The existence of the PM Center and Supersite will clearly enhance the activities of the EARC. There will be greater interaction with outstanding scientists in toxicology, dosimetry, exposure, and epidemiology. There will be additional resources for the EARC, especially in the areas of analytical chemistry, exposure assessment and biostatistics. The PM Center will benefit dramatically from the NIEHS Center in a number of crucial areas. The research that has been proposed in the PM Center has a particularly important gap that collaboration with this Center can address - the role of gene-environment interactions in the causation of health effects associated with exposure to PM. Scientists from the EARC will work with investigators from the Adult Cancer and the Respiratory Effects Research Cores to develop research projects that address genetic and genetic epidemiologic issues in the causation of asthma and other related chronic respiratory health effects.

In addition to the exposure-related research described below, there are other important interdisciplinary activities between the NIEHS Center and the PM Center. Dr. John Peters is the Director of the Epidemiology Core of the PM Center and will direct research across Cores on 1) the study of traffic density patterns on health effects associated with airborne particulate matter; and 2) bioaerosols. EARC members Drs. Colome, Froines and Avol are also participants in this research effort. Dr. Arthur Winer from the EARC participates with Dr. Peters and Center Respiratory Effects Core colleagues in the Children's Health study. The Exposure Assessment and Analytical Facility Core is now a joint Core between the two Centers.

Drs. Froines and Hinds and Mr. Avol attend the monthly Executive Committee meetings of the NIEHS Center. Dr. Froines, Hinds, Peters, and Gauderman attend the monthly PM Center Executive Committee meetings. Research priorities are defined at the two Center Executive Committee meetings as well as at weekly EARC/PM Center meetings.

The research described below relates directly to exposure assessment, but Dr. Froines and others in the PM Center will be developing an extensive toxicologic research program that will be linked to the exposure assessment effort especially through the use of the particle concentrator. The animal toxicologic studies undertaken as part of the particle concentrator effort will be coupled with investigations to characterize PM, so that the research is intimately linked. The findings from this research will be used to define epidemiologic research priorities within the PM Center and SCEHSC. Exposure assessment research carried out under the joint auspices of the PM Center and the NIEHS Center will include several areas:

• Aerosol Characterization
• Ultrafine Aerosol Studies
• Characterization of Other Aerosol Constituents (PAHs, Metals, Oxidants)
• Aeroallergen Studies
• Personal Exposure studies
• Exposure Modeling and Trajectory Aerosol Modeling
• Traffic density as a means to study mobile sources

Aerosol Characterization, Ultrafine Aerosol Studies and Characterization of Other Aerosol Constituents include the development of a mobile Particle Instrumentation Unit (PIU) that will be used for mechanistic aerosol field studies as well as studies in this and other Research Cores that require state-of-art PM measurements. Other studies within this area include characterization of ambient ultrafine aerosols prior to planned toxicologic studies.

Specific projects in the category of PM Characterization provide the information that is needed to understand the relationship between PM sources and receptors, as well as providing insight into the factors that affect the spatial and temporal variability of PM characteristics. These projects are: 1) Comprehensive characterization of Particulate Matter in the Los Angeles Basin (LAB) and correlations between particle size distribution, chemical composition and gaseous co-pollutants; 2) Determination of the occurrence, frequency and prevalence of PM2.5 sub-modes in different locations of the LAB; 3) Study of PM formation and growth mechanisms in different locations of the LAB; 4) Determination of the seasonal and spatial variation of ultrafine, accumulation and coarse PM in the LAB and their relation to sources. Modeling efforts will include trajectory aerosol modeling, regional exposure modeling, the SMOG air quality model and the REHEX Regional Exposure Model. The study on mobile sources estimates exposure to and examines the influence of mobile source emissions on respiratory effects in the participating schoolchildren using information on traffic density and proximity of roadways.

This project represents an extension and continuation of earlier described work on exposure assessment of multiple chemical agents. 1,3-butadiene (BD) and styrene (ST) are activated by cytochrome P450 systems and deactivated by glutathione conjugation and hydrolysis, suggesting interactions may occur in humans exposed to such mixtures. Previous studies from CIIT have demonstrated that the interactions occur in mice in vivo exposed to the mixtures and suggested the deactivation pathways were affected to a larger extent than activation process. The project seeks to demonstrate the importance of metabolic interactions during each of the activation and deactivation pathways and how these interactions determine the outcome of chemical interactions. To achieve this goal, three aims of this research will be pursued:

• To determine how BD affects the biotransformation of ST to styrene oxide (SO) and how ST influences the oxidation of BD to butadiene monoepoxide (the interactions along the activation pathways);
• To determine how SO interferes with glutathione conjugation and hydrolysis of butadiene epoxides and how butadiene epoxides affect SO deactivation (the interactions along deactivation pathways);
• To integrate the interactions along the BD-ST activation and deactivation pathways into cohesive toxicokinetic model(s) to predict synergistic, antagonistic, or independent effects of chemical mixtures.

Part of the first aim has been completed. In this project, we examined the interaction between ST and BD in terms of the formation of their reactive metabolites. The experiments used rat liver microsomes, incubated in a closed atmosphere containing air or a mixture of air and BD. Both ST and BD were oxidized to the corresponding epoxides whose presence could be detected when epoxide hydrolase was inhibited by cyclohexene oxide (CO). A concentration dependent decrease in SO was noted over an atmosphere of BD varying from 5000 to 50000 ppm. Under these conditions, inhibition of SO by BD ranged from 24 to 70 %, with an IC50 of 8900 ppm. These results show that the methodology developed for study of the interaction has been developed and that BD does inhibit ST metabolism. Experiments to determine the effects of ST on BD metabolism are currently being performed. Aims 2 and 3 will be carried out upon completing the remaining task of Aim 1. We anticipate developing relationships with Dr. Ross and his colleagues in the Adult Cancer Core because of their interests in the importance of genetic polymorphism in bioactivating enzymes and detoxification processes. We consider the potential for gene-environment interactions important in understanding the interactive relationship between butadiene and styrene. This research will also require interaction with the Analytical Facility Core.

In addition to studies of toxicokinetic modeling researchers in the EARC will continue to conduct research in the areas described above which are separate from the PM Center research. In addition to linking with scientists interested in gene-environment interactions and interindividual susceptibility EARC faculty will also interact with members of the Adult Cancer Research Core to investigate issues of biotransformation and bioactivation of PAHs especially with the formation of quinones, nitro PAHs and other polar compounds capable of acting as adjuvants of asthma and lung carcinogens. Dr. Froines will specifically interact with members of the adult cancer core on issues of DNA methylation and carcinogenesis. Drs. Avol, Winer, and Colome will continue to provide exposure assessment expertise to the Respiratory Effects Research Core on the Children's Health Study and other related investigations described in that section.

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The State of California has determined diesel particulate is a human lung carcinogen, but the issue remains controversial especially with respect to the risk assessment. There is also general recognition of the importance of non-cancer health effects associated with diesel exposure. In a recent meeting on research priorities sponsored by the California Air Resources Board (ARB), there was keen interest in a number of research areas associated with diesel particulate, including the role of diesel in the exacerbation of asthma, the identification of susceptible populations, the identification of specific causative agents associated with a range of health effects, the need for improved exposure assessment in epidemiologic studies of diesel, and the requirements for improved study design and inclusion of biomarkers into the assessment of exposure and health outcomes. The EARC will take the lead to develop new research agendas associated with diesel that will involve the entire Center.