Arsenic Methylation and Bladder Cancer Risk in Case–Control Studies in Argentina and the United States Craig Steinmaus, MD Michael N. Bates, PhD Yan Yuan, MPH Dave Kalman, PhD Raja Atallah, PhD Omar A. Rey, MD Mary L. Biggs, MPH Claudia Hopenhayn, PhD Lee E. Moore, PhD Bruce K. Hoang, MD Allan H. Smith, PhD Objective: We sought to assess whether the metabolism of arsenic impacts a person’s susceptibility to bladder cancer. Methods: Urinary methylation products were measured in subjects from Argentina (114 cases and 114 controls) and the United States (23 cases and 49 controls). Results: In Argentina, the adjusted odds ratio (OR) for subjects with a high proportion of ingested arsenic excreted as monomethylarsonate (%MMA) was 2.17 (95% confidence interval [CI] = 1.02– 4.63) in smokers and 0.48 (95% CI = 0.17–1.33) in nonsmokers. In the United States, the adjusted ORs for high %MMA in subjects with arsenic intakes less than and greater than 100 g/d were 1.20 (95% CI = 0.27–5.38) and 2.70 (95% CI = 0.39 –18.6). Conclusions: Overall, these results are consistent with data from Taiwan suggesting that some individuals who excrete a higher proportion of ingested arsenic as MMA are more susceptible to arsenic-related cancer. ( J Occup Environ Med. 2006;48: 478 – 488) I norganic arsenic (InAs) occurs natu- rally in the groundwater and surface water of many parts of the world, and millions of people worldwide are exposed to drinking water containing this known human carcinogen. 1–8 In- gested arsenic has been associated with cancer of the skin, bladder, lung, and possibly other organs, with the highest relative risks found for cancer of the bladder. 9 The excess risks associated with these exposures may be quite high. 9 –13 The National Research Council has estimated that the excess cancer risks associated with lifetime exposures to arsenic at the new US standard of 10 g/L may be approximately 1 in 300. 9 These risks may be even greater in suscep- tible subpopulations if they exist. The US drinking water standards for carcinogens other than arsenic have been set at levels associated with risks between 1 in 10,000 and 1 in 1,000,000. 14 Importantly, the new US standard of 10 g/L only applies to public water systems. Approxi- mately 15% of the US population obtain their water from private wells. 15 Although the number of pri- vate wells with high arsenic levels is unknown, arsenic concentrations ap- preciably greater than 10 g/L have been documented in some private wells in many states in the United States. 16 –18 The primary metabolic pathway of ingested InAs in humans is methyl- ation. 19 –21 Once ingested, InAs is methylated to monomethylarsonic acid (MMA5), which is reduced to monomethylarsonous acid (MMA3). From the Arsenic Health Effects Research Program, School of Public Health, University of California, Berkeley (Drs Steinmaus, Bates, Smith, Moore, Mr Yuan, Ms Biggs); Division of Occupational and Environmental Medicine, University of California, San Francisco (Drs Steinmaus, Hoang); School of Public Health and Community Medicine, University of Washington, Seattle (Drs Kalman, Atallah); Facultad de Medicina, Universidad Catolica de Co ´rdoba, Co ´rdoba, Argentina (Dr Rey); Fred Hutchinson Cancer Research Center and School of Public Health and Community Medicine, University of Washington, Seattle (Ms Biggs); College of Public Health and Markey Cancer Control Program, University of Kentucky, Lexington (Dr Hopenhayn); and Occupational Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland (Dr Moore). Address correspondence to Allan H. Smith, Arsenic Health Effects Research Program, School of Public Health, 140 Warren Hall, University of California, Berkeley, CA 94720-7360; E-mail: ahsmith@uclink.berkeley.edu. Copyright © 2006 by American College of Occupational and Environmental Medicine DOI: 10.1097/01.jom.0000200982.28276.70 478 Arsenic Methylation and Bladder Cancer Risk • Steinmaus et al