The comparative pathobiology of alpha 2u-globulin nephropathy

alpha 2u-Globulin nephropathy is an important toxicologic syndrome that occurs in male rats following exposure to a number of important industrial and environmental chemicals. A low, but significant incidence of renal neoplasia develops in male rats as a chronic sequela to the disease. Studies on the pathogenesis of alpha 2u-globulin nephropathy have demonstrated that this protein is produced in large amounts in the male rat, that reversible binding occurs between chemicals and/or their metabolites and alpha 2u-globulin, and that this complex is resistant to proteolytic hydrolysis, leading to accumulation in renal lysosomes and subsequent cytotoxicity and cell death. This results in marked exposure-related increases in cell proliferation that persist for at least one year, providing exposure continues. This sustained increase in renal cell proliferation can promote initiated cells to form preneoplastic foci and renal neoplasia in male rats. Since this syndrome is highly species and sex specific, it is important to determine the relevance of these data for human risk assessment. The scientific considerations involved in high to low dose and species to species extrapolation are discussed.