Hazard identification and dose response of inhaled nickel-soluble salts

A substantial body of occupational epidemiology data has shown that exposure to mixed soluble and insoluble nickel causes the development of lung and nasal cancer. However, due to coexposure of these populations to soluble and insoluble forms of nickel, and limitations in exposure measurements, the contribution of soluble nickel is difficult to determine. Soluble nickel was negative in an NTP inhalation bioassay, while there was some evidence for tumorigenicity in rats for less soluble nickel oxide, and there was clear evidence for tumorigenicity of insoluble nickel subsulfide in rats. Results of parenteral assays follow a similar pattern, but provide evidence of weak carcinogenicity of soluble nickel. Kinetic factors also indicate that exposure to soluble nickel alone has a low carcinogenic potential. Overall, we conclude that the carcinogenic activity of insoluble nickel compounds should not be used to predict the carcinogenic potential of water-soluble nickel salts. The overall data suggest a nonlinear dose-response relationship for carcinogenicity, but the data are insufficient to determine the doses at which such nonlinearities occur. Under the U.S. EPA's 1996 proposed "Guidelines for Carcinogen Risk Assessment," inhaled soluble nickel compounds would be classified as "cannot be determined," because the existing evidence is composed of conflicting data. A reference concentration of 2 x 10(-4) mg Ni/cu x m was calculated, based on lung fibrosis in male rats observed in the NTP study.