Introduction |
A human study showed that TCE levels in blood and breath increased rapidly after initiation of a 4-hour exposure to 100 ppm, reaching near steady-state within an hour from the start of the exposure. The blood TCE levels fell rapidly when exposure ceased (Agency for Toxic Substances and Disease Registry 1997).
Case reports of human poisoning after ingestion of TCE indicate that gastrointestinal absorption is also substantial (Kleinfeld and Tabershaw 1954; Defalque 1961).
Because of its lipid solubility, TCE accumulation occurs in organs containing high levels of adipose tissue. Data from human studies indicate that body fat and the liver accumulate the greatest portion of absorbed TCE (Agency for Toxic Substances and Disease Registry 1997). |
Half-Life |
A relatively small amount of absorbed TCE is exhaled unchanged; most of an absorbed dose is metabolized and excreted in the urine.
After exposure to air concentrations between 50 and 380 ppm, approximately 58% of an absorbed dose appears in urine as metabolites (Monster, Boersma et al. 1976; Monster, Boersma et al. 1979). The time between TCE inhalation and urinary excretion of trichloroethanol is relatively short (biologic half-life approximately 10 hours) compared with the urinary excretion of trichloroacetic acid (biologic half-life approximately 52 hours). Trichloroacetic acid is theoretically detectable in urine for at least a week after TCE exposure (Sato, Nakajima et al. 1977; Monster, Boersma et al. 1979).
No studies have provided evidence of saturation of TCE metabolism in humans, at least for short-term inhalation exposure to high concentrations up to 315 ppm (Agency for Toxic Substances and Disease Registry 1997). |
Metabolic Pathways |
TCE undergoes metabolism by two major pathways:
- cytochrome P450 (P450) - dependent oxidation
- conjugation with glutathione (GSH)
The mutagenic and carcinogenic potential of TCE is generally thought to be due to reactive intermediate biotransformation products rather than the parent molecule itself.
Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include:
- chloral hydrate
- dichloroacetate
- trichloroacetate
In humans, TCE is metabolized primarily in the liver. One study (Lipscomb, Garrett et al. 1997) reported significant variability in TCE metabolism in a sample of 23 human hepatic microsomal samples. The results indicate that humans are not uniform in their capacity for cytochrome P450-dependent metabolism of TCE. An increased activity of this metabolic pathway may increase susceptibility to TCE induced toxicity in the human.
Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ (Davidson and Beliles 1991; Lash, Fisher et al. 2000). Dichlorovinylcysteine (DVC), in particular, is also mutagenic and may cause DNA damage in mammalian cells in vitro and in vivo (NTP 2004). |
Species vs. Susceptibility |
Although the pathways for metabolism of TCE in mice, rats, and humans appear to be qualitatively similar, quantitatively differences among species may substantially alter the effective dose of reactive metabolite(s) that is delivered to a target organ (Bruckner, Davis et al. 1989).
It has been estimated that humans metabolize approximately 20 times less TCE on a body weight basis than rats at similar exposure levels. Consequently, humans metabolize approximately 60 times less TCE on a body weight basis than mice (Goeptar, Commandeur et al. 1995).
Species differences in TCE metabolism might explain observed differences in susceptibility to specific TCE-related diseases. Liver cancer, for example, occurs mainly in strains of mice that generate high levels of trichloroacetic and dichloroacetic acids as TCE metabolites in liver cells. By contrast, rats that metabolize more TCE via glutathione conjugation are prone to renal cancer.
Because of such species-specific effects, caution must be used when extrapolating adverse effects from experimental animals to humans (Kimbrough, Mitchell et al. 1985; Fan 1988; Goeptar, Commandeur et al. 1995; Kaneko, Wang et al. 1997; Lash, Fisher et al. 2000). |
