Faculty Bibliography

In the United States, the incidence rates of multiple myeloma in Blacks are more than twice those in Whites, but the etiology of this cancer is poorly understood. A population-based case-control interview study of 571 subjects (365 White, 206 Black) with multiple myeloma and 2,122 controls (1,155 White, 967 Black) living in three areas of the United States (Georgia, Michigan, New Jersey) offered the opportunity to investigate the relationship with smoking and alcohol drinking and to evaluate whether these factors might contribute to the excess risk of multiple myeloma in Blacks. For Blacks and Whites of either gender, there were no significantly elevated risks associated with ever use of cigarettes or alcoholic beverages and no consistent patterns with either intensity or duration of use. These data support previous studies indicating that smoking and drinking are not related causally to the risk of multiple myeloma, and thus cannot account for the racial disparity in incidence rates

Urinary mutagenicity has been used in occupational and epidemiological studies for over two decades as a cost-effective, general biomarker of exposure to genotoxic agents. However, few studies have compared urinary mutagenicity to additional biomarkers determined among low- and high-exposed groups. To address this issue, we evaluated the relationship between urinary mutagenicity and other types of biomarkers in a cross-sectional study involving 15 workers exposed to the urinary bladder carcinogen benzidine (BZ, high exposure), 15 workers exposed to BZ-dyes (low exposure), and 13 unexposed controls in Ahmedabad, India. Urinary organics were extracted by C18/methanol and evaluated for mutagenicity in the presence of S9 in the Salmonella strain YG1024, which is a frameshift strain that overproduces acetyltransferase. The results were compared to biomarker data reported recently from the same urine samples (Rothman et al., Proc. Natl Acad. Sci. USA, 93, 5084-5089, 1996) that included a metabolite biomarker (the sum of the urinary levels of BZ + N-acetylbenzidine + N,N'-diacetylbenzidine) and a DNA adduct biomarker [a presumptive N-(3'-phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine (C8dG-ABZ) DNA adduct in exfoliated urothelial cells]. The mean +/- SE urinary mutagenicity (revertants/micromol of creatinine) of the low-exposure (BZ-dye) workers was 8.2 +/- 2.4, which was significantly different from the mean of the controls (2.8 +/- 0.7, P = 0.04) as was that of the mean of the high-exposure (BZ) workers (123.2 +/- 26.1, P < 0.0001). Urinary mutagenicity showed strong, positive correlations with urinary metabolites (r = 0.88, P < 0.0001) and the level of the presumptive C8dG-ABZ urothelial DNA adduct (r = 0.59, P = 0.0006). A strong association was found between tobacco use (bidi smoking) and urinary mutagenicity among the controls (r = 0.68, P = 0.01) but not among the exposed workers (r = 0.18, P = 0.11). This study confirms the ability of a biomarker such as urinary mutagenicity to detect low-dose exposures, identify additional genotoxic exposures among the controls, and correlate strongly with urinary metabolites and DNA adducts in the target tissue (urinary bladder epithelia) in humans

Epidemiologic evidence on the relation between exposure to metals and cancer is reviewed. Human exposure to metals is common, with wide use in industry and long-term environmental persistence. Historically, the heaviest metal exposures occurred in the workplace or in environmental settings in close proximity to industrial sources. Among the general population, exposure to a number of metals is widespread but generally at substantially lower levels than have been found in industry. The carcinogenicity of arsenic, chromium, and nickel has been established. Occupational and environmental arsenic exposure is linked to increased lung cancer risk in humans, although experimental studies remain inconclusive. Experimental studies clearly demonstrate the malignant potential of hexavalent(VI) chromium compounds, with solubility being an important determining factor. Epidemiologic studies of workers in chromium chemical production and use link exposure to lung and nasal cancer. Experimental and epidemiologic data show that sparingly-soluble nickel compounds and possibly also the soluble compounds are carcinogens linked to lung and nasal cancer in humans. Some experimental and epidemiologic studies suggest that lead may be a human carcinogen, but the evidence is inconclusive. Although epidemiologic data are less extensive for beryllium and cadmium, the findings in humans of excess cancer risk are supported by the clear demonstration of carcinogenicity in experimental studies. Other metals, including antimony and cobalt, may be human carcinogens, but the experimental and epidemiologic data are limited

O6-Alkylguanine-DNA alkyltransferase (AGT) activity was assessed in peripheral blood lymphocytes among 23 mortuary science students before and after 9 weeks in a laboratory course in techniques of embalming. Formaldehyde exposure was established by environmental monitoring. The average air concentration of formaldehyde during embalming was about 1.5 ppm. At the pre-exposure sampling, baseline DNA repair capacity tended to be reduced in subjects who reported a prior history of embalming (p = 0.08). From pre- to post-exposure, 17 subjects decreased in DNA repair capacity, while only 6 increased (p < 0.05). Analysis of variance, including adjustment for age, sex, and smoking status, confirmed these findings. Among the eight subjects who had no embalming experience during the 90 days before study, seven had decreased and one had increased AGT activity during the period of study (p < 0.05). For those with prior embalming experience, 10 subjects decreased in AGT activity, while 5 increased (p < 0.05). Although the major chemical exposure in embalming practice was to formaldehyde, no clear link was established between amount of formaldehyde exposure and AGT activity

A pooled reanalysis of twelve case-control studies on sinonasal cancer and occupation from seven countries was conducted in order to study associations with occupations other than wood- and leather-related occupations. The pooled data set included a total of 930 cases (680 men and 250 women) and 3,136 controls (2,349 men and 787 women). All the studies included a detailed occupational history for cases and controls. Each job was coded using the same classifications for occupation and industry. Two approaches were used in the analysis: systematic analysis of occupations; a priori analysis using a preestablished list of occupations and industries. The results confirmed associations observed in several studies not included in this analysis. For agricultural workers, significant excesses were observed for squamous cell carcinoma among women (OR = 1.69) and men (OR = 3.72 for ten years or more of employment as an orchard worker), and adenocarcinomas among men (OR = 2.98 for ten years or more of employment). Associations with textile occupations were observed for adenocarcinoma among women (OR = 2.60) and squamous cell carcinoma among men (OR = 5.09 for fiber preparers, 3.01 for bleachers). Elevated risks for both histologic types were observed among men employed in food manufacturing (OR = 3.25, adenocarcinoma), or as food preservers (OR = 13.9, squamous cell carcinoma), and among men employed as cooks (OR = 1.99, squamous cell carcinoma). A positive association with squamous cell carcinoma was observed for male transport equipment operators (OR = 1.21), and also with adenocarcinoma for male motor-vehicle drivers (OR = 2.50). A number of other associations were observed in the systematic analysis

Somatic cell mutations arising in vivo in reporter genes and in cancer-associated genes may now be measured in humans. Background mutation levels and mutational responses following various mutagen exposures are reviewed in this chapter. The detection methods are compared for similarities and differences based on the underlying biology of the systems. Currently available data on molecular mutational spectra are reviewed and the utility of such information is discussed in terms of mutagen exposure characterization and for defining the mutagenic basis of carcinogenesis. In addition to the reporter gene assays, recently developed assays for mutation in cancer-associated genes are considered. The strengths and limitations of using somatic cell mutations for cancer epidemiology and areas for future research are discussed

Multiple studies in the general population have suggested that subjects with the glutathione S-transferase M1 (GSTM1)-null genotype, who lack functional GSTM1, are at higher risk for bladder cancer. To evaluate the impact of the GSTM1-null genotype on bladder cancer caused by occupational exposure to benzidine and to determine its influence on benzidine metabolism, we carried out three complementary investigations: a case-control study of bladder cancer among workers previously exposed to benzidine in China, a cross-sectional study of urothelial cell DNA adducts and urinary mutagenicity in workers currently exposed to benzidine in India, and a laboratory study of the ability of human GSTM1 to conjugate benzidine and its known metabolites in vitro. There was no overall increase in bladder cancer risk for the GSTM1-null genotype among 38 bladder cancer cases and 43 controls (odds ratio, 1.0; 95% confidence interval, 0.4-2.7), although there was some indication that highly exposed workers with the GSTM1-null genotype were at greater risk of bladder cancer compared to similarly exposed workers without this allele. However, the GSTM1 genotype had no impact on urothelial cell DNA adduct and urinary mutagenicity levels in workers currently exposed to benzidine. Furthermore, human GSTM1 did not conjugate benzidine or its metabolites. These results led us to conclude that the GSTM1-null genotype does not have an impact on bladder cancer caused by benzidine, providing a contrast to its association with elevated bladder cancer risk in the general population

Fluorescence in situ hybridization (FISH) is a powerful new technique that allows numerical chromosome aberrations (aneuploidy) to be detected in interphase cells. In previous studies, FISH has been used to demonstrate that the benzene metabolites hydroquinone and 1,2,4-benzenetriol induce aneuploidy of chromosomes 7 and 9 in cultures of human cells. In the present study, we used an interphase FISH procedure to perform cytogenetic analyses on the blood cells of 43 workers exposed to benzene (median = 31 ppm, 8-hr time-weighted average) and 44 matched controls from Shanghai, China. High benzene exposure (> 31 ppm, n = 22) increased the hyperdiploid frequency of chromosome 9 (p < 0.01), but lower exposure (< or = 31 ppm, n = 21) did not. Trisomy 9 was the major form of benzene-induced hyperdiploidy. The level of hyperploidy in exposed workers correlated with their urinary phenol level (r = 0.58, p < 0.0001), a measure of internal benzene dose. A significant correlation was also found between hyperdiploidy and decreased absolute lymphocyte count, an indicator of benzene hematotoxicity, in the exposed group (r = -0.44, p = 0.003) but not in controls (r = -0.09, p = 0.58). These results show that high benzene exposure induces aneuploidy of chromosome 9 in nondiseased individuals, with trisomy being the most prevalent form. They further highlight the usefulness of interphase cytogenetics and FISH for the rapid and sensitive detection of aneuploidy in exposed human populations

An expanded cohort study of 74,828 benzene-exposed and 35,805 unexposed workers were followed during 1972 to 1987, based on a previous study in 12 cities in China. A small increase was observed in total cancer mortality among benzene-exposed compared with unexposed workers (relative risk [RR] = 1.2). Statistically significant excesses were noted for leukemia (RR = 2.3), malignant lymphoma (RR = 4.5), and lung cancer (RR = 1.4). When risks were evaluated by leukemia subtype, only acute myelogenous leukemia was significantly elevated (RR = 3.1), although nonsignificant excesses were also noted for chronic myelogenous leukemia (RR = 2.6) and acute lymphocytic leukemia (RR = 2.3). A significant excess was also found for aplastic anemia

We present a validation study of a quantitative retrospective exposure assessment method used in a follow-up study of workers exposed to benzene. Assessment of exposure to benzene was carried out in 672 factories in 12 cities in China. Historical exposure data were collected for 3179 unique job titles. The basic unit for exposure assessment was a factory/work unit/job title combination over seven periods between 1949 and 1987. A total of 18,435 exposure estimates was developed, using all available historical information, including 8477 monitoring data. Overall, 38% of the estimates were based on benzene monitoring data. The highest time-weighted average exposures were observed for the rubber industry (30.7 ppm) and for rubber glue applicators (52.6 ppm). Because of its recognized link with benzene exposure, the association between a clinical diagnosis of benzene poisoning and benzene exposure was evaluated to validate the assessment method that we used in the cohort study. Our confidence in the assessment method is supported by the observation of a strong positive trend between benzene poisoning and various measures, especially recent intensity of exposure to benzene