Response to Smith et al

lites after repeated ingestion of sodium metaarsenite by volunteers. Biological monitoring of arsenic exposure of gallium arsenide-and inorganic arsenic-exposed workers by determination of inorganic arsenic and its metabo-lites in urine and hair. Am Ind Hyg Assoc J 50:606-612 (1989). micronuclei in exfoliated bladder cells of persons who chronically ingest arsenic-contaminated water in Nevada. Monson RR. Arsenic in drinking water and urinay cancers: a preliminary report. J Geol Chem Health (in press). Response to Smith et al. Smith et al.'s criticisms of our commentary in EHP (102:354-356) fall into four general categories: arsenic methylation and detox-ification; the recalculation of the slope factor for ingested arsenic; differences between U.S. and Taiwanese populations; and recent epidemiological analyses. As discussed below, we stand by our earlier conclusion that the dose-response relationship for arsenic carcinogenicity is likely to be nonlin-ear, and we feel that there is no basis for dismissing the methylation saturation hypothesis as one possible explanation for nonlinear-ity. We offer the following response to Smith et al.'s criticisms. Arsenic methylation: We acknowledge that the issue of arsenic methylation and detoxification is complex; however, we believe that the methodological limitations we observed in the Hopenhayn-Rich et al. (1) article on arsenic methylation weaken their argument that human studies do not support a methylation threshold hypothesis for arsenic. Moreover, we call readers' attention to several recent studies that suggest that percent inorganic arsenic in urine is not as sensitive an indicator of the saturation of the methylation pathway as is the ratio of the percentage of urinary metabo-lites, MMA to DMA. Hughes et al. (2) demonstrated an increase in the relative percentage of MMA to DMA (per administered dose of arsenic) excreted in the urine of mice, with increase in dose. In single oral doses ranging from 0.5 to 5000 pg/kg, the ratio of MMA to DMA increased by approximately a factor of 10 from the lowest to the highest group. The relative percent of inorganic arsenic bound to tissue also increased with dose. The authors propose that inorganic arsenic binds to macromolecules and does not appear in urine until the binding becomes saturated. Therefore, inorganic arsenic is not as sensitive an indicator of saturation of the methylation pathway as is the concentration of methylated metabolites. Similarly, in an epidemiological study of humans exposed to elevated levels of arsenic in drinking water in Mexico, Del Razo et al. (3) report that the MMA:DMA ratio in …