NIH Exposure Biology Workshop – Executive Summary

The National Institute of Environmental Health Sciences (NIEHS) and the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) hosted the NIH Exposure Biology Workshop at the Grandover Resort in Greensboro, NC on May 16–17, 2006. The workshop identified research opportunities for the Exposure Biology Program (EBP) within the Genes and Environment Initiative (GEI), a trans-NIH initiative aimed at accelerating understanding of how genetic and environmental risk factors influence human health and disease.

The workshop included a series of plenary sessions and break-out discussion groups focused on current advances and information on Technology Development for assessing environmental exposures and biological response, Pathogenic Mechanisms related to environmental exposures and disease, and Exposure Applications for toxicants and toxins, dietary factors and physical activity. Special sessions focused on training, and ethical and social implications of potential research activities. A summary of the workshop highlights is presented by research theme.

Sensor Technology. Technologies are currently available, or can be easily re-engineered and adapted, to inform about point-of-contact exposures (environmental sensors), biological response indicators (biological sensors), and measures of diet and physical activity.

New initiatives in new technology should consider the following:

• Data collection, field implementation, and complexity: Determine the need for one-time or continuous measurements, the breadth of analytes to be measured, and the desired field application. For example, personal dosimeters are wearable or portable devices that can provide one-time or continuous (time-weighted average) measurement of point-of-contact exposures or blood analytes (e.g., glucose concentration). Such devices could be adapted simply and easily to measure other biological indicators. Sensors are the ultimate technology because they measure continuously, are completely self-contained, and require little user intervention, making them easily deployed in field applications. Available sensing technologies could be adapted to provide real-time, simultaneous measurement of multiple analytes in a single sample or device. Because they have the most sophisticated and complex design, they require intermittent instrument calibration.
• Spatial and temporal scaling: Select sensing technologies that provide information at the desired scale, from the macro (ambient environmental) to the molecular or nano (intracellular). Molecular assays based on global changes in metabolites (metabolomics) or proteins (proteomics) are relatively high-throughout approaches to the analysis of biomarkers in samples of blood and urine. These “omics” approaches can be incorporated into a micro- or even nano-scale devices, such as chip-based and microfluidics platforms, effectively decreasing sequencing costs, and enabling multiplexed sampling from minute samples. Combining new molecular and nano-scale technologies with imaging approaches can provide real-time information about molecular signaling, protein activity, and protein-protein interactions at the cellular or sub-cellular levels.
• Specifications: All new sensing technologies should strive to achieve the following specifications:
  1. Rapid response time
  2. Analyte specific detection
  3. Varied and appropriate concentration range
  4. Optimized operating conditions e.g. temperature range, background environment
  5. Portable
  6. Quantitative/Sensitive/Accurate
  7. Generalizable platform
  8. Inexpensive to deploy
• Define the exposure goal: It is important that the environmental health community specify to technology developers what they want to measure; that is, the specific analytes and/or markers, in what sample matrices, at what concentration, and with what temporal and spatial resolution. This understanding will lead to shared design goals, thereby creating a partnership between the health and technology communities.
• Short- and long-term investments: Short-term strategies should be adopted to achieve specific, attainable goals and deliverables (devices, assays) that inform about specific priority classes of exposure, and can be adapted to future applications of other exposure classes. This will likely include point-of-contact environmental sensors, personal dosimeters, and sensors based on molecular assays (proteomics, metabolomics, imaging). More long-term investments should target high-risk, high-benefit technologies, such as lab-on-a-chip technologies and biological sensors, that incorporate multiplexed sensing capabilities for concurrent detection and quantification of environmental agents, physical activity parameters, and geospatial referencing.
• Improvements to dietary assessment needed: Computer-assisted and web-based food intake assessments, telephone reporting techniques, and reporting/monitoring methods based on wireless technology including cellular telephones and personal digital assistant (PDA) devices are desirable options that can complement existing Food Frequency Questionnaires. These new methods build on existing infrastructure that is already widespread and well accepted.
• Physical activity assessment tools are available: New technology developments are currently on the market and can be adapted to health research. Accelerometers and pedometers and other devices to monitor physiologic parameters of energy expenditure and metabolism, such as heart rate, respiratory rate and oxygen exchange, should be considered. Wireless features could be incorporated in these devices to allow simultaneous monitoring of physical activity, physiologic responses, geographic location, and external environmental conditions. Ideally, physical activity and dietary intake assessment could be incorporated into one wireless device that could include automated data retrieval.
• Consider physiology and behavior when assessing psychosocial stressors: Psychosocial stressors elicit wide-ranging biomedical effects on endocrine, immune and neurological systems. Technology development for this class of exposures will require methods that address both behavioral and biologic aspects of the exposure and response. Fortunately, existing psychometrics batteries are adequate for developing behavioral measures of psychosocial stress. Measures of biologic response can be pursued using sensing technologies developed for other environmental agents.

Biomarker Development and Validation. Methods for measuring biological indicators are diverse and new developments are emerging rapidly, particularly in the medical field. Many of these could be adapted simply and easily to measure relevant biological indicators of exposure.

There are several principles that should be considered in biomarker development:

• Focus on the disease: Target environmental diseases with a genetic origin, such as asthma, neurodegenerative conditions, and heart disease to drive biomarker development. Identifying priority diseases will narrow down the scope of relevant environmental exposure and genetic measures that will be required to adequately address gaps in knowledge about gene-environment interactions.
• Develop both dynamic and stable response indicators: Metabolomics and genomics are attractive approaches to develop short-term measures of biological response. While these “markers” may prove to be early/sensitive markers of disease, it is unlikely that they will be long-term signatures of response. DNA and protein adducts may provide a longer term “memory” of previous exposures and should be actively pursued. DNA modification (methylation or damage/repair) may also provide long-term responses to environmental forms of stress.
• Biosamples need to be noninvasive: Focus on minimally-invasive biosamples for biomarker development, such as blood, urine, saliva, breath, skin, buccal and nasal cells. It is important to validate these more peripheral markers with organ-specific measures; thus, parallel animal and controlled human exposure studies can provide important data for biomarker validation, including functional characterization.
• Pursue biomarkers first in small-scale studies: To the extent possible, promising biomarkers should be tested (validated) initially in small-scale population studies before application to large-scale studies and programs.
• Consider the biological context: Molecular responsetargets should be developed and validated within a biological framework; that is, the marker must be shown to reflect specific molecular and cellular mechanisms, signaling and response networks and pathways, and complex interconnections and feedback modules that exist at the subcellular, cellular, and organ levels.

Standardized Approaches to Sample and Assay Development. Standardization approaches should be developed and adopted for sample collection, processing, storage, and labeling of molecules. This includes establishing criteria for assessment of technical sensitivity and specificity, data reproducibility and variability. Utilizing standardized approaches will minimize technical variability to improve biological discovery.

Leverage Existing Studies. Existing research studies should be leveraged to enhance the cost- and time-efficiency of access to existing supplies of biological specimens, particularly human specimens that have already been collected and stored in NIH-supported studies and by other agencies.

Biosample and Data Repository. A biosample repository should be developed to support specific projects where shared specimens will be generated, distributed and analyzed across multiple research centers. The repository would include existing biosamples, amassed from existing studies and new samples generated over the course of the program. A repository of laboratory analytical standards to be used in validation of assays and in achieving cross-platform and inter-laboratory harmonization should be adopted. Similarly, a near-term activity should involve aggressively mining existing data sets, from past or ongoing on biomarker studies, to develop new information about potential targets for biomarker discovery, development and validation.

New Approaches to Data Integration. New approaches to integrate biomarker data, across technology platforms, model systems, timescales and spatial dimensions, and with genetic susceptibility factors are needed. Current databasing capabilities are adequate for the storage, access, retrieval, and integration of multiple data sources and types within a single information system; however, specific requirements for information technology and computational methods must complement the research goals and objectives and the types of data to be generated and analyzed.

Program Management. Adopt a research framework that is comprehensive and includes clearly articulated milestones, policies and procedures for data/sample access, publications, privacy/informed consent, and other ethical and legal issues. Public consultation should occur before commencing participant-based research initiatives and establishing research policies. Clear, explicit goals and guidelines and/or requirements in these areas will enhance efficiencies in the research enterprise, and contribute to overcoming potential barriers to rapid, robust progress.

Training in Environmental Genomics. New strategies for training are essential to pursue the opportunities in the emerging field of environmental genomics, a requisite discipline for exposure science. Pre- and post-doctoral training programs with new curriculum development and co-mentorship was strongly endorsed by the workshop participants.

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