5.1. Exposure data

Dichloromethane is a chlorinated solvent that was first synthesized in the 1840s, and is produced by hydrochlorination of methanol or by direct chlorination of methane. Dichloromethane has been used in paint stripping, aerosol spray products, in the manufacture of polycarbonate plastic and hydrofluorocarbons, in the production of synthetic fibres, in metal cleaning, in printing-press cleaning, as an extraction solvent for certain foods, and in the production of refrigerants. Annual world production in 2005 to 2010 was estimated at between 764 000 and 814 000 tonnes.

The principal occupational exposures to dichloromethane have been from its use in paint stripping, spray painting, and metal and printing-press cleaning. Occupational exposures of more than 1000 mg/m³ were measured in the paint, printing, and chemical manufacturing industries before 2000. More recently reported levels have been lower, except for some printing plants in Japan where values were estimated at being up to about 900 mg/m³. The main current source of exposure to the general population is through the use of consumer products containing dichloromethane. Recent reports of ambient air concentrations around industrial areas in some countries are as high as 200 µg/m³, and groundwater concentrations can remain high for many decades after spills. Several jurisdictions (including the USA, the European Union, and Japan) have moved to reduce the use and release of various volatile organic compounds, including dichloromethane. These measures have included reducing or banning dichloromethane use in paint strippers and cosmetics.

5.2. Human carcinogenicity data

Two cohort studies of workers exposed to dichloromethane (as well as acetone and methanol, but not 1,2-dichloropropane) in the USA reported findings for cancers of the liver and biliary tract, based on small numbers. One of the studies reported a positive association for cancer of the liver and biliary tract, while the other did not. Only one study reported a standardized mortality ratio separately for cancer of the biliary tract (SMR, 20). Cancer of the biliary tract constituted three of the four liver cancers in the study with a positive association, and both of the liver cancers in the other. Given that cancer of the biliary tract normally represents a small proportion of cancers of liver and biliary tract combined, these proportions are very high. In a case series of cancer of the biliary tract (histologically identified as cholangiocarcinoma) among printing workers in Japan, most of the cases were exposed to dichloromethane, and all except one of these were also exposed to 1,2 dichloropropane. The high risk of this rare cancer in one cohort study of workers without exposures to other likely risk factors and among exposed printing workers in Japan is consistent with a causal association, but the number of exposed cases was small and the printing workers had other potentially confounding exposures, notably to 1,2 dichloropropane.

Two cohort studies and three case–control studies in several countries evaluated non-Hodgkin lymphoma (NHL), and all except one cohort study reported increased risks among workers exposed to dichloromethane. While positive associations for NHL were consistent among studies using different designs and in several countries, most subjects were exposed to several solvents (some of which have been previously associated with NHL) and the risk estimates were based on small numbers.

There were several studies that assessed other cancer sites, but these data were regarded as inadequate.

5.3. Animal carcinogenicity data

There were six studies of carcinogenicity with dichloromethane in mice: two studies of oral administration (one with drinking-water in males and females, and one by gavage in males and females), three studies of inhalation (two in males and females, one in females), and one study in which dichloromethane was injected intraperitoneally in males. Dichloromethane increased the incidence of hepatocellular carcinoma in three studies in male mice (two by inhalation, one in drinking-water), and in three studies of inhalation in female mice. Dichloromethane increased the incidence of hepatocellular adenoma or carcinoma (combined) in two studies of inhalation in male mice and three studies by inhalation in female mice. Dichloromethane increased the incidence of bronchiolo-alveolar carcinoma in two inhalation studies in male mice and three inhalation studies in female mice, and bronchiolo-alveolar adenoma or carcinoma (combined) in three inhalation studies in male mice and three inhalation studies in female mice. Dichloromethane increased the incidences of haemangioma of the liver and of all organs (including the liver) in one inhalation study in male mice, and may have increased the incidence of haemangioma or haemangiosarcoma (combined) in the liver in one inhalation study in female mice.

There were seven studies of carcinogenicity with dichloromethane in rats: two oral administration studies (one drinking-water study in males and females and one gavage study in males and females), five inhalation studies (four in males and females, one in pregnant females and their male and female offspring). Dichloromethane increased the incidence of fibroma of the subcutis in two inhalation studies in male rats and fibroma or fibrosarcoma of the subcutis in one inhalation study in male rats. Dichloromethane caused salivary gland sarcomas in one inhalation study in male rats (the sialodacryoadenitis virus was detected in these rats; the effect of this virus on carcinogenesis is unknown). Dichloromethane increased the incidence of mammary gland adenoma or fibroadenoma (combined) in two inhalation studies in female rats and one inhalation study in male rats. The incidence of mammary gland adenoma was also increased in another inhalation study in males and another one in females. Dichloromethane caused a minimal increase (positive trend test) in hepatocellular adenomas and carcinomas (combined) in female rats in one oral administration (drinking-water) study.

There was one inhalation study on dichloromethane in male and female Syrian hamsters in which there was an increase in the incidence of malignant lymphoma in females.

5.4. Mechanistic and other relevant data

Dichloromethane is a volatile lipophilic compound that is readily absorbed after oral, inhalation, or dermal exposure, and distributed systemically. Two important metabolic pathways for the metabolism of dichloromethane have been characterized in humans and experimental animals. One pathway is CYP2E1-mediated, which ultimately generates carbon monoxide (CO) and carbon dioxide (CO₂) as stable end products. One of the intermediates, formyl chloride, is reactive with nucleophiles. glutathione conjugation, catalysed primarily by glutathione S-transferase theta-1 (GSTT1), is the other important metabolic pathway, and results in the formation of reactive metabolites, including formaldehyde and S-chloromethyl glutathione. CYP2E1-mediated metabolism is predominant at lower concentrations, but can be easily saturated, with glutathione S-transferase-mediated metabolism eventually predominating at higher concentrations.

Oxidative and glutathione S-transferase (GST)-mediated metabolism of dichloromethane are qualitatively similar between humans and rodents, but quantitative differences exist across species, tissues, and cell types, and among individuals. Differences in GSTT1 expression and localization may be important determinants of site-specific carcinogenicity caused by dichloromethane.

In human cells, dichloromethane induces micronucleus formation and sister-chromatid exchange, but not DNA–protein cross-links and DNA damage. In experimental animals, dichloromethane-induced genotoxicity is associated with the GST pathway. Studies in non-mammalian systems in vitro showed evidence of mutagenicity, particularly in systems with GST activity. Evidence for the role of GSTT1 in genotoxicity in humans is mixed. Overall, the genotoxicity of dichloromethane appears to be strongly associated with GST-mediated metabolism, consistent with the formation of reactive metabolites through this pathway.

Hepatic, neurological, renal, splenic, reproductive, and developmental toxicity have also been reported in humans or experimental animals.

There is little evidence for non-genotoxic mechanisms of carcinogenesis with dichloromethane.

No studies with dichloromethane in humans have investigated whether GSTT1 polymorphisms are associated with cancer. One study has reported an association between a CYP2E1 polymorphism and non-Hodgkin lymphoma in dichloromethane-exposed individuals; however, the functional significance of this polymorphism is unknown.

Overall, given the extensive evidence for genotoxicity, particularly in association with a metabolic pathway that is operative in humans, the Working Group concluded that the mechanistic evidence for dichloromethane carcinogenesis is strong.