 3 publications

References 35 publications

Association of the Frequency and Quantity of Alcohol Consumption With Gastrointestinal Cancer

Association of the Frequency and Quantity of Alcohol Consumption With Gastrointestinal Cancer

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

Translesion DNA Synthesis Across Lesions Induced by Oxidative Products of Pyrimidines: An Insight into the Mechanism by Microscale Thermophoresis

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