NIOSH Publication No. 2005-106: Mixed Exposures Research Agenda - A Report by the NORA Mixed Exposures Team	December 2004

Biomarkers

3 Priorities for a Research Agenda

The preceding sections have outlined research needs for hazard identification, effects studies, exposure assessment, biomarkers, risk assessment, and controls. Because research funds are limited, and many worthy needs have been identified, the NORA Mixed Exposure Team recommends the following research needs as among the highest priorities. These priorities were developed based on the following criteria (evaluated using the background in the preceding sections):

1. The lack of available data, with research not elsewhere supported.
   
   
2. The possibility that research would make a difference for worker protection.
   
   
3. The research should improve our basic understanding of mixed exposures.

On the basis of these criteria, the NORA Mixed Exposures Team recommends the following high priority research topics (NOTE: This list is not in a priority order.):

• Develop and implement new surveillance methods to determine the number of workers exposed to specific mixtures, identify the range of exposure concentrations, and identify health effects associated with mixed exposures.
  
  
• Develop research strategies that promote collaboration between occupational health professionals and workers in ranking and characterizing mixed exposure within specific occupations and industries. Such assessment will also facilitate dissemination of research findings.
  
  
• Conduct research to better understand the toxicology (biological mechanisms) for mixed exposures.
  
  
• Develop methods to understand and integrate experimental data from the molecular to the whole organism level. For example, developing the ability to use data from proteomics and/or 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 via 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, develop, 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 PPE; evaluating the mixtures’ potential to adversely affect the protection provided by the controls.

Clearly, awareness is growing both in the United States and worldwide of the need for meaningful research on the toxicology and health risk assessment of mixed exposures, not only in the occupational context but for environmental, pharmaceutical, and clinical exposures as well. A strong commitment of resources, as well as deliberate strategic planning, is required to define research agendas and design studies that will effectively provide for risk assessment and reduction of mixed occupational exposure hazards.

When studies are proposed within the priority areas outlined above, or for any of the other research needs described elsewhere in this report, the following factors should be considered in selecting the test mixtures:

• Ability to detect interactions or joint toxicity, that is, beyond that predict-ed based on individual component toxicity;
  
  
• Number of affected workers who will benefit;
  
  
• Severity of combined effect under study.

Application of these principles should help avoid the promotion of studies of specific binary mixtures that have limited utility for advancing the science or improving prevention and interventions for many workers but have some particular academic interest.

Conclusions

The topic of mixed exposures is broad. The vast number of permutations, considering studies of binary mixtures alone is astronomical. To promote long-term progress in understanding the basic principles of action for mixed exposures, the team hopes these priorities will lend focus to a very complex area.

 

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Appendix

Glossary of Key Mixed Exposure Terms^*

To facilitate communication, it is essential that the key mixed-exposure terms are defined. The need for agreement of definitions takes on added importance when communications among several scientific disciplines, numerous agencies (government, nongovernment, U.S. and international), professional associations, and the public are necessary. Many terms require understanding to shape the mixed-exposures research agenda. This Appendix is provided to reduce potential confusion when discussing mixed exposures and this report.

The list of terms requiring definitions was generated from a review of the literature. Certain definitions were adapted in an attempt to make them more applicable to occupational health.

^*Adapted from Hertzberg et al. 1998.

Additivity	When the effect of the mixed exposure is equal to the sum of the effects of the individual components. The terms effect and sum must be explicitly defined. Effect may refer to the measured response or the incidence of adversely affected species. The sum may be a weighted sum (see also dose additivity) or a conditional sum (see also response additivity).
Antagonism	When the effect of the mixed exposure is less than that suggested by the component toxic effects. Antagonism must be defined by identifying the type of additivity (dose or response addition) from which the combination effect deviates.
Chemical antagonism	Refers to a reaction between the components that has formed a new chemical. The toxic effect produced is less than that suggested by the components’ toxic effects.
Chemical classes	Groups of components that are similar in chemical structure and biologic activity, and that frequently occur together in environmental samples, usually because they are generated by the same industrial process. The composition of these mixtures is often well controlled so that the mixture can be treated as a single chemical. Dibenzo-dioxins are an example.
Chemical mixture	Any set of two or more chemical substances. May also be referred to as a whole mixture or as the mixture of concern. (See also complex mixture and simple mixture.)
Chemical synergism	When a reaction between the components has occurred and a new chemical is formed, the toxic effect produced is greater than that suggested by the components’ toxic effects and may be different from effects produced by any of the components by themselves.
Complex mixture	A mixture containing so many components that any estimation of its toxicity based on its components’ toxicities contains too much uncertainty and error to be useful. The chemical composition may vary over time or with different conditions under which the mixture is produced. Complex mixture components may be generated simultaneously as by-products from a single source or process, intentionally produced as a commercial product, or may coexist because of disposal practices. Gasoline is an example.
Component	Single chemicals or stressors that make up a chemical mixture or mixed exposure. Chloroform is an example of a component in a disinfection by-product mixture.
Dose additivity	When the effect of the combination is equal to the effect expected from the equivalent dose of an index chemical or other stressor (chemical or other stressor as the basis for standardization of toxicity of components in a mixed exposure). The equivalent dose is the sum of component doses scaled by their potency relative to the index chemical or stressor.
Exposure	Contact of a chemical, physical, or biological agent with the outer boundary of an organism. Exposure is quantified as the concentration (or intensity for physical agents) of the agent in the medium in contact integrated over the time duration of that contact.
Inhibition	Refers to the mechanism whereby exposure to one stresor that alone has no effect on a certain biologic activity reduces the adverse effect associated with exposure to another stressor.
Mixed exposures	Exposures to either chemical mixtures, different substances at different times, simultaneous exposure to multiple substances, or simultaneous exposure to a chemical substance and another stressor.
Multiple exposures	Exposure to chemical substances at different times or simultaneous exposure to more than one chemical substance and another stressor. Simultaneous exposure to chemical solvents and noise is both a mixed and multiple exposure. Daily exposure to benzene is a multiple exposure.
Potentiation	Refers to the mechanism whereby exposure to one stressor that alone has no effect on a certain biologic activity increases the adverse effect associated with exposure to another stressor.
Response additivity	When the response (rate, incidence, risk, or probability) of effects from the mixed exposure is equal to the conditional sum of component responses as defined by the formula for the sum of independent event probabilities.
Simple mixture	A mixture containing two or more identifiable components, but few enough components that the mixture’s toxicity can be adequately characterized by a combination of the components’ toxicities and the components’ interactions.
Synergism	When the toxic effect of the mixed exposure is greater than that suggested by the component toxic effects

Biomarkers