Document ID: chunk:federal_register_of_legislation:F2013C00288:reg:1:p4
Version: federal_register_of_legislation:F2013C00288
Segment Type: reg
Provision Reference: reg 1 (pt 4/10)
Character Range: 2745008–2748038

exposure is strong for non-Hodgkin Lymphoma but less convincing than for kidney cancer, and more limited for liver and biliary tract cancer. Less human evidence is found for an association between TCE exposure and other types of cancer, including bladder, oesophageal, prostate, cervical, breast, and childhood leukaemia. Further support is derived from positive results in multiple rodent bioassays, similar toxicokinetics between rodents and humans, mechanistic data supporting a mutagenic mode of action for kidney tumours.

    1.5.2         Review of Available Values/Information
Some epidemiological studies indicate a possible association between exposure to TCE and an increased cancer risk, with IARC (1995) noting elevated risk for cancer of the liver and biliary tract and a modestly elevated risk for non-Hodgkin's lymphoma in three cohort studies. In animals, TCE induces tumours at several sites and in different species. Tumours have been seen in mouse liver and lung and rat kidney and testis. On the basis of the available information, most current reviews by IARC (1995), WHO (2011), CCME (2007) and US EPA (2011) consider TCE to be carcinogenic (with responses tending to increase with dose), via all routes of exposure.

The potential mode of action (MoA) for TCE is reviewed and discussed in the current WHO DWG (2011) and US EPA (2011) review.

The WHO DWG (2011) review concluded that the MoA for tumour induction by TCE may be attributed to non-genotoxic processes (related to cytotoxicity, peroxisome proliferation and altered cell signalling); genotoxic processes, (such as the production of genotoxic metabolites (e.g., chloral and DCVC[1])); or the production of reactive oxygen species related to peroxisomal induction in the liver. The potential role of several mutagenic or carcinogenic metabolites of TCE cannot be ignored. Hence TCE appears to be at least weakly genotoxic and evaluation of carcinogenicity on the basis of a non-threshold approach is considered appropriate (as is undertaken in the current WHO DWG (2011) and WHO Air Quality Guidelines (2000)).

The most recent US EPA review (2011) provides a detailed assessment of genotoxicity (of TCE and metabolites) and mutagenicity. With respect to genotoxicity, although it appears unlikely that TCE, as a pure compound, causes point mutations, there is evidence for TCE genotoxicity with respect to other genetic end points, such as micronucleus formation. In addition, several TCE metabolites have tested positive in genotoxicity assays. It is noted that uncertainties with regard to the characterisation of TCE genotoxicity remain, particularly because not all TCE metabolites have been sufficiently tested in the standard genotoxicity screening battery to derive a comprehensive conclusion. However, the metabolites that have been tested, particularly DCVC, have predominantly resulted in positive data, supporting the conclusion that these compounds are genotoxic.

The MoA relevant to specific target organs in laboratory animals has