PFOA is a peroxisome proliferator (PPAR agonist) and exerts morphological and biochemical effects characteristic of PPAR agonists. These effects include increased beta-oxidation of fatty acids, increases in several cytochrome P-450 (CYP450)-mediated reactions, and inhibition of the secretion of very low-density lipoproteins and cholesterol from the liver. These effects on lipid metabolism and transport result in a reduction of cholesterol and triglycerides in serum and an accumulation of lipids in the liver. The triad of tumors observed (liver, Leydig cell, and pancreatic acinar-cell) is typical of many PPAR agonists and is believed to involve nongenotoxic mechanisms. The hepatocellular tumors observed in rats are likely to have been the result of the activation of the peroxisome proliferator activated receptor alpha (PPARalpha). The tumors observed in the testis (Leydig-cell) have been hypothesized to be associated with an increased level of serum estradiol in concert with testicular growth factors. The mechanism responsible for the acinar-cell tumors of the pancreas in rats remains the subject of active investigation. The mechanism resulting in the hepatocellular tumors in rats (PPARalpha activation) is not likely to be relevant to humans. Similarly, the proposed mechanism for Leydig-cell tumor formation is of questionable relevance to humans. Acinar tumors of the pancreas are rare in humans, and the relevance of the these tumors, as found in rats, to humans is uncertain. Epidemiological investigations and medical surveillance of occupationally exposed workers have not found consistent associations between PFOA exposure and adverse health effects.

Wyeth-14,643 (WY) and ammonium perfluorooctanoate (C8) belong to a diverse class of compounds which have been shown to produce hepatic peroxisome proliferation in rodents. From previous work, WY, but not C8, has been shown to produce hepatocellular carcinoma in rats, while C8 has been shown to produce Leydig cell adenomas. In addition, based on a review of bioassay data a relationship appears to exist between peroxisome-proliferating compounds and Leydig cell adenoma and pancreatic acinar cell hyperplasia/adenocarcinoma formation. To further investigate the relationship between peroxisome-proliferating compounds and hepatic, Leydig cell, and pancreatic acinar cell tumorigenesis, a 2-year feeding study in male CD rats was initiated to test the hypothesis that peroxisome proliferating compounds induce a tumor triad (liver, Leydig cell, pancreatic acinar cell), and to examine the potential mechanism for the Leydig cell tumors. The study was conducted using 50 ppm WY and 300 ppm C8. The concentration of WY in the diet was decreased to 25 ppm on test day 301 due to increased mortality. In addition to the ad libitum control, a second control was pair-fed to the C8 group. Interim sacrifices were performed at 1- or 3-month intervals. Peroxisome proliferation measured by beta-oxidation activity and cell proliferation were measured in the liver and testis at all time points and in the pancreas beginning at the 9-month time point (cell proliferation only). Serum hormone concentrations (estradiol, testosterone, LH, FSH, and prolactin) were also measured at each time point. Increased relative liver weights and hepatic beta-oxidation activity were observed in both the WY- and C8-treated rats at all time points. In contrast, hepatic cell proliferation was significantly increased only in the WY-treated group. Neither WY nor C8 significantly altered the rate of Leydig cell beta-oxidation or Leydig cell proliferation when compared to the control groups. Moreover, the basal rate of beta-oxidation in Leydig cells was approximately 20 times less than the rate of hepatic beta-oxidation. There were no biologically meaningful differences in serum testosterone, FSH, prolactin, or LH concentrations in the WY- and C8-treated rats when compared to their respective controls. There were, however, significant increases in serum estradiol concentrations in the WY- and C8-treated rats at 1, 3, 6, 9, 15, 18, and 21 months. At 12 months, only the C8-treated rats had elevated serum estradiol concentrations when compared to the pair-fed control. Histopathological evaluation revealed compound-related increases in liver, Leydig cell, and pancreatic acinar cell tumors in both WY- and C8-treated rats. The data support the hypothesis that the peroxisome-proliferating compounds induce the previously described tumor triad. In addition, both C8 and WY produced a sustained increase in serum estradiol concentrations that correlated with the potency of the 2 compounds to induce Leydig cell tumors (i.e., WY caused a more consistent sustained increase in serum e...

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