Hepatotoxicity and carcinogenicity in female Sprague-Dawley rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): A pathology working group reevaluation

Risk assessment for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been based in part on the incidences of liver neoplasms in female Sprague-Dawley (SD) rats reported in a 2-year study conducted by Dow Chemical Corporation and published in 1978. In the years subsequent to the Dow report, the criteria for the diagnosis of proliferative hepatocellular lesions in the rat have been refined based upon ongoing study of these lesions. Because of this, PATHCO, Inc., was requested to conduct an independent review of the liver slides from the Dow TCDD study in order to assess how the current terminology might impact on interpretation of proliferative liver lesions in rats compared to the terminology used in the past. In March 1990, a pathology working group (PWG) was convened to review proliferative lesions in the livers of the female rats. The results of the PWG's evaluation of the microslides indicated a trend in tumor incidence similar to that published in 1978 but with a lower incidence of tumors in the middle and high dose females. Based on the morphologic findings, including the fact that the tumors were predominantly benign and usually associated with lesions of hepatic toxicity, the PWG considered this study to demonstrate a weak oncogenic effect of TCDD in the livers of female SD rats. As a result of its review, the PWG noted that in order to establish a relationship between the toxic hepatitis and the hepatocellular neoplasms, an independent review and grading of the toxic lesions in all female rats would be required. This subsequent review found that in the middle and high dose groups, tumors were observed only in animals with toxicity. In the low dose animals, there was an increase in the incidence and multiplicity of eosinophilic foci and a slight increase in the incidence of hepatotoxicity of a minimal degree of severity compared to controls, but there was no increase in the incidence of hepatocellular neoplasms. There appeared to be a distinct correlation between the presence of overt hepatotoxicity and the development of hepatocellular neoplasms.