Arsenic, internal cancers, and issues in inference from studies of low-level exposures in human populations

Abstract

Epidemiologic data from regions of the world with very high levels of arsenic in drinking water (>150 microg/L) show a strong association between arsenic exposure and risk of several internal cancers. A causal interpretation of the data is warranted based on the strength and consistency of study findings. At lower levels of exposure (<100 microg/L), in the absence of unambiguous human data, extrapolation from the high-exposure studies has been used to estimate risk. Misclassification of exposure usually results in depressing observed levels of risk, and studies conducted in populations with exposures below 100 microg/L have been limited by the challenge of estimating past exposures, a critically important aspect of studying relative small increases in risk. Relatively small study size contributes to the variability of findings in most studies and makes interpretation of results all the more challenging. The effects on risk estimates of exposure misclassification and small study size under various scenarios are graphically illustrated. Efforts are underway to improve exposure assessment in a large case-control study of bladder cancer in a region of the United States with moderately elevated levels of arsenic in drinking water.

Figure 1

Estimates of the odds ratio (OR) from 2,000 simulated case-control studies with 100 cases and 100 controls (upper panels) or 1,000 cases and 1,000 controls (lower panels) for a binary exposure with probability of 0.1. The true ORs are 1.0 (open bars) or 2.0 (shaded bars with hatched lines, with true value denoted by vertical dash line). Exposure subject to misclassification as defined by sensitivity (the probability an exposed individual is truly exposed) and specificity (the probability a non-exposed individual is truly non-exposed).