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NIOSH Publication No. 2005-106:Mixed Exposures Research Agenda - A Report by the NORA Mixed Exposures
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December 2004 |
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Contents
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| 1 Introduction | |
Background |
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Identifying Mixture Hazards |
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| 3 Priorities for a Research Agenda | |
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2005-106.pdf (Full Document)
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| Related Resources/Publications: |
Foreword
In April 1996, the National Institute for Occupational Safety and Health (NIOSH) and its partners unveiled the National Occupational Research Agenda (NORA). NORA was developed by NIOSH and more than 500 partners in the public and private sectors to provide a framework to guide occupational safety and health research into the next decade. This effort to guide and coordinate research for the entire occupational safety and health research community is focused on 21 priority areas. The areas are divided into three categories: (1) disease and injury, (2) work environment and workforce, and (3) research tools and approaches.
One of the identified NORA priority areas in the environment and workforce category is the study of mixed exposures. Combining government researchers and industry experts, a NORA Mixed Exposures Team was established to facilitate the study of occupational mixed exposures. Workers from agriculture, construction, mining and other industries are commonly exposed to combinations of chemical substances, biological or physical agents, and other stressors. Knowledge is limited of the potential health effects of mixed exposures. Additional nonwork-related exposures (such as the consumption of alcohol or tobacco or the use of insect repellents, cosmetics, or other chemicals) and individual susceptibility also add to the complexity of exposure and resulting biological responses. New approaches are needed to identify additive, synergistic, antagonistic, or potentiation effects from multiple exposures (sequential or simultaneous). Identifying these effects can help characterize worker exposure, conduct research at environmentally relevant levels, improve laboratory and statistical analysis methods, and develop hazard controls that take into account the components of the mixtures.
Research has shown that physiological interactions from mixed exposures can lead to an increase in severity of the harmful effect. For example, exposure to noise and the solvent toluene results in a higher risk of hearing loss than exposure to either stressor alone. Exposure to carbon monoxide and methylene chloride produces elevated levels of carboxyhemoglobin, reducing the blood’s ability to carry oxygen in our bodies. The problem of mixed exposures is multifaceted, given the large number of combinations that occur every day in a variety of workplaces and in our everyday life experiences.
This report is the product of the NORA partnership team formed from experts inside and outside the public sector. The NORA Mixed Exposures Team examined the literature, cataloged ongoing research, and identified significant research gaps. Through examination of knowledge gaps and opportunities to leverage overlapping interests, the team identified key areas in which new research could significantly advance the science needed to develop future interventions. Those products, once implemented, could be used to reduce the risk of occupational disease and injury to workers.
The intent of this document is to articulate many of the issues involved with mixed exposures as well as to recommend research strategies and define research priorities that could lead to improved interventions for protecting workers from mixed exposures. We hope that this document will facilitate further dialogue about mixed exposures and generate keen interest among occupational safety and health researchers to devote attention to this important research area. In particular, we envision that this document could be used as the working paper for a future workshop on mixed exposure research needs and could help stimulate new outcome-focused research proposals. NIOSH will use the priorities outlined in this document (and refined through future workshops) as a tool for directing our internal research program, and for guiding our extramural activities.
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 John Howard, M.D. Director, National Institute for Occupational Safety and Health Centers for Disease Control and Prevention |
Executive Summary
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. They are listed below:
- 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.
- 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.
- Conduct research to better understand the toxicology (biological mechanisms) of mixed exposures.
- 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.
- Develop methods that can be used to measure and predict deviations from additivity.
- Develop and validate mechanism-based exposure-response models.
- Develop the concept of the virtual human by means of PB/PK simulation.
- Develop default parameters for mechanistically based risk estimation and extrapolation models.
- Develop biosensors or measurement technologies (such as micro-arrays with advanced signal processing) that indicate whole mixture toxicity.
- Identify, validate, and characterize the health outcome for biomarkers of exposure and response for workers exposed to mixtures.
- 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.
* Proteomics: The study and analysis of protein structure and function.
† Genomics: The study of the structure and function of large numbers of genes observed simultaneously.1. Introduction
BackgroundThe importance of mixed-exposure research for controlling the occupational environment and the decision to address this issue are driven by the following factors: (1) the concern for the known and perceived health risks from mixed exposures in the workplace, (2) the existing regulatory mandates, and (3) the current state of science.
Two examples of known or perceived health risks with toxicological endpoints and consequences from mixed exposures are (1) loss of hearing because of noise and chemical interaction and (2) synergistic carcinogenesis of asbestos and smoking. Other examples show more uncertainty. The Gulf War syndrome and the mixed-exposure-associated health effects from jet fuel (JP-8) exposures are far from clear. This lack of clarity stems from the complex nature of the mixtures involved and their related biological consequences. These mixtures not only interact within the human system, they can also undergo chemical transformations in the environment. Examples of this transformation are the conversion of some chlorinated hydrocarbons into toxic phosgene in the presence of ultraviolet light and the enhanced transport of radionuclides into the lungs when adsorbed by respirable dust.
Regulatory mandates in 29 CFR* 1910.1000 provide exposure limits for air contaminants
* Code of Federal Regulations . See CFR in references.
in general industry. This regulation specifies an exposure additivity formula to compute reduced workplace exposure limits for chemical mixtures. Lacking, however, are detailed guidelines to help occupational hygienists apply the additivity formula, determine its appropriateness for different situations, and identify the degree to which sufficient protection is provided. For example, little information is available to guide occupational hygienists on when to apply the exposure additivity formula, when to consider the effects of multiple exposures as independent, and when synergistic or antagonistic effects may be expected.
The U.S. labor force continues to grow both as a percentage of the overall population and in total number. In 1998, 138 million people (67% of the population) made up the American workforce. The workforce is expected to grow to 158 million in 2010 [Fullerton and Toossi 2001]. The fundamental mission of the National Occupational Research Agenda (NORA) is to shape research aimed at delivering on the NIOSH vision to provide “. . . safety and health at work for all people.” With more than 5,900 workers killed on the job in 2001 and far more dying prematurely of occupational disease, we are short of realizing our national goal of a safe and healthful workplace for all [BLS 2002].
Over the past 20 years, the topic of mixture research has witnessed a transition from outright avoidance to carrying out simple, descriptive studies of binary mixtures to planning and carrying out sophisticated studies using new technologies in biological and computational sciences. The complete elucidation of the human genome, the related developments in genomics and proteomics, and the exponential growth of computational technologies provide essential opportunities to deal with the effects of mixture exposures on complex biological systems. The current state of science is right for addressing research in the complex area of multiple stressors.
National Occupational Research Agenda (NORA)
One of the principal goals for the NORA initiative is to develop research priority areas leading to the protection of the workers’ health. Since occupational exposures to chemical mixtures and multiple stressors is the rule rather than the exception, we are committed to finding ways to tackle the complex area of health effects of such mixed exposures.
The impetus behind the NORA Mixed Exposures Research Agenda is the need to answer three fundamental questions:
- How can we detect mixed exposure effects and gain information sufficient for scientifically based decision making?
- How can we predict mixed exposure effects?
- Which intervention or avoidance strategies will be most effective for mixed exposures?
In fact, all exposures are mixed exposures in the sense that none occur in isolation from exposures to other simultaneous or sequential stressors inside or outside the workplace. Because NORA cannot plausibly address the full universe of possible mixed exposures, the scope of research targets must be limited.
Thus the identification and prioritization of key exposures is a very important step in developing a research agenda and protecting the health of workers.
Identifying Mixed Exposures
Mixtures of concern may be identified by the following three criteria:
- A large number of workers are exposed to the mixture.
- The health outcomes of exposure to these mixtures are of a nature or magnitude that cannot be explained with our current knowledge of single exposures.
- Exposures to these mixtures have health outcomes predicted from known effects of individual exposures that are also known to occur together.
For the first criterion, Table 1 illustrates the magnitude of worker exposure to some of the most widely encountered workplace mixtures.
For the second criterion, identification is driven by health problems. For example, a strong interaction of asbestos exposure with cigarette smoking was recognized after increased lung cancer rates were observed among asbestos workers.
For the third criterion, identification is driven by the knowledge of individual components’ physiological effects. An example of this is exposure to methylene chloride with co-exposure to carbon monoxide. Both agents reduce the blood’s capacity to carry oxygen by formation of carboxyhemoglobin, thereby potentially increasing the risk of cardiovascular health effects.
Table 1. Common mixed exposures for workers.
Sources: National Occupational Exposure Survey and National Occupational Health Survey of Mining [NIOSH 1990, 1991].
Exposure agent(s)
Disease or outcome (known or suspected)
Estimated number of workers exposed
Fuels and combustion products
Cancer, chronic obstructive pulmonary disease, pulmonary function changes, chemical pneumonia, central nervous system (CNS) effects, liver or kidney damage, irritation of eyes, skin, or mucous membranes
> 10,000,000
Chemicals and noise
Hearing loss
4,700,000
Welding fume
Cancer, respiratory disease, metal fume fever, eye damage, neurological impairment
760,000
Asphalt fumes
Irritation, chronic obstructive pulmonary disease, cancer
470,000
Chemicals and radiation
Cancer, immune dysfunction, eye and skin damage, CNS effects (from the chemical exposures)
400,000
Metalworking fluids
Contact or irritating dermatitis; hypersensitivity pneumonitis (that is, hypersensitive pulmonary alveolitis); suspected to cause cancers of some organs
340,000
Any chemical, physical, or biological insult on the body is a form of stress; therefore, multiple stressors can include chemicals, drugs, and physical and biological agents [Yang 2000]. However, the domain of multiple stressors may be much wider and certainly should include psychological stress. Although some of these stressors may have been studied individually and reported in the literature, little or no information is available about the possible combined actions of multiple stressors. Stress is defined as a state of disharmony or threatened homeostasis [Chrousos and Gold 1992]. If the homeostasis is disrupted because of physical or psychological stress including social and socioeconomic stress, intricate neural and biochemical events in the brain and in the endocrine and immune systems act jointly to counter the effects of stress and to reestablish homeostasis [Ember 1998]. If homeostasis is not reset, debilitating illness can result.
Identifying mixed exposure hazards requires a two-tiered approach. First, a better understanding of work processes and materials is needed. Ideally, such information will be collected as close to the workplace as possible. The second tier of research (on which much of this report is based) involves development of stronger scientific methods with which to measure potential health effects resulting from mixed exposures. Mixed-exposure research will require the development and refinement of mathematical and physiological models that can be used to estimate the effects of stressors on whole body systems. To be successful, substantial improvements are needed in our knowledge of biological mechanisms of toxicity, chemical structure-function relationships, and dose-response relationships. Such knowledge would in turn lead to the development of biological screening tools and improve our ability to model exposure-effect relationships. Advances in this direction should be fostered, at least initially, by focusing mixed model research on systems that have already been defined.
Toxicological research and the complex science needed to measure the combined heath effects of multiple stressors on the human body are limited by the quality of exposure data. In other words, our understanding of potential health effects resulting from mixed exposures is only as good as our understanding of what workers are exposed to throughout their working lives. The fact that both mixed exposures and exposure assessment methods were among the top 21 research priorities for NORA illustrates the fundamental and interrelated importance of finding better ways to understand real-world exposure patterns in the modern work environment and to determine associated health risks.
Scope
This document sets forth a research agenda for occupational exposure to mixtures that should serve as a blueprint for building a national research program. By identifying high-priority research areas, this agenda should influence the allocation of research resources. Developing a public health approach for preventing disease and injury resulting from mixed exposures is a daunting task. Workers are commonly exposed to multiple agents—as mixtures of agents, as separate simultaneous exposures, or as sequential exposures. Mixed exposures present a seemingly intractable problem for health professionals dealing with occupational safety and health issues, environmental health issues, and food and pharmaceuticals to name a few. The present substance-by-substance or stressor-by-stressor approach to hazard control is inadequate. The true risk to workers is likely to be underestimated when considering each stressor independently. This document identifies priority research needs for occupational safety and health. For the various agencies and stakeholders with an interest in mixed exposures, this research agenda clarifies areas of mutual interest, discusses new technologies and research tools, and improves our common understanding for dealing with mixed exposures.
For the purposes of this document, mixed exposures include chemical mixtures as well as mixed stressors such as exposure to physical agents (for example, noise, heat, radiation, and vibration) or other physiological stresses associated with work (for example, psychological stress). Chemical mixtures may be intrinsically complex mixtures (diesel exhaust, fuels) or identifiable component mixtures (benzene-toluene-xylene) that are sometimes called simple mixtures. Exposure to these agents may occur simultaneously or sequentially, producing cumulative risks for workers. Outside the workplace, workers will be exposed to other agents (such as pharmaceuticals, food additives, alcohol, or tobacco smoke) that may interact with various workplace chemical and physical agents, potentially creating new and unhealthful or unsafe conditions. This document will not address food and pharmaceuticals explicitly, although the importance of these exposures is recognized. In addition, issues related to individual susceptibility (which a separate NORA Team addresses) will not be the focus of this document.
The research agenda described in the following sections reviews various approaches that have been taken to address the problem of mixed exposures including hazard identfication, effects, exposure and risk assessment, and control.
With each approach, the team has identified knowledge gaps and opportunities for intervention. Finally, in recognition that resources are always limited, the final section of the research agenda seeks to identify principles for prioritizing mixed-exposure research as well as a few high-priority activities that, if completed, would provide the greatest leverage in offering useful public health guidance.
Abbreviations
ACGIH American Conference of Governmental Industrial Hygienists AIHA American Industrial Hygiene Association ATSDR Agency for Toxic Substances and Disease Registry CDC Centers for Disease Control and Prevention CFR Code of Federal Regulations CNS central nervous system CPWR Center to Protect Workers’ Rights DoD U.S. Department of Defense DNA deoxyribonucleic acid DOE U.S. Department of Energy EPA U.S. Environmental Protection Agency GC-MS gas chromatography-mass spectrometry HI hazard index LD 50 lethal dose of a compound for 50% of the animals exposed MAK Maximum Workplace Concentration (Maximale Arbeitsplatz Konzentration) MSDSs material safety data sheets MSHA Mine Safety and Health Administration NIEHS National Institute of Environmental Health Sciences NIOSH National Institute for Occupational Safety and Health NORA National Occupational Research Agenda OSHA Occupational Safety and Health Administration PAHs polycyclic aromatic hydrocarbons PB/PD physiologically based pharmacodynamic PB/PK physiologically based pharmacokinetic PPE personal protective equipment psi pounds per square inch QSAR qualitative or quantitative structure-activity relationship RfC reference concentration RfD reference dose SARs structure-activity relationships STEL short-term exposure limit TAFE Technical and Further Education (New South Wales) TEF toxicity equivalence factor TLV threshold limit value TNO Toegepast-Natuurwetenschappelijk Onderzoek (Netherlands Organization for Applied Scientific Research) TTC target organ toxicity concentration TTD target organ toxicity dose WOE weight of evidence WPAFB Wright Patterson Air Force Base
Acknowledgments
This report was written and developed by the members of the Mixed Exposures Team. Editorial review and camera copy production were provided by Susan Afanuh, André Allen, Laura Boyle, Anne Hamilton, Jane Weber, and Wendy Wippel. The document was based in part on a report to the committee that was prepared for Geo-Centers, Inc., by Life Systems, Inc. under Indefinite Delivery Contract No. DAMD17–98–D–0016 and Subcontract No. GC 3182–98–LSI–002. This task was co-funded by the U.S. Department of Defense (DoD), the National Institute for Environmental Health Sciences (NIEHS), and the National Institute for Occupational Safety and Health (NIOSH). The authors would also like to acknowledge the outstanding reviews received from Matt Gillen (NIOSH), Melinda Pon (Mine Safety and Health Administration), Michael Valoski (MSHA), Hana Pohl, Ph.D. (Agency for Toxic Substances and Disease Registry), John P. Groten, Ph.D. (Netherlands Organization for Applied Scientific Research), Gunnar Johanson (Institute of Environmental Medicine, Sweden), Keith Motley (Occupational Safety and Health Administration [OSHA]), Kevin Cummins (OSHA Office of Occupational Medicine), and Ann Mason, Ph.D. (American Chemistry Council).
Members of the NORA Mixed Exposures Team
Vincent Castranova, Ph.D. (NIOSH)
Judith Graham, Ph.D. (American Chemistry Council)*
Frank Hearl, P.E., Team Leader (NIOSH)*
Robert Herrick, Sc.D. (Harvard University)*
Richard Hertzberg, Ph.D. (U.S. Environmental Protection Agency)*
Mark D. Hoover, Ph.D. (NIOSH)
Alan Lunsford, Ph.D. (NIOSH)*
Margaret MacDonell, Ph.D. (U.S. Department of Energy, Argonne National Laboratory)*
Joe L. Mauderly, D.V.M. (Lovelace Respiratory Research Institute)*
Moiz Mumtaz, Ph.D. (Agency for Toxic Substances and Disease Registry [ASTDR])*
Peter Robinson, Ph.D. (Mantech Inc.—DoD Wright Patterson Air Force Base)*
Sharon Silver, Ph.D. (NIOSH)
Pam Susi (CPWR)*
Raymond Yang, Ph.D. (Colorado State University)*Past Members
Nancy Bollinger, M.S. (NIOSH)*
John Bucher, Ph.D. (NIEHS)
Gregory Burr, Ph.D. (NIOSH)
Hank Gardner, Dr., P.H. (Colorado State University)*
Manuel Gomez, Dr., P.H. (American Industrial Hygiene Association)
Hugh Hansen, Ph.D. (ATSDR)
Vera Kommineni, Ph.D., D.V.M. (NIOSH)
Daniel Lewis, Ph.D. (NIOSH)*
Douglas Trout, M.D. (NIOSH)* Contributing authors for this document
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