GENE DEFICIENCY AND OCCUPATIONAL ENVIRONMENTAL FACTORS 383

2. Rehn, L.: Blasengeschwulste bei Fuchsin-Arbeitern. Arch. Klin. Chir., 5 0 588, 1895.

3. Hueper, T.: Experimental production of bladder tumours in dogs by administration of beta-naphthylamine. J. Indust. Hyg. Toxicol., 2 0 46, 1938.

4. Case, R. A. M., Hosker, M. E. and McDonald, D. B.: Tumours of the urinary bladder in workmen engaged in manufacture and use of certain dyestuff intermediates in the British chemical industry. Brit. J . Indust. Med., 11: 75, 1954.

5 . Shinka, T., Sawada, Y., Morimoto, S., Fujinaga, T., Nakamura, J. and Ohkawa, T.: Clinical study on urothelial tumors of dye workers in Wakayama City. J. Urol., 146: 1504, 1991.

6. Shinka, T., Miyai, M., Sawada, Y., Inagaki, T. and Okawa, T.: Factors affecting the occurrence of urothelial tumors in dye workers exposed to aromatic amines. Int. J. Urol., 2 243,1995.

7. Hirvonen, A.: Genetic factors in individual responses to environ- mental exposures. J. Occup. Environ. Med., 37: 37, 1995.

8. Bell, D. A,, Taylor, J. A,, Paulson, D. F., Robertson, C. N., Mohler, J . L. and Lucier, G. W.: Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen- metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J. Natl. Cancer Inst., 85: 1159, 1993.

9. Brockmoller, J., Kerb, R., Drakoulis, N., Staffeldt, B. and Roots, I.: Glutathione S-transferase M1 and its variants A and B as host factors of bladder cancer susceptibility: a case-control study. Cancer Res., 5 4 4103, 1994.

10. Daly, A. K., Thomas, D. J., Cooper, J., Pearson, W. R., Neal, D. E. and Idle, J . R.: Homozygous deletion of gene for glutathione S-transferase M1 in bladder cancer. Brit. Med. J., 301: 481, 1993.

11. Lin, H. J., Han, C. Y., Bernstein, D. A., Hsiao, W., Lin, B. K. and Hardy, S.: Ethnic distribution of the glutathione transferase Mu 1-1 (GSTM1) null genotype in 1473 individuals and appli- cation to bladder cancer susceptibility. Carcinogenesis, 15: 1077, 1994.

12. Nakachi, K., Imai, K., Hayashi, S. and Kawajiri, K.: Polymor- phisms of the CYPlAl and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population. Cancer Res., 5 3 2994, 1993.

EDITORIAL COMMENT

It is estimated that at least half of urothelial cancers are caused by environmental carcinogens. Today, cigarette smoking is the most frequently identified bladder carcinogen and is estimated to be re- sponsible for 47% of bladder cancer deaths in men and 37% in women.' Industrial aromatic amine exposure has largely been elim- inated from the United States workplace but cohorts, such as that described in this report, provide a unique opportunity for the study of environmental and host risk factors for urothelial cancer and methods for their early detection.

The authors previously reported that 10.3% of dyestuff workers in Wakayama City had bladder cancer with as little as 4 months of exposure, and that there was a mean latency period of 25 years from exposure to the diagnosis of bladder cancer (reference 5 in article). There was a 3.3% incidence of bladder cancer in individuals exposed

with occupational exposure to arylamines ranges from 3.9 to 150 for P-naphthylamine and 14 to 130 for benzidine.2 These wide differ- ences in risk ratios may reflect different levels of exposure and different carcinogenic potentials. Individual susceptibility may also account for some of these differences but genetic susceptibility may be overcome in situations with high levels of exposure to potent carcinogens when the majority of exposed individuals have bladder c a n ~ e r . ~

The family of glutathione transferases detoxifies aromatic hydro- carbons by catalyzing their conjugation to glutathione.' The absence of glutathione-S transferase M1 results in decreased detoxification of carcinogens and these metabolic deficiencies may predispose individ- uals to bladder cancer. Bell et al have previously suggested that up to 25% of urothelial cancers may be accounted for by alterations in glutathione S-transferase M1 (reference 8 in article). In the present study 137 men alive and followed for a t least 20 years from last exposure to aromatic amines were examined for genomic glutathione-S transferase M1 alterations and decreased expression of the enzyme product. The prevalence of glutathione S-transferase M1 deficiency in these 137 men was similar to that in the general Japanese male population. By multivariate analysis, length of expo- sure to aromatic amines and work in small factories, where health and safety practices were considered inadequate, were strongly as- sociated with the risk of urothelial cancer. While glutathione S-transferase M1 deficiency was not independently associated with urothelial cancer, the odds ratio of 1.6 is strilungly similar to the odds ratio of 1.7 described by Bell et al for the white population in their study (reference 8 in article).

This cohort provides an opportunity to examine other genetic and host factors that may contribute to bladder carcinogenesis, including polymorphisms in N-acetyltransferase. This enzyme detoxifies arylamines via N-acetylation. Slow acetylators may be at higher risk for bladder cancer due to the build-up of N-hydmxy bypducts that covalently bind with hemoglobin and react with urothelial DNA. The spectrum of mutations within the p53 gene in the bladder tumors of these workers may provide clues as to the mechanism of carcinogen induced DNA damage and to the relative contribution of carcino- gen exposure and genetic s~ceptibility.~ Unfortunately, the authors could not examine the influence of cigarette smoking as these data were not recorded by the Labor Standards Inspection Office.

Seth P. Lerner Scott Department of Urology Baylor College of Medicine Houston, Texas

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2. Vineis. P.. Martone. T. and Randone, D.: Molecular epidemiology of bladder cancer: known chemical causes of bladder cancer: occupation and smoking. Urol. Oncol., 1: 137, 1995.

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to P-naphthylamine compared to a 12% incidence in individuals exposed to benzidine. The relative risk for bladder cancer associated