Hepatic carcinogens

Halogenated compounds, found in high concentrations in seaweeds consumed in Japan and Hawaii, have been suspected of being carcinogenic, largely based on epidemiological extrapolation (high incidences of hepatic carcinoma). However, direct human causation has not been estabUshed (107). 

Human data as well as studies in animals have provided negative evidence of carcinogenicity for endosulfan (Hack et al. 1995 Hoechst 1988b, 1989a). However, endosulfan promoted the development of altered hepatic foci in rats initiated with nitrosodiethylamine (Fransson-Steen et al. 1992). Although the mechanism of tumor promotion of endosulfan is not known, it has been suggested that it involves inhibition of cellular communication (Kenne et al. 1994). A brief discussion of this topic is provided in Section 2.5 under Cancer Effects. 

Hepatic peroxisome proliferation, characterized by liver enlargement due to hyperplasia and hypertrophy, has been proposed as a basis for differences in species susceptibility to trichloroethylene carcinogenicity. Peroxisomes are membrane-bound organelles which contain enzymes generally involved in lipid metabolism. 

Klaunig et al. (1991) found that hepatocyte DNA synthesis increased significantly in male mice exposed to trichloroethylene by gavage for up to 14 days, but no such increase was seen in female mice or in renal DNA synthesis in either sex. Similar exposures in rats produced increases in renal DNA synthesis in males, but no such increase in females, or in hepatic DNA synthesis in either sex. These results correlate well with observed species- and gender-specific trichloroethylene carcinogenicity, and the study authors suggest that trichloroethylene acts as a tumor promoter to induce proliferation of previously initiated cells. 

The mechanism of action for liver toxicity and carcinogenicity may involve the formation of reactive products (Bonse and Henschler 1976 Bonse et al. 1975 Fisher et al. 1991 Larson and Bull 1992b). Methods for reducing the destructive damage caused by these intermediates, or for blocking their formation through inhibition of metabolic pathways may prove effective in reducing hepatic toxicity but are not currently available for clinical use. 

Carcinogenic agents include chemicals in the environment, such as aniline and benzene, which are associated with the development of bladder cancer and leukemia, respectively. Environmental factors, such as excessive sun exposure, also may result in cancer. Viruses, including the human papilloma virus and hepatitis B, maybe associated with the development of cancer. Some of the chemotherapy agents cause secondary cancers after therapy has been completed. Numerous factors may contribute to the development of cancer. 

Chronic animal studies of organophosphates are few in number, but those that do exist provide a useful base from which to draw toxicological insight. In rats and mice exposed orally to tricresyl phosphate for 2 years, endocrine effects were found in a dose-response pattern and hepatic effects were found. Ovarian interstitial hyperplasia was also observed but was not dose related. No chronic-duration MRLs could be derived because of the limited number of studies. Tricresyl phosphate, a component of certain hydraulic fluids, produced no evidence of carcinogenic activity in assays with rats and mice (NTP 1994). However, another component, tributyl phosphate, was associated with an increased incidence of bladder tumors in rats and mice (FMC 1994a, 1994b). 

Prolonged residence in the intestine or urinary bladder lumen could allow time for significant reaction with tissue components however, N-glucuronyloxy-AAF was only weakly carcinogenic at local subcutaneous sites of application (89). Enzymatic deacetylation to N-glucuronyloxy-AF has been detected in hepatic tissue but this activity in different species does not correlate with their relative susceptibility to AAF hepatocarcinogenesis (94). On the other hand, the alkaline pH-induced conversion to a reactive derivative may play an important role in urinary bladder carcinogenesis (87) by AAF and other arylamides in those species or individuals where normal urine pH is alkaline (e.g. normal rabbit urine pH is 8.5-9.0). 

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 aminoacyl-tRNA synthetases are necessary for protein synthesis in all tissues, their importance in chemical carcinogenesis is difficult to assess. Mutation induction by this pathway has been studied extensively (123), yet metabolic activation in a carcinogen-target tissue has not been demonstrated. The only exception is hepatic prolyl-tRNA synthetase activation of N-hydroxy-Trp-P-2 however, hepatic O-acetylation of this substrate also occurs to an appreciable extent (12). Further investigations involving the use of specific enzyme inhibitors would be helpful in addressing this problem. 

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). 

Additional information on hepatic lesions in species other than the rat and mouse would be useful in evaluating the risk to humans for both noncarcinogenic and carcinogenic effects from hexachloroethane exposure. 

Moreover, the involvement of hydroxyl radicals in the nickel mediated enhancement of lipid peroxidation has been suggested [348], which may have implications in the carcinogenicity of nickel compounds. The enhancement of lipid peroxidation might be the result of depletion in the level of hepatic glutathione peroxidase. 

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