In rats, TCAB also induced malignant schwannoma, and cancers of the biliary system and oral mucosa.15 This spectrum of rodent tumours encompasses those observed with other AhR agonists previously ...evaluated as Group 1 carcinogens (eg, dioxins, dioxin-like polychlorinated biphenyls, and 2,3,4,7,8-pentachlorodibenzofuran). Specifically, in mice and rabbits, TCAB causes chloracne, and in chronically exposed rodents, TCAB induces CYP1A1 and CYP1A2, wasting syndrome, thymic atrophy, as well as hyperplasia and chronic inflammation in multiple tissues.15 TCAB activates AhR in rats, mice, and chicken embryos; in vitro, TCAB binds to mouse AhR, and activates rat and rainbow trout AhR.15-18 These mechanistic data provided strong evidence that TCAB modulates receptor-mediated effects, induces chronic inflammation, and alters cell proliferation.
Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high-production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these ...chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent species- and sex-specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure.
Styrene is widely used in industrial settings, leading to important occupational exposure. Currently it is classified by IARC as “possibly carcinogenic to humans” based on limited evidence of an ...association with lymphohaematopoietic cancers. Several recent studies suggest increased risk of lung cancer may be associated with exposure to styrene. We conducted a systematic search and a meta-analysis of epidemiologic studies of exposure to styrene and incidence or mortality of lung cancer. Of 167 papers retrieved, 50 were found to provide pertinent data after screening the abstracts; 42 of these were occupational cohort studies conducted in 3 main work settings: chemical production, reinforced plastics manufacturing, and styrene-butadiene rubber production. There was significant overlap in the populations among published papers, which reported data from 7 separate cohorts and one pooled international cohort, some parts of which were also published separately. Meta-analysis showed an excess risk of lung cancer among workers ever exposed to styrene (RR 1.14, 95% CI 1.04–1.24, I263%). The association was stronger when the analysis was limited to the reinforced plastics industry, where co-exposures are less important than in other industries (RR 1.20, 95% CI 1.10–1.31, I272%). Meta-analysis of exposure-response relations in the subset of studies that reported quantitative or categorical exposure data are ongoing and will be reported.
We sought to determine whether hypoxia-induced radioresistance is mediated by the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha).
We used 2 mouse embryonic fibroblast cell lines ...transformed with H-ras and TAg, 1 HIF-1alpha+/+ and the other HIF-1alpha-/-. Cell were exposed to either 95% air and 5% CO2 (normoxic conditions) or 0.2% O2, 94.8% N2, and 5% CO2 (hypoxic conditions) for 4 hours. Cells were then irradiated and subjected to clonogenic survival assays.
Whereas neither +/+ ras/TAg nor -/- ras/TAg cells expressed HIF-1alpha under normoxic conditions, hypoxia induced expression of HIF-1alpha only in +/+ ras/TAg cells, confirming the absence of HIF-1alpha in -/- ras/TAg cells. Clonogenic survival curves for +/+ ras/TAg and -/- ras/TAg cells under normoxia and hypoxia demonstrated that hypoxia increased radioresistance in both cell lines to the same degree. At 1-log cell kill, the +/+ ras/TAg and -/- ras/TAg cells had an identical oxygen enhancement ratio of 1.28 +/- 0.09 and nearly identical oxygen enhancement ratios at 2-log cell kill.
In our system of transformed mouse embryonic fibroblasts, hypoxia-mediated radiation resistance is independent of HIF-1alpha.
Alcohol drinking is a major risk factor for head and neck cancer (HNC). This risk may be modified by alcohol dehydrogenase (ADH) genes, particularly ADH1B and ADH1C, that oxidise ethanol to its ...carcinogenic metabolite, acetaldehyde. A meta-analysis was conducted to assess the association between ADH1B and ADH1C and HNC risk. Twenty-nine studies from 28 articles identified from a literature search were included. Summary odds ratios (meta-ORs) were generated using random effect models. A reduced risk for HNC was associated with carrying the ADH1B*2 and ADH1C*1 alleles that confer faster metabolism of ethanol to acetaldehyde meta-OR ADH1B, 0.50; 95% confidence interval (CI): 0.37-0.68, 13 studies; meta-OR ADH1C, 0.87; 95% CI: 0.76-0.99, 22 studies. ADH1B*2 and ADH1C*1 alleles appear to be protective for HNC, possibly due to: (i) decreasing the opportunity for oral microflora to produce acetaldehyde locally from a prolonged systemic circulation of ethanol, (ii) preventing ethanol from acting as a solvent for other carcinogens, and (iii) decreasing the amount of ethanol a person consumes since a consequent peak in systemic acetaldehyde could cause discomfort. These results underscore the importance of ADH1B and ADH1C in the association between alcohol consumption and the risk for HNC.
Objective and systematic methods to search, review, and synthesize published studies are a fundamental aspect of carcinogen hazard classification. Systematic review is a historical strength of the ...International Agency for Research on Cancer (IARC) Monographs Program and the United States National Toxicology Program (NTP) Office of the Report on Carcinogens (RoC). Both organizations are tasked with evaluating peer-reviewed, published evidence to determine whether specific substances, exposure scenarios, or mixtures pose a cancer hazard to humans. This evidence synthesis is based on objective, transparent, published methods that call for extracting and interpreting data in a systematic manner from multiple domains, including
) human exposure,
) epidemiological evidence,
) evidence from experimental animals, and
) mechanistic evidence. The process involves multiple collaborators and requires an extensive literature search, review, and synthesis of the evidence. Several online tools have been implemented to facilitate these collaborative systematic review processes. Specifically, Health Assessment Workplace Collaborative (HAWC) and Table Builder are custom solutions designed to record and share the results of the systematic literature search, data extraction, and analyses. In addition, a content management system for web-based project management and document submission has been adopted to enable access to submitted drafts simultaneously by multiple co-authors and to facilitate their peer review and revision. These advancements in cancer hazard classification have applicability in multiple systematic review efforts. https://doi.org/10.1289/EHP4224.
Objectives To discuss the important role of occupational studies in identifying carcinogens and suggest how it could be still greater. Method The contribution of occupational studies to the IARC ...monographs is reviewed. Results Occupational epidemiology has made important contributions beyond developing knowledge to protect workers’ health, notably in identifying carcinogens of concern for the general population. The IARC Monographs have evaluated many carcinogens for which occupational studies have provided key evidence. The recent classifications of diesel engine exhaust, trichloroethylene and polychlorinated biphenyls (PCBs) as human carcinogens, which depended heavily on data from occupational studies, are illustrative. In the evaluation of PCBs, for example, occupational cohort studies showing an exposure-related increase in the risk of malignant melanoma were pivotal for the conclusion of sufficient evidence of carcinogenicity. Despite such noteworthy contributions, the number of occupational studies that are ultimately informative tends to be relatively small relative to the number reviewed. The most informative studies tend to have common features, including clear reporting of methods and results, well-defined outcomes, quantitative estimates of exposure, adequate control of major confounders, and state of the art analytical methods, often with internal analyses of exposure-response. In contrast, studies that are too broadly focused and those with crude classifications of exposure or outcome, analyses by external comparisons alone or poor reporting of the methods and results are often less informative in the final evaluation. Conclusions While occupational studies are important for carcinogen identification, their relevance could be further enhanced with improvements in study design, methods and reporting.
Objectives To present extensions to the International Agency for Research on Cancer (IARC) Monographs process, providing examples of application of meta-data to identifying carcinogenic hazard ...identifications and research gaps, and the potential use for guiding cancer control efforts. Qualitative and quantitative approaches will be contrasted. Method The IARC evaluation process typically employs summary level meta-data, in the form of systematic reviews, and pooled- and meta-analyses. Results IARC has heavily relied on published occupational epidemiological studies to identify specific carcinogens in the workplace and to form a scientific basis for the protection of workers worldwide. The evaluations of carcinogenic risk are made by international working groups of independent scientists and are qualitative in nature. Meta-analyses prepared for IARC working groups can complement the qualitative process and have been crucial in several instances; for example, in identifying sufficient evidence for lung and bladder cancer in painters and limited evidence for increased risk of bladder cancer among dry cleaners exposed to tetrachloroethylene and among professional drivers (bus, taxi, truck) with high exposure to outdoor air pollution. Since IARC does not provide recommendations for regulation or legislation, meta-relative risks can also be used to calculate attributable fractions to guide cancer control efforts, for agents in which a causal association is assumed and exposure prevalence has been well-characterised. Conclusions The IARC Monographs Programme is an authoritative source for the identification of carcinogenic hazards in the environment. Applying meta-analyses to the IARC process can be a useful tool for informing hazard identification and providing guidance for cancer control efforts.
Soy isoflavones, structurally similar to endogenous estrogens, may affect breast cancer through both hormonally mediated and non-hormonally related mechanisms. Although the effects of soy are not ...well understood, some breast cancer survivors increase their soy intake post-diagnosis in attempt to improve their prognosis. Therefore, we examined the role of soy isoflavone intake and the risk of breast cancer recurrence by hormone receptor status, menopausal status, and tamoxifen therapy. A cohort of 1,954 female breast cancer survivors, diagnosed during 1997-2000, was prospectively followed for 6.31 years and 282 breast cancer recurrences were ascertained. Isoflavone intake was assessed by mailing modified Block and supplemental soy food frequency questionnaires to participants, on average 23 months post-diagnosis. Risk of breast cancer recurrence, measured by hazard ratios (HR) and 95% confidence intervals (CI), was estimated using multivariable delayed entry Cox proportional hazards models. Suggestive trends for a reduced risk of cancer recurrence were observed with increasing quintiles of daidzein and glycetin intake compared to no intake among postmenopausal women (P for trend: P = 0.08 for daidzein, P = 0.06 for glycetin) and among tamoxifen users (P = 0.10 for daidzein, P = 0.05 for glycetin). Among postmenopausal women treated with tamoxifen, there was an approximately 60% reduction in breast cancer recurrence comparing the highest to the lowest daidzein intakes (>1,453 vs. <7.7 μg/day; HR, 0.48; 95% CI, 0.21-0.79, P = 0.008). Soy isoflavones consumed at levels comparable to those in Asian populations may reduce the risk of cancer recurrence in women receiving tamoxifen therapy and moreover, appears not to interfere with tamoxifen efficacy. Further confirmation is required in other large prospective studies before recommendations regarding soy intake can be issued to breast cancer survivors.
Abstract Tobacco use, and in particular cigarette smoking, is the single largest preventable cause of cancer in the European Union (EU). All tobacco products contain a wide range of carcinogens. The ...main cancer-causing agents in tobacco smoke are polycyclic aromatic hydrocarbons, tobacco-specific N -nitrosamines, aromatic amines, aldehydes, and certain volatile organic compounds. Tobacco consumers are also exposed to nicotine, leading to tobacco addiction in many users. Cigarette smoking causes cancer in multiple organs and is the main cause of lung cancer, responsible for approximately 82% of cases. In 2012, about 313,000 new cases of lung cancer and 268,000 lung cancer deaths were reported in the EU; 28% of adults in the EU smoked tobacco, and the overall prevalence of current use of smokeless tobacco products was almost 2%. Smokeless tobacco products, a heterogeneous category, are also carcinogenic but cause a lower burden of cancer deaths than tobacco smoking. One low-nitrosamine product, snus, is associated with much lower cancer risk than other smokeless tobacco products. Smoking generates second-hand smoke (SHS), an established cause of lung cancer, and inhalation of SHS by non-smokers is still common in indoor workplaces as well as indoor public places, and more so in the homes of smokers. Several interventions have proved effective for stopping smoking; the most effective intervention is the use of a combination of pharmacotherapy and behavioural support. Scientific evidence leads to the following two recommendations for individual action on tobacco in the 4th edition of the European Code Against Cancer: (1) “Do not smoke. Do not use any form of tobacco”; (2) “Make your home smoke-free. Support smoke-free policies in your workplace”.
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