Risk Assessment Strategies and Techniques for Combined Exposures

Abstract

Consideration of cumulative risk is necessary to evaluate properly the safety of, and the risks associated with, combined exposures. These combined exposures (“mixtures”) commonly occur from exposure to: environmental contaminants in air, soil, and water; pharmaceuticals and dietary supplements; consumer and personal care products; food additives and residues; and nonchemical stressors (e.g., physical and psychosocial). Risk assessments of mixtures of chemicals are more complex than those of single chemicals for two major reasons: (1) in combining chemicals to estimate mixture risk, it is necessary to rely on multiple assumptions; and (2) the potential for pharmacokinetic and/or pharmacodynamic interactions among mixture components. Additional difficulties exist for complex environmental mixtures, which typically contain a large fraction of total mixture mass of unknown identity and toxicity. The influence of data type, quality and quantity on the risk assessment approach is illustrated. Guidance is provided on when whole mixture risk assessment approaches are possible and when component-based approaches are needed. Advantages and disadvantages of whole mixture risk assessment approaches are discussed, including concerns due to unknown mixture mass and the current status of sufficient similarity methodology. Component-based methods based on dose-addition represent the majority of chemical mixture risk assessments that have been conducted to date; both hazard index-based (Hazard Index, Target Organ Toxicity Hazard Index, Interaction-Weighted Hazard Index) and index chemical (Relative Potency Factor and Toxic Equivalency Factor) approaches are reviewed. There is recognition of the need to consider the cumulative effects of both chemical and nonchemical stressors, but standard methods with a history of use are not available.