The Agency for Toxic Substances and Disease Registry (ATSDR) and the United States (US) Environmental Protection Agency (EPA) Office of Solid Waste and Emergency Response (OSWER) list arsenic as a major concern for Superfund sites and the environment at large. Arsenic is clearly linked to skin, bladder, and lung cancer occurrence in populations highly exposed to arsenic occupationally, medicinally, or through contaminated drinking water (Agency for Toxic Substances and Disease Registry, 1999; IARC, 1987). While these studies have identified important adverse health effects, they cannot provide risk information at lower levels of exposure such as those commonly found in the US. Additionally, precise measurement of exposure is critical to assessing risk in populations consuming relatively trace amounts of arsenic. In New Hampshire, domestic wells serve roughly 40% of the population, and about 10% of these contain arsenic concentrations in the controversial range of 10 to 50 micrograms/l. New Hampshire, along with other states in New England, has among the highest bladder cancer mortality rates in the country. Therefore, we are conducting a population-based epidemiologic study in New Hampshire (1) to assess the risk of skin and bladder cancer associated with arsenic exposure in a US population, (2) to evaluate methods of quantifying individual exposure to arsenic at low to moderate levels, and (3) to explore alternative models of determining the dose-response relationship at the lower end of exposure. Our findings to date indicate that toenail arsenic concentrations are a reliable, long-term biomarker of total arsenic exposure and reflect arsenic intake by drinking water containing 1 microgram/l or more. We found that urinary arsenic cannot be detected consistently in a population for which drinking water arsenic is primarily below 50 micrograms/l. Lastly, our data suggest that use of a biologic marker along with alternative statistical approaches may aid detection of the levels at which arsenic may affect cancer occurrence in the US.