Strategy

Research Strategy

Management Strategy

Funding Strategy

Information Resources Strategy

NERC was conceived to help meet the increasingly apparent need for information on the respiratory health risks of combined inhalation exposures to complex mixtures of air contaminants.

As we currently implement the Clean Air Act, our environmental air quality regulations focus largely on single pollutants, pollutant classes, and sources, which are reviewed and debated one at a time. As a natural response to this cycle, research on the health effects of air pollution has also largely focused on one pollutant, pollutant class, or source at a time. Multiple pollutants are often considered in epidemiological studies, but only a few of the many actually present in the environment, and usually in the context of their influence on the estimates of effects of the pollutant of current concern. Complex mixtures such as engine emissions, wood smoke, roofing tar fumes, etc., have been addressed in laboratory studies, but the mixture is typically treated as a single exposure material. Although the roles of certain physical-chemical species are sometimes determined (such as the mutagenicity of organic compounds extracted from soot), laboratory studies have neither fully analyzed the atmospheres nor determined the roles of the full spectrum of component species.

Of course, people never breathe one environmental air pollutant, or pollutants from one source, at a time - they are always exposed to very complex, ever-changing mixtures of air contaminants from many sources. High stakes are associated with correctly attributing health effects to the proper air contaminants, or combinations of contaminants, and thus correctly judging both the health-effectiveness and cost-effectiveness of alternate management strategies aimed at controllable pollutants and sources. Paradoxically, as levels of regulated air pollutants fall due to progressive controls, the uncertainty that EPA faces in correctly estimating and effectively mitigating the remaining health effects is growing. The effects of exposures to environmental air pollutants can be difficult to distinguish from the effects of home and workplace exposures. Many pollutants from many sources can affect the same health outcome. Few biological markers can link health effects to specific pollutants. Exposures to combinations of pollutants or sequences of exposures to different pollutants are likely to be more important than we presently understand. Some pollutants can enhance the effects of others. A mixture of pollutants, each within its individually acceptable concentration, could present a combined health risk that is larger than expected, or a risk of a different nature than expected. Health effects could be ascribed to the wrong pollutant or source.

Congress, researchers, regulators, industry, and the public are increasingly aware that the "single pollutant" approach can not ultimately provide an adequate understanding of the true relationship between air quality and health. Despite longstanding awareness of this dilemma, the "pollutant mixtures" problem has largely been avoided due to its great complexity and inertial pressures to continue the historical regulatory-research cycle. There has been little effort to develop research strategies for approaching these problems directly and no solicitations through which to fund the complex, dedicated research necessary to make substantial progress. The Clean Air Act is not the problem; Section 103 gives a clear mandate for research on “complex mixtures” and “combinations” of air pollutants. To date however, this mandate has largely been ignored. At the time NERC was created, there was no other substantive research initiative aimed specifically at developing a foundation of new information serving as a platform for testing the contributions of individual pollutants to the effects of mixtures, testing statistical strategies for dealing with pollutant mixtures, and considering alternate air pollution research and management strategies.

Funding to initiate NERC was designated by Congress in the FY-1998 EPA appropriation. From the outset, it was planned that, while EPA is the most appropriate lead sponsor, support would also be obtained from other stakeholder organizations within and outside the federal government. Today (early 2005), NERC is funded by 15 “Affiliate” sponsors, including three federal agencies, three industry associations, and nine corporations. Other sponsors have provided support at different times during the program, and there is continuous effort to broaden and expand sponsorship.

Strategy

The NERC strategy involves four key interrelated components: a research strategy; a management strategy; a funding strategy; and an information resources strategy.

Research Strategy

The research strategy addresses two interrelated information needs: 1) an exposure composition- and concentration-response database encompassing several different, but overlapping, mixtures of air contaminants; and 2) contemporary head-to-head comparisons of the health hazards of complex source emissions of regulatory relevance. The database will allow statistical analyses of the type that can detect composition-response relationships that persist as the mix of air pollutants changes. Such analyses are severely restricted by the lack of a composition-concentration-response database of sufficient scope, detail, and uniformity. In addition, pair-wise comparisons among exposures will place the relative health hazards of common source emissions into better context. For example, there has never been a detailed direct comparison of the hazards of diesel and gasoline emissions, moreover, there have never been thorough studies of the effects of repeated exposure to wood smoke, street dust, or coal emissions.

Of course, exposure-response data cannot be generated for every possible combination of air pollutants. It is entirely plausible, however, to begin an initiative by producing and analyzing a database encompassing pollutant species contained in a limited number of common source emissions. Doing so will provide a test of the utility of this general approach to the “mixtures” problem, and at the same time ensure that the work will yield substantial benefit by comparing the effects of important source emissions. If the “database” approach proves successful, a foundation will have been laid for expanding the range of pollutants included in the analysis. The 12 exposure atmospheres and 5 general categories of health outcomes listed in Table 1 comprised the original NERC research matrix. Exposures to simulated on-road contemporary (circa 2000) diesel engine emissions and hardwood (oak) smoke are completed. Exposures to simulated on-road gasoline engine emissions (circa 1996 engines using current national average fuel) are underway. Exposures to paved road dust and simulated “downwind” coal combustion emissions are anticipated to follow next. The exposures are prioritized for study and defined as the program progresses; thus, the final list of exposures may differ in number and type from those recommended initially. This allows the program to respond to findings and current issues (e.g., evolving source types and emissions) as the construction of the database progresses.

Table 1. Initial NERC Research Matrix of 12 Exposures and 5 Categories of Health Outcomes (Exposures Not Ordered in Priority)
	Cytotoxicity & Inflamation	Allergies & Asthma	Defenses Against Infection	Heart & Lung Function	Cancer
Gasoline exhaust (on-road, off-road)	+	+	+	+	+
Road dust (paved, unpaved)	+	+	+	+	+
Wood smoke (hardwood, softwood)	+	+	+	+	+
Tobacco smoke	+	+	+	+	+
Cooking fumes (vegetable, meat)	+	+	+	+	+
Coal combustion emissions	+	+	+	+	+

Each exposure atmosphere is studied using a common exposure, analytical, and health assay protocol. Using a consistent protocol, whether or not all analytes or effects are expected for a given exposure, allows the data from all exposures to be combined and analyzed as a single composition-concentration-response database. Each study contributes a “layer” in the database (Figure 1). The combined database will support analyses of the contributions of individual components, physical-chemical classes of components, and combinations of components to the health outcomes across exposures (i.e., as the “mixture” changes). This is primarily a hypothesis-generating strategy, although the underlying general hypothesis is that certain exposure components and/or combinations of components will be shown to most closely co-vary with the presence and magnitude of the different health outcomes. Causality, mechanisms of response, and interactions among specific combinations of air contaminants will remain largely to be confirmed by follow-on hypotheses-testing studies.

Figure 1. The Composition-Response Database Will Consist of
"Layers" of Data from Individual Studies

Animals are exposed to one of multiple concentrations (dilutions) of each atmosphere, along with a clean air negative control group. All exposure levels are selected to fall within the range of plausible human exposures, albeit occupational or “hot spot” exposures at the higher levels. The use of multiple treatment groups allows evaluation of exposure-response trends and provides a view of the shape of the exposure-response curve and some indication of the no-effects level. A “significant” exposure-related effect can thus be defined by a combination of trend tests, multiple comparisons among groups and multivariate analysis of effects of exposure on clusters of health outcomes. The exposures are characterized at the greatest practical level of detail, equivalent, for example, to the speciation in the EPA Supersites program, environmental source apportionment studies, etc. The characterization of exposure encompasses the physical-chemical classes summarized in Table 2 and includes many individual species within most classes.

Table 2. Characterization of Exposure
Particles:	Gases:
Mass concentration	CO
Size distribution	CO2
Number counts	NOx
Morphology	SO2
Size-specific chemistry	HC
Extractable fraction (& OC/EC)	NH3
Mutagenicity of extracts
Particle Extract and SVOC:
Ammonium Sulfate Nitrate Elements	n-alkanes, cycloakanes alkanes Branched alkanes, alkenes Furans, benzofurans Volatile aromatics Phenols (+methoxy) Carbonyls	oraganic acids alkaloids nitrosamines PAHs (+oxy, nitro) Hopanes Steranes Aliphatic alcohols Carbohydrates

Health responses are measured using several animal models and endpoints encompassing the general categories of health outcomes listed in Table 1. The health assays summarized in Table 3 include several endpoints for each outcome type.

The exposure studies are conducted by a multidisciplinary team of nine LRRI and two external investigators who produce, analyze, interpret, and publish data, and four external contractors who perform additional analyses (Table 4). No team member works in isolation; each necessarily coordinates with others. The Study Director, Dr. Matt Reed, has responsibility for day-to-day coordination of study activities. In addition to the standardized study protocol, lung gene alterations are analyzed using microarrays by Dr. George Leikauf, University of Cincinnati . While these analyses are being performed for each atmosphere, the protocol for gene response analysis is exploratory, and thus not sufficiently standardized to be considered part of the “core” protocol. Excess exposure space and biological samples are available to the broader scientific community for ancillary studies on a case-by-case, non-interference, cost-recovery basis, but without charge for exposures and other activities required by the core study protocol.

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Management Strategy

Because of the complexity and multi-sponsor nature of the program, the Center's management approach is a keystone to its success. The management and advisory structure of NERC were established before its research strategy was developed. The Center functions as one of the research programs of LRRI and takes advantage of the unique resources of the privatized, government-owned, LRRI-leased Inhalation Toxicology Research Institute facility. Its management staff and most of its research staff are employees of LRRI. Its Director is also a Vice President of LRRI, which ensures that the Center receives a high level of LRRI top management commitment.

Biosketches of all Center personnel are available on request, and those of LRRI staff can be accessed via the LRRI web site . The Center's Director, Dr. Joe L. Mauderly, has extensive experience in the management of large, long-term, complex, collaborative, and jointly funded research programs and is broadly recognized in the air pollution and health research fields. Dr. Matt Reed is the Study Director of the research comprising the Center's core research matrix, and has general responsibility for coordinating protocols, animal resources, exposures, health assessments, atmospheric measurements, data management and analysis, quality assurance, and report generation. Ed Barr is the LRRI Exposure Operations Manager and manages the design, development, and operation of Center exposure resources. Dr. Jake McDonald is the Center's atmospheric scientist and has responsibility for designing and conducting measurements of the atmospheres. Stephanie Taulbee is the LRRI Quality Assurance Manager and manages the Center's Quality Assurance program. Steve Gaa is the center's data auditor. The Center has a formal Quality Assurance Plan, which is available on this site.

A large measure of the responsibility for developing the Center's research strategy and guiding its operation has been vested in the Center's External Scientific Advisory Committee (ESAC). The ESAC was formed upon initiation of the Center, and was integral to developing the Center's research strategy. By express intent, all Center work is designed in consultation with the ESAC and all major decisions require ESAC approval. Although a range of stakeholder sectors is represented by ESAC membership, the Committee is constituted separately from financial sponsorship and does not function as a representative body. Advice and comment is solicited from all Center sponsors, but sponsorship does not "buy" ESAC membership. Organizations contributing to the Center's support must do so with the understanding that approval authority is vested in the ESAC. The current members of the ESAC are listed in Table 4. Drs. Glen Cass, Georgia Institute of Technology (deceased) and Jon Samet, Johns Hopkins University (emeritus) were members of the original Committee.

The NERC management strategy aims to incorporate the best current thinking and broad consensus into the design of the research. In part, this is accomplished by conducting peer expert workshops to review options and elicit recommendations for key components of the program. This approach has been used to develop the statistical framework of the experimental design, select the health assays for the core protocol, and to select the methods for generating each of the exposures. The workshops are comprised of invited experts, and the ESAC and sponsors have open invitations as well. Summary reports are prepared following each workshop. Based on input from the workshops, NERC management develops specific plans for sponsor comment and ESAC approval.

The Center leverages its investment by encouraging and facilitating collaborative research by other investigators. Considerable financial and human resources are expended to conduct the work described above. The generation and detailed analysis of the exposure atmospheres, and the exposure of animals and collection of biological samples would be very difficult for most research groups to accomplish. There are numerous analytical and health evaluations that could be added to those included in the core protocol. To the extent feasible, the studies are open to complementary research by internal or external investigators on a first-come-first-served, non-interference, cost-recovery basis. In this manner, much ancillary research can be conducted and many exploratory hypotheses can be tested in a cost-effective manner. The range of potential collaborations include:

• Exposure of additional, special-purpose animals or in vitro test systems on a space-available basis
• Provision of biological or exposure material samples
• Measurement of additional (non-core) health endpoints in study animals

The additional costs incurred by these collaborations must be paid from non-Center resources, but costs incurred in the course of planned Center research (e.g., exposure atmosphere development, generation, and analysis) are not charged to collaborators. External scientists are also encouraged to collaborate with NERC scientists to submit complementary research proposals for non-Center funding, based on the use of Center resources.

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Funding Strategy

NERC is funded by multiple sponsors. The accurate, objective assessment of the contributions of individual pollutants, sources, and co-factors to the adverse health effects associated statistically with air pollution is of concern to regulatory agencies, regulated industries, health and environmental advocacy groups, and the public alike. From the beginning, it was envisioned that although EPA is the most appropriate lead sponsor, the funding of NERC would be most appropriately shared among multiple federal, state, and private stakeholders. LRRI's initial commitment to the program included agreement to work toward developing the necessary support from a broad range of sponsors. Federal organizations supporting NERC and individual non-federal organizations contributing a minimum of $25,000/year are designated as Center “ Affiliate Sponsors ”. Lesser contributions are welcomed, but do not qualify for Affiliate status. Many Affiliates provide larger amounts. Non-federal support is received by LRRI, a not-for-profit, 501(c)(3) organization, as tax-deductable donations and designated solely for NERC use. Affiliates welcomed to all Center meetings and workshops, and advice and comments are sought from all. Affiliate status provides neither membership on the ESAC nor a representative portion of control over Center activities. This arrangement ensures objectivity in the conduct and reporting of research and prevents the work from being brought to a standstill by conflicting sponsor viewpoints and agendas. Affiliates have continuous access to the status and results of NERC research, including annual ESAC/Affiliate meetings and prepublication copies of papers accepted for publication.

Information Resources Strategy

A searchable public database of literature citations pertaining to the exposures and health effects under study by the NERC is maintained on the Center's web site ( Information Resources ). The database contains citations from bibliographic services, pre-electronic database literature (i.e., pre-1980s), and federal agency technical reports. Users access this information by either a user-directed search (i.e., entering search terms), or by viewing or downloading prepared lists of citations (topical reports). The information is organized by categories replicating the cells of the research matrix shown in Table 1. The database is updated annually, and contains over 22,000 citations.

Center staff continually maintain and update the web site and its information resources, and respond to inquiries from users. Limited document retrieval services are provided at no cost. Additional fee-based information retrieval services and e-mail literature updates are provided by the LRRI library, which can be contacted accessed via the NERC web site. These services are self-supporting and are not provided using Center funds.

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