A substantial body of occupational epidemiology data has shown that exposur
e to mixed soluble and insoluble nickel causes the development of lung and
nasal cancer. However, due to coexposure of these populations to soluble an
d insoluble forms of nickel, and limitations in exposure measurements, the
contribution of soluble nickel is difficult to determine. Soluble nickel wa
s 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 wea
k carcinogenicity of soluble nickel. Kinetic factors also indicate that exp
osure to soluble nickel alone has a low carcinogenic potential. Overall, we
conclude that the carcinogenic activity of insoluble nickel compounds shou
ld not be used to predict the carcinogenic potential of water-soluble nicke
l salts. The overall data suggest a nonlinear dose-response relationship fo
r carcinogenicity, but the data are insufficient to determine the doses at
which such nonlinearities occur. Under the U.S. EPA's 1996 proposed "Guidel
ines for Carcinogen Risk Assessment," inhaled soluble nickel compounds woul
d be classified as "cannot be determined," because the existing evidence is
composed of conflicting data. A reference concentration of 2 x 10(-4) mg N
i/cu(.)m was calculated, based on lung fibrosis in male rats observed in th
e NTP study. (C) 2000 Academic Press.