Issues that must be addressed for risk assessment of mixed exposures: The US EPA experience with air quality

Humans are routinely exposed to a complex mixture of air pollutants in both their outdoor and indoor environments. The wide diversity of these exposure scenarios and potential for regional transport present the health scientist with a challenge of how to appropriately address complex air pollution mixtures. Similarly, regulators are faced with mixture issues ranging from exposures, to health outcomes, and to associated uncertainties that are in need of more definitive and strategic information to support informed decisions. This article provides a perspective of an empiricist on the background related to the issue of air pollution mixtures. Historic and current regulatory platforms for dealing with mixtures are described. Using the topic of particulate air pollution, general guidance through the nuances of potential interactions among PM constituents is provided, along with alterative approaches and examples, and how these support scientific and regulatory agendas. The impact of new cell and molecular technologies is inevitable, and we must be prepared to take advantage of these and other cross-cutting methods as they become available. Such innovative approaches hold the secret to high-throughput biologic dissection of component interactions and mixture profiles, which will aid in the assessment of risk.