12 August 2008

SCIENCE: Assessing Cumulative Health Risks from Exposure to Environmental Mixtures—Three Fundamental Questions

Article in Environmental Health Perspectives (2007) Vol 115 No. 5, Pages 825-832 by Ken Sexton of University of Texas School of Public Health, Brownsville, Texas, USA and Dale Hattis of The George Perkins Marsh Institute, Clark University, Worcester, Massachusetts, USA.


Differential exposure to mixtures of environmental agents, including biological, chemical, physical, and psychosocial stressors, can contribute to increased vulnerability of human populations and ecologic systems. Cumulative risk assessment is a tool for organizing and analyzing information to evaluate the probability and seriousness of harmful effects caused by either simultaneous and/or sequential exposure to multiple environmental stressors. In this article we focus on elucidating key challenges that must be addressed to determine whether and to what degree differential exposure to environmental mixtures contributes to increased vulnerability of exposed populations. In particular, the emphasis is on examining three fundamental and interrelated questions that must be addressed as part of the process to assess cumulative risk: a) Which mixtures are most important from a public health perspective? and b) What is the nature (i.e., duration, frequency, timing) and magnitude (i.e., exposure concentration and dose) of relevant cumulative exposures for the population of interest? c) What is the mechanism (e.g., toxicokinetic or toxicodynamic) and consequence (e.g., additive, less than additive, more than additive) of the mixture’s interactive effects on exposed populations? The focus is primarily on human health effects from chemical mixtures, and the goal is to reinforce the need for improved assessment of cumulative exposure and better understanding of the biological mechanisms that determine toxicologic interactions among mixture constituents.


It is well established that people are exposed to a diverse and dynamic mixture of environmental stressors as a routine part of their existence, and there is clear evidence that toxicity can be modified by simultaneous or sequential exposure to multiple environmental agents (Carpenter et al. 2002; Hertzberg and Teuschler 2002). We know, for example, that exposure to tobacco smoke and asbestos (Erren et al. 1999) or radon (Morrison et al. 1998) multiplicatively increases the risk of lung cancer over what would be expected from simple addition of the effects from the agents acting separately. Similarly, exposure to aflatoxin-contaminated food and hepatitis B infection greatly increases the risk of hepato-cellular carcinoma (Kuper et al. 2001), exposure to noise and toluene results in higher risk of hearing loss than from either stressor alone (Franks and Thais 1996), exposure to poly-cyclic aromatic hydrocarbons and ultraviolet radiation increases toxicity to aquatic organisms (Oris and Geisy 1985), and adults with increased perceived stress (Cohen et al. 1999) and children of parents experiencing stress (Boyce et al. 1995) are more susceptible to viral respiratory infections.

Risk assessments have, nevertheless, focused mainly on the narrow question of harm from exposure to individual chemicals in a specific environmental medium via a single route or pathway [U.S. Environmental Protection Agency (EPA) 2003]. Although there is an expanding body of work on cumulative exposures and combined effects on people (Agency for Toxic Substances and Disease Registry 2002; Carpenter et al. 2002; Monosson 2005; U.S. EPA 2000; Yang 1994) and on ecosystems (Bryce et al. 1999; Dale et al. 1998; U.S. EPA 1998), adequate and appropriate data are rarely available to conduct a rigorous assessment of cumulatve risk. In this article, we briefly review three fundamental and interrelated questions that must be addressed as part of the cumulative risk assessment process. Which environmental mixtures are most important from a public health perspective? What is the nature and magnitude of cumulative exposures for populations of interest? What is the mechanism and consequence of combined effects on exposed populations? ...


Cumulative risk assessment is currently hampered by three interrelated problems: a) Relatively little is known about the magnitude, duration, frequency, and timing of cumulative exposure to important environmental mixtures. b) Scant evidence is available on whether mixture-related effects are antagonistic, synergistic, or additive at exposure levels typically encountered by people. c) There is inadequate knowledge and insufficient understanding about interactive mechanisms of toxicity that occur among mixture constituents. In the near-term, quantitative assessment of cumulative risks depends not only on targeted research but also on development of science-based methods and procedures for using existing exposure and effects data to characterize mixture-related health risks with an acceptable degree of precision. This will unavoidably involve science policy decisions about how best to bridge the gap between the scarcity of hard scientific evidence and the need to estimate cumulative risks as an integral part of risk management decisions.

Cumulative risk assessment will be most useful to decision makers when it can help answer a fundamental question: “Do the uncertainty/safety factors built into the conventional risk assessment process adequately protect public health and ecologic resources from cumulative effects with a sufficient margin of safety?” To be relevant, therefore, cumulative risk assessment must provide guidance about which, if any, of the innumerable environmental mixtures that are part of our day-to-day lives represent important health risks, where “important” means there is a reasonable likelihood that combined effects of mixture constituents at realistic exposure levels constitute a serious health risk that is not adequately accounted for by traditional risk assessment methods.

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