Workers are continuously exposed to a wide variety of chemical substances, biological agents, physical agents, and other stressors encountered both in and out of the workplace. Each stressor has the potential to cause a physiological effect, whether it is a prescribed pharmaceutical, consumed food, cleaning product, automotive exhaust emission, solvent, ultraviolet radiation, noise, whole-body vibration, or social or psychological stress. Mixed exposures may produce acute or chronic effects or a combination of acute and chronic effects, with or without latency. Other exposures in combination with certain stressors may produce increased or unexpected deleterious health effects, or they may combine or interact in the environment to create a new exposure risk. Exposures to mixed stressors can produce health consequences that are additive, synergistic, antagonistic, or can potentiate the response expected from individual component exposures. This is the complex problem that faces environmental scientists and public health officials in setting and carrying out public health policy for the general environment, consumer product and food and drug safety, and the protection of workers. Because the issue of mixed exposures affects all of these areas, it was selected as one of the priority areas of the National Occupational Research Agenda (NORA) to leverage collaborative research efforts for better understanding the complex interactions of mixed exposures. The mixed exposures research agenda includes the elements generally found in public health responses: surveillance, evaluation and research, and controls and interventions. Health surveillance is needed to identify mixtures with adverse health effects that cannot be explained by the toxicity of the individual components in a mixed exposure. Exposure surveillance is needed to identify workers exposed to mixtures with observed potential effects. To create manageable priorities for research and worksite interventions, systems are needed for ranking mixed exposures on the basis of knowledge about health effects and the degree to which exposure is likely to occur. In addition, the research agenda describes a variety of evaluation tools that can be used to assess the risk of exposure to various mixtures. Additional research is needed to develop better tools for toxicity analysis, exposure-response modeling, and physiologically based pharmacokinetic and pharmacodynamic (PB/PK and PB/PD) modeling. An approach based on observed health effects and observed exposures is needed to control exposures to mixtures and to assure that protective technologies are not compromised by multiple simultaneous exposures. For example, when the service life of respirator cartridges is reduced by the presence of an interfering agent, it should be determined whether that agent is toxic. Finally, the research agenda identifies intervention opportunities and information dissemination needs to assure that the outcomes of the developed research can be applied to preventing harmful effects of mixed exposures. Because resources are limited, the Mixed Exposures Team identified several research needs as top priorities, including: 1. Develop and implement new surveillance methods to identify the number of workers exposed to these mixtures, the range of exposure concentrations, and health effects associated with the mixed exposures. 2. Develop research strategies that promote collaboration between occupational health professionals and workers in ranking and characterizing mixed exposures within specific occupations and industries. Such assessment will also facilitate dissemination of research findings. 3. Conduct research to better understand the toxicology (biological mechanisms) of mixed exposures. 4. Develop methods to understand and integrate experimental data from the molecular level to the whole organism. For example, researchers should develop the ability to use data from proteomics and genomics studies and extrapolate these to whole body systems. 5. Develop methods that can be used to measure and predict deviations from additivity. 6. Develop and validate mechanism-based exposure-response models. 7. Develop the concept of the virtual human by means of PB/PK simulation. 8. Develop default parameters for mechanistically based risk estimation and extrapolation models. 9. Develop biosensors or measurement technologies (such as micro-arrays with advanced signal processing) that indicate whole mixture toxicity. 10. Identify, validate, and characterize the health outcome for biomarkers of exposure and response for workers exposed to mixtures. 11. Determine the effects of mixtures on engineering controls and personal protective equipment (PPE); evaluating each mixture's potential to adversely affect the protection provided by the controls. Through these research advances, policymakers and regulators may be better able to assess the true risk involved in most occupational and environmental exposures that include multiple stressors and mixed-chemical exposures.