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Contaminated Water Supplies at Camp Lejeune: Assessing Potential Health Effects
sented below according to organ system and in some sections divided to consider toxic effects separately from carcinogenic effects.
TCE, even in high doses, produces only a modest degree of injury of hepatocytes in laboratory animals. Klaassen and Plaa (1966) compared the acute hepatotoxicity of TCE with that of other common halogenated aliphatic hydrocarbons (halocarbons) in male mice dosed by intraperitoneal injection. The dose of TCE required to produce an increase in serum alanine-aminotransferase activity, 1.6 mL/kg, was almost as high as the dose that was lethal in 50% of test animals, 2.2 mL/kg. Oxidative stress was assessed by measuring thiobarbituric-acid-reactive substances in the livers of male Fischer rats that received one intraperitoneal injection of TCE at 0, 100, 500, or 1,000 mg/kg (Toraason et al. 1999). Thiobarbituric-acid-reactive substances were increased in the 500- and 1,000-mg/kg groups. Hepatic concentrations of 8-hydroxy-2′-deoxyguanosine adducts, induced in DNA by oxygen-based radicals, were also increased at 500 mg/kg and presumably at 1,000 mg/kg. It should be recognized that the 500- and 1,000-mg/kg doses produced stage II and stage III-IV anesthesia, respectively. Channel et al. (1998) gave male B6C3F1 mice TCE at 0, 400, 800, or 1,200 mg/kg in corn oil by gavage 5 days/week for 8 weeks. Transient increases in cell and peroxisome proliferation, centered around day 10, were observed only at the highest dose. There were no differences from controls in the incidences of hepatocellular apoptosis or necrosis. Thiobarbituric-acid-reactive substances were significantly increased in the groups treated with TCE at 800 and 1,200 mg/kg on days 6-14. 8-Hydroxy-2′-deoxyguanosine adducts in liver DNA were significantly increased throughout much of the study with TCE at 1,200 mg/kg. Buben and O’Flaherty (1985) saw a modest increase in serum alanine aminotransferase and decrease in hepatic glucose-6-phosphatase activity in mice given TCE at 500 mg/kg or greater in corn oil by gavage five times a week for 6 weeks. Mice receiving as little as 100 mg/kg per day had an increase in relative liver weight. It is clear that TCE, even when given repeatedly to mice and rats at narcotic doses, has little ability to damage hepatocytes.
Adverse effects of TCE on the liver are usually attributed to metabolites of the cytochrome P-450-mediated oxidative pathway (Bull 2000). Buben and O’Flaherty (1985) reported that plots of their mouse subchronic-hepatotoxicity data against urinary-metabolite excretion values indicated that TCE’s effects are directly related to the extent of its metabolism. As described in Chapter 3, TCE is oxidized by cytochrome P-450s (notably CYP2E1 at low to moderate TCE doses) to chloral, which is converted to chloral hydrate. That intermediate has a short half-life; it is rapidly oxidized to trichloroacetic acid, which is reduced to trichloroethanol (Lash et al. 2000a). Relatively small amounts of dichloroacetic acid may arise from trichloroacetic acid or other metabolites. Induction of CYP2E1 in rats with pyridine increases the toxicity of TCE to isolated rat hepatocytes (Lash et al. 2007). High concentrations of trichloroacetic acid and dichloroacetic acid are not toxic to hepatocytes freshly isolated from B6C3F1 mice (Bruschi and Bull 1993); the researchers proposed that trichloroacetic acid and dichloroacetic acid cause peroxisome proliferation and the ensuing generation of reactive moieties that deplete glutathione and can cause oxidative injury. Dichloroacetic acid does not induce peroxisome proliferation in male B6C3F1 mice in the same dose range at which it produces hepatic tumors (DeAngelo et al. 1999). Laughter et al. (2004) found that high oral doses of TCE increased liver weight, peroxisome proliferation, and hepatocellular proliferation in male mice. Those effects appeared to be due primarily to trichloroacetic acid’s activating a nuclear protein known as the peroxisome-proliferator-activated receptor alpha (PPARα). PPARα-dependent changes seen in gene expression may contribute to the carcinogenicity of TCE in mouse liver.
TCE-induced hepatic injury is not a common finding in humans and was rarely reported in patients when TCE was used as an anesthetic (Lock and Reed 2006). Clearfield (1970) described hepatocellular degeneration in two men who intentionally inhaled extremely high vapor concentrations of TCE for their intoxicating effects. In contrast, James (1963) saw only small foci of fatty accumulation in the liver