For definition of Groups, see Preamble Evaluation.
Vol.: 63 (1995) (p. 75)
Chem. Abstr. Name: Trichloroethene
Trichloroethylene, a chlorinated solvent, has been produced commercially since the 1920s in many countries by chlorination of ethylene or acetylene. Its use in vapour degreasing began in the 1920s. In the 1930s, it was introduced for use in dry cleaning, but it has had limited use in that way since the 1950s. Currently, 80-90% of trichloroethylene worldwide is used for degreasing metals. Use for all applications in western Europe, Japan and the United States in 1990 was about 225 thousand tonnes.
Trichloroethylene has been detected in air, water, soil, food and animal tissues. The most heavily exposed people are those working in the degreasing of metals, who are exposed by inhalation.
5.2 Human carcinogenicity data
Three cohort studies were considered to be particularly relevant for the evaluation of trichloroethylene. Two of these studies, conducted in Sweden and Finland, involved people who had been monitored for exposure to trichloroethylene by measurement of trichloroacetic acid in urine. The levels in samples from most of the people in the two cohorts indicated relatively low levels of exposure. The third study, from the United States, covered workers exposed to trichloroethylene during maintenance of military aircraft and missiles, some of whom were also exposed to other solvents.
A fourth cohort study included all workers in an aircraft manufacturing company in the United States. This study was considered less relevant, as only one-third of the jobs in the plant entailed exposure to trichloroethylene and the exposures of the workers could not be classified.
In none of the available cohort studies was it possible to control for potential confounding factors, such as those associated with social class with regard to cervical cancer and smoking in respect of urinary bladder cancer.
Case-control studies have been conducted to investigate a number of cancer sites, including a multisite study from Montréal, Canada, in which other cancer cases were used as controls. Most of these studies do not provide risk estimates for exposure to trichloroethylene separately but only for groups of chemicals.
The results of the three most informative cohort studies consistently indicate an excess relative risk for cancer of the liver and biliary tract, with a total of 23 observed cases, whereas 12.87 were expected. The risk for these cancers was not elevated in the fourth, less informative cohort study. Results for liver cancer were given separately in the study from Finland and for the maintenance workers in the study in the United States. A total of seven cases were observed, whereas 4.00 were expected. Three case-control studies of primary liver cancer indicated elevated relative risks for people exposed to solvents, but only a few of the subjects in each study reported exposure to trichloroethylene.
With regard to non-Hodgkin's lymphoma, the results of the three most informative cohort studies were consistent; the data indicated a modest excess relative risk, with 27 cases observed and 18.9 expected. The risk for non-Hodgkin's lymphoma was not increased in the fourth, less informative study. In a case-control study covering all malignant lymphomas, an elevated odds ratio for exposure to trichloroethylene was indicated on the basis of seven exposed cases. The risk for non-Hodgkin's lymphoma was not increased among people assumed to have been exposed to trichloroethylene in the study in Montréal.
A twofold risk for cervical cancer was observed in two cohort studies.
The occurrence of cancer of the kidney was not elevated in the cohort studies; however, a study of German workers exposed to trichloroethylene revealed five cases of renal cancer whereas no case was found in an unexposed comparison group. The study may, however, have been initiated after the observation of a cluster. A case-control study and the multisite cancer study, both from Montréal, Canada, provided discordant results with regard to cancer of the kidney.
The incidence of urinary bladder cancer was not increased in the two cohort studies from Sweden and Finland, whereas slightly increased numbers of deaths were seen in the two United States cohorts. The incidence of urinary bladder cancer was not increased in people assumed to be exposed to trichloroethylene in the Montréal study.
Data on cancer incidence or mortality have been reported from five areas in which groundwater was contaminated with trichloroethylene. A weak association between contamination and the incidence of leukaemia was indicated in two of these studies, from Massachusetts and New Jersey, United States. The cohort studies of trichloroethylene-exposed workers did not indicate an association with the occurrence of leukaemia. Two studies, from Finland and New Jersey, suggested a marginal increase in the occurrence of non-Hodgkin's lymphoma in areas with contaminated groundwater.
Overall, the most important observations are the elevated risk for cancer of the liver and biliary tract and the modestly elevated risk for non-Hodgkin's lymphoma in all three of the most informative cohort studies. Two of these studies reported data for primary liver cancer separately. Finally, the suggested marginally increased risk for non-Hodgkin's lymphoma in areas with trichloroethylene-contaminated groundwater is noted.
5.3 Animal carcinogenicity data
Trichloroethylene, with and without stabilizers, was tested for carcinogenicity by oral administration in two adequate experiments in mice. The studies showed significant increases in the incidences of benign and malignant liver tumours. Of seven studies in which trichloroethylene was given orally to rats, most were inconclusive because of reduced survival or a too short treatment. In two of the studies, the incidence of uncommonly occurring renal-cell tumours was significantly increased in male rats, and in one study an increased incidence of interstitial-cell testicular tumours was seen.
Trichloroethylene was tested for carcinogenicity by inhalation in four experiments in mice. One study showed an increased incidence of lymphomas, one study showed increased incidences of liver tumours, and three studies showed increased incidences of lung tumours. One of three experiments in which rats were exposed by inhalation showed an increased incidence of interstitial testicular tumours and a marginal increase in that of renal-cell tumours in males. No increase in tumour incidence was observed in one study in hamsters exposed by inhalation.
In limited studies, trichloroethylene and its proposed metabolite trichloroethylene oxide did not increase the incidence of skin tumours or local sarcomas in mice when administered by topical application or subcutaneous injection.
5.4 Other relevant data
In rodents, trichloroethylene is rapidly absorbed from the gastrointestinal tract and through the lungs, whereas absorption of the vapour through the skin is negligible. The major pathway is oxidative metabolism leading to the formation of chloroacetic acids. Mice showed consistently higher rates of oxidative biotransformation than rats. A minor pathway in rodents and humans involves the formation of mercapturic acids.
The acute toxicity of trichloroethylene in rodents and humans is low. After high doses of trichloroethylene are administered repeatedly to rodents, damage is seen in liver and kidney (in mice and rats) and in lung (in mice only). Repeated exposure of humans in the workplace appears to have no marked toxic effects on the kidney or liver. Trichloroethylene is a more potent peroxisome proliferator in the livers of mice than of rats.
The available studies show no consistent effect of trichloroethylene on the human reproductive system. Trichloroethylene is metabolized to trichloroacetic acid in the placenta or fetus of many species. There is little evidence of toxic effects in developing rats or mice.
Studies of structural chromosomal aberrations, aneuploidy and sister chromatid exchange in peripheral lymphocytes of workers exposed to trichloroethylene were inconclusive.
Pure trichloroethylene did not induce chromosomal aberrations, dominant lethal mutations, sister chromatid exchange or unscheduled DNA synthesis in rodents, whereas an increased induction of micronuclei and DNA single-strand breaks/alkaline labile sites was observed.
In single studies with human cells in vitro, trichloroethylene of low purity slightly increased the frequencies of sister chromatid exchange and unscheduled DNA synthesis. Pure trichloroethylene did not induce gene mutation in human cells. In mammalian cells in vitro, pure trichloroethylene induced cell transformation, sister chromatid exchange and gene mutation, but not chromosomal aberrations. In fungi, trichloroethylene (pure or of unspecified purity) induced aneuploidy, gene mutation and mitotic recombination and induced gene conversion in the presence of metabolic activation.
Gene mutation or DNA damage was usually not induced in prokaryotes by pure trichloroethylene, while preparations containing epoxide stabilizers were mutagenic. Sulfur-containing metabolites formed by a minor trichloroethylene biotransformation pathway were genotoxic in bacteria and cultured renal cells.
There is limited evidence in humans for the carcinogenicity of trichloroethylene.
There is sufficient evidence in experimental animals for the carcinogenicity of trichloroethylene.
Trichloroethylene is probably carcinogenic to humans (Group 2A).
In making the overall evaluation, the Working Group considered the following evidence:
(i) Although the hypothesis linking the formation of mouse liver tumours with peroxisome proliferation is plausible, trichloroethylene also induced tumours at other sites in mice and rats.
(ii) Several epidemiological studies showed elevated risks for cancer of the liver and biliary tract and for non-Hodgkin's lymphoma.
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Suppl. 7 (1987) (p. 364)
See Also: Toxicological Abbreviations Trichloroethylene (EHC 50, 1985) Trichloroethylene (ICSC) Trichloroethylene (WHO Food Additives Series 10) TRICHLOROETHYLENE (JECFA Evaluation) Trichloroethylene (FAO/PL:1968/M/9/1)