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Worker genetic susceptibility to mutagenic risk.

Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-004192, 2010 Aug; :1-11
One of the NIOSH's primary research objectives is "the identification and investigation of the relationships between hazardous working conditions and associated occupational diseases". A critical part of this process is understanding the complex relationship between workers' genetic make-up and workplace exposures, because it is becoming increasingly important in identifying workers at the greatest risk for developing occupational diseases and for providing possible interventions to reduce that risk and prevent disease. A potential model population for the study of such occupational gene-environment interactions and for the development of related interventions is provided by workers exposed to the carcinogen vinyl chloride (VC), because they represent an important segment of the petrochemical industry workforce and because much is known about the carcinogenic pathways for VC that could account for different health risks in similarly exposed workers. The purpose of this research has been to identify specific biomarkers of acquired and inherited genetic risk in VC-exposed workers that account for different cancer outcomes. This research has identified several important acquired and inherited genetic risk factors for VC-induced cancer. The acquired genetic risks were identified as specific mutant biomarkers in VC-exposed workers' blood samples in the proteins of a major oncogene and a major tumor suppressor gene that correlated with the genetic changes in the resultant tumors. These biomarkers were found to occur in a highly statistically significant dose-response relationship with regard to estimated cumulative VC exposure. Furthermore, these biomarkers have been identified not only in VC-exposed workers with cancers but also in VC-exposed workers without any apparent neoplastic disease, even in workers exposed only below the current permissible exposure limit. However, at any given VC exposure level, some workers will have none, one or both mutant biomarkers. This individual variability was found to be due to inherited genetic differences in the proteins that metabolize VC or repair the mutagenic damage it produces. These biomarkers of inherited genetic risk in metabolism and repair were found to be statistically significantly associated with the occurrence of the biomarkers of acquired genetic risk regardless of the level of VC exposure. These results can be utilized in the workplace for improvement of both primary and secondary prevention of VC-related cancer. For example, the fact that the mutant biomarkers of acquired genetic risk are statistically elevated even in workers exposed only below the current permissible exposure limit suggests that the current limit is not adequately protective. In fact, a new risk assessment could be based on the presence of these biomarkers, since exposures below one-quarter of the current permissible exposure limit demonstrate no statistically significant increase in these biomarkers. Furthermore, individuals with either the acquired or inherited biomarkers who are clearly at increased risk for the development of cancer could be targeted for specific secondary preventive interventions designed to address their particular genetic defect and avoid the occurrence of cancer. Such studies are currently underway for both the acquired and inherited genetic risks. Finally, it should be emphasized that although these studies have been focused on VC-exposed workers, this model should have much broader implications, since many other workplace chemical exposures are metabolized and repaired by the same pathways (and thus would be affected by the same inherited genetic susceptibilities) and results in similar genetic mutations (Le., similar acquired genetic susceptibilities) and thus would be suitable targets for the same types of preventive approaches, so these results could be relevant for many other workers.
Work-environment; Hazards; Diseases; Genes; Genetics; Exposure-levels; Risk-factors; Carcinogens; Health-hazards; Cancer; Biomarkers; Mutagens; Neoplastic-agents; Metabolism; Statistical-analysis; Workers
Paul W. Brandt-Rauf, Dr.P.H., M.D., ScD., Office of the Dean, School of Public Health, University of Illinois at Chicago, 1603 West Taylor Street, Chicago, IL 60612
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Final Grant Report
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National Institute for Occupational Safety and Health
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University of Illinois