oral dose of 2,000 mg/kg (Forkert and Birch 1989). Clara cells of the bronchiolar epithelium showed necrotic changes within 1 hour of dosing and most Clara cells were severely vacuolated by 24 hours. Twenty percent of the lung burden at 4 hours was covalently bound. The study indicates that the highly metabolic Clara cells are targets of trichloroethylene toxicity in the respiratory tract.

Human Studies

There are few reports of noncancer pulmonary toxicity in trichloroethylene-exposed humans. A study of respiratory findings in gun factory workers exposed to multiple solvents indicated significant effects of smoking and exposure to solvents, with smoking having the most important effect on asthma-related symptoms. Trichloroethylene was only one of many solvents to which the workers were exposed (Cakmak et al. 2004).

Toxicokinetics and Mode of Action

Pulmonary toxicity induced by trichloroethylene is associated with cytochrome P-450-dependent bioactivation to reactive metabolites (see Figure 7-1). The predominant pathway of trichloroethylene metabolism is oxidation via the cytochrome P-450 system, mainly by CYP2E1, although other P-450 enzymes including CYP1A1/2, CYP2B1/2, CYP2C11/6, and CYP2F have been implicated (Guengerich et al. 1991; Nakajima et al. 1992a; Forkert et al. 2005). Oxidative metabolism of trichloroethylene yields the primary metabolites chloral, trichloroethylene oxide, and dichloroacetyl chloride. Chloral, a predominant metabolite of trichloroethylene, is rapidly converted to chloral hydrate, which then undergoes oxidation and reduction by aldehyde-dehydrogenase and alcohol-dehydrogenase enzymes to form trichloroacetic acid and trichloroethanol (Green and Prout 1985; Dekant et al. 1986a). Clara cells isolated from the mouse lung are known to efficiently metabolize trichloroethylene to chloral and trichloroacetic acid. Recent studies of recombinant (r) cytochrome P-450s and rodent and human lung microsomes revealed that rat and human rCYP2E1, rCYP2F, and rCYP2B1 were all capable of mediating trichloroethylene metabolism to chloral hydrate (Forkert et al. 2005). Rat rCYP2E1 exhibited greater affinity than rat rCYP2F4 and rCYP2B1 and human rCYP2E1. More recently, the same investigators (Forkert et al. 2006) suggested that CYP2F2 might play a greater role than CYP2E1 in the metabolism of trichloroethylene in the mouse lung. Treatment of CYP2E1-null and wild-type mice with trichloroethylene led to bronchiolar damage that correlated with the formation of dichloroacetyl adducts in the Clara cells. These findings provide evidence

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