Alpha2u-Globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat

This report describes conditions under which EPA's Risk Assessment Forum advises EPA risk assessors against using information on certain renal tubule tumors or nephrotoxicity to assess human risk. Risk assessment approaches generally assume that chemicals producing tumors in laboratory animals are a potential cancer hazard to humans. For most chemicals, including many rodent kidney carcinogens, this extrapolation remains appropriate. The scientific studies reviewed by the Technical Panel indicate, however, that some other chemicals induce accumulation of alpha_2u-globulin (a_2u-g), a low-molecular-weight protein, in the male rat kidney. The a_2u-g accumulation initiates a sequence of events that appears to lead to renal tubule tumor formation. Female rats and other laboratory mammals administered the same chemicals do not accumulate low-molecular-weight protein in the kidney and they do not develop renal tubule tumors. Since humans appear to be more like other laboratory animals than like the male rat, in this special situation, the male rat is not a good model for assessing human risk.

The analysis of the scientific studies and related science policy set out in this report each stress the need for full scrutiny of a substantial set of data to determine when it is reasonable to presume that renal tumors in male rats result from a process involving a_2u-g accumulation and to select appropriate procedures for estimating risks to humans under such circumstances. The report also defines situations that suggest different approaches and it calls for research to clarify unanswered questions regarding the mechanisms accounting for the response in male rats.

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