Molecular Mechanisms and Models of Exposure

1. Molecular Mechanisms and Models of Exposure *The word pombe means beer in Swahili, and this yeast was originally isolated in millet beer from eastern Africa.

2. Research Translation Core Applying toxicogenomic models of exposure and molecular biomarkers/biosensors to new systems for detecting, assessing and minimizing the effects of toxic substances on human and environmental health. Requires the following components: Partnering with government agencies; Technology transfer; and Communicating with broad audiences. Must also discuss how the Research Translation Core will interact with the other research projects and cores in fulfilling the goals of this core.

3. Accountability The NIEHS considers research supported by the SBRP to be an accountable enterprise. This accountability derives from the supposition that the evolution and maturation of hypothesis-driven basic research leads to increased opportunities for the translation of results into applied, "product-oriented" research directions. It is this evolution combined with the integration of biomedical and non-biomedical research within a thematic framework that allows for environmental synthesis and its application to real-life problems facing the nation's cleanup efforts. The knowledge gained through these efforts, ultimately, should reduce the burden of human illness and dysfunction from environmental causes.

4. Community Outreach Core Integrating Superfund-related science and Native cultural traditions for equitable environmental stewardship of Indian Reservations: A Tribal Regional Workbench approach • SBRP defines community outreach to be "extending support or guidance to communities, community advocates or community organizations living in proximity to or affected by hazardous waste sites." Community outreach activities should be done in conjunction with the EPA, the ATSDR • o Sponsoring short courses or workshops • o Increasing access to relevant information and serving as a resource • o Education on health and technical issues • o Establishing collaborative projects among communities, investigators and other colleagues to address environmental problems (e.g., partnering with tribes in determining exposure pathways specific and relevant to their traditional and cultural practices).

5. International Conference: Biomarkers for Toxicology and Molecular Epidemiology, New Tools for 21st-Century Problems The National Center for Environmental Health/Agency for Toxic Substances and Disease Registry (NCEH/ATSDR) March 15-17, 2004, in Atlanta, Georgia. Examine ways that cutting-edge biotechnology/molecular tools may be applied to several public health problems through technology transfer. Discuss the latest developments in biosensor and other new analytical technologies that can be utilized for rapid, field-usable exposure assessments of environmental chemicals as well as for chemical terror agents. Evaluate the latest developments in the application of molecular "omics" technologies (genomics, proteomics, and metabolomics). These biomarker classes can be used to evaluate early responses to toxic agents such as arsenic in drinking water, which is a global public health problem that affects the United States and many other countries. Examine these new molecular tools in relation to populations at special risk for toxicity from chemicals (e.g., children). Attendees will seek to determine ways that these modern tools can be used to provide improved risk assessments for protecting children against environmental chemicals. Our Outreach Core will be presenting at the Geospatial Research, Analysis, and Services Program of NCEH/ATSDR during May 2004

6. Seminar on Biosensors for Environmental Monitoring ("Risk-e-Learning" Web-Based Seminar, March 16th, sponsored by the NIEHS SBRP and the EPA Technology Innovation Program). • Drs. Bruce Hammock and Michael Denison from the University of California-Davis will present their work in the development of miniaturized, fast, sensitive bioassay systems for use in environmental research and monitoring at hazardous waste sites. Dr. Ian Kennedy, also from UC-Davis, will discuss his advances in nanotechnology and the use of MEMs (Micro Electro Mechanical system) fabrication techniques to make a micro-sized instrument for optical detection of trace amounts of chemicals in aqueous solutions.One of the goals of SBRP is the development of methods and technologies to detect, assess and evaluate the effects of toxic substances on human health. Conducting the studies needed to obtain such information requires a staggering number of analyses. However, analytical costs often preclude running the number of samples required. To address the issue of high analysis costs for environmental monitoring and the need for markers of exposure and their analysis, these researchers have developed immunochemical methods of analysis and other integrated immunochemical techniques for monitoring toxic substances in humans and the environment. • The advantages of immunoassay include sensitivity, selectivity, speed of analysis cost effectiveness and adaptability. They can be used to monitor individual chemicals, metabolites or bound species. Immunoassay is not a replacement for GC or HPLC, but is an important tool for the analytical chemist and can provide a cost-effective alternative.

7. The NIEHS is has expressed interest in the exposure assessment topics below. We are developing partnerships with regionally-based organizations that could greatly benefit from advances along these lines:EXPOSURE ASSESSMENT • Use of biomarkers of exposure and effect or biological samples in site-specific decision making • Value of information provided by measured biomarkers of exposure, and methods of increasing their value • Integrated measures of dose, does the biomarker really reflect exposure from multiple routes and multiple media? Scientific approaches to test this hypothesis • Communicating risks: reconciling the "stories" of environmental measurements, biological measurements, and modeled outcomes • Utilization of advanced technologies for exposure assessment • Nanotechnology and other advanced technologies for continuous site monitoring Biomarkers of Environmentally Associated Disease: Technologies, Concepts, & Perspectives Written by Samuel H. Wilson , William A. Suk , Bergman , Berwick , Perry Blackshear Published by CRC Press (19 June, 2002)

8. The new knowledge gained from SBRP model animal research can be applied to development toxicology in at least three important ways: In developing more effective assays to test for environmental toxicants In assessing the risks of known toxicants In investigating toxicological mechanisms, the understanding of which will allow developments of new therapeutic approaches to toxicant-induced defects. Source: National Research Council (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment Committee on Developmental Toxicology, Board on Environmental Studies and Toxicology. Washington, DC: National Academy Press. Thus far, with transgenic mice, “little use has been made of sensitized strains and reporter strains to improve toxicant detection and to learn more about mechanisms of toxicity.” (p. 187) Wen Xie and Ronald M. Evans THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 276, No. 41, Issue of October 12, pp. 37739–37742, 2001. “The humanized mouse system represents a major step toward generating a humanized rodent toxicologic model and thus provides an advanced way to explore the interface between the environment and the human genome. Dr. Karin: Develop transgenic mice and cell lines that will be highly sensitive to chemical induced oxidative stress. Dr. Tukey: Developing animal models and cell lines to screen for AhR specific environmental contaminants.

9. Figure 1 (Adapted from DeCaprio, 1997); cited in Funding Opportunities Application of Biomarkers to Environmental Health and Risk AssessmentFY 2004 Science to Achieve Results (STAR) Program. EPA’s SPECIFIC AREAS OF INTEREST EPA, through the STAR program, is interested in supporting research that provides validation, interpretation and/or application of currently known biomarkers. Of special interest is the use of multiple biomarkers that can fill knowledge gaps across different points of the exposure-dose-effect continuum and/or that can be applied in a clinical setting. Any of the following areas are of interest: • Animal or epidemiology studies that explore the relationship between biomarkers of exposure and measures of subclinical disease (early biological effect or altered structure/function). Additionally, these studies could be expanded to explore the relationship between the subclinical disease measure and the actual clinical disease. • Mechanistic studies (e.g., using genomics or proteomics) of toxicant response linked to clinical disease. For example, the identification of the functional relevance of proteins where genetic polymorphisms have been found to modify the effect of an environmental exposure on a disease endpoint. • Studies to validate the utility of biomarkers for use in large population studies (e.g., reliability, predictive value, sensitivity, specificity, affordability, applicability to the general population and susceptible subpopulations).

10. The NCT aims to use and promote toxicogenomics as a means to guide federal agencies and legislators in developing guidelines and laws that regulate the levels of various chemicals in the environment. This knowledge will reduce the likelihood of needless and expensive over-regulation as well as potentially dangerous underregulation of environmental toxicants, as new guidelines will be based on defensible scientific standards and information rather than on estimates and educated opinions. The NCT is currently doing the groundbreaking research needed to develop and demonstrate the techniques that will become tomorrow’s routine testing methods in toxicogenomics. In the near future, toxicogenomics will likely have a significant impact on three key areas of human health: risk assessment, exposure assessment, and understanding human susceptibility to disease. http://www.niehs.nih.gov/nct/nctpub.pdf

11. The National Academies National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council Calls for the development of “Integrative Science,” –science committed to bridging barriers that separate traditional modes of inquiry.

13. Identifies four interlocked, components of sustainability science Highlights the REGION as the most amenable geographic scale for integrating theory and practice Source: National Research Council (1999) Our Common Journey: A Transition Toward Sustainability.

14. RWBC Mission: Create innovative research-learning partnerships, planning support systems, and educational tools to enable sustainable city-region development. More than a Web site! • Multidisciplinary conceptual framework for sustainability science • Federated network for information integration and knowledge sharing, through collaborative projects • Service learning and workforce development opportunities for students (internships) • Ethics, research methods and the philosophy of science (guides)

15. University of California, San Diego _ Superfund Basic Research Program_ Urban Studies and Planning Program– San Diego Supercomputer Center – Center for U.S.-Mexican Studies– SIO, Cal(IT)2, Libraries, Medical School San Diego State University– Graduate Program in City Planning – Department of Geological Sciences- Ed.Center on Computational Science and Engineering Mexican Academic Institutions– CICESE – COLEF (El Colegio de la Frontera Norte) Non-profit organizations– TELESIS- San Diego Baykeeper, and Ja Jan Coalition- San Diego River Park Foundation- Conservation Biology Institute- Association of Collegiate Schools of Planning - Global Planning Educators Association Network Government Agencies– INFORMATICA (A Municipal GIS Institute of Tijuana)– SANDAG, County of San Diego, City of San Diego– San Diego Regional Water Quality Control Board Industry– Industrial Environmental Association (IEA)- Earthstar Geographics, Solid Terrain Modeling A Federated Network of Partners

16. San Diego Regional Water Quality Control Board Mayor of San Diego SANDAG (SWG_RCP, indicators, tribal, Border 2012) EPARegion 9 U.S. Environmental Protection Agency (Eugenia, Border Team, Superfund/Tribal contact), EPA science and science policy San Diego River Conservancy Camp Pendleton (Superfund) San Diego Baykeeper/ Ja Jan Coalition Tribal letters (Campo EPA, NTEC, David connection?) TELESIS (evaluation) UCSD Tech Transfer Office Edenspace San Diego Environmental Professionals Association Industrial Environmental Association CICESE/ COLEF SEMARNAT Research Translation and Community Outreach Partners

17. San Diego-Tijuana City-Region Sustainability Science + New Regionalism + Information & Visualization Technology + Ethics and Env. Justice

18. Regional Science and Technology for Sustainability Workshops Africa Nov. 13-15, ‘01 Abuja, Nigeria Asia Feb. 4-6, ‘02 Chiang Mai, Thailand Europe Feb. 27-March 1-6, ‘02 Bonn, Germany Latin America March 4-6, ‘02 Santiago, Chile Integration and Synthesis May 21-24, ‘02 Mexico City, Mexico N. America March 24-25, ‘02 Ottawa, Canada Series of regional workshops around the world designed to broaden and deepen an agenda for science and technology for sustainability. Network for Science and Technology for Sustainability Corell, Robert. 2002

19. Driven by increasingly influential legislation and agreements at the European and International levels, sustainable development has, since the late eighties, emerged as one of the core elements of planning policy and practice. The metropolitan or "city-regional" scale is now widely regarded as the most appropriate scale for strategic planning.

20. . Equity and Urbanization along the U.S.-Mexico Border: The Prospect of Sustainable City-Regions • The Regional Workbench Consortium (RWBC): A federated research and learning network image source:http://www.jpl.nasa.gov/srtm/california.html#PIA03330 The border region—a 2000-mile-long, 125-mile-wide strip extending from the Pacific Ocean to the Gulf of Mexico—was scarcely inhabited at the beginning of this century. The total population which now exceeds 11.8 million—6.3mUS, 5.5mMexico (up from only 1 million in 1960) is expected to grow to 19.4 million by 2020. Population in the San Diego-Tijuana city-region is expected to increase from ~4.2M people in 2002 to ~6.4M by 2020; GRP 1999: San Diego ($104B) Baja Coastal ($16B); Per-capita water usage per day, Baja Coastal = ~ 57 gallons, San Diego = 200 gallons SDCWA (2000).

21. Binational Conference 2000 NIEHS interest in the the U.S.-Mexico Border

22. MISSION STATEMENT As a partnership among federal, state, local, and U.S. tribal governments, the mission of the Border 2012 Program is: To protect public health and the environment in the U.S.-Mexico border region, consistent with the principles of sustainable development. Border residents suffer disproportionately from many environmental health problems, including water-borne diseases such as hepatitis A and respiratory problems such as asthma. The elderly and children are most at risk. Tribal communities and residents of some unincorporated communities also are at greater risk because of inadequate or non-existent water supplies.

24. The U.S.-Mexico border region is shared by two nations, ten states (four in the U.S. and six in Mexico), and 64 municipalities (39 in Mexico and 25 in the U.S.). There are 26 U.S. federally recognized Native American tribes in the border region, which range from 9 to 17,000 members.

25. U.S. / Mexico Border Region Mapping Gateway • TELESIS internet-based mapping services provide access to public health, epidemiological, demographic, environmental, topographic, and imagery information describing the health conditions along the United States/Mexico Border Region and selected state pairs. In partnership with our SBRP Outreach Core, this work was presented, by invitation, at the annual SBRP conference this year. Integrating PerspectivesNov. 9 – 12, 2003Dartmouth CollegeHanover, NH

26. Partnership with TELESIS

27. May 29, 2003 RWBC EXPO

28. RWBC hosting SANDAG’s Regional Planning Committee, May 5, 2003

33. Outreach to the Public UCSD-TV documentary series, On-line interactive narratives

34. Federated project data base *Biosphere*Hydrosphere*Lithosphere*Atmosphere*Humans as components of ecosystems

35. The Research Translation Core will promotes greater understanding and application of biomarkers, biosensors (biomolecules/nanoparticles), bioremediation, phytoremediation and mouse toxicologic models. To move SBRP research from bench to demonstration to commercial use, the Core will help translate the development of new cell lines, transgenic animal models, bioassays, and biomolecular detection systems into applications for exposure monitoring and risk assessment (e.g., new methods of testing for toxicants in water/soil/sediment samples). Through tech transfer and commercial partnerships, SBRP advances in transgenic bioremediation and phytoremediation technologies will promoted as new biological systems/tools for the environmental restoration of contaminated water, soil and sediments (e.g., transgenic plants that can bioaccumulate heavy metals, bacterial methods to detoxify heavy metals). Promising advances in nanotechnology will spur cross-project collaboration in multidisciplinary efforts to create new fieldable types of biomolecules/nanoparticles that can be used as biosensors for toxin detection. RESEARCH TRANSLATION CORE

36. Research Translation Core AIMS Applying toxicogenomic models of exposure and molecular biomarkers/biosensors to new systems for detecting, assessing and minimizing the effects of toxic substances on human and environmental health. Transfer SBRP research and technology into public and private sector applications that can improve the detection, assessment and remediation of Superfund toxicants (e.g., molecular biomarkers, biosensors/nanoparticles, bioremediation, phytoremediation and mouse toxicologic models). Create a communications network that interactively relates SBRP research findings to the needs of regional, state and federal government agencies charged with protecting human health and the environment-- including the San Diego Regional Water Quality Control Board, City of San Diego, County of San Diego, San Diego Association of Governments, EPA, Camp Pendleton, San Diego River Conservancy, and SEMARNAT (Mexico’s EPA). Continue building our SBRP Regional Workbench Consortium’s (RWBC) Web site. Augment the RWBC’s collection of toxicant and mitigation data by digitally converting paper-based historical archives, federating on-line distributed databases, and mapping water quality samples collected by science-based citizen groups (Baykeeper, Ja Jan Coalition, San Diego River Park Foundation).

37. Research Translation Core AIMS (cont.) Applying toxicogenomic models of exposure and molecular biomarkers/biosensors to new systems for detecting, assessing and minimizing the effects of toxic substances on human and environmental health. In partnership with UCSD’s Office of Technology Transfer (TechTIPS), organize technology showcases, entrepreneurs/innovators forums, intellectual property awareness seminars and educational workshops that will invite and attract both academic and industry representatives—thereby fostering the commercial development and utilization of innovative SBRP technologies. Communicate to broad audiences through periodic workshops; short symposia; participation in regional, national and international conferences; and web-based methods including on-line geographic information systems (GIS), interactive narratives and 3D visualization. Also develop more traditional communication tools including the translation of complex research findings into print and materials intended for the lay public based on communication best practices.

39. Camp Pendleton Superfund Site • The Marine Corps has nine known areas of contamination. Waste generation operations at this site include maintenance and repair of vehicles (trucks, tanks, and aircraft); landfill operations; waste disposal areas, such as scrap yards; and fire fighting drill areas. The base contains wetlands, streams, and rivers which feed into the Pacific Ocean. This land is the only remaining undeveloped area between Los Angeles and San Diego. • Groundwater and soils are contaminated with volatile organic compounds (VOCs), spent oils, fuels, polychlorinated biphenyls (PCBs), pesticides, metals and herbicides. Though groundwater provides drinking water to the entire installation, the current drinking water supply is within drinking water standards.

40. The Department of Toxic Substances Control, or DTSC, protects California and Californians from exposures to hazardous wastes. More than 1,000 scientists, engineers and specialized support staff work in nine offices statewide. DTSC is a department of the California Environmental Protection Agency, or Cal/EPA.   • An estimated 90,000 properties throughout the State - including former industrial properties, school sites, military bases, small businesses and landfills - are contaminated, or believed contaminated, with some level of toxic substances. Some of these are "brownfields," sites that often sit idle or underused, contributing to both urban blight and urban sprawl. • DTSC cleans-up or oversees approximately 220 hazardous substance release sites at any given time and completes an average of 125 cleanups each year. An additional 250 sites are listed on DTSC's CalSites database of properties that may be contaminated. Expediting cleanups is an important goal of the program, and a series of "Brownfields" initiatives support that effort. • San Diego Field Office 9174 Sky Park Court, Suite 150

41. OEHHA’s mission is to protect and enhance public health and the environment by scientific evaluation of risks posed by hazardous substances. • OEHHA’s visionTo be California’s leading scientific organization for evaluating risks to human and ecological health.” • I contacted OEHHA’s Chief of Integrated Risk Assessment (David Seigel)

42. Southern California Coastal Water Research Project The SCCWRP is a joint powers agency focusing on marine environmental research. An important part of our mission is to ensure that the data we collect and synthesize effectively reaches decision-makers, scientists and the public. The world-wide web provides us a new opportunity to achieve this goal. A number of our annual reports are now on-line and key-word searchable. Bight’03 Southern California Regional Marine Monitoring. More than $31M is spent each year on monitoring in the southern California Bight (SCB), but most of this effort is focused on site-specific assessments. Time and again, however, resource managers have recognized the need to develop management strategies for the entire SCB in order for their site-specific management to be successful. The Southern California Coastal Water Research Project (SCCWRP) is helping to address this need by coordinating cooperative regional monitoring efforts. The most recent of these efforts is taking place right now and is referred to as Bight’03.

43. COMMUNITY OUTREACH CORE

44. Community Outreach Core: AIMS Integrating Superfund-related science and Native cultural traditions: A Tribal Regional Workbench approach to enabling equitable environmental stewardship of Indian Reservations • Build a Tribal Regional Workbench Web site in collaboration with the Campo Indian Reservation (San Diego) and the National Tribal Environmental Council’s Superfund Program. The aim is to help build Tribal capacity to negotiate with entities of regional governance (where regional plan-making is underway to deal with hazardous waste management, water quality regulations, land conservation, economic development, etc.). • Share SBRP-generated knowledge and tools for exposure monitoring, risk assessment, and environmental restoration (e.g., new methods of testing for toxicants in water/soil/sediment samples and phytoremediation) with Tribal communities affected by hazardous waste sites and transboundary flows of toxicants (including across the U.S.-Mexico Border). • Sponsor a set of regional workshops to improve the Tribal community's awareness and understanding of biomarkers, bioremediation and environmental health issues in ways that are sensitive to traditional and cultural practices. This will involve UCSD faculty as well as partners from the USEPA Office of Environmental Justice; EPA Border 2012; Environmental Justice Resource Center at Clark Atlanta University; Indigenous Environmental Network; Agency for Toxic Substances and Disease Registry (ATSDR) Office of Tribal Affairs (OTA); EPA Office of Prevention, Pesticides, and Toxic Substances (OPPTS); EPA Office Pollution Prevention & Toxics Tribal Environmental Network; and the Forum on State and Tribal Toxics Action (FOSTTA).

45. Community Outreach Core: AIMS (cont.) Integrating Superfund-related science and Native cultural traditions: A Tribal Regional Workbench approach to enabling equitable environmental stewardship of Indian Reservations Host a national gathering of tribal leaders and scientists on the theme of "Cross fertilizing science and tribal wisdom in environmental stewardship." Develop a model or a set of “best practices” for knowledge production, consensus-building, collaboration, and policy-making among tribal leaders, tribal and state EPAs, and the federal EPA. Create new approaches to doing science and environmental research—new epistemologies that challenge the divide between Western science and traditional Native systems of knowledge. Communicate data, maps, and stories to tribal leaders and agency officials via workshops, conference, and other public presentations. Co-author a series of papers, articles, and other publications with Tribal and other partners, in the spirit of broadly disseminating the lessons learned and some of the stories we may gather. The Community Outreach Core will facilitate internship and field research opportunities for graduate and undergraduate students at the university and will also include a plan specifying how we will measure milestones and outcomes. We anticipate this effort becoming a national model for interdisciplinary, technology-based participatory research among scientists, social scientists, and diverse publics.

46. San Diego County has more Indian reservations than any other county in the United States. Total land holdings are just over 124,000 acres, or about 193 square miles of the 4,205 square miles in San Diego County.  There are 20,000 Native Americans living in San Diego County. Indian reservations in San Diego County

47. Over 430 NPL sites are on, adjacent or within 50 miles of Indian Lands. Transboundary impacts of superfund toxicants affect Tribal lands (reservations, allotments, trust lands, resources & populations). Tribes may have rights - i.e., religious freedom, treaty uses, treaty rights and traditional and customary areas that extend many miles beyond Indian lands. Tribes should be involved in decisions about sites that may impact their resources. Open government to government communication is essential. Developing relationships with EPA, State, and Tribal officials is necessary. Tribal consultation and Tribal involvement needs to happen early and often. Currently, Tribes have no authority to list or delist a site on the NPL. This poses a problem when a state governor will not concur or list a site, or if State or Federal governments are Potentially Responsible Parties (PRPs). Tribes strongly advocate for the development of site hazard ranking, assessment and cleanup criteria that protect Tribal Traditional Lifeway activities, including the use of Tribal resources for cultural, subsistence and ceremonial purposes. Superfund is an important issue for Tribes

48. Tribal Perspectives on Superfund2003 National Site Assessment SymposiumCherokee Nation, by Jason White Tribal Risk Assessment Risk assessment must account for unique ways tribal members use watershed resources for food, recreation, & cultural & ceremonial purposes. Tribal cultural values and environmental concerns may not be adequately addressed in risk assessment protocols.

49. National Tribal Environmental CouncilSuperfund Project, Tribal Recommendations The goal of the Tribal Workgroup is to make recommendations on how to improve the involvement of tribes in the Superfund program. Tribal perspectives on Superfund Priorities Abstract from the EPA's 2003 National Site Assessment Symposium The Agency for Toxic Substances and Disease Registry (ATSDR)Office of Tribal Affairs (OTA) OTA assists with tribal-specific environmental health needs resulting from exposure to hazardous waste sites and pollution. EPA Office of Prevention, Pesticides, and Toxic Substances (OPPTS) Tribal Strategic Plan, 2003-2008 Federal Water Quality Standards for Waters in Indian Country EPA Office Pollution Prevention & Toxics Tribal Environmental NetworkForum on State and Tribal Toxics Action (FOSTTA)EPA Tribal Pesticide ProgramEPA Tribal Bioassessment and Biocriteria Programs The American Indian Environmental Office (AIEO)Border 2012 Tribes