Update - Fall 1999

The Health Effects Institute

Update - Fall 1999

CONTENTS

HEI issues comprehensive report on the effects of prenatal exposure to methanol vapors

PM inventory website to be launched

HEI joins U.S. delegation to WHO ministerial assembly, presents key findings

HEI research presented at international epidemiology meeting

HEI initiates metals studies

HEI issues comprehensive report on the effects of prenatal exposure to methanol vapors

A newly issued HEI Research Report is expected to figure prominently in future risk assessments of methanol, a widely used chemical and potential new fuel. The report, Reproductive and Offspring Developmental Effects Following Maternal Inhalation Exposure to Methanol in Nonhuman Primates, by Thomas Burbacher and colleagues at the University of Washington presents comprehensive data on methanol pharmacokinetics and toxicity in nonhuman primates (monkeys), a species that has a much closer resemblance to humans in its response to methanol than rodents. The Report is now available in electronic form on HEI’s web site and will be published in late October.

Part I of the Report describes methanol disposition and reproductive toxicity in adult female monkeys; Part II presents data on the growth and development of the infant offspring which were exposed to methanol in utero. The Research Report also includes a commentary on the study by the HEI Review Committee.

The study was a key element in HEI’s methanol research program. This program had its origins in the efforts by government, industry, and other groups in the late 1980s to develop alternative fuels. At that time methanol was a leading candidate to substitute for gasoline or diesel fuels. More recently, methanol has emerged as a promising energy source to provide the hydrogen to power fuel cells. Although substituting methanol for petroleum-based fuels would reduce the levels of some air pollutants, its expanded use could increase exposures of the general population to methanol vapors through ingestion of contaminated drinking water, inhalation of methanol vapors, and skin contact.

The human risks associated with ingesting methanol are well known. Methanol occurs naturally in plants and body tissues; however, it is highly toxic when sufficient quantities of liquids such as wood alcohol are consumed. The body has the capacity to metabolize the low doses of methanol to which people are regularly exposed. It cannot handle high doses, however, because too much methanol overwhelms the body’s ability to remove its toxic metabolite (formate). Little scientific information is available to answer questions such as: What would happen if people inhaled low-levels of methanol on a daily basis? If their ability to remove formate is compromised are they at greater risk?

A 1987 HEI Special Report, (Automotive Methanol Vapors and Human Health: An Evaluation of Existing Scientific Information and Issues for Future Research) estimated that the levels of methanol in ambient air would increase about 1,000-fold (from 1 to 30 parts per billion to 1 to 10 parts per million [ppm]), and might occasionally reach 200 ppm in enclosed spaces if the U.S. motor vehicle fleet were converted to methanol. The Report concluded that inhaling these concentrations of methanol for short periods of time would not be predicted to affect formate production, and thus should not present a health risk. However, the Report also noted that information on the effects of long-term inhalation of methanol vapors was lacking, particularly in susceptible populations such as pregnant women and the developing fetus.

HEI’s methanol research program addressed these issues. Three HEI Research Reports on studies in rodents (Weiss et al.; Pollack et al) and nonhuman primates (Medinsky et al.) have already been published. The fourth study by Dr. Burbacher and colleagues was a complex inhalation study which involved two cohorts of nonhuman primates (Macaca fascicularis ) and was funded by both HEI and the National Institute of Environmental Health Sciences.

Burbacher and colleagues exposed two groups of adult female monkeys to methanol vapors (0, 200, 600, or 1,800 ppm) for two hours a day, seven days a week. The animals were exposed to methanol before breeding, during breeding and during pregnancy. The investigators studied the effects of repeated methanol exposures and pregnancy on blood concentrations of methanol and formate. Because high doses of methanol damage the central nervous system, the infants were examined at regular intervals during the first nine months of life to assess their growth and neurobehavioral development.

Burbacher found that exposure to methanol, at the concentrations used in this study, did not affect the health of the adult animals prior to or during pregnancy. There also was no apparent effect of methanol on reproductive performance. Despite an increase in blood methanol concentrations, formate concentrations remained at baseline levels during the entire course of the study for all exposure groups. Thus, there was no accumulation of the toxic intermediate. Prenatal exposures to 200 ppm or 600 ppm methanol did not adversely affect infant birth weight, growth, or physical development. The most concerning finding was severe wasting that occurred after one year of age in two offspring in the 1,800 ppm exposure group. Overall, there was no robust effect of prenatal methanol exposure on most measures of neurobehavioral development of the infant monkeys during the first nine months of life. The HEI Review Committee noted that an improved understanding of methanol neurobehavioral toxicity will result from evaluation at later stages of development when more sophisticated tests of cognitive performance can be conducted and when latent effects may emerge.

Electronic copies of Research Report #89 can be obtained here. The bound version can be ordered from HEI by e-mail at pubs@healtheffects.org. For further information, please contact Dr. Maria Costantini at mcostantini@healtheffects.org.

PM inventory website to be launched

Epidemiological evidence from studies conducted in the 1990s has renewed concerns about the health effects of ambient particles. In 1997, the U.S. environmental Protection Agency (EPA) decided to retain the current National Ambient Air Quality Standards (NAAQS) for particulate matter (PM) with an aerodynamic diamtere of 10 um or smaller and add standards for particulate matter with an aerodynamic diameter of 2.5 um or smaller to increase public health protection. In 1998, the European Union (EU) adopred limit values for PM and called for new research on fine particles to determine whether this fraction should also be regulated. Even as the new standards were enacted, many questions remained and it was recognized that additional research on the health effects of PM was needed to resolve key outstanding issues. The EPA is currently evaluating the available evidence for PM as part of its mandated periodic review of the PM NAAQS, and the EU is planning to review the new scientific information about PM in 2003.

HEI, in collaboration with the EPA, is now developing a new website to present PM-related studies to aid PM research efforts and support the activities of the National Research Council Committee on Research Priorities for Airborne Particulate Matter. Based in part an initial effort by the National Academy of Sciences to develop a database of PM-related research, the site, scheduled to debut at the end of October, will provide information on projects funded by both the public and private sectors in all areas of PM research. The information compiled will be of use to funding organizations in their planning efforts and to research scientists anxious to establish collaborations.

The website, which can be found at www.pmra.org, will be updated and maintained by HEI. It will include a database of current research activities on PM both in the U.S. and abroad and provide links to other organizations involved in PM research. In addition, pages within the site will announce upcoming funding opportunities and scientific meetings and provide a forum to facilitate the exchange of information among scientists, funding organizations, and regulators. For more information on the website, or to suggest additional PM research that might be included in the database, please contact Dr. Maria Costantini at mcostantini@healtheffects.org.

HEI joins U.S. delegation to WHO ministerial assembly, presents key findings

At the joint invitation of the World Health Organization (WHO) and the U.S. Environmental Protection Agency (EPA), Robert O’Keefe, Director of Program Strategy at HEI, served as one of two non-governmental experts on the U.S. delegation to WHO’s ministerial-level Conference on Environment and Health, held this summer in London, England. The U.S. delegation was co-led by Peter Robertson, then Deputy Administrator of the EPA, and Ricardo Martinez, Administrator of the National Highway Traffic Administration. The Ministerial Assembly, held every five years, was attended by over 70 ministers of environment and health and serves as a key decision-making body to adopt a range of measures for the protection of health and the environment in WHO member nations and to lay the groundwork for guiding new research for the next five years.

In the context of issues, which ranged from climate change to the precautionary principle, the U.S. delegation focused on children as a population that may be especially sensitive to environmental threats, on traffic safety measures, and on air pollution and health. In addition to serving on the delegation, Mr. O’Keefe contributed to the conference with the presentation "Diesel Technology and Health Effects, New Findings and Key Issues," which outlined diesel health effects, projected emissions of diesel particulate emissions in the United Kingdom, and recent research in Erfurt, Germany, on the effects of fine particles in asthmatics. He also discussed potential control strategies being taken by industry to reduce emissions from mobile sources in Europe.

Participation in the WHO meeting is part of HEI’s growing international presence as it seeks, through open competition, to fund the best and most relevant research proposals, which increasingly originate in Europe and Asia, and as it participates in modest partnerships with the European Commission, the European Chemical Industry, and others. Taken together, HEI’s increasingly diverse research portfolio and its understanding of research and regulatory activities in Europe and Asia contribute to enhancing the utility of HEI studies in different regulatory settings and make the best international science available to HEI sponsors in the U.S. For further information, please contact Robert O’Keefe at HEI or by e-mail at rokeefe@healtheffects.org.

HEI research presented at international epidemiology meeting

In September 1999, over 500 scientists met in Athens, Greece for the joint conference of the International Society for Environmental Epidemiology and the International Society for Exposure Analysis. The conference attracts environmental scientists from around the world, and in recent years has become a major venue for the presentation of new research on the health effects of air pollution. HEI investigators participated in a number of sessions. In addition, HEI sponsored two symposiums.

Biomarkers and Molecular Epidemiology in Risk Assessment was co-sponsored by HEI and the U.S. EPA, and was organized by Drs. Soterios Kyrtopoulos of the National Hellenic Research Foundation (Greece), Radim Šrám of the Institute of Experimental Medicine (Czech Republic), and Richard Albertini of the University of Vermont (USA). The symposium was chaired by Dr. Debra Kaden of HEI and Dr. Lucas Neas of the U.S. EPA. Drs. Kaden and Harri Vainio of IARC (France) introduced the use of biomarkers in epidemiology studies. Dr. Rogene Henderson of the Lovelace Institutes (USA) presented the dilemma posed by the chemical 1,3-butadiene, which has large species differences for cancer susceptibility. Dr. Kaden presented information from Dr. Mike Waters of the U.S. EPA indicating butadiene can cause genetic changes in both rodents and people, and suggested biomarkers can provide a tool in understanding species differences in susceptibilities.

Drs. Albertini and Richard Hayes of the US National Cancer Institute discussed two large, multinational research efforts examining biomarkers for butadiene in Czech and Chinese populations occupationally exposed to butadiene. Dr. Albertini’s study is funded by HEI (see HEI Update Spring 1999). Results of both studies were remarkably consistent, and indicated several biomarkers as useful indicators of exposure. Dr. Regina Santella of Columbia University (USA) discussed biomarkers of urban air pollution genotoxicity, and Dr. Šrám presented results of a study examining biomarkers for air pollution in relationship to birth outcomes in Teplice, Czech Republic. Dr. Kyrtopoulos then presented information on DNA adducts to urban air pollutants in several European cities. Dr. Paolo Boffetta of IARC (France) concluded the symposium by summarizing key points and future prospects for the use of biomarkers in epidemiology studies.

Air Pollution and Health: A European Approach (APHEA) and National Morbidity, Mortality, and Air Pollution Study (NMMAPS): A Collaboration of Two Multi-Center Studies, presented the plans for, and current progress of, a joint analysis of the European 32-city APHEA2 study, sponsored by the European Commission, and the US-wide NMMAPS study, sponsored by HEI. The symposium, chaired by Dr. Aaron Cohen of HEI and Dr. Ross Anderson of St. Georges Hospital Medical School in the UK, featured presentations from lead investigators Drs. Klea Katsouyanni (APHEA2), and Jonathan Samet (NMMAPS), who discussed the need to better understand how similarities and differences in the effects of air pollution on morbidity and mortality vary across countries, in order to better inform public health decisions. Dr. Giota Touloumi, from the University of Athens, described how investigators from each study had already applied each others’ analytic methods to data from a single European and US city, and learned how different analytic methods could produce variability in the results. Such methodologic work is essential to interpreting apparent differences in results among countries. Investigators from the two studies have met twice to plan the collaboration (see HEI Update Fall 1998), and will be seeking support to conduct the joint analysis.

For more information about HEI’s 1,3-butadiene research program, contact Dr. Debra Kaden at HEI or by e-mail at dkaden@healtheffects.org. For more information on NMMAPS and the APHEA II/NMMAPS collaboration contact Dr. Aaron J. Cohen at HEI or by e-mail at acohen@healtheffects.org.

HEI initiates metals studies

Metals are used in a number of ways in motor vehicles. As well as being part of the structure, metals are also used in batteries, brake pads, catalytic converters (to reduce hydrocarbon, CO and nitrogen oxide emissions), and fuel additives (as octane boosters or to reduce particulate emissions). Since metals persist in the environment, and since a number are known to have toxic effects ranging from carcinogenicity to neurotoxicity, increasing attention is being given to metals that are emitted from motor vehicles. In response to this interest in metals, HEI issued RFPA 98-4, Research on Metals Emitted by Motor Vehicles in 1998. Three studies, soon to be underway, have been selected through this application process.

Two of the studies will examine aspects of the toxic potential of manganese, which may be present in tailpipe emissions if the octane booster methylcyclopentadienyl manganese tricarbonyl (MMT) is introduced into gasoline. At low levels, manganese is an essential trace element required for many enzymes, some of which are important for central nervous system function. Long-term exposure to higher levels is associated with manganism, a condition similar to, but not identical to Parkinson’s disease. One of the manganese studies will investigate a possible mechanism for brain cell death associated with exposure to high levels of manganese. The hypothesis of this study is that manganese exposure increases calcium transport into mitochondria, and that this, in turn, increases mitochondrial permeability and may result in cell death. A second manganese study will determine in vivo the rates of influx and efflux of manganese at the blood brain barrier (the complex of cells and tissue structures through which substances must pass in order to be transported into or out of brain neurons.) Rats will be the experimental animal. The influence of age on transport will be determined by using rats of various ages.

A third study of metals has a more general focus. This study will characterize emissions from current on-road vehicles and use data to construct source profiles for tailpipe, brake-wear and tire-wear emissions. To accomplish this, emissions will be measured in two heavily-traveled tunnels. This information will be supplemented with data from: (1) videotapes made during the periods of measurement; (2) cold start dynamometer measurements; and (3) parking garage road dust to apportion different emission components to tire-wear, brake-wear, or tailpipe emissions. For more information about HEI’s metals research program, contact Dr. Martha Richmond at HEI or by e-mail at mrichmond@healtheffects.org or Dr. Jane Warren at jwarren@healtheffects.org.