Development of α_2u-Globulin Nephropathy and Adrenal Medullary Pheochromocytomas in Male Rats Following Exposure to Stoddard Solvent IIC

Abstract

Stoddard solvent IIC is widely used as a solvent in paints and varnishes, and for dry cleaning and other grease removal applications. Because concern exists regarding the long-term effects of occupational exposure in industrial settings, the toxicity and carcinogenicity of Stoddard solvent IIC were evaluated in male and female F344/N rats and B6C3F₁ mice. Rats and mice were exposed to 0, 138, 275, 550, 1100, or 2200 mg/m³ Stoddard solvent IIC by whole-body inhalation for 3 mo, and to 0, 138 (male rats), 550, 1100, or 2200 (female rats and male and female mice) mg/m³ for 2 yr. The kidney, liver, and adrenal medulla were targets of Stoddard solvent IIC toxicity in rats. After 3 mo of exposure, male rats developed lesions characteristic of α_2u-globulin nephropathy. Male and female rats displayed increased liver weights and/or clinical pathology changes suggestive of hepatic injury, although no accompanying histopathologic changes were observed. After 2 yr, increased incidences of adrenal medullary pheochromocytomas provided some evidence of carcinogenicity in male rats. Renal tubule adenomas were slightly increased in male rats after 2 yr, and may have been related to exposure. In mice, there was no chemical-related toxicity after 3 mo, with the exception of increased liver weights in male mice exposed to 2200 mg/m³. After 2 yr, the incidences of hepatocellular adenomas were increased in female mice exposed to 2200 mg/m³; however, these increases were marginal and associated with increases in body weight. There was no evidence of Stoddard solvent IIC carcinogenicity in female rats or male mice. In summary, inhalation exposures of Stoddard solvent IIC resulted in renal toxicity and adrenal medullary pheochromocytomas in male rats. The liver also appeared to be a site of toxicity in male and female rats and mice.

The authors acknowledge the assistance of Dr. J. H. Roycroft in the execution and interpretation of these studies. The help of Drs. J. K. Haseman, J. R. Bucher, J. R. Hailey, and G. S. Travlos with data interpretation and Dr. C. S. Smith with chemistry-related issues is highly appreciated. In addition, the authors are grateful to Drs. Abraham Nyska and June Dunnick for reviewing this article while in manuscript.