BOARD MEETING DATE: April 4, 2003
AGENDA NO. 15

Approve General Work Plan and Criteria for Brain Tumor & Air Pollution Foundation

SYNOPSIS: 

At the February 7, 2003 meeting, the Board approved the establishment of the Brain Tumor & Air Pollution Foundation to support research on the relationship of air pollution exposure on the incidence of brain tumors. Staff has begun the work to establish this Foundation, and the Foundation Board of Directors held its organizational meeting on March 31, 2003. This action is to approve the general workplan and criteria for the Foundation.

COMMITTEE: 

None

RECOMMENDED ACTION:

Approve the general work plan for the Brain Tumor and Air Pollution Foundation.

Barry R. Wallerstein, D.Env.
Executive Officer

Background

At the February, 2003, meeting, the Board approved the establishment of the Brain Tumor and Air Pollution Foundation, and approved an initial transfer of $438,000 from the FY2002-03 penalty revenue to assist in the funding of this Foundation. The Board also directed that the Foundation establish an operating plan, and bring the operating plan back to the Board for approval.

The initial Directors of the Foundation are AQMD Board Members Supervisor Michael Antonovich, Supervisor Jim Silva, and Councilman Hal Bernson, as well as Robert Davidson, President & CEO of Surface Protection Industries. Dr. Keith Black of Cedars-Sinai/Maxine Dunitz Neurosurgical Institute will forego being a Foundation Director to eliminate any potential conflict of interest in the event the Foundation determines to fund research by an entity with which Dr. Black is affiliated. However, Dr. Black will assist the Foundation and provide his invaluable advice based on his expertise in the field of brain tumor research. Dr. Burke will recommend a replacement for Dr. Black on the foundation board in the near future.

The goal of the Brain Tumor and Air Pollution Foundation is to increase understanding of the impact of air pollution on the incidence of brain tumors. The Foundation will support research to determine whether particular components of air pollution are associated with a higher risk of brain cancer, and whether certain segments of the population, such as children, are at greater risk.

Proposal

The Foundation Board conducted its first meeting on March 31, 2003 and adopted a general workplan and a process to determine the research projects to undertake (Attachment 1). The Foundation Board identified several areas for initial research projects. These research areas, recommended by staff and summarized below, were initially developed based on input from physicians and scientists at local universities and medical centers. The number of areas for research and the number of specific projects will be further determined by the level of funding available. Total first year funding of $950,000 will be sought. Staff will evaluate and submit, as appropriate, funding requests to other institutions to supplement AQMD’s contribution. The research areas listed are subject to the amount of available funds.

More detailed research plans within the scope of the research areas identified below are expected in May 2003.  These plans will be presented to the Foundation Board, and the Foundation Board will determine which projects to fund based on qualifications of the research team, relevance and clarity of research plan and cost.

The following are the initial areas for research and suggested actions the Foundation could take.

Epidemiological research

1.	Initial Assessment of Brain Tumor Risk
	A study of a cohort recruited by the American Cancer Society has found an association of particulate air pollution and lung cancer. This is a large database of individuals living in the major metropolitan areas of the U.S that have been followed for about 20 years. The database for these individuals also contains information on other cancer types, such as brain tumors. This existing database on cancer incidence and air pollution levels can be used for an initial assessment of brain tumor risk.
2.	Associations of Air Pollution and Brain Tumor Incidence
	There is also an extensive database compiled by the cancer registries in Los Angeles and other counties. This database can be integrated with past air pollution monitoring data and estimated historical exposures to air pollution levels can be compared with the incidence of brain tumors. This type of study can provide a determination of whether there are any associations between air pollutant exposures and the risk for tumors.

Laboratory studies

3.	Study to Determine if Pollution Exposure Indicators Are Present in Brain Tumor Patients
	Recent animal studies have demonstrated that inhaled small particles can enter the blood stream and cross the blood-brain barrier to enter brain tissue. There are available tissue samples from brain tumor patients that can be analyzed for markers of air pollutants such as particulates, metals, or other substances. This type of study can determine if there are indicators of pollution exposure in brain tumor patients.
4.	Assess Potential for Tissue Changes from Exposure to Air Pollutants
	A recent report indicates that exposure to air pollutants can produce alterations in biochemical markers and lesions in brain tissue. Preliminary studies have found changes in levels of substances related to the inflammatory process in brain tissue of animals exposed to air pollutants. Proposed research would develop animal models to assess the potential for changes in brain tissue that may be related to brain cancer formation in laboratory animals exposed to air pollutants.

Fiscal Impacts

The initial funding for the Foundation’s efforts has previously been approved by the Board and $438,000 of penalty revenue has been transferred from the General Fund to date. Additional first year funding of up to $512,000 will be sought including grant funding from other sources. A maximum draft general budget for the first year funding is as follows:

Brain Tumor & Air Pollution Foundation
Research Project Year-One Budget

Attachment

Attachment 1 - Draft Proposed Work Plan Brain Tumor and Air Pollution Foundation

Mission Statement

The mission of the Brain Tumor and Air Pollution Foundation is to increase understanding of the impact of air pollution on the incidence of brain tumors. The Foundation will support research to determine whether particular components of air pollution are associated with a higher risk of brain cancer, whether certain segments of the population, such as children, are at greater risk, and determination of better prevention or treatment options.

Overview

The Foundation will utilize the scientific expertise in the fields of brain tumors, epidemiology and air pollution and the resources of southern California medical centers and universities to conduct a comprehensive and scientifically rigorous study on the association between air pollution and brain tumors. Brainstorming sessions with researchers from local universities have been conducted, and several areas for potential research have been identified. An extensive data base already exists on brain tumors and good models of air pollution exposure in southern California have been developed. Initial studies would utilize these existing data to investigate possible associations between air pollution exposures and brain tumor incidence. Further, the finding that ultra fine particles can cross the blood brain barrier and enter the brain, and the recent findings of an association between air pollution levels and brain lesions in animals require further investigation.

Proposal for Work Plan

The initial funding for the Foundation’s efforts has previously been approved by the AQMD Governing Board and is currently $438,000 from penalty revenue collected in the first half of FY 02-03, and transferred from the General Fund. An approximately equivalent additional amount may occur from penalty fees collected in the second half of FY 02-03.

This proposal is for consideration by the Foundation Board at its initial meeting on March 31, 2003 to adopt a work plan process to determine the research projects to undertake. Several areas for initial research projects, summarized below, were initially developed in brainstorming sessions of scientists from local universities. The proposed work plan is for the Foundation to solicit proposals for research projects in these areas. The number of areas for research and the number of specific projects conducted will be determined by the level of funding available. The research areas are listed in terms of priority subject to the amount of available funds.

Research proposals that are responsive to the Foundation’s solicitation will be reviewed for technical merit by the Foundation staff with assistance from scientific and medical experts in the field of brain tumors and air pollution. The reviewers will be approved by the Foundation Board. The results of the technical review will be presented to the Foundation Board, and the Foundation Board will determine which projects to fund based on assigned personnel, project design and cost.

The following are the proposed initial areas for research projects the Foundation could undertake.

Epidemiological research

1. Initial Assessment of Brain Tumor Risk

A study of a cohort recruited by the American Cancer Society has found an association of particulate air pollution and lung cancer. This is a large database of individuals living in the major metropolitan areas of the U.S that have been followed for about 20 years. The database for these individuals also contains information on other caner types, such a brain tumors. This existing database on cancer incidence and air pollution levels can be used for an initial assessment of brain tumor risk.

2. Associations of Air Pollution Exposure and Brain Tumor Incidence

There is also an extensive database on cancer incidence compiled by the cancer registries in Los Angeles and other counties. This database can be integrated with past air pollution monitoring data and exposure models to estimate historical exposures to air pollution levels. Such estimated exposures can then be compared to the incidence of brain tumors. This type of study can provide a determination of any associations between air pollutant exposures and the risk for tumors.

Laboratory studies

3. Study to Determine if Pollution Exposure Indicators Are Present in Brain Tumor 
    Patients

Recent animal studies have demonstrated that inhaled ultrafine particles can enter the blood stream, cross the blood-brain barrier, and enter brain tissue. There are available tissue samples from brain tumor patients that can be analyzed for markers of air pollutants such as particulates, metals, or other substances. This type of study can determine if there are indicators of pollution exposure in brain tumor patients.

4. Assess Potential for Tissue Changes from Exposure to Air Pollutants

A recently published report indicates that exposure to air pollutants can produce alterations in biochemical markers and lesions in brain tissue. Preliminary studies have found changes in levels of substances related to the inflammatory process in brain tissue of animals exposed to air pollutants. Proposed research would develop animal models to assess the potential for changes in brain tissue that may be related to brain cancer in laboratory animals exposed to air pollutants.

Additional Background and Significance

Primary benign and malignant brain tumor incidence is estimated to reach 40,000 this year.¹ Malignant brain tumors comprise almost half of these tumors.  The diagnosis of brain tumor is devastating; depending on the location and pathology of the tumor, patients may suffer cognitive impairment and physical disability.  These sequelae may cause not only emotional but financial devastation for the patients and their families.

Environmental and genetic factors have been implicated in the etiology of brain tumors.² The list of potential etiologic factors includes physical, chemical and biological agents. Recently, ultra fine particles were shown to enter the circulation from the lungs and cross the blood brain barrier and accumulate in the brain.^{11, 12}  Additionally, in a study of canines in Mexico City, a highly polluted area, animals were found to exhibit lesions in brain tissue when compared to animals from a less polluted city.¹³

Air pollution is an environmental factor that has been linked to cancer, lung and cardiovascular diseases.  Air pollution contains fine particulate matter and gaseous pollutants caused mainly by combustion emissions. Stringent air pollution regulations limit the concentration of fine particulate matter with a mean aerodynamic diameter of less than 2.5 microns (PM_2.5).³  The relationship between exposure to PM_2.5 and excess mortality is well established. ^4,5,6   Multiple factors are responsible for the toxicity of PM_2.5, the Clean Air Act lists 188 hazardous air pollutants, yet not all causative agents have been identified.⁷ Setting limitations of PM_2.5 concentrations may not be sufficient to reduce cancer risk. 

Lung disease and lung cancer are usually associated with air pollution; however, some scientists found that prolonged exposure to air pollution (bus drivers and tramway employees) resulted in increased risk of developing several other types of cancer, including lung, laryngeal, renal, bladder, skin, pharyngeal, rectal and liver cancers.⁸  There was a standardized incidence ratio (SIR) of 1.6-1.7 for brain cancer.⁸  In other words, more cases of brain cancer occurred than what were expected. The researcher’s sample of brain tumor patients was too small to generalize; therefore, a study with a larger population of brain tumor patients is required. 

In one study of California air pollution, the highest concentrations of hazardous air pollutants (HAPs) were found in urban areas, specifically the Los Angeles Basin, San Francisco Bay Area, and in San Diego.⁷ Researchers calculated hazard indices for target organ systems.  Total hazard indices for central nervous system effects were slightly over 5% for all census tracts and total hazard indices were greater than 1.  For estimated lifetime individual cancer risks, the mean cumulative individual cancer risk was 3.0E^-4, with a maximum of 2.8E^-3 and a minimum of 3.7E^-5.⁷  Individuals living in California, especially the urban areas of Los Angeles, San Francisco and San Diego are at an increased risk for developing cancer.

Molecular markers, also known as biomarkers, have been used to establish mechanisms of action resulting in disease.⁹  Studies have shown that there is a relationship between high chromosomal aberration levels and increased cancer risk¹⁰   In one study of non-smoking bus drivers, exposed to high levels of air pollution, the subjects were found to have high levels of chromosomal aberrations.¹⁰   Biomarkers of air pollution should be studied in brain tumor patients.  

Exposure to air pollution may result in increased brain cancer risk.  Additionally, the interactions between any genetic factors responsible for brain cancer and genotoxic effects of air pollution are not well defined.    There is no published research to date evaluating the impact of exposure to high concentrations of air pollutants in Los Angeles County with genetic factors on brain cancer incidence.  Considering the evidence that increased air pollutants cause increased levels of chromosomal aberrations, which lead to an increased risk of cancer, it would seem appropriate to study demographic, behavioral and genetic factors in brain tumor and control patients in Los Angeles County to determine the impact that air pollution has on brain tumor incidence. 

References 

1. CBTRUS. Statistical Report: Primary Brain Tumors in the United States, 1995-1999.  2002.  Central Brain Tumor Registry of the   United States.

2. Inskip, P. D., Linet, M. S, and Heineman, E. F. Etiology of brain tumors in adults. Epidemiologic Reviews 17(2), 382-414. 1995.

3. Dellinger, B., Pryor, W. A., Cueto, R., Giuseppe, L., Squadrito, V. H., and Deutsch, W. A. Role of free radicals in the toxicity of airborne fine particulate matter. Chemical Research in Toxicology. 14, 1371-1377. 2001.

4. Dockery, D. W., Schwartz, J., and Spengler, J. D. Air pollution and daily mortality: Association with particulates and acid aerosols. Environmental Research 14(10), 1371-1377. 1992.

5. Samet J, Zeger S, Berhane K: The association of mortality and particulate air pollution, Particulate Air Pollution and Daily Mortality.   Cambridge  : HEI, 1995,

6. Laden, R., Neas, L. M., Dockery, D. W., and Schwartz, J. Association of fine particulate matter from different sources with daily mortality in six   U.S.  cities. Environmental Health Perspectives 108, 941-947. 2000.

7. Morello-Frosch RA, Woodruff TJ, Axelrad DA, et al: Air toxics and health risks in   California  : the public health implications of outdoor concentrations. Risk Analysis. 20:273-291, 2000

8. Soll-Johanning H, Bach E, Olsen JH, et al: Cancer incidence in urban bus drivers and tramway employees: a retrospective cohort study. Occupational & Environmental Medicine. 55:594-598, 1998

9. Molecular Epidemiology: Principles and Practices.   San Diego  : Academic Press, 1993,

10. Knudsen, L. E., Norppa, H., Gamborg, M. O., Nielsen, P. S., Okkels, H., Soll-Johanning, H., Raffin, E., Jarventaus, H., and Autrup, H. Chromosomal aberrations in humans induced by air pollution: influence of DNA repair and polymorphisms of glutathione S-transferase M1 and N-acetyltransferase 2. Cancer Epidemiology, Biomarkers & Prevention. 8(4 Pt 1), 303-310. 1999.

11. Nemmar A, Vanbilloen H, Hoylaerts MF, Hoet PH, Verbruggen A, Nemery B. Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster.  American Journal of Respiratory and Critical Care Medmedicine. 164(9):1665-8,2001

12. Takenaka S, Karg E, Roth C, Schulz H, Ziesenis A, Heinzmann U, Schramel P, Heyder J. Pulmonary and systemic distribution of inhaled ultrafine silver particles in rats. Environmental Health Perspectives109 (Suppl 4):547-51, 2001

13. Calderon-Garciduenas, L et al.  Air pollution and brain damage.  Toxicologic Pathology 30(3):373-89, 2002.

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