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. Lyon, France: International Agency for Research on Cancer, IARC Technical Publication No. 42. 2010 Jul; 42:145-153
Human cancer studies: The chief venue of Perc exposure is dry-cleaning shops, which generally have fewer than ten employees, so assembling an occupational cohort could be difficult. Dry-cleaning workers could be recruited through the media, rather than shop by shop with shop management as the gatekeeper. Morning exhaled-breath specimens on a Saturday, highly correlated with the previous day's time-weighted average (McKernan et al., 2008), could be the criterion for inclusion in a study. Assembling a new occupational cohort could be difficult. In the United States, dry-cleaning workers could be recruited by various means (see discussion of overarching issues for further discussion). Morning exhaled-breath specimens on a Saturday, highly correlated with the previous day's time-weighted average (McKernan et al., 2008), could be the criterion for inclusion in a study. Data from the two U.S. dry-cleaning cohorts could be pooled for analysis (Blair et al., 2003; Ruder et al., 2001) and for a cancer incidence study. Identification of cohorts of workers outside the United States should also be explored. The Nordic study could be expanded into a cohort (Lynge et al., 2006). Brain tumor is also a potential target for Perc. The working group is aware of several large brain case-control studies (NCI, NIOSH, Interphone), which will be analyzed in the next year or two for an association between exposure to chlorinated solvents and risk of brain cancer (Inskip et al., 2001; Ruder et al., 2006; Cardis et al., 2007) Genetic susceptibility studies: 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 the liver and 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, CYP3A4 and other genes coding for enzymes that metabolize Perc or its metabolites, should also be investigated. Studies should also be conducted using entire genome scans to identify new susceptibility genes. Mechanistic studies: With respect to mechanistic data, a major research gap is that MOAs are not sufficiently characterized or tested, for any of the Perc-induced adverse effects. Studies are needed that evaluate the GSH pathway of Perc metabolism, including genotoxicity studies, and that identify intermediates in the oxidative pathway. Lastly, adequate PBPK models have not been developed that allow for predictions of metabolism and differences in metabolism between species for a number of key metabolites. Immunologic mechanism may be involved in lymphomagenesis from solvents (Vineis et al., 2007) and this should also be an area of future research. Brain tumor is also a potential target for DCM, and Perc, and has not been adequately studied for TCE. Clearly more epidemiological study and analysis of existing epidemiological literature is need for Perc. However, the further development of the types of mechanistic data and toxicokinetic data that have been elucidated for TCE needs to be developed for Perc and will aid in the design and interpretation of epidemiological studies.
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