A novel bottom-up approach to bounding low-dose human cancer risks from chemical exposures

The uncertainties associated with extrapolating model-based cancer risks from high to low doses and animal-based cancer risks to humans are examined. It is argued that low-dose linear extrapolation based on statistical confidence limits calculated from animal data is designed to account for data uncertainty, model-selection uncertainty, and model-fitting instability. The intent is to err on the side of safety, that is, overstating rather than understating the true risk. The tendency toward conservatism in predicting human cancer risks from animal data based on linear extrapolation is confirmed by a real-data analysis of the various sources of uncertainty involved in extrapolating from animals to humans. Along with the tendency toward conservatism, a high degree of overall uncertainty in the interspecies extrapolation process is demonstrated. It is concluded that human cancer risk estimates based on animal data may underestimate the true risk by a factor of 10 or may overestimate that risk by a factor of 1,000.

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USE OF MICRONUCLEUS EXPERIMENTS FOR THE DETECTION OF HUMAN CANCER RISKS: A BRIEF OVERVIEW

Proceedings of the Shevchenko Scientific Society. Medical Sciences ◽

10.25040/ntsh2021.02.05 ◽

2021 ◽

Vol 65 (2) ◽

Author(s):

Armen Nersesyan ◽

◽

Miroslav Mišík ◽

Andriy Cherkas ◽

Viktoria Serhiyenko ◽

...

Keyword(s):

Blood Cells ◽

Environmental Control ◽

Human Cancer ◽

Occupational Exposures ◽

Human Biomonitoring ◽

Target Cells ◽

Cancer Risks ◽

Wide Range

Introduction. Micronuclei (MN) are small extranuclear DNA-containing structures that are formed as a consequence of structural and numerical chromosomal aberrations. The advantage of MN experiments compared to conventional chromosomal analyses in metaphase cells is that the scoring is by far less time consuming and laborious. MN experiments are currently widely used for the routine screening of chemicals in vitro and in vivo but also for environmental control and human biomonitoring Objectives. The purpose of this review was to collect data on the use of MN experiments for the detection of increased cancer risks as a consequence of environmental, lifestyle and occupational exposures and the detection/diagnosis of different forms of cancer. Methods. Analysis of the literature on methods for MN experiments with humans; as well as the use of this technique in different areas of research. Results. To date, a wide range of protocols for human biomonitoring studies has been developed for the measurement of MN formation in peripheral blood cells and in epithelial from different organs (buccal and nasal cavity, cervix and bladder). In addition to MN, other nuclear anomalies can be scored which reflect genetic instability as well as acute toxicity and the division of target cells. Conclusions. The evidence is accumulating that MN can be used as a diagnostic tool for the detection of increased cancer risks as well as for the early diagnosis of cervical and bladder cancer

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Use of Mechanistic Models to Estimate Low-Dose Cancer Risks

Risk Analysis ◽

10.1111/j.1539-6924.1994.tb00073.x ◽

1994 ◽

Vol 14 (6) ◽

pp. 1033-1038 ◽

Cited By ~ 12

Author(s):

Kenny S. Crump

Keyword(s):

Low Dose ◽

Mechanistic Models ◽

Cancer Risks

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Time to repeal the Delaney Clause

Human & Experimental Toxicology ◽

10.1177/096032719401300903 ◽

1994 ◽

Vol 13 (9) ◽

pp. 602-603

Author(s):

H Elizabeth Driver

Keyword(s):

Current Knowledge ◽

Human Cancer ◽

Accurate Determination ◽

Cancer Risks ◽

Federal Food ◽

Genotoxic Carcinogens ◽

Mechanisms Of Carcinogenesis ◽

Williams Test ◽

Important Progress

The Delaney Clause of the Federal Food, Drug, and Cosmetic Act, enacted in 1958, prohibits the addition to the human food supply of any chemical that had caused cancer in humans or animals. The aim was to prevent cancer in humans. The scientific knowledge on causes of cancer and mechanisms of carcinogenesis in the 1950s can be rationalised to justify enactment of this Clause at that time. Since then, important progress in the fields of mechanism of carcinogenesis and cancer causation, and in analytical chemistry permitting accurate determination of trace amounts of chemicals, suggests that the Clause requires modification based on current knowledge. The documented human carcinogens are DNA reactive or genotoxic. Thus, the Clause should emphasise prohibition of the addition to human foods of proven genotoxins that are likely human cancer risks by contemporary standards. Such genotoxic carcinogens are those reliably positive in a battery of three tests: the Ames test in Salmonella typhimurium; the Williams test with evidence of DNA repair in hepatocytes; and direct documentation of DNA adduct formation in the 32P-postlabelling technique of Randerath.

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“Potential Human Cancer Risks From Exposure to PCBs: A Tale of Two Evaluations”: Response to ATSDR Comments

Critical Reviews in Toxicology ◽

10.1080/10408440490891116 ◽

2004 ◽

Vol 34 (6) ◽

pp. 503-505

Author(s):

R. Golden ◽

J. Doull ◽

W. Waddell ◽

J. Mandel

Keyword(s):

Human Cancer ◽

Cancer Risks

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Meta-analysis and trial sequential analysis of LncRNA H19 polymorphic variants on susceptibility to cancer

10.21203/rs.3.rs-16371/v1 ◽

2020 ◽

Author(s):

Kunpeng Wang ◽

Zheng Zhu ◽

Yiqiu Wang ◽

Dayuan Zong ◽

Peng Xue ◽

...

Keyword(s):

Subgroup Analysis ◽

Sequential Analysis ◽

Cancer Susceptibility ◽

Human Cancer ◽

Meta Analysis ◽

Population Based ◽

Trial Sequential Analysis ◽

Control Group ◽

Cancer Risks ◽

Polymorphic Variants

Abstract Background: Although myriad researches upon the associations between LncRNA H19 polymorphic variants (rs2839698 G﹥A, rs3024270 C﹥G, rs2107425 C﹥T, rs2735971 A﹥G and rs217727 G﹥A) and the susceptibility to cancer have been conducted, these results remained contradictory and perplexing. Basing on that, a systematic review and updated meta-analysis was conducted to anticipate a fairly precise assessment about these associations. Methods: We retrieved the electronic databases EMBASE, PubMed and Web of Science for valuable academic studies before October 1st, 2019. Ultimately, 24 of which were encompassed after screening, and the available data was extracted and integrated. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) was adopted to evaluate the strength of these associations. For multi-level investigation, subgroup analysis derived from source of controls together with genotypic method was preformed. Eventually, 24 articles altogether embodying 52 studies were included. Results: The results illuminated that LncRNA H19 SNPs mentioned above were all irrelevant to cancer susceptibility. Nevertheless, crucial results were found concentrated in population-based control group when subgroup analysis by source of controls were performed in H19 mutation rs2839698 and rs2735971. Meanwhile, in the stratification analysis by genotypic method, apparent cancer risks were discovered by TaqMan method in H19 mutation rs2107425 and rs3024270. Then, trial sequential analysis (TSA) demonstrated that the results about such associations were firm evidence of effect, except rs2735971 polymorphism. Conclusion: Therefore, this meta-analysis indicated that LncRNA H19 SNPs were not associated with the susceptibility to human cancer. However, after the stratification analysis, inconsistent results still existed in different genotypic method and source of control. Thus, more high-quality studies on cancer patients of different factors were needed to confirm these findings.

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