Hepatocarcinogenicity

On the basis of these differences in species response it was concluded that phthalates do not pose a significant health hazard to humans. This view is home out by the EU Commission decision of July 25, 1990 which states that DEHP shall not be classified or labeled as a carcinogenic or an irritant substance (42). This has been reaffirmed in a comprehensive review (43) which concludes that "peroxisome proliferators constitute a discrete class of nongenotoxic rodent hepatocarcinogens and that the relevance of thek hepatocarcinogenic effects for human hazard assessment is considered to be negligible."... 

Liver cancer can also be a consequence of exposure to hepatotoxic chemicals. Natural hepatocarcinogens include fungal aflatoxins. Synthetic hepato-carcinogens include nitrosoamines, certain chlorinated hydrocarbons, polychlorinated biphenyls (PCBs), chloroform, carbon tetrachloride, dimethyl-benzanthracene, and vinyl chloride.Table 5.15 lists the chemical compounds that induce liver cancer or cirrhosis in experimental animals or... 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Bull RJ, Templin M, Larson JL, et al. 1993. The role of dichloroacetate in the hepatocarcinogenicity of trichloroethylene. Toxicol Lett 68 203-211. 

Daniel FB, DeAngelo AB, Stober JA, et al. 1992. Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F, mouse. Fundam Appl Toxicol 19 159-... 

Elcombe CR, Rose MS, Pratt IS. 1985. Biochemical, histological, and ultrastructural changes in rat and mouse liver following the administration of trichloroethylene Possible relevance to species differences in hepatocarcinogenicity. Toxicol Appl Pharmacol 79 365-376. 

NMOR is a potent hepatocarcinogen in the rat and induces tracheal and nasal cavity tumors in the Syrian golden hamster (43, 44, 45). It is formed readily from nitrite and morpholine in vitro and administration of these precursors to rodents causes tumors indicative of NMOR formation in vivo (44, 55, 56), NMOR has been detected in crankcase emissions of diesel engines and in factories engaged in rubber and tire manufacturing (57, 58). 

Bolton, J. L. Acay, N. M. Vukomanovic, V. Evidence that 4-ally 1-o-quinones spontaneously rearrange to their more electrophilic quinone methides potential bioactivation mechanism for the hepatocarcinogen safrole. Chem. Res. Toxicol. 1994, 7, 443 450. 

Huber WW, Grasl KB, Schulte HR (1996) Hepatocarcinogenic potential of di(2-ethylhexyl) phthalate in rodents and its implications on human risk. Crit Rev Toxicol 26 365-481... 

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

Although several N-methyl-substituted arylamines have been shown to be carcinogenic (184-186), metabolic activation pathways have been investigated primarily for the hepatocarcinogenic aminoazo dyes, N-methyl-4-aminoazobenzene (MAB) and its 3 -methyl derivative (9,21, 22,187,188). N-Hydroxy-N-methyl arylamines are generally regarded as proximate carcinogenic metabolites (22,187,189) and have been shown to be converted to electrophilic N-sulfonyloxy derivatives by hepatic sulfotransferases (9,187) or to reactive N-arylnitrones by air oxidation (21). 

Rizzi MB, Dagli ML, Jordao AA, Penteado MV and Moreno FS. 1997. Beta-carotene inhibits persistent and stimulates remodeling c-GT-positive preneoplastic lesions during early promotion of hepatocarcinogen-esis. Int J Vitam Nutr Res 67 415-422. 

Hendricks, J.D., T.R. Meyers, D.W. Shelton, J.L. Casteel, and G.S. Bailey. 1985. Hepatocarcinogenicity of benzo[a]pyrene to rainbow trout by dietary exposure and intraperitoneal injection. Jour. Natl. Cancer Inst. 74 839-851. 

Cyclopropenoid Fatty Acids. Cottonseed contains cyclopropenoid fatty acids (CPFA) which must be investigated to determine their effects on humans and other monogastric animals. Related to this is the hepatocarcinogenicity of whole kernel glandless cottonseed and cottonseed oil in rainbow trout, Salmo gairdeneri, (22-24). However, the Food and Drug Administration (FDA) has adopted the position that fish are not sufficiently related to man to necessitate the FDA changing its acceptance of cottonseed and its byproducts in human foods (25). 

Maslansky CJ, Williams GM. 1981. Evidence for an epigenetic mode of action in organochlorine pesticide hepatocarcinogenicity A lack of genotoxicity in rat, mouse, and hamster hepatocytes. J Toxicol Environ Health 8 121-130. 

Williams GM. 1980. Classification of genotoxic and epigenetic hepatocarcinogens using liver culture assays. Ann NY Acad Sci 349 273-282. 

In animals, mirex has been shown to be a nonmutagenic hepatocarcinogen (see Sect. 2.2.2.7,... 

In animal studies, mirex (a nonmutagenic hepatocarcinogen) promoted mouse skin squamous carcinomas and papillomas after initiation with 7,12-dimethyl-benz[a]anthracene (DMBA) for 1 week. Mirex, also, potentiated the promotional potency of the phorbol ester tumor promoter, 12-0 -tetradecanoylphorbol-13-acetate (TPA). There was a 90% incidence (activation) of the c-Ha-ras tumor gene in these co-promoted tumors. When both mirex and TPA gave a similar tumor yield, only the TPA response was associated with biochemical markers of enhanced cell proliferation, induction of epidermal ornithine decarboxylase activity and increased DNA synthesis, and hyperplasia. Thus, there is evidence for a dual effect of mirex during co-promotion first, as an independent tumor promoter with a mechanism different than that of phorbol esters and second, as a compound that also potentiates skin tumor promotion by TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). 

Miyagawa M, Takasawa H, Sugiyama A, et al. 1995. The in vivo-in vitro replicative DNA synthesis (RDS) test with hepatocytes prepared from male B6C3F, mice as an early prediction assay for putative nongenotoxic (Ames-negative) mouse hepatocarcinogens. Mutat Res 343 157-183. 

Caitley, R. C. et al. (1998) Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans Regulatory Toxicology and Pharmacology. 27, 47-60. 

Larson JL, Wolf DC, Butterworth BE. 1994b. Induced cytotoxicity and cell proliferation in the hepatocarcinogenicity of chloroform in female B6C3Fi mice comparison of administration by gavage in com oil vs ad libitum in drinking water. Fund Appl Toxicol 22 90-102. 

Dichlorobenzidine is an effective inducer of its own metabolic activation (Iba 1987a). The enhancement of 3,3 -dichlorobenzidine mutagenesis has been associated with the induction of cytochrome P-450d (Iba and Thomas 1988), and may result in the elevation of its carcinogenicity. In other animal studies, 3,3 -dichlorobenzidine was also shown to be a potent inducer of hepatic microsomal enzymic activities mediated by cytochrome-P-448 and P-450 (Iba and Sikka 1983 Iba and Thomas 1988). Consequently, it has been suggested that the hepatocarcinogenicity of 3,3 -dichlorobenzidine may be due, at least in part, to the induction of hepatic cytochrome P-488 and DNA-adduction. 

Orotic acid incorporation into nuclear and cytoplasmic RNA is decreased in polycythemic mice [136]. Aflatoxin Bi, a known hepatocarcinogen which induced polysomal disaggregation in the livers of rats, also inhibits the in vivo incorporation of intraperitoneally injected orotic acid into liver RNA [137]. On the other hand, the incorporation of orotic acid into free nucleotides and the RNA of the monkey kidney is rapidly increased twofold after castration and is restored to normal within seven days by the administration of testosterone [134]. It is of interest to note that, in experiments with rats, administration of orotic... 

Accumulating evidence suggests that aldrin is not a likely human carcinogen and that it acts as a species-specific hepatocarcinogen in mice through nongenotoxic mechanisms. ... 

The hepatocarcinogenicity of DDT by the oral route has been demonstrated and confirmed in several strains of mice. Liver cell tumors have been produced in both sexes and in CE mice were found to have metastasized to the lungs. However, the tumorigenic potential of DDT was negligible in monkeys after dosing for 15-22 years. Of 35 monkeys administered 20mgDDT/kg, 5 days/week for 130 months, only 1 developed hepatocellular carcinoma after a latency period of 20 years. Despite numerous studies, there is no conclusive, unequivocal, or consistent evidence linking... 

The hepatocarcinogenicity of dieldrin in mice has been confirmed in several experiments, and in some cases, the liver cell tumors metastasized. No excess of tumors has been observed in a number of bioassays in rats and one bioassay in Syrian golden hamsters. ... 

Cunningham MF, Matthews HB Relationship of hepatocarcinogenicity and hepatocellular proliferation induced by mutagenic noncarcinogens vs carcinogens. Toxicol Appl Pharmacol 110 505-513, 1991... 

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