Abstract CN08-03: How does air pollution cause cancer?

In October 2013, the International Agency for Research on Cancer (IARC) evaluated outdoor air pollution and associated particulate matter (PM) as group 1 (known) human carcinogens for the lung and probable carcinogens for the bladder. Although the IARC monograph on outdoor air (Vol. 109) will not be published until late 2014, this talk reviews some of the main mechanistic data that supported this evaluation. The IARC working group consisted of four sub-groups: epidemiology, animal cancer, exposure, and mechanistic data. Six people comprised the mechanistic sub-group, and this talk is an overview of their review of the literature, which covered more than 30 years and 800 publications on the genetic and related effects of air pollution. More than 2,500 measurements of the mutagenicity in Salmonella (Ames assay) of outdoor air samples from around the world showed that the mutagenicity of outdoor air ranges over 6 orders of magnitude in potency (revertants/m3); however, the mutagenic potency of the extractable organics from the PM ranges only over 1 order of magnitude. This indicates that the general chemical composition and mutagenic potency of the PM is similar around the world; what varies is the amount of this PM per cubic meter of air, i.e., its concentration. Worldwide, air is generally more mutagenic during working hours (due to traffic) and during winter (due to heating emissions). More than 90 measurements compared genotoxicity biomarkers between people whose daily work involved chronic exposure to outdoor air/traffic (traffic police, toll takers, gate keepers, street vendors, etc.) versus people without such exposures (typically office workers). Approximately 90% of these studies found that chronic exposure to traffic exhaust enhanced a range of such biomarkers, including cytogenetic damage, DNA damage (DNA adducts and strand breaks), altered telomere length, altered gene expression, and epigenetic changes (DNA methylation). Some of these biomarkers are associated with increased risk for cancer and provide mechanistic support for how air pollution causes cancer—i.e., by causing DNA damage, mutation, and/or altered gene expression. A large number of studies showed that organic extracts of outdoor PM induced DNA adducts in mammalian cells in culture as well as in rodents, and oxidative DNA damage and DNA strand breaks are also induced not only in people exposed chronically to air pollution but to cells in culture and rodents exposed to outdoor PM. Efforts are underway to associate through global positioning coordinates the air mutagenicity data in Salmonella relative to PM concentrations and the lung cancer risk values relative to PM concentrations from epidemiology studies. Such data will provide additional evidence for the linkage between air mutagenicity and lung cancer risk. A growing literature is indicating the important role of epigenetic changes (DNA methylation) associated with air pollution, resulting in increased risk for cancer and other diseases associated with air pollution due to altered gene expression. A substantial literature documents the genotoxic effects of air pollution in plants, including DNA damage, chromosome aberration, and gene mutation. Collectively, the large body of data reviewed by the mechanistic sub-group provided strong mechanistic support for the ability of various components of outdoor air pollution to cause DNA damage, which if not repaired, could be processed into mutations (primarily G to T base substitutions) in key cancer-associated genes (TP53 and KRAS), leading to lung and possibly bladder cancer. The nitroarenes, primarily from diesel exhaust, are the likely cause of the bladder cancer due to their conversion to aromatic amines, which are known bladder carcinogens. Polycyclic aromatic hydrocarbons (PAHs) clearly play a large role in both the lung and bladder carcinogenesis associated with outdoor air pollution. Citation Format: David M. DeMarini. How does air pollution cause cancer? [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN08-03.