Several therapeutic agents and industrial chemicals induce liver tumors in rodents through the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The cellular and molecular events by which PPARα activators induce rodent hepatocarcinogenesis has been extensively studied and elucidated. This review summarizes the weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis and identifies gaps in our knowledge of this MOA. Chemical-specific and mechanistic data support concordance of temporal and dose-response relationships for the key events associated with many PPARα activators including a phthalate ester plasticizer di(2-ethylhexyl) phthalate (DEHP) and the drug gemfibrozil. While biologically plausible in humans, the hypothesized key events in the rodent MOA, for PPARα activators, are unlikely to induce liver tumors in humans because of toxicodynamic and biological differences in responses. This conclusion is based on minimal or no effects observed on growth pathways, hepatocellular proliferation and liver tumors in humans and/or species (including hamsters, guinea pigs and cynomolgous monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Overall, the panel concluded that significant quantitative differences in PPARα activator-induced effects related to liver cancer formation exist between rodents and humans. On the basis of these quantitative differences, most of the workgroup felt that the rodent MOA is "not relevant to humans" with the remaining members concluding that the MOA is "unlikely to be relevant to humans". The two groups differed in their level of confidence based on perceived limitations of the quantitative and mechanistic knowledge of the species differences, which for some panel members strongly supports but cannot preclude the absence of effects under unlikely exposure scenarios.
Preliminary results from the National Toxicology Program (NTP) bioassays of furan given by gavage indicate the induction of hepatocellular carcinomas in male F-344 rats and in both sexes of B6C3F1 mice, and cholangiocarcinomas in both sexes of rats. To assess the genotoxicity of furan, chemically induced unscheduled DNA synthesis was evaluated in the in vivo hepatocyte DNA repair assay. Furan did not induce unscheduled DNA synthesis in hepatocytes isolated after single gavage treatment of male F-344 rats (5, 30, and 100 mg/kg) or male B6C3F1 mice (10, 50, 100, and 200 mg/kg). Furan induced cytotoxicity and enhanced cell proliferation were evaluated in livers of rats and mice as events that also might give rise to mutations and/or drive tumor formation. The labeling index (LI, percentage of hepatocyte nuclei in S-phase) was measured histoautoradiographically following a single gavage administration of furan (30 mg/kg, male rats; 50 mg/kg, male mice) followed by an injection of 3H-thymidine 2 hr prior to sacrifice. Hepatocellular necrosis and a sharp increase in LI (23.9 for mice and 17.8 for rats vs. less than 0.5 for controls) was observed 48 hr after treatment with furan, indicative of restorative cell proliferation secondary to cytotoxicity. Hepatocyte proliferation was evaluated also at the highest NTP bioassay dose (15 mg/kg/day for mice and 8 mg/kg/day for rats, 5 days/week) by labeling with 3H-thymidine administered via a 6 day osmotic pump implanted subcutaneously. Necrosis and inflammation were observed along the subcapsular visceral surface of the left or caudate liver lobes, likely due to diffusion of furan directly through the stomach to the liver. After 6 weeks of furan administration, male and female rats, but not mice, exhibited bile duct hyperplasia as well as metaplasia in the areas of fibrosis along the subcapsular visceral surface of the left or caudate liver lobes. The fold increase in hepatocyte LI in treated animals relative to the combined controls measured at weeks 1, 3, and 6 ranged from 39 to 5 for male mice, 18 to 51 for male rats, and 12 to 19 for female rats. Taken together, these data suggest that mechanisms other than direct DNA-reactivity might explain the profile of oncogene mutations observed in the mouse liver tumors, including selective promotion of different subpopulations of preneoplastic cells and/or mutational events secondary to sustained cell proliferation or inflammation. The extensive amount of furan-induced cell proliferation subsequent to cytotoxicity likely had a significant impact on tumor development, and such data should be considered in risk evaluations for this compound.
A. Human StudiesInhalation is the major route of occupational exposure to carbon disulfide. Investigations in volunteers and occupationally exposed workers suggest that equilibrium between inhaled and exhaled CS2 is generally attained during the first 2 hr of Initially, the fraction of inhaled CS2 absorbed was relatively constant over a wide range of exposure concentrations, with approximately 70 to 80% of the inhaled carbon disulfide a b s~r b e d .~' .~~~~~~~ At equilibrium, retention of inhaled CS2 declined to approximately 15 to 45% of the inhaled vapor.61,2239289 It is interesting to note a report that described retention of inhaled CS2 in individuals not previously exposed to this agent that was greater than in those who were chronically exposed to CS2.289 Although the mechanism of the decreased retention with chronic exposure is not known, this observation does suggest caution in extrapolation of acute human exposure data to the chronic exposure situation.Percutaneous absorption is a second potential source of occupational exposure to CS2. Dutkiewicz and Baranowska" evaluated skin absorption by immersion of the hand in aqueous CS2 solutions (0.33 to 1.67 g/Q) for 1 hr. Absorption of CS2 was quantitated by two methods: indirectly by determining CS;? elimination by the lung; and by measurement of the CS2 concentration in the aqueous solutions before and after immersion of the hand. Absorption rates determined by solution analysis were found to range from 0.232 to 0.789 mg/cm2/ hr and were approximately 10 times higher than rates calculated from lung excretion of CS2. Further calculations indicated that only 3% of cutaneously absorbed CS2 was eliminated by the lung. Using the solution data, these investigators also calculated that immersion of a hand for 1 hr in a viscose rayon washing bath containing 0.1 mg/g CS2 would result in a total dose of 17.5 mg. One potential difficulty with this study, however, was that no precautions were described to prevent loss of CS2 from the solutions due to volatilization. Failure to adequately control for this variable would result in an overestimate of percutaneous absorption.Following inhalation exposure the primary route of excretion for unmetabolized CS2 is exhalation from the lung. In 1943, McKee et a1.'56 estimated that 6 to 10% of exposure. 148,156,250,254,296 Volume 11, Issue 3 CRC Critical Reviews in Toxicologyidentification of metabolite(s) responsible for the hepatotoxic effects of high-dose exposure to CS2, particularly in phenobarbital pretreated rats. The formation of the toxic metabolite(s) is thought to involve activation of CS2 by the microsomal mixed function oxidase system. Formation of Water-Soluble MetabolitesAn early study by Strittmatter et a1.226 characterized the overall disposition of the radiolabel in guinea pigs after inhalation of 35S-carbon disulfide. A small fraction (8 to 17%) of the total radioactivity recovered during the 48 hr after various inhalation exposures (13.6 ppm for 8 hr; 20.6 ppm for 16 hr, 25.7 ppm for 40 hr) was exhaled as CS2. ...
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