Trichloroethylene carcinogenicity

This study, like that of Fisher and Allen (1993), incorporated a linear multistage model. However, the mechanism of trichloroethylene carcinogenicity appears to be non-genotoxic, and a non-linear model (as opposed to the linearized multistage model) has been proposed for use along with PBPK modeling for cancer risk assessment. The use of this non-linear model has resulted in a 100-fold increase in the virtually safe lifetime exposure estimates (Clewell et al. 1995). 

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. 

Ruden C. (2001) The use and evaluation of primary data in 29 trichloroethylene carcinogen risk assessments. Regulatory Toxicology and Pharmacology 34 3-16. 

Trichloroethylene use has declined as a result of environmental concerns. However, trichloroethylene may replace some 1,1,1-trichloroethane appHcations. Perchloroethylene used in small businesses for dry cleaning will be regulated for emissions under the same guidelines as those that govern the large chemical producers. This will cause replacement of perchloroethylene for those appHcations where recovery is uneconomical. Methylene chloride has been classified as a suspected carcinogen and its use will decline in aerosol and paint stripping appHcations because of health concerns. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of trichloroethylene are indicated in Tables 2-1 and 2-2 and Figures 2-1 and 2-2. 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for trichloroethylene. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancer health effects only and do not reflect a consideration of carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure. 

Several retrospective cohort studies of workers exposed to unquantified levels of trichloroethylene have been conducted. All of these studies have limitations that restrict their usefulness for evaluating the carcinogenicity of trichloroethylene. None has shown clear, unequivocal, evidence that trichloroethylene exposure is linked to increased cancer risk. 

An update of a previous study (Axelson et al. 1978), Axelson (1986) evaluated an expanded cohort of 1,424 men (levels of trichloroethylene exposure inferred from measured urinary metabolite concentrations) and found a significant increase in incidences of bladder cancer and lymphomas, and a lower than expected incidence of total cancer mortality. A further update of this work (Axelson et al. 1994) expanded the cohort to include 249 women, tracking cancer morbidity over 30 years, and found no correlation between exposure concentration or exposure time and cancer incidence at any site. The highest standardized incidence ratio noted in this study was 1.56 (95% Cl of 0.51-3.64) for 5 cases of non-Hodgkin s lymphoma observed in men. Although four of these cases occurred in persons exposed for at least 2 years, and 3 cases had a latency of 10 years or more, urinary levels of TCA showed that 4 of the 5 cases were exposed to the lowest levels of trichloroethylene (urinary levels of TCA 0-49 mg/L). The study authors mentioned that a urinary TCA level below 50 mg/L corresponds to a trichloroethylene exposure concentration of about 20 ppm. The study authors concluded that "this study provides no evidence that trichloroethylene is a human carcinogen, i.e., when the exposure is as low as for this study population."... 

Some laboratory studies with rats and mice have linked trichloroethylene exposure to various types of cancers. Several of these studies, however, should be viewed cautiously, since the tumorigenic activity might be influenced by the presence of direct-acting compounds, namely the epoxides (e.g., epichlorohydrin) added as stabilizers in trichloroethylene. Epoxides are known to be very reactive, and some, such as epichlorohydrin, are potent carcinogens themselves. 

Monte Carlo simulation, an iterative technique which derives a range of risk estimates, was incorporated into a trichloroethylene risk assessment using the PBPK model developed by Fisher and Allen (1993). The results of this study (Cronin et al. 1995), which used the kinetics of TCA production and trichloroethylene elimination as the dose metrics relevant to carcinogenic risk, indicated that concentrations of 0.09-1.0 pg/L (men) and 0.29-5.3 pg/L (women) in drinking water correspond to a cancer risk in humans of 1 in 1 million. For inhalation exposure, a similar risk was obtained from intermittent exposure to 0.07-13.3 ppb (men) and 0.16-6.3 ppb (women), or continuous exposure to 0.01-2.6 ppb (men) and 0.03-6.3 ppb (women) (Cronin et al. 1995). 

Cancer. Workers who have been exposed to trichloroethylene show no higher incidence of cancer than controls in numerous epidemiologic studies (Axelson et al. 1978 Hardell et al. 1981 Malek et al. 1979 Novotna et al. 1979 Paddle 1983 Spirtas et al. 1991 Tola et al. 1980). Studies that did show an increased incidence of specific cancers in exposed workers were complicated by exposures to other chemicals, including known human carcinogens (Antilla et al. 1995 Blair et al. 1979 Hardell et al. 1994 Henschler et al. 1995). 

Animal studies have shown that tumors can result from both inhalation (Fukuda et al. 1983 Henschler et al. 1980 Maltoni et al. 1986) and oral exposure (Aima et al. 1994 Henschler et al. 1984 NCI 1976 NTP 1990) to trichloroethylene. Unfortunately, some of these studies (NCI 1976) are limited in that they use carcinogenic epoxide stabilizers with the trichloroethylene, which may contribute to the carcinogenicity. The studies also show different responses depending on the sex, species, and strains of animals used and do not point to a particular target organ for increased tumor incidence. Other studies are flawed because of excess... 

Degradation of trichloroethylene by anaerobes via reductive dehalogenation can be problematic because a common product is vinyl chloride, a known carcinogen (Ensley 1991). In an anaerobic colunm operated under methanogenic conditions, 100% transformation of injected tetrachloroethylene and trichloroethylene to... 

Group A5 Not suspected as a human carcinogen. Trichloroethylene is not suspected to be a human carcinogen on the basis of properly conducted epidemiologic studies in humans. 

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