National Industrial Chemicals Notification and Assessment Scheme

9.3Metabolism

In the major metabolic pathways, trichloroethylene is metabolised by cytochrome P-450, possibly P4502E1, to a transient epoxide (trichloroethylene oxide) which may undergo intramolecular rearrangement in two different ways. One pathway leads to chloral which is hydrolysed to chloral hydrate. A recent study (Green et al., 1997) has demonstrated that the specific enzyme responsible for transformation of trichloroethylene to chloral hydrate is cytochrome P4502E1. Chloral hydrate is converted by alcohol dehydrogenase or chloral hydrate dehydrogenase to form trichloroethanol and trichloroacetic acid which are eliminated in the urine. Trichloroethanol is excreted either in the free form or conjugated with glucuronide (Miller & Guengerich, 1983). The other pathway leads to the formation of dichloroacetyl chloride which then forms dichloroacetic acid (Dekant et al., 1984; Green & Prout, 1985) or trichloroethylene oxide may hydrolyse to form formic acid, glyoxylic acid and carbon dioxide (Dekant et al., 1984; Green & Prout, 1985). The main metabolic pathways of trichloroethylene are shown in Figure 4.

Another minor pathway in rats, mice and humans is conjugation of trichloroethylene in the liver with glutathione by glutathione-S transferase (Figure 5). Both the 1,2-dichloro and the 2,2-dichloro isomers of dichlorovinyl glutathione are found in the liver. The dichlorovinyl glutathione is transported to the kidneys where it is transformed into a cysteine compound, dichlorovinyl cysteine. Dichlorovinyl cysteine is concentrated in the proximal tubule cells. This compound is metabolised either by N-acetyl transferase to the mercapturic acid which is excreted in the urine or by -lyase to form a thiol. The thiol is an unstable, highly reactive intermediate forming a thioketene which can react with cellular nucleophiles. Both the isomers 1,2-dichlorovinylcysteine and to a lesser extent 2,2-dichlorovinylcysteine are substrates for -lyase. The glutathione metabolites were detected in the urine of volunteers exposed to 40, 80 and 160 ppm for 6 h. These metabolites were excreted slowly with considerable amounts detected in the urine 48 h after the end of exposure (Bernauer et al., 1996). The ratio of the two isomers of N-acetyl-S-(dichlorovinyl)-L-cysteine,1,2- and 2,2- excreted in urine is different in rats and humans (Bernauer et al., 1996). The proportion of the two isomers are similar in human urine while rats excrete more of the 2,2- isomer. The 1,2- dichlorovinylcysteine is a better substrate for renal - lyase than the 2,2- isomer. Bioactivation of the 1,2- isomer may lead to the formation of chlorothioketene and the 2,2- isomer to the less cytotoxic thioaldehyde (Commandeur et al., 1991).

Figure 5- Metabolism of trichlorethylene via glutathione conjugation

Trichloroethylene metabolism has been shown to be saturable at lower doses in rats than in mice. In rats, metabolic saturation occurs after administration of 200-500 mg/kg trichloroethylene orally while in mice saturation is only seen at 2000 mg/kg of oral trichloroethylene or at inhalation doses of 2000 ppm (Stott et al., 1982; Buben & O'Flaherty, 1985; Prout et al., 1985). After administration of 2000 mg/kg, 78% of the dose in rats was exhaled as unchanged trichloroethylene but only 14% in mice (Prout et al., 1985). There is no evidence that the metabolic pathway is saturable in humans, however, the exposure levels used in human studies were considerably lower (maximum 380 ppm) than those used in animal studies. Saturation of metabolism in humans has been predicted at relatively high concentrations (2000 ppm) by mathematical models (Feingold & Holaday, 1977).

The rate of biotransformation of trichloroethylene in mice is much higher than in rats and blood levels of trichloroethanol and trichloroacetic acid were 4 and 6 times higher than those in rats (Fisher et al., 1991).

A number of commonly used drugs or chemicals are able to modify the metabolism of trichloroethylene. Phenobarbitone is an inducer of some forms of cytochrome P-450 and has been shown to stimulate the metabolism and binding of trichloroethylene. Ethanol has a dual effect on the metabolism of trichloroethylene in rats. At low doses it inhibits the metabolism of trichloroethylene giving rise to high blood levels (Jakobson et al., 1986). High doses of ethanol, however, enhance the metabolism of trichloroethylene to trichloroacetic acid (Kaneko et al., 1994). Other substances competitively inhibiting the metabolism of trichloroethylene are 1,1,1-trichloroethane (Savolainen, 1981), tetrachloroethylene, isopropanol, pyrazole and tetraethylthiuram disulfide (Jakobson et al., 1986).

9.4Excretion

Trichloroethylene, following oral or inhalation exposure, is mainly excreted in the urine as trichloroethanol and trichloroacetic acid in animals and humans. In humans, about 48 to 85% of inhaled trichloroethylene is excreted as metabolites by urinary excretion and approximately 8% in the faeces. About 10 to 28% of trichloroethylene is exhaled unchanged in the breath. Small amounts of trichloroethanol are also excreted in the breath while trichloroacetic acid has been identified in bile.

The elimination kinetics of trichloroethanol and trichloroacetic acid differ in humans. Studies in volunteers have shown that during inhalation exposure to trichloroethylene, trichloroethanol levels in blood rise steadily with no plateau being reached within a 6 h exposure period. Trichloroethanol is excreted rapidly once exposure to trichloroethylene stops and most of the trichloroethanol is excreted in the urine within 24 h. Some accumulation of trichloroethanol occurs with repeated exposure but elimination is rapid once exposure ceases. The half-life of trichloroethanol in human blood is approximately 10-12 h (Ertle et al., 1972; Muller et al., 1972; Muller et al., 1974).

Trichloroacetic acid is tightly and extensively bound to plasma proteins in humans and has a half-life in blood of 70-100 h. Repeated exposure causes trichloroacetic acid to accumulate in blood with the metabolite being excreted very slowly once exposure has ceased.

The levels of trichloroethylene and its metabolites trichloroacetic acid and trichloroethanol were measured in blood and urine of a worker following acute poisoning, to investigate the kinetics of trichloroethylene (Yoshida et al, 1996). Accidental ingestion of trichloroethylene had occurred as a result of a fall into a reservoir bath during maintenance. The worker had been in the bath for 3 to 5 mins and was in deep coma with chemical burns and pneumonia on admission. Trichloroethylene was detected in urine for the first two days (43.4 mg/day on the first day and 13.3 mg/day on the second day) suggesting that it may be directly excreted in urine prior to metabolism. Trichloroethylene levels in blood fell rapidly and biphasically. Trichloroethanol levels however, increased for up to 4 days after ingestion and then decreased biphasically with a half life of 53 h in the rapid phase and 269 h in the slow phase. This elimination pattern and the half-life of trichloroethanol observed in blood, differed from previous studies in volunteers following inhalation exposure (Nomiyama, 1971; Monster et al., 1976). In these studies, inhalation of trichloroethylene resulted in maximum trichloroethanol concentration in blood immediately after inhalation followed by an exponential decrease with a half-life of 10 to 15 h. The difference in the study by Yoshida et al (1996) is attributed by the authors to delayed formation of trichloroethanol from trichloroethylene stored in adipose tissue.

Yoshida et al (1996) also observed that trichloroethanol and trichloroacetic acid were excreted in urine bi-phasically with the amount of trichloroethanol excreted being twice that of trichloroacetic acid for the first two days. Subsequently the ratio of trichloroethanol to trichloroacetic acid excretion became approximately 1:2. The excretion of trichloroacetic acid is slow in humans because of protein binding.

Some studies have reported sex differences in the urinary excretion of trichloroethylene metabolites. The urinary levels of trichloro compounds and trichloroethanol were significantly higher in men than in women workers exposed to trichloroethylene while the urinary levels of trichloroacetic acid did not differ between the two sexes (Inoue et al., 1989). However, one study reported that urinary trichloroacetic acid levels were greater in women than in men within 24 h of exposure (Nomiyama & Nomiyama, 1971).

Physiologically based pharmacokinetic (PBPK) models predict that humans have a lower rate of metabolism than mice but higher than rats (Allen & Fisher, 1993). A PBPK model used to predict the differences in body weight, fat content and sex found that women and obese people would be expected to have lower concentrations but longer residence times of blood trichloroethylene because of their higher fat content.

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