NONCANCER RISK ASSESSMENT FOR NICKEL COMPOUNDS - ISSUES ASSOCIATED WITH DOSE-RESPONSE MODELING OF INHALATION AND ORAL EXPOSURES

This report presents the results of noncancer dose-response modeling f or inhalation and oral exposures to nickel compounds using the NOAEL/L OAEL and benchmark dose (BMD) approaches. Several key issues associate d with the implementation of the BMD approach were examined. Primary a mong them are difficulties associated with use of data for which the d ose-response shape is poorly defined: nonuniqueness of maximum likelih ood estimates and lower bounds equal to zero. In addition, several gen eralizable properties of the ''hybrid approach'' for modeling continuo us endpoints were identified. A hybrid modeling approach allows one to consider ''biological significance'' on an individual (rather than gr oup) basis; differences between individual- and group-based biological significance in the definition of benchmark response (BMR) levels are elucidated. In particular, it is shown that BMDs defined using group- based BMRs may be more like LOAELs than NOAELs. Application of cross-c hemical and cross-endpoint comparisons suggest that, for chronic inhal ation exposure, nickel sulfate appears to be as toxic or more toxic th an nickel subsulfide and nickel oxide, although the high response rate s for the latter two compounds at the lowest chronically administered concentration make such conclusions problematic. A nickel reference co ncentration could be derived based on the most sensitive benchmark con centration for chronic inhalation exposure to nickel sulfate, 1.7 x 10 (-3) mg Ni/m(3) for lung fibrosis in male rats. Analyses of oral studi es of nickel sulfate and nickel chloride suggest that an appropriate b asis for the nickel oral reference dose would be a BMD of 4-5 mg Ni/kg /day, based on increased prenatal mortality. (Uncertainty factors were not determined and neither an RfD nor an RfC was derived in this pape r.) The BMD approach provides appropriate quantitative support for tox icological judgment; this paper addresses specific issues associated w ith the role of the BMD approach in noncancer risk assessment. Resolut ion of these and other issues may require the accumulation of a number of case studies such as the one presented here. (C) 1998 Society of T oxicology.