For definition of Groups, see Preamble Evaluation.
VOL.: 63 (1995) (p. 159)
Chem. Abstr. Name: Tetrachloroethene
5.1 Exposure data
Tetrachloroethylene is one of the most important chlorinated solvents worldwide and has been produced commercially since the early 1900s. Most of the tetrachloroethylene produced is used for dry cleaning garments; smaller amounts are used in the production of chlorofluorocarbons and for degreasing metals. About 513 thousand tonnes were used in all applications in western Europe, Japan and the United States in 1990.
Tetrachloroethylene has been detected in air, water, food and animal and human tissues. The greatest exposure occurs via inhalation, and workers in dry cleaning and degreasing are the most heavily exposed. Individuals living or working in the vicinity of such operations have been shown to be exposed to lower concentrations.
5.2 Human carcinogenicity data
Results relevant to assessing the relationship between exposure to tetrachloroethylene and cancer risk are available from five cohort studies. In one study in Finland and one in four states of the United States, exposure was specifically to tetrachloroethylene; biological monitoring was conducted in the Finnish study. In a cohort study in Missouri, United States, in which follow-up was from 1948 to 1978, tetrachloroethylene was the chemical to which predominant exposure had occurred since about 1960. Data for a few cancer sites were reported in two other cohort studies, one in Louisiana and one in Utah, United States, in which exposure was to both tetrachloroethylene and other chemicals. Although data on different levels or duration of exposure were available in some of the cohort studies, the number of observed cases in each category was generally too small to allow adequate statistical power for testing for a dose-response relationship. Data from six relevant case-control studies have also been reported.
In the two cohort studies in which results for oesophageal cancer were reported, namely the four-state United States and Missouri studies, the relative risks were 2.6 and 2.1. Lack of data on smoking or alcohol consumption, both strong risk factors for this cancer, indicates caution in interpreting this observation.
The relative risks for cervical cancer were increased in three cohort studies in which such results were reported; however, potential confounding factors associated with socioeconomic status could not be adjusted for.
Elevated relative risks for non-Hodgkin's lymphoma were observed in all three cohort studies in which such results were reported.
With respect to cancer of the kidney, no consistent pattern of elevated risk was seen in the three cohort studies in which such results were reported. Although a case-control study conducted in Montréal, Canada, showed an odds ratio of 3.4, this was not statistically significant, and the exposure in question was to degreasing solvents and not specifically to tetrachloroethylene. In the cohort study in Missouri, the relative risk for urinary bladder cancer was elevated but not statistically significant; little or no information was available from other studies.
Five studies of people exposed to drinking-water contaminated with tetrachloroethylene have been reported. In four of these, no consistent pattern of risk for any specific cancers was observed. In the fifth study, in Massachusetts, United States, although the increase in the relative risk for leukaemia was significant, the result was based on only two cases. No consistent evidence for an elevated risk for leukaemia was seen in the cohort studies.
In summary, there is evidence for consistently positive associations between exposure to tetrachloroethylene and the risks for oesophageal and cervical cancer and non-Hodgkin's lymphoma. These associations appear unlikely to be due to chance, although confounding cannot be excluded and the total numbers in the cohort studies combined are relatively small.
5.3 Animal carcinogenicity data
Tetrachloroethylene was tested for carcinogenicity by oral administration in one experiment in mice, and a significant increase in the incidence of hepatocellular carcinomas was observed in animals of each sex. A study in rats treated orally was inadequate for an evaluation of carcinogenicity. Tetrachloroethylene was tested for carcinogenicity by inhalation in one experiment in mice and in one experiment in rats. The incidence of hepatocellular adenomas and carcinomas was significantly increased in mice of each sex, and the incidence of mononuclear-cell leukaemia was significantly increased in rats of each sex. A nonsignificant increase in the incidence of uncommonly occurring renal-cell adenomas and adenocarcinomas was also observed in male rats. Tetrachloroethylene did not induce skin tumours in mice after administration by topical application in one study.
A presumed metabolite of tetrachloroethylene, tetrachloroethylene oxide, did not increase the incidence of local tumours in mice when given by topical application or subcutaneous injection.
5.4 Other relevant data
Tetrachloroethylene is rapidly absorbed after inhalation and from the gastrointestinal tract, but dermal absorption from the gaseous phase is negligible. The biotransformation of tetrachloroethylene is species- and dose-dependent; mice consistently had a greater capacity to biotransform tetrachloroethylene than rats. Two metabolic pathways have been demonstrated in rodents: cytochrome P450-catalysed oxidation and, as a minor route, glutathione conjugation.
Tetrachloroethylene shows only low acute toxicity in humans and in experimental animals. After repeated administration, the major target organ is the liver in mice and the kidney in rats. Tetrachloroethylene induced peroxisome proliferation in mouse liver after oral administration; a marginal response was observed in mouse kidney and rat liver.
Disturbances of sperm quality and fertility have been observed among dry cleaners exposed to tetrachloroethylene in a few studies of limited size. The results of studies of women exposed to tetrachloroethylene in dry cleaning shops and other settings are generally consistent in showing an increase in the rate of spontaneous abortions; however, other solvents were also present in most of these workplaces. Effects on other reproductive outcomes such as stillbirths, congenital malformations and low birth weight could not be evaluated in these studies.
Tetrachloroethylene can cross the placenta of rats and is metabolized in the placenta or fetus to trichloroacetic acid. Tetrachloroethylene appears to have little toxicity in developing rats and rabbits; high atmospheric concentrations produced delayed fetal development in mice in one study.
The frequencies of gene conversion and gene mutation were not increased in yeast recovered from mice treated with tetrachloroethylene in vivo. Tetrachloroethylene increased the frequency of DNA single-strand breakage/alkaline-labile sites in the liver and kidney of mice in vivo in one study, but binding to DNA was not demonstrated in mouse liver.
It did not induce gene mutation (in a single study), chromosomal aberrations, sister chromatid exchange (in a single study) or DNA damage in mammalian cells in vitro. In single studies, it induced morphological transformation in virus-infected rat embryo cells but not in BALBc/3T3 cells. The only study available showed no induction of gene mutation by tetrachloroethylene in insects. Tetrachloroethylene did not usually induce gene conversion in yeasts; the results with regard to induction of aneuploidy in one study were inconclusive. Tetrachloroethylene did not increase the frequency of mutations in bacteria, except in one study in which a metabolic activation system consisting of liver and kidney fractions, which favours glutathione conjugation and further activation, was used. The metabolites formed from tetrachloroethylene in rats by minor biotransformation pathways, S-1,2,2-trichloroglutathione and derived sulfur conjugates, were genotoxic in bacteria and cultured renal cells.
The frequency of H-ras mutations was lower in hepatocellular tumours from tetrachloroethylene-treated mice than in tumours from control animals, whereas the frequency in hepatocellular tumours from trichloroethylene-treated mice was not significantly different from that in controls. The frequency of K-ras mutations was higher in liver tumours from tetrachloroethylene-treated mice than in tumours from control animals.
There is limited evidence in humans for the carcinogenicity of tetrachloroethylene.
There is sufficient evidence in experimental animals for the carcinogenicity of tetrachloroethylene.
Tetrachloroethylene is probably carcinogenic to humans (Group 2A).
In making the overall evaluation, the Working Group considered the following evidence:
(i) Although tetrachloroethylene is known to induce peroxisome proliferation in mouse liver, a poor quantitative correlation was seen between peroxisome proliferation and tumour formation in the liver after administration of tetrachloroethylene by inhalation. The spectrum of mutations in proto-oncogenes in liver tumours from mice treated with tetrachloroethylene is different from that in liver tumours from mice treated with trichloroethylene.
(ii) The compound induced leukaemia in rats.
(iii) Several epidemiological studies showed elevated risks for oesophageal cancer, non-Hodgkin's lymphoma and cervical cancer.
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Suppl. 7 (1987) (p. 355)Synonyms
See Also: Toxicological Abbreviations Tetrachloroethylene (EHC 31, 1984) Tetrachloroethylene (HSG 10, 1987) Tetrachloroethylene (ICSC) TETRACHLOROETHYLENE (JECFA Evaluation) Tetrachloroethylene (UKPID)