Evaluating Chemical Mixtures in Epidemiological Studies to Inform Regulatory Decisions

BACKGROUND: Epidemiological studies are increasingly going beyond the evaluation of health effects of individual chemicals to consider chemical mixtures. To our knowledge, the advantages and disadvantages of addressing chemical mixtures for informing regulatory decisions—as opposed to obtaining a more comprehensive understanding of etiology—has not been carefully considered. OBJECTIVES: We offer a framework for the study of chemical mixtures in epidemiological research intended to inform regulatory decisions. We identify a) the different ways mixtures originate (product source, pollution source, shared mode of action, or shared effect on health outcome), b) the use of indicator chemicals to address mixtures, and c) the requirements for epidemiological studies to be informative for regulatory purposes. DISCUSSION: The principal advantage of considering mixtures is to obtain a more complete understanding of the role of the chemical environment as a determinant of health. Incorporating other exposures may improve the assessment of the net effect of the chemicals of interest. However, the increased complexity and potential loss of generalizability may limit the value of studies of mixtures, especially for mixtures based on mode of action or shared health outcomes. Our recommended strategy is to successively assess the marginal contribution of individual chemicals, joint effects with other specific chemicals, and hypothesis-driven evaluation of mixtures rather than applying hypothesis-free data exploration methods. Although more ambitious statistical approaches to mixtures may, in time, be helpful for guiding regulation, the authors believe conventional methods for assessing individual and combined effects of chemicals remain preferable. https://doi.org/10.1289/EHP11899