The Health Effects Institute

Update - Spring 2000

CONTENTS

HEI Issues Report on Cardiac Effects of Exposure to Particulate Matter
HEI’s Strategic Plan 2000–2005 Targets Mixtures, Accountability, Technology
Looking Forward, Looking Back: Reflections as HEI Enters its 20th Year
HEI Issues Butadiene Reports
Top European Union Official to Keynote Annual Conference 2000 in Atlanta
HEI Sponsors Workshop on Mobile Source Air Toxics
Brian Leaderer Appointed to HEI Review Committee
HEI Board Approves Special Committee on Emerging Technologies
HEI Senior Staff Promoted
An HEI Departure
HEI Publications Take on a New Look

HEI Issues Report on Cardiac Effects of Exposure to Particulate Matter

In February, the Research Report Mechanisms of Morbidity and Mortality from Exposure to Ambient Air Particles, by Dr. John Godleski and colleagues at the Harvard School of Public Health, was published on HEI’s website. HEI supported this study (which will appear in hard copy in March) to determine if normal dogs and dogs with cardiopulmonary conditions exposed to particulate matter (PM) showed changes in cardiac, pulmonary response, or inflammatory parameters. The study was an initial effort to test whether there may be a plausible biological mechanism to explain findings from epidemiologic studies which suggest an association between low levels of fine particulate air pollution and an increase in cardiopulmonary morbidity and mortality.

Godleski and colleagues exposed dogs via inhalation to concentrated ambient particles (CAPs) derived from Boston air with a particle concentration up to 1 to 16 times the level of the current National Ambient Air Quality Standard (NAAQS) for PM2.5. CAPs’ effects were measured in 12 normal dogs. In 6 of the animals, the investigators induced coronary occlusion to model humans with ischemic heart disease and evaluated CAPs’ effects on electrocardiogram (ECG) wave patterns. Investigators also performed sophisticated analyses of each dog’s ECG to measure possible PM effects on heart rate variability (HRV), which is influenced by the involuntary nervous system, and T wave alternans, a change in the heart beat pattern. (Among the measures currently used to predict further heart problems in humans with cardiovascular disease, HRV and T wave alternans have not been established as predictive parameters in normal humans or other species.) Pulmonary mechanical functions and markers of inflammation were also evaluated.

The study’s most significant finding was that CAPs affected one of the major ECG signs of myocardial ischemia in humans, known as elevation of the ST segment, in dogs in which coronary occlusion was induced. CAPs-exposed animals showed a shortened time to ST segment elevation and an increased magnitude of the ST segment compared to controls. This finding, if substantited, suggests that exposure to PM may make patients with ischemic heart disease more susceptible to developing potentially fatal cardiac effects. If substantiated in further studies with a larger number of dogs, this finding may help to explain the previously described association between increased PM levels and cardiopulmonary morbidity and mortality. Animals with induced coronary occlusion also showed other changes in cardiac and respiratory parameters after CAPs exposure.

The investigators also reported that normal dogs showed CAPs-induced changes in HRV and average heart rate (which fluctuated widely from day-to-day during the course of the study), decreases in T wave alternans, and changes in respiratory parameters (such as breathing rates and air flow rates). The investigators did not identify whether the variability in responses was due to day-to-day fluctuation of a specific component of the particulate mixture. Moreover, the investigators reported that CAPs had little or no effect on inflammatory mediators, suggesting that changes in cardiac and pulmonary responses occurred in the absence of significant airway inflammation.

Godleski and colleagues interpreted their findings in normal dogs to indicate that CAPs influenced the nervous system’s control of the heart but did not necessarily induce arrhythmia. This interpretation may be reasonable, but the statistical approach the investigators used to identify changes in HRV is not clearly applicable to the small number of dogs tested. In addition, it is not apparent whether it is appropriate to extrapolate these results to humans because the human and canine cardiovascular systems differ in critical features. Furthermore, the clinical significance of changes in HRV or T wave alternans in normal dogs, or in humans who do not have preexisting heart disease, is currently unknown.

The findings generated in this innovative exploratory study may have important implications for future research on the health effects of particle exposure and for shaping policy regulating particulate pollution. Further studies are required to confirm or to modify the conclusions drawn. Such studies would need to involve larger numbers of dogs, humans, or other species and CAPs exposure at different geographic locations where PM components may differ.

For more information about this Report, please contact Dr. Geoffrey Sunshine at HEI or by e-mail at gsunshine@healtheffects.org. To learn more about HEI’s PM research program, please contact Dr. Maria Costantini at HEI or by e-mail at mcostantini@healtheffects.org, or Dr. Aaron Cohen at acohen@healtheffects.org.

HEI’s Strategic Plan 2000–2005 Targets Mixtures, Accountability, Technology

HEI has completed its HEI Strategic Plan for the Health Effects of Air Pollution 2000–2005. After extensive consultations with HEI sponsors and other stakeholders from environmental organizations, industry, and research—including a widely attended Public Meeting on the Draft Plan at HEI’s 1999 Annual Conference in San Diego—HEI has targeted a set of activities for the next five years.

In brief, HEI will apply an international perspective to three key areas of science:
-  air pollution mixture, with a focus on particulate matter (PM) and gases, diesel exhaust, and air toxics;
-  health effects of emerging fuels and technologies; and
-  impact of air quality regulations (accountability).

In responding to the many useful comments, HEI decided not to focus on two other areas of research described in the draft plan, single pollutants (like ozone and carbon monoxide) in isolation and the health effects of climate change (although an HEI role in assessing the technologies emerging in response to the climate change debate was strongly supported).

An overarching theme for HEI’s work is an increasingly international perspective based on the increasingly global nature of environmental questions. Current trends in environmental regulation and industrial development are converging in a manner that encourages a consistent approach to providing a scientific base to inform decisions in the U.S., Europe, and Asia. HEI will continue building ties with government, industry, and the scientific community in Europe and will make similar efforts in Asia as opportunities arise.

Air Pollution Mixture   Polluted air is a complex mixture of vapor, liquid, and solid components, which varies in composition across the U.S. and around the world due to the differences in weather, topography, and various pollution sources. HEI will seek to implement an hypothesis-driven approach to understanding the effects.

In its efforts to study the air pollution mixture, HEI has targeted three submixtures of interest: PM and gaseous pollutants, air toxics, and diesel emissions. In the PM area, HEI plans to build on its own recent research (and that of others). This work has investigated components of the PM mixture that are most toxic—an issue essential in implementing PM regulatory standards—and the effects or contribution of gaseous pollutants, such as ozone, to the adverse effects of PM. Efforts to move forward on broader epidemiologic studies of the health effects of PM and gases will be particularly important.

HEI’s recent air toxics work has addressed uncertainties in projecting human risk of exposure to low levels of benzene and 1,3-butadiene and in defining exposure to aldehydes. HEI will build on that work and refine its research directions as the U.S. Environmental Protection Agency develops priorities under the Urban Air Toxics Strategy. One topic of interest is likely to be polycyclic organic matter, a broad mixture of compounds found on diesel and other combustion particles as well as in the semivolatile phase, whose contributions to health effects are not understood but may be important. In its studies on diesel exhaust, HEI’s recent endeavors have been directed toward questions about carcinogenicity. In planning future research directions, HEI will broaden its scope to include acute and noncancer health effects and mechanisms of those effects as well as to consider further research to improve estimation of diesel risk.

Health Effects of Emerging Fuels and Technologies   Although technology is often the solution to reducing pollution, new technologies can create new challenges (witness the recent example of MTBE). In recent years, concerns about climate change, fuel availability, and air pollution have led to dramatically increased development of engine and emission-control technologies and fuels, particularly diesel. HEI intends to take a more systematic, initiating role in rapid assessments and research, seeking out alternative approaches to dealing with pollutant emissions, carbon-dioxide production, fuel economy and availability, and engine performance.

Impact of Air Quality Regulations (Accountability)   This challenging and important area of research came from suggestions by HEI sponsors. As air pollution declines, demand grows for better techniques to assess the benefits of efforts to further reduce exposure. HEI expects to (1) organize a multidisciplinary, multistakeholder discussion to plan research on a conceptual level, (2) continue to fund the development of the National Morbidity, Mortality, and Air Pollution Study (NMMAPS) model for a national surveillance of the acute effects of air pollution, and (3) fund research to develop methods for measuring benefits. HEI’s Research and Review Committees and staff are now working with sponsors and others to fund and implement the plan.

To order a copy of the HEI Strategic Plan, please call or fax HEI, or e-mail your request to pubs@healtheffects.org. The Plan can also be found here (PDF format, 5.4 MB).

Looking Forward, Looking Back: Reflections as HEI Enters its 20th Year

December 1980 was a tumultuous and portentous time in history. There were American hostages in Iran and an oil embargo, there were still two superpowers, and the desktop PC was but a twinkle in the eyes of Apple and IBM. Lead was still in some U.S. gasoline, while most autos in Europe did not yet have catalytic converters. The U.S. Environmental Protection Agency (EPA) was gearing up to implement the 1977 Amendments to the Clean Air Act. Amidst those events, the Health Effects Institute was born on December 12, 1980.

HEI resulted from the vision of then–EPA Administrator Douglas Costle and leaders of the worldwide motor vehicle industry led by Cummins Engine CEO Henry Schacht. To its founders, HEI would test the hypothesis that an independent, jointly funded, high-quality research institute could provide the "friendly facts" (as Administrator Costle called them), which could be trusted by all parties and serve as the basis for better air quality decisions in the decades to come.

Nearly two decades later, much has changed. Energy prices, even after recent jumps, are comparatively low; the desktop computer dwarfs the capacity and speed of room-sized mainframes of 20 years ago; the Internet has linked computers worldwide; and after substantial success in reducing automotive and other air pollution, Europe, the U.S., and Asia now vie for leadership in taking the next steps to address continuing air quality problems.

Despite the passage of time, and the change that has come with it, certain things have not changed—and some problems have become even harder to solve. An explosion of new epidemiology studies since the early 1990s, driven in part by the availability of low-cost, high-powered computers, have raised the concern that particulate matter (PM), even at the lower levels we have achieved, is causing illness and mortality. Our rapidly expanding ability to map the human genome and detect gene alterations is raising new questions about how to assess the effects of pollution on environmental health. Moreover, a global debate about the impact of climate change has spurred a host of emerging technologies to improve fuel efficiency and reduce the emission of greenhouse gases, technologies that may themselves cause new problems as well as solve old ones.

Through all this, HEI, under the leadership of its founding Chair Archibald Cox, has steadily built an international reputation for timely, relevant, credible, and high-quality science to inform air quality decisions. At such key junctures as the Carbon Monoxide Multicenter Study in the mid-1980s, sustained toxicology and epidemiology research on diesel exhaust in the 1990s, or our more recent reanalysis and research on the health effects of PM, HEI has consistently delivered science that made a difference in improving public and private decisions.

HEI will, of course, pause for a moment later this year to celebrate 20 years of accomplishment. More importantly, however, during this milestone year, we hope to spark (at our Annual Meeting this April and in the months to follow) reflection on what the last 20 years have taught us and how, as we move forward to implement the HEI Strategic Plan 2000–2005, we can redouble our efforts to put science into action in the service of better public and private decision-making worldwide.

I hope you will join me during this year, in both the celebration and the learning, as we move forward together into the new century.

Dan Greenbaum
President

HEI Issues Butadiene Reports

HEI recently published five independent studies from the initial phase of its 1,3-butadiene research program in HEI Research Report Number 92, 1,3-Butadiene: Cancer, Mutations, and Adducts. The five studies are part of HEI’s ongoing air toxics research program aimed at reducing the uncertainties in estimating the human health risks associated with exposure to butadiene. The Report is available here and will appear in hard copy in March.

1,3-Butadiene is an environmental air pollutant that is found in emissions from motor vehicles and stationary sources as well as in cigarette smoke. It is widely used in the manufacture of resins, plastics, and synthetic rubber. Ambient exposures to butadiene (0.3 to 10 ppb) are orders of magnitude lower than those that occur in occupational settings (10 to 300,000 ppb). Such exposures are, however, a public health concern because butadiene may be a human carcinogen. The Clean Air Act Amendments of 1990 list butadiene as a hazardous air pollutant and a mobile source toxic air pollutant. Moreover, there has been worldwide regulatory interest in the potential health effects of occupational and ambient exposures to butadiene.

The nature and goals of the five studies varied. Some studies aimed to further understanding of the potential role of different butadiene metabolites in carcinogenesis by measuring endpoints potentially related to the carcinogenic process (mutations and DNA adducts as well as tumors) and comparing the results in rats and mice, which differ in their carcinogenic response to butadiene. Mutation studies evaluated the molecular nature of mutations as well as mutagenic potency of butadiene metabolites. Two studies developed sensitive methods for identifying and measuring biomarkers for use in characterizing exposure and biological effects.

The research conducted by the investigators included:
- Dr. Rogene Henderson of the Lovelace Respiratory Research Institute (LRRI) exposed mice and rats to butadiene diepoxide to determine whether these species differ in their carcinogenic response to this inhaled metabolite.
- Drs. Leslie Recio of the Chemical Industry Institute of Toxicology (CIIT) and Vernon Walker of the New York State Department of Health compared the mutagenicity of butadiene monoepoxide and butadiene diepoxide in mice and rats.
- Dr. Ian Blair of the University of Pennsylvania developed methods for measuring DNA adducts derived from butadiene metabolites in the tissues and urine of rats and mice with the goal of comparing their levels in the two species and identifying possible biomarkers. Dr. James Swenberg of the University of North Carolina at Chapel Hill developed a sensitive method for detecting adducts formed between butadiene metabolites and a blood protein (hemoglobin) and measured them in animals and humans exposed to butadiene.

The investigators shared tissues from animals that were exposed by inhalation to butadiene or its metabolites at either CIIT or LRRI and, in some cases, developed collaborative ventures.
The Report also contains the HEI Statement, a nontechnical summary of the five studies, and three Commentaries on the studies prepared by the HEI Health Review Committee.

For more information about out air toxics research program, please contact Dr. Debra Kaden at HEI or by e-mail at dkaden@healtheffects.org. To order a copy of Research Report Number 92, please call or fax HEI, or e-mail your request to pubs@healtheffects.org.

Top European Union Official to Keynote Annual Conference 2000 in Atlanta

Mr. James Currie, Director General of Directorate General-Environment of the European Commission, will provide the Keynote address at the 2000 HEI Annual Conference, "Exploring Exposure and Risk Issues." Mr. Currie leads the European environmental protection agency in its efforts to implement Europe-wide clean air and water standards.

The conference - which will be held at the Emory Conference Center Hotel in Atlanta, Georgia, from Sunday, April 9, to Tuesday, April 11 - opens with a session on data-access issues. The session will provide a forum for discussing constructive solutions to data access and sharing, with perspectives offered by representatives of government, industry and the scientific community. Dr. Donald Kennedy of Stanford University, a member of HEI’s Board of Directors and Editor-in-Chief of Science, will chair the discussion.

The remainder of the program will focus on issues of exposure and risk as they relate to various components of air pollution. In this context, findings from studies designed to improve exposure assessment of a number of pollutants, including MTBE, benzene, diesel, and particulate matter (PM), will be discussed. Dr. Jonathan Samet and colleagues from Johns Hopkins and Harvard Universities will present the final results of a major epidemiology study funded by HEI, the National Morbidity, Mortality, and Air Pollution Study (NMMAPS). Topics of discussion include a detailed analysis of mortality and air pollution in the 20 largest U.S. cities, exploration of possible reasons for differences in the findings among the 90 largest cities, and assessment of PM effects on morbidity in 14 selected cities.

Dr. Daniel Krewski and colleagues from the University of Ottawa will present the preliminary findings of another large epidemiology study funded by HEI, the Epidemiology Reanalysis Project. This project, which includes the reanalysis of the Harvard Six Cities and American Cancer Society cohort studies of mortality and air pollution, also explores various analyses to explain possible discrepancies among different areas of the country.

Highlights of the conference include a luncheon address by Dr. Norine Noonan, Assistant Administrator of the U.S. Environmental Protection Agency’s Office of Research and Development, and the presentation of over 50 posters during two scheduled poster sessions.

A preconference minisymposium on emerging technologies in molecular biology and their application to environmental health issues will be held on Sunday morning. Although there is no extra charge for attending this symposium, separate registration is required.

HEI Sponsors Workshop on Mobile Source Air Toxics

In response to a request from the U.S. Environmental Protection Agency (EPA) and in cooperation with key stakeholder groups, HEI sponsored a workshop entitled "Mobile Source Air Toxics: Exposure and Risk" on February 8, 2000, in Washington, DC. The workshop—which was attended by 100 participants, including representatives from the federal government, state and local agencies, industry, and environmental groups—arose from the EPA’s need to reassess current regulations governing emissions of air toxics from mobile sources. Proposed draft regulations are expected to be released this April, with final regulations due in December. As part of its assessment process and to help inform its future rule-making, the EPA is seeking greater understanding of the similarities and differences in underlying methodologies used at the state and federal levels to assess risks which may be associated with these air toxics.

The workshop featured presentations by technical experts from the EPA and state and local agencies, outlining their respective approaches to characterizing exposure to and risks from representative mobile source air toxics (e.g., benzene, butadiene, and formaldehyde). During the presentations and discussion, other stakeholder groups, including industry and environmentalists, as well as independent experts invited by HEI to respond to the information and ideas presented, made the following points:

Participants strongly recommended a comprehensive research strategy, including improved ambient monitoring, further information on personal exposure/time-activity patterns, additional work on exposure modeling, and expanded information on health risk.

The workshop was designed to illustrate the major issues underlining future decisions and not to come to conclusions about what next regulatory steps EPA should or should not take to reduce exposure to mobile-source air toxics. That said, many participants voiced opinions on what actions should follow. Their opinions are included in the package of materials and presentations that emerged from the workshop.  The program may be found here, and copies of the presentations can be ordered from HEI by phone or by e-mail at pubs@healtheffects.org. For further information about the workshop or about HEI’s Air Toxics Program, please contact Dr. Debra Kaden at HEI or by e-mail at dkaden@healtheffects.org.

Brian Leaderer Appointed to HEI Review Committee

Dr. Brian P. Leaderer was recently appointed a member of the HEI Health Review Committee by the HEI’s Board of Directors. Widely regarded as a leading expert in exposure assessment, particularly as it applies to epidemiologic studies, Dr. Leaderer is a Professor of Epidemiology (Environmental Health) at Yale University School of Medicine and a Fellow at the John P. Pierce Laboratory in New Haven. Dr. Leaderer received his undergraduate degree in engineering at Manhattan College and a Ph.D. in epidemiology at Yale, where he has spent most of his professional career. His research has focused on indoor and outdoor air pollution, and he has an in-depth understanding of the types of measurements and models that will be the focus of upcoming HEI Investigators’ Reports. Dr. Leaderer has served on a number of national and international committees on air quality and risk assessment, including several U.S. Environmental Protection Agency advisory groups, and was a member of the Expert Panels that produced the 1999 HEI Special Report, Diesel Emissions and Lung Cancer, and the 1996 Special Report, The Potential Health Effects of Oxygenates Added to Fuel.

HEI Board Approves Special Committee on Emerging Technologies

HEI’s Board of Directors has approved the formation of a new committee, the HEI Special Committee on Emerging Technologies, to aid HEI in identifying and studying technologies and fuels of the future before potential problems arise from their introduction and use.

The committee, which will include members from industry, government, and academia, will be chaired by HEI Research Committee member Dr. Robert Sawyer, Class of 1935 Professor of Energy (Emeritus) and Professor of the Graduate School at the University of California, Berkeley. Dr. Sawyer has worked extensively with both industry and the regulatory community in addressing air pollution issues. Physical scientists and engineers knowledgeable about engine and control technology, emissions characterization, and fuels and fuel additives, as well as toxicologists, will comprise the committee.

HEI has long had a role in investigating new fuels and technologies, including both research (diesel exhaust, methanol, MTBE and other ethers, and manganese) and assessments (methanol, manganese, diesel exhaust, and MTBE). Its contributions, however, have not been as extensive or timely as they could have been because of difficulty in identifying future technologies and fuels early enough to conduct research before their widespread use. Creation of the Special Committee—which will enhance the identification process—coincides with HEI’s plan to systematically evaluate emerging technologies and fuels to anticipate concerns about health effects, climate change, and fuel economy. (See article on the HEI Strategic Plan in this issue.)

The committee (or working groups derived from it) will help HEI meet its new research goals by (1) surveying and evaluating alternative technologies addressing a given issue (such as controlling diesel particulate emissions), (2) participating in writing critical reviews of some specific areas (such as cerium as a fuel additive), and (3) identifying key emissions and health effects research issues for HEI and industry.

HEI Senior Staff Promoted

In February, HEI’s Board of Directors and President Dan Greenbaum announced two important promotions, those of Bob O’Keefe to Vice President and Dr. Jane Warren to Director of Science. "As we enter this new century with the challenges and opportunities it brings," Dan commented, "we are extremely fortunate to have these capable individuals at HEI to ensure that we implement the HEI Strategic Plan 2000–2005 with skill and success."

Under Bob’s leadership, HEI has steadily built a growing presence both domestically and internationally, an effort requiring an enhanced level of senior management with Board and staff, and strengthened contact with key constituents externally. As a result of his skill and expertise, Bob has taken on important leadership roles (e.g., building our presence in Europe and Asia, and representing HEI before the Clean Air Science Advisory Committee [CASAC], the Clean Air Act Advisory Committee [CAAAC], and other public bodies). As Vice President, Bob will manage key internal and external efforts to carry out HEI programs, expand his role in designing and implementing HEI’s national and international presence, and represent HEI before U.S. and international decision-making bodies.

Following Dr. Kathleen Nauss’s departure last fall, Jane stepped in immediately to take on the joint management of HEI’s research and review processes. Jane has integrated the two staffs into a more cohesive whole, working with staff to enhance efficiency and mobilize production of the extraordinarily high volume of particulate matter and other research currently under way. As HEI’s Director of Science, Jane will lead our scientific program, serve as principal liaison to both the Research and Review Committees, and play a crucial role in representing HEI in the broader scientific community.

An HEI Departure

Last November, Dr. Kathleen Nauss, HEI’s Director for Scientific Review and Evaluation, announced her decision to leave HEI. Kathy joined HEI in 1987, working with the Research Committee to initiate the National Toxicology Program/HEI Collaborative Ozone Research Project among other projects. In 1990, she became Director for Scientific Review and Evaluation, in which role she oversaw the review and publication of nearly 100 HEI Research Reports on a wide range of topics, helped streamline the HEI Review Process, and was the lead author of the 1995 HEI Special Report, Diesel Exhaust: Emissions, Exposure, and Effects. In announcing her departure, Kathy noted her desire to devote more of her time to scientific rather than administrative activities and to move from full-time to part-time work. At its November meeting, the HEI Review Committee and staff gathered to thank Kathy for her extensive contributions to HEI and to science.

HEI Publications Take on a New Look

Regular readers of HEI publications will notice a change in the appearance of HEI Research Reports and other HEI literature. As we enter the year 2000—and celebrate 20 years since HEI’s founding—we thought the timing was appropriate to modernize the design of HEI Publications. Those involved in the process have endeavored to maintain a link with the past, while giving a fresh, new look to the overall appearance of our publications. Our goal is to establish common design elements throughout the various publications in the HEI series, including Investigator’s Reports, Special Reports, HEI Communications, and Update.

This new look—HEI’s first in many years—reflects much deeper improvements in the way we review and publish our reports. We have streamlined every step of our review process and now publish all reports in full on the Internet, while maintaining the very high standards of quality you have come to expect from HEI.

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