Identification of Research Needs to Resolve the Carcinogenicity of High-priority IARC Carcinogens. Views and Expert Opinions of an IARC/NORA Expert Group Meeting, Lyon, France, 30 June - 2 July 2009. IARC Technical Publication No. 42. Lyon, France: International Agency for Research on Cancer, 2010 Jul; 42:120-135
Pooled or Meta-analysis: The NAS stated that there were weaknesses in the available meta-analyses. As outlined by Scott and Chiu (2006) meta-analyses of high-quality studies should be able to determine if estimated relative risks or odds ratios in cohort and case-control studies are consistent, robust, and insensitive to individual study inclusion, with no indication of publication bias or significant heterogeneity. A meta-analyses approach is warranted given the modest relative risk estimates and the relative rarity of the cancers observed, and therefore the limited statistical power of individual studies. Pooled analyses of the biomonitoring studies (measuring TCA metabolites) (Anttila et al., 1995; Axelson et al., 1994; Hansen et al., 2001) should also be explored. Primary studies: Any planned cohort studies should endeavor to obtain, at a minimum, current and retrospective department-specific measured exposure levels of TCE and other exposure agents. A cohort without multiple solvent exposures, such as the manufacture of kitchen utensils, using TCE for a final degreasing after assembly-line production, would be desirable. Scott and Chiu (2006) noted that known inaccuracies exist between cancer incidence and death certificate recording for some of the cancer sites that have been associated with TCE exposure such as liver and biliary cancer and NHL. Studies evaluating cancer incidence rather than mortality are desirable especially when looking at NHL. Scott and Chiu (2006) noted that evaluation of lymphomas and TCE exposure is complicated by (1) the use of different ICD codes in the different studies (ICD codes for lymphomas have changed over time, and different studies have used different ICD revisions and (2) understanding of the biology of NHL has changed; lymphomas can be either B cell or T cell and thus lymphomas in the past may have been diagnosed as multiple myeloma or leukemia. If possible medical records or data on molecular markers of lymphoma should be obtained to provide more information on the diagnosis of lymphohematopoietic cancers. Studies evaluating liver cancer should look for possible interaction with lifestyle factors. Genetic susceptibility: Future human studies should include genotyping of GST variants. Since the glutathione conjugation pathway is not active in GST-null individuals, it can be hypothesized that kidney cancer risk will be low among GST-null individuals and high among GST-nonnull individuals. Where possible, retrospective GST genotyping could be done on stored specimens. Genetic variants in the CYP2E1 and other CYP genes, as well as any other genes coding for enzymes that metabolize TCE or its metabolites, should also be investigated. Other candidate genes for genetic susceptibility includes those involve in regulating immune function. Studies should also be conducted using entire genome scans to identify new susceptibility genes. Research is needed to determine whether there are specific metabolites that appear to be the agent of carcinogenesis for specific sites. The multiple MOAs from multiple metabolites make comparisons between chlorinated solvents difficult to study and can account for differences in exposures and pharmacokinetic and pharmacodynamic characteristics of exposed populations contributing to variable responses in a number of studies. Information is needed on pathway effects, especially epigenetic changes induced by TCE and its metabolites. Research is needed to determine whether the effects on particular pathways be key to the lack of site concordance for some endpoints between animals and human data for TCE (e.g., a particular pathway disturbance will manifest as susceptibility to differing tumor sites between species). Studies evaluating epigenetic changes induced by TCE and its metabolites are also useful for determining potential MOAs involved with TCE-induced effects. Immunologic mechanism may be involved in lymphomagenesis from solvents (Vineis et al., 2007) and this should also be an area of future research.
Cancer; Carcinogens; Carcinogenesis; Carcinogenicity; Air-contamination; Air-quality; Air-quality-control; Air-quality-measurement; Air-quality-monitoring; Environmental-contamination; Environmental-hazards; Environmental-health; Environmental-pollution; Environmental-protection; Water-analysis; Worker-health; Occupational-exposure; Occupational-hazards; Metabolites; Case-studies; Exposure-assessment; Exposure-levels; Exposure-limits; Animals; Animal-studies; Humans; Epidemiology; Biological-agents; Chemical-analysis; Chemical-reactions; Chemical-synthesis; Solvents; Solvent-vapors; Solvent-vapor-degreasing
Identification of Research Needs to Resolve the Carcinogenicity of High-priority IARC Carcinogens. Views and Expert Opinions of an IARC/NORA Expert Group Meeting, Lyon, France, 30 June - 2 July 2009, IARC Technical Publication No. 42