Research recommendations for selected IARC-classified agents.

OBJECTIVES: There are some common occupational agents and exposure circumstances for which evidence of carcinogenicity is substantial but not yet conclusive for humans. Our objectives were to identify research gaps and needs for 20 agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. DATA SOURCES: For each chemical agent (or category of agents), a systematic review was conducted of new data published since the most recent pertinent International Agency for Research on Cancer (IARC) Monograph meeting on that agent. DATA EXTRACTION: Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. DATA SYNTHESIS: Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress, and immuno- and hormonal modulation. CONCLUSIONS: Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.

Air pollution combustion emissions: characterization of causative agents and mechanisms associated with cancer, reproductive, and cardiovascular effects.

Combustion emissions account for over half of the fine particle (PM(2.5)) air pollution and most of the primary particulate organic matter. Human exposure to combustion emissions including the associated airborne fine particles and mutagenic and carcinogenic constituents (e.g., polycyclic aromatic compounds (PAC), nitro-PAC) have been studied in populations in Europe, America, Asia, and increasingly in third-world counties. Bioassay-directed fractionation studies of particulate organic air pollution have identified mutagenic and carcinogenic polycyclic aromatic hydrocarbons (PAH), nitrated PAH, nitro-lactones, and lower molecular weight compounds from cooking. A number of these components are significant sources of human exposure to mutagenic and carcinogenic chemicals that may also cause oxidative and DNA damage that can lead to reproductive and cardiovascular effects. Chemical and physical tracers have been used to apportion outdoor and indoor and personal exposures to airborne particles between various combustion emissions and other sources. These sources include vehicles (e.g., diesel and gasoline vehicles), heating and power sources (e.g., including coal, oil, and biomass), indoor sources (e.g., cooking, heating, and tobacco smoke), as well as secondary organic aerosols and pollutants derived from long-range transport. Biomarkers of exposure, dose and susceptibility have been measured in populations exposed to air pollution combustion emissions. Biomarkers have included metabolic genotype, DNA adducts, PAH metabolites, and urinary mutagenic activity. A number of studies have shown a significant correlation of exposure to PM(2.5) with these biomarkers. In addition, stratification by genotype increased this correlation. New multivariate receptor models, recently used to determine the sources of ambient particles, are now being explored in the analysis of human exposure and biomarker data. Human studies of both short- and long-term exposures to combustion emissions and ambient fine particulate air pollution have been associated with measures of genetic damage. Long-term epidemiologic studies have reported an increased risk of all causes of mortality, cardiopulmonary mortality, and lung cancer mortality associated with increasing exposures to air pollution. Adverse reproductive effects (e.g., risk for low birth weight) have also recently been reported in Eastern Europe and North America. Although there is substantial evidence that PAH or substituted PAH may be causative agents in cancer and reproductive effects, an increasing number of studies investigating cardiopulmonary and cardiovascular effects are investigating these and other potential causative agents from air pollution combustion sources.

Source apportionment of indoor, outdoor, and personal PM2.5 in Seattle, Washington, using positive matrix factorization.

As part of a large exposure assessment and health-effects panel study, 33 trace elements and light-absorbing carbon were measured on 24-hr fixed-site filter samples for particulate matter with an aerodynamic diameter <2.5 microm (PM2.5) collected between September 26, 2000, and May 25, 2001, at a central outdoor site, immediately outside each subject's residence, inside each residence, and on each subject (personal sample). Both two-way (PMF2) and three-way (PMF3) positive matrix factorization were used to deduce the sources contributing to PM2.5. Five sources contributing to the indoor and outdoor samples were identified: vegetative burning, mobile emissions, secondary sulfate, a source rich in chlorine, and a source of crustal-derived material. Vegetative burning contributed more PM2.5 mass on average than any other source in all microenvironments, with average values estimated by PMF2 and PMF3, respectively, of 7.6 and 8.7 microg/m3 for the outdoor samples, 4 and 5.3 microg/m3 for the indoor samples, and 3.8 and 3.4 microg/m3 for the personal samples. Personal exposure to the combustion-related particles was correlated with outdoor sources, whereas exposure to the crustal and chlorine-rich particles was not. Personal exposures to crustal sources were strongly associated with personal activities, especially time spent at school among the child subjects.

Source apportionment of PM2.5 at an urban IMPROVE site in Seattle, Washington.

The multivariate receptor models Positive Matrix Factorization (PMF) and Unmix were used along with the EPA's Chemical Mass Balance model to deduce the sources of PM2.5 at a centrally located urban site in Seattle, WA. A total of 289 filter samples were obtained with an IMPROVE sampler from 1996 through 1999 and were analyzed for 31 particulate elements including temperature-resolved fractions of the particulate organic and elemental carbon. All three receptor models predicted that the major sources of PM2.5 were vegetative burning (including wood stoves), mobile sources, and secondary particle formation with lesser contributions from resuspended soil and sea spray. The PMF and Unmix models were able to resolve a fuel oil combustion source as well as distinguish between diesel emissions and other mobile sources. In addition, the average source contribution estimates via PMF and Unmix agreed well with an existing emissions inventory. Using the temperature-resolved organic and elemental carbon fractions provided in the IMPROVE protocol, rather than the total organic and elemental carbon, allowed the Unmix model to separate diesel from other mobile sources. The PMF model was able to do this without the additional carbon species, relying on selected trace elements to distinguish the various combustion sources.