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Cite This: Environ. Sci. Technol. XXXX, XXX, XXX−XXX
Complex Air Pollution Mixtures Formed by Irradiation of Hydrocarbons Elicit an Array of Toxicological Responses M. Ian Gilmour,*,† Jonathan D. Krug,‡ Stephen H. Gavett,† Mehdi Hazari,† David M. DeMarini,† and Daniel L. Costa§ †
National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United States ‡ National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United States § Air in a Changing Environment National Program, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, United States impacts from mixtures of CPs using objective measures of exposure and health outcomes remain a major challenge in air quality assessment and communication. To address this issue, Canada introduced an Air Quality Health-based Index (AQHI) that calculates the potential hazard from the aggregate exposure to O3, NO2, and PM2.5. We have extended this concept by first using a reaction chamber to generate two photochemically reacted, simulated atmospheres (SAs) with similar AQHI values but different distributions of the organics relative to the PM and gas phase. SA-PM had high SOA PM and low O3/NO2 concentrations, whereas SA-O3 had high O3/NO2 and low SOA PM concentrations (Figure 1). We then evaluated these atmospheres for their (a) cytotoxicity and mutagenicity in Salmonella using the Ames assay and (b) ability to induce lung injury, inflammation, and pulmonary and cardiac effects in both healthy rats and mice and animal models that mimicked human disease. This represents the first toxicological evaluation of complex atmospheres with known AQHI values, the results of which are described in five research articles in this issue of ES&T. The first paper summarizes the generation and physical chemistry of the two atmospheres,1 and the second describes pidemiology studies over the past five decades have their mutagenic potencies.2 The remaining three papers detail provided convincing evidence that air pollution exposure is exposures and pathophysiological responses to one or both associated with multiple adverse health outcomes, including atmospheres in healthy animals and animal models of human increased mortality. Air pollution is a complex mixture of disease.3,4,5 SA-O3 was more mutagenic and induced more particles, vapors, and gases emitted from natural and arrhythmias in healthy adult mice than did SA-PM. The greater anthropogenic sources that may undergo subsequent phototoxicity of SA-O3 was likely driven by the presence of a chemical transformation to form new products such as ozone multitude of secondary reaction products in the gas phase, as (O3), nitrogen dioxide (NO2), and secondary organic aerosols evidenced by the higher concentrations of formaldehyde, (SOA). To protect human health from impacts of air pollution, glyoxal, and methylglyoxal in SA-O3 relative to SA-PM. the United States and other nations have developed and Pathophysiological responses in selected animal models of implemented air quality standards for the major criteria air disease, i.e., diabetes, allergic asthma, and influenza infection,4 pollutants (CPs): O3, NO2, and particulate matter (PM2.5 and were less dramatic but still significant, with SA-O3 inducing PM10), as well as for sulfur dioxide, carbon monoxide, and lead. greater effects overall than SA-PM. In general, the pathophysioA color-coded air quality index (AQI) communicates daily air logical responses were mild and transient, suggesting that the quality to the public and provides guidance for who may be at atmospheres were not particularly potent at altering these end risk from exposure. points. However, how these effects would reveal across a large Although there are clear circumstances where single population with diverse health status remains an open and pollutants may dominate and impart specific health effects, pressing question. This point was highlighted by the induction for example, high ozone increasing asthma hospitalizations or higher PM2.5 increasing cardiovascular mortality, CPs often track with each other, making it difficult to distinguish Received: February 9, 2018 individual pollutant effects. Thus, predicting potential health
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This article not subject to U.S. Copyright. Published XXXX by the American Chemical Society
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DOI: 10.1021/acs.est.7b04857 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
Environmental Science & Technology
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Figure 1. Kinetic profile of secondary air pollutant formation following irradiation (UV on) of precursor chemicals to yield atmospheres containing either a high PM but low oxidant gas concentration (SA-PM) or a low PM but high oxidant gas concentration (SA-O3).
chronic exposures to these type of atmospheres, which are the reality for most people. Despite the limitations of this first-ever toxicological assessment of atmospheres with known AQHI values, the technological and toxicological approaches outlined in these reports provide a credible means to assess the potential health effects of real-world, multipollutant mixtures. A future challenge will be to apply validated in vitro test systems that are predictive of adverse health outcomes to expedite high-throughput screening of different levels and types of air pollution mixtures.
of altered cardiac function by the otherwise less-potent SA-PM and exacerbation of responses in Vitamin D deficient mice.5 This study permitted a tentative test of policy assumptions regarding health impacts based on an AQHI. The research provides a framework for comparing the relative toxicological potencies of various multipollutant atmospheres in cells and laboratory animals, the results of which can identify end points that may be sensitive effect-indicators, providing guidance for policy makers. For example, although PM in polluted air is a documented cause of human lung cancer; the role of the gas phase in human carcinogenicity has been unclear. The current study provided strong evidence for the mutagenicity of the gas phase secondary reaction products, as well as induction of mutations found frequently in lung tumors of nonsmokers. Likewise, SA-O3 was more potent than SA-PM at inducing cardiac and respiratory effects, further implicating the gas-phase reaction products in health effects in vivo. No changes were observed with apical immune end points following immunization, viral infection, or exacerbation of allergic asthma; however, some reductions in cytokine expression were noted for SA-O3, indicating that the exposures could alter immune signaling and potentially affect subsequent infectious or allergic challenges. A major caveat of these studies is that the PM2.5 was wholly formed as SOA and did not comprise other common constituents such as metals and elemental carbon. Thus, the finding that SA-PM was not particularly bioactive suggests that other types of PM2.5 found in urban airsheds may have more of a health impact than particles formed through the photooxidation of hydrocarbons. Toxicological approaches appropriately applied should be able to enlighten these questions. It may never be fully possible to directly link objective empirical testing approaches to all health-based policy guidelines, or to bridge human exposure and health uncertainties across a spectrum of outcomes in at-risk populations. Wellstructured studies incorporating realistic exposures and relevant health end-points, however, can lay a framework for defensible risk estimates to ensure with greater confidence public health protection along the exposure and biologic continuum. Future studies utilizing irradiated combustion emissions are critically needed to more fully examine the relative contributions to health outcomes of atmospheric PM derived from both primary sources and secondary reactions. Furthermore, the toxicological investigations conducted here were acute in nature, and knowledge is lacking of effects from intermittent and more
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AUTHOR INFORMATION
Corresponding Author
*Phone: +1-919-541-0015; e-mail:
[email protected]. ORCID
M. Ian Gilmour: 0000-0002-3070-6704 Jonathan D. Krug: 0000-0002-7045-7650 Mehdi Hazari: 0000-0003-0280-9690 David M. DeMarini: 0000-0001-8357-7988 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Drs. Scott Jenkins and Aimen Farraj for their careful review of this manuscript. The research described in this manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that contents necessarily reflect the views and policies of the Agency, nor does the mention of trade names or commercial products constitute endorsement or recommendation for use.
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REFERENCES
(1) Krug, J. D.; Lewandowski, M.; Offenberg, J. H.; Turlington, J. M.; Lonneman, W. A.; Modak, N.; Krantz, Q. T.; King, C.; Jaoui, M.; Gavett, S. H.; Gilmour, M. I.; DeMarini, D.; Kleindienst, T. E. The photochemical conversion of surrogate emissions for use in toxicological studies: role of particulate- and gas-phase products. Environ. Sci. Technol. 2018, in press. 10.1021/acs.est.7b04879. (2) Zavala, J.; Krug, J. D.; Warren, S. H.; Krantz, Q. T.; King, C.; McKee, J.; Gavett, S. H.; Lewandowski, M.; Lonneman, W. A.; Kleindienst, T. E.; Maier, M.; Higuchi, M.; Gilmour, M. I.; DeMarini, D. M.Evaluation of an air quality health index for predicting the B
DOI: 10.1021/acs.est.7b04857 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
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mutagenicity of simulated atmospheres. Environ. Sci. Technol. 2018, in press .10.1021/acs.est.8b00613. (3) Hazari, M.; Stratford, K.; Krantz, Q. T.; King, C.; Krug, J. D.; Farraj, A.; Gilmour, M. I., Comparative cardiopulmonary effects of particulate matter- and ozone-enhanced smog atmospheres in mice. Environ. Sci. Technol.. 2018, in press. (4) Hargrove, M. M.; Snow, S. J.; Luebke, R. W.; Wood, C. E.; Krug, J. D.; Krantz, Q. T.; King, C.; Copeland, C. B.; McCullough, S. D.; Gowdy, K. M.; Kodavanti, U. P.; Gilmour, M. I.; Gavett, S. H.Effects of simulated smog atmospheres in rodent models of metabolic and immunologic dysfuntion. Environ. Sci. Technol. 2018, in press. 10.1021/acs.est.7b06534. (5) Stratford, K.; Haykal-Coates, N.; Thompson, L.; Krantz, Q. T.; King, C.; Krug, J. D.; Gilmour, M. I.; Farraj, A.; M, H.Early-life persistent vitamin D deficiency alters cardiopulmonary responses to particulate matter-enhanced atmospheric smog in adult mice. Environ. Sci. Technol. 2018, in press. 10.1021/acs.est.7b04882.
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DOI: 10.1021/acs.est.7b04857 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
