Tania Carreón

NAT2 slow acetylation and bladder cancer in workers exposed to benzidine

This study expands a previous study of NAT2 polymorphisms and bladder cancer in male subjects occupationally exposed only to benzidine. The combined analysis of 68 cases and 107 controls from a cohort of production workers in China exposed to benzidine included 30 new cases and 67 controls not previously studied. NAT2 enzymatic activity phenotype was characterized by measuring urinary caffeine metabolite ratios. PCR‐based methods identified genotypes for NAT2, NAT1 and GSTM1. NAT2 phenotype and genotype data were consistent. A protective association was observed for the slow NAT2 genotype (bladder cancer OR = 0.3; 95% CI = 0.1 = 1.0) after adjustment for cumulative benzidine exposure and lifetime smoking. Individuals carrying NAT1wt/*10 and NAT1*10/*10 showed higher relative risks of bladder cancer (OR = 2.8, 95% CI = 0.8–10.1 and OR = 2.2, 95% CI = 0.6–8.3, respectively). No association was found between GSTM1 null and bladder cancer. A metaanalysis risk estimate of case‐control studies of NAT2 acetylation and bladder cancer in Asian populations without occupational arylamine exposures showed an increased risk for slow acetylators. The lower limit of the confidence interval (OR = 1.4; 95% CI = 1.0–2.0) approximated the upper confidence interval for the estimate obtained in our analysis. These results support the earlier finding of a protective association between slow acetylation and bladder cancer in benzidine‐exposed workers, in contrast to its established link as a risk factor for bladder cancer in people exposed to 2‐naphthylamine and 4‐aminobiphenyl. Study findings suggest the existence of key differences in the metabolism of mono‐ and diarylamines. Published 2005 Wiley‐Liss, Inc.

Gliomas and farm pesticide exposure in women: the Upper Midwest Health Study.

An excess incidence of brain cancer in male farmers has been noted in several studies, but few studies have focused on women. The National Institute for Occupational Safety and Health Upper Midwest Health Study evaluated effects of rural exposures for 341 female glioma cases and 528 controls, all adult (18–80 years of age) nonmetropolitan residents of Iowa, Michigan, Minnesota, and Wisconsin. On average, controls lived longer on farms than did cases. After adjusting for age, age group, education, and farm residence, no association with glioma was observed for exposure to arsenicals, benzoic acids, carbamates, chloroacetanilides, dinitroanilines, inorganics, organochlorines, organophosphates, phenoxys, triazines, or urea-based or estrogenic pesticides. An increased risk of glioma was observed for carbamate herbicides but was not statistically significant (odds ratio = 3.0; 95% confidence interval, 0.9–9.5). No association was observed between glioma and exposure to 12 widely used specific pesticides, after adjustment for age, age group, education, and any other pesticide exposure. These results were not affected after exclusion of proxy respondents (43% of cases, 2% of controls). Women were less likely than men to have applied pesticides, but more likely to have laundered pesticide-contaminated clothes. Storing pesticides in the house was associated with a statistically non-significant increased risk. Results show that exposure to pesticides was not associated with an increased risk of intracranial gliomas in women. Other farm-related factors could be etiologic factors and will be discussed in future reports.

Cohort mortality study of workers at seven beryllium processing plants: update and associations with cumulative and maximum exposure.

Objectives To extend follow-up of cause-specific mortality in workers at seven beryllium processing plants and to estimate associations between mortality risk and beryllium exposure. Methods 9199 workers were followed for mortality from 1940 through 2005. Standardised mortality ratios (SMRs) were estimated based on US population comparisons for lung, nervous system and urinary tract cancers, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and categories containing chronic beryllium disease (CBD) and cor pulmonale. Associations with maximum and cumulative exposure were calculated for a subset of the workers. Results Overall mortality in the cohort compared with the US population was elevated for lung cancer (SMR 1.17; 95% CI 1.08 to 1.28), COPD (SMR 1.23; 95% CI 1.13 to 1.32), and the categories containing CBD (SMR 7.80; 95% CI 6.26 to 9.60) and cor pulmonale (SMR 1.17; 95% CI 1.08 to 1.26). Mortality rates for most diseases of interest increased with time-since-hire. For the category including CBD, rates were substantially elevated compared to the US population across all exposure groups. Workers whose maximum beryllium exposure was ≥10 μg/m3 had higher rates of lung cancer, urinary tract cancer, COPD and the category containing cor pulmonale than workers with lower exposure. Significant positive trends with cumulative exposure were observed for nervous system cancers (p=0.0006) and, when short-term workers were excluded, lung cancer (p=0.01), urinary tract cancer (p=0.003) and COPD (p<0.0001). Conclusion These findings reaffirm that lung cancer and CBD, and suggest that COPD and nervous system and urinary tract cancers, are related to beryllium exposure. Cigarette smoking and exposure to other lung carcinogens are unlikely to explain these elevations.

Joint Associations Between Genetic Variants and Reproductive Factors in Glioma Risk Among Women

In a pooled analysis of 4 US epidemiologic studies (1993-2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12-13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.

The genetic and environmental factors involved in benzidine metabolism and bladder carcinogenesis in exposed workers.

Genetic susceptibility to bladder cancer in individuals exposed to arylamines may be explained by interindividual metabolic differences that lead to arylamine bioactivation or detoxification. In this article, occupational bladder cancer risk factors and the evidence that links benzidine exposure to bladder cancer are reviewed. Benzidine metabolism is described and compared with that of other aromatic amines. Metabolic polymorphisms and bladder cancer in the context of occupational exposure to aromatic amines are also reviewed, and the environmental and genetic relationships of benzidine exposure and genetic susceptibility are outlined. Only a few studies of bladder cancer genetic susceptibility in populations exposed occupationally to arylamines have been published. The results of these case-control studies show conflicting results, reflecting metabolic differences between monoarylamines and diarylamines such as benzidine. Additional studies and pooled analyses of existing data are needed to establish if individuals are at higher risk of bladder cancer given the presence of certain alleles that make them more susceptible to this disease.

Use of the “Exposome” in the Practice of Epidemiology: A Primer on -Omic Technologies

The exposome has been defined as the totality of exposures individuals experience over the course of their lives and how those exposures affect health. Three domains of the exposome have been identified: internal, specific external, and general external. Internal factors are those that are unique to the individual, and specific external factors include occupational exposures and lifestyle factors. The general external domain includes sociodemographic factors such as educational level and financial status. Eliciting information on the exposome is daunting and not feasible at present; the undertaking may never be fully realized. A variety of tools have been identified to measure the exposome. Biomarker measurements will be one of the major tools in exposomic studies. However, exposure data can also be obtained from other sources such as sensors, geographic information systems, and conventional tools such as survey instruments. Proof-of-concept studies are being conducted that show the promise of exposomic investigation and the integration of different kinds of data. The inherent value of exposomic data in epidemiologic studies is that they can provide greater understanding of the relationships among a broad range of chemical and other risk factors and health conditions and ultimately lead to more effective and efficient disease prevention and control.

Biological Markers of Carcinogenic Exposure in the Aluminum Smelter Industry—A Systematic Review

Exposure monitoring programs have been used in the aluminum smelter industry for decades to decrease the risk of cancer from exposure to polycyclic aromatic hydrocarbons (PAHs). Biological monitoring of PAHs incorporates all routes of exposure. Measuring postshift urinary 1-hydroxypyrene (1OHP), a metabolite of pyrene, determines workers daily PAH exposures, while measuring DNA adducts reflect chronic exposures to PAHs. We reviewed the scientific literature to identify changes over time in (1) 1OHP levels, (2) DNA adduct levels, and (3) other contributing factors associated with 1OHP and DNA adduct levels in the aluminum smelter industry. No trends were observed in 1OHP and DNA adduct levels. This could be due to variable selection of study populations and poorly identified job tasks that prevent comparison of jobs across plants and times, unassessed worker exposure variability, and the impact of cumulative exposures. Thus, it cannot be demonstrated that the use of biological monitoring to estimate PAH exposures has brought about an exposure reduction in the industry. Future studies should be aimed at follow-up in workplaces where dermal and inhalation exposure interventions have been employed. Inconsistent findings were also observed in the analysis of CYP1A1, GSTM1, and GSTP1 polymorphisms and their effect on biomarker levels.

Endogenous antibody responsiveness to epidermal growth factor receptor is associated with immunoglobulin allotypes and overall survival of patients with glioblastoma

BACKGROUND Immunoglobulin γ marker (GM) and κ marker (KM) allotypes, hereditary antigenic determinants of γ and κ chains, respectively, have been shown to be associated with immunity to a variety of self and nonself antigens, but their possible contribution to immunity to the tumor-associated antigens epidermal growth factor receptor (EGFR) and EGFR variant (v)III has not been evaluated. The aim of the present investigation was to determine whether the interindividual variation in endogenous antibody responsiveness to EGFR and EGFRvIII is associated with particular GM, KM, and Fcγ receptor (FcγR) genotypes and whether antibody levels were associated with the overall survival of patients with glioblastoma. METHODS A total of 126 Caucasian participants with glioblastoma were genotyped for several GM, KM, and FcγR alleles and characterized for IgG antibodies to EGFR and EGFRvIII antigens. RESULTS The anti-EGFR antibody levels associated with GM 3/3 homozygotes and GM 3/17 heterozygotes were similar (15.9 vs 16.4 arbitrary units [AU]/µL) and significantly lower than those associated with GM 17/17 homozygotes (19.6 AU/µL; nominal P = .007). Participants homozygous for the GM 21 allele also had significantly higher levels of anti-EGFR antibodies than GM 5/5 homozygotes and GM 5/21 heterozygotes (20.1 vs 16.0 and 16.3 AU/µL; nominal P = .005). Similar associations were found with immune responsiveness to EGFRvIII. Higher anti-EGFR and anti-EGFRvIII antibody levels were associated with enhanced overall survival (16 vs 11 mo, nominal P = .038 and 20 vs 11 mo, nominal P = .004, respectively). CONCLUSIONS GM allotypes contribute to humoral immunity to EGFR in glioblastoma.