For definition of Groups, see Preamble Evaluation.
VOL.: 73 (1999) (p. 131)
Chem. Abstr. Name: Trichloromethane
Occupational exposure to chloroform may occur during its production and use as a solvent and chemical intermediate. The general population may be exposed as a result of its presence in chlorinated drinking-water, ambient air and some foods.
5.2 Human carcinogenicity data
Two cohort studies of cancer and drinking-water quality were carried out in the United States. One conducted in Maryland showed excess mortality from cancers of the liver and breast in association with water chlorination, while that conducted in Iowa showed increased risks for cancers of the colon and lung and skin melanoma associated with chloroform concentrations in drinking-water.
Eight case–control studies have been reported on bladder cancer in relation to chlorinated drinking-water in the United States. Significant results were obtained in five studies, but there was little consistency in the risk pattern in subgroups defined by sex or surrogate measures of chloroform intake. Significant increasing trends in the risk for bladder cancer were seen in two studies. The study in Colorado showed increasing risk with years of exposure to chlorinated water; the study in Iowa showed increasing risk with lifetime intake of trihalomethanes (from drinking-water), but only in men and not in women.
Seven case–control studies addressed the risk for cancers of the large bowel in association with consumption of chlorinated water. In two of these studies, lifetime exposure to trihalomethanes was assessed. Two studies showed significant associations with rectal cancer. Overall, however, the results were inconsistent with regard to the subsite of the large bowel and sex, and the quality of the studies varied widely.
Exposure to chloroform in the workplace was addressed in two case–control studies, both of which had limited statistical power. The study on brain cancer gave negative results. The other included a number of sites (but not the brain) and showed associations with cancers of the prostate and lung, but no association was seen with bladder cancer.
The presence of various water chlorination by-products, including trihalomethanes, is likely to be highly correlated. Although chloroform is the most ubiquitous, the other by-products therefore may act as confounders in studies of water-mediated exposure. In addition, important sources of chloroform other than drinking-water were ignored in the majority of the studies.
Although the epidemiological evidence for an association between consumption of chlorinated drinking-water and the risk for some cancers, particularly those of the urinary bladder and rectum and possibly of the colon, seems to favour an interpretation of mild excess, a causal inference cannot be made with regard to chloroform because of incomplete control for confounding by other water impurities and other factors and lack of concordance in the results for men and women. Use of surrogate indicators for exposure to chloroform adds to the uncertainty.
5.3 Animal carcinogenicity data
Chloroform was tested for carcinogenicity in several experiments in mice, rats and dogs. In three studies by oral administration and in one study by inhalation exposure in mice, it produced renal tubule tumours and, in one study, hepatocellular tumours. In three studies by oral administration in Osborne-Mendel rats, chloroform produced renal tubule tumours. No increased incidence of tumours was observed in one study in dogs.
5.4 Other relevant data
Chloroform is metabolized by oxidative and reductive pathways. Under normal conditions, oxidative metabolism is the major pathway, and reductive metabolism does not play a significant role. Oxidative metabolism of chloroform results in the generation of phosgene, which either reacts with water to give carbon dioxide and hydrogen chloride or binds covalently to tissue macromolecules. The formation of carbon dioxide as a metabolite of chloroform has been shown in a number of studies in both rodents and humans in vivo.
The metabolism of chloroform is more rapid in mice than in rats, and human tissues (liver and kidney) have the lowest activity. CYP2E1 is the predominant enzyme involved in the metabolism of chloroform in both rodent and human tissues.
There is a consistent, tissue-, species-, strain- and sex-specific pattern in the rate of metabolism, cytotoxicity and cell proliferation produced by chloroform in rodent liver and kidney. Under the conditions of the high-dose regimens used in cancer bioassays in which tumours are produced, chloroform induced cytotoxicity and regenerative cell proliferation in the target organs for cancer. These findings are consistent with a mode of action for tumorigenesis in the liver and kidney of rodents that involves cytotoxicity.
Chloroform has been tested for developmental toxicity in mice and rats by gavage and inhalation. Fetal toxicity in the form of growth retardation has been observed in several studies, concurrent with evidence of maternal toxicity. Malformations were observed in one study in rats exposed by inhalation. In a continuous breeding study, no reproductive effects were noted.
No data were available on the genetic and related effects of chloroform in humans. There is weak evidence for the genotoxicity of chloroform in experimental systems in vivo and in mammalian cells, fungi and yeast in vitro. It was not mutagenic to bacteria.
There is inadequate evidence in humans for the carcinogenicity of chloroform.
There is sufficient evidence in experimental animals for the carcinogenicity of chloroform.
Chloroform is possibly carcinogenic to humans (Group 2B).For definition of the italicized terms, see Preamble Evaluation.
Previous evaluations: Vol. 1 (1972); Vol. 20 (1979); Suppl. 7 (1987)Synonyms
See Also: Toxicological Abbreviations Chloroform (EHC 163, 1994) Chloroform (HSG 87, 1994) Chloroform (ICSC) Chloroform (WHO Food Additives Series 14) CHLOROFORM (JECFA Evaluation) Chloroform (PIM 121) Chloroform (CICADS 58, 2004) Chloroform (IARC Summary & Evaluation, Supplement7, 1987) Chloroform (IARC Summary & Evaluation, Volume 1, 1972) Chloroform (IARC Summary & Evaluation, Volume 20, 1979)