Environmental Interactions at Harvard
Since 1854, when John Snow removed the handle from the Broad Street water pump and thereby halted a London cholera wave, public health researchers have concentrated on the problems of crowded urban conditions. The Kresge Center for Environmental Health has followed that tradition by working to understand the problems of cities and proposing standards and measures to protect public health.
Established in 1958 as the Division of Environmental Health Sciences and Engineering at the Harvard School of Public Health (HSPH), the interdepartmental consortium of researchers and teachers was renamed the Kresge Center in 1966. James Whittenberger was the center's first principal investigator and the architect of environmental science at the HSPH. The center began receiving NIEHS funding soon after that institute's establishment in 1962. In fact, the Kresge Center grant was the second grant awarded by the NIEHS, and is the longest continually awarded grant in the institute's history.
Whittenberger, "one of the giants in environmental science" according to Joseph Brain, director of the center's respiratory biology and inhalation toxicology core, had a strong interest in respiratory physiology but felt that the center should expand its focus beyond his own physiological emphasis. He attracted colleagues such as Benjamin Ferris, a pioneer in occupational respiratory health, and Mary Amdur, who developed early animal models for studying respiratory health. In this fashion, the Kresge Center branched out into areas including toxicology, environmental medicine, radiation biology, and occupational health.
As a result of this expansion, the Kresge Center has initiated and participated in groundbreaking environmental research throughout its history and has continually contributed to public health policy formation, not only in the United States, but also abroad. In addition, researchers at the Kresge Center have devised and implemented a variety of new tools for conducting public health research. Now under the direction of John B. Little, a Simmons Professor of Radiobiology at the HSPH since 1982, the center has five core research programs: radiobiology and experimental carcinogenesis, biochemical and environmental toxicology, respiratory biology and inhalation toxicology, environmental epidemiology, and occupational health.
"The goal of the center is interaction," says David Christiani, a professor of occupational medicine. "It's a conceptual enterprise that involves bringing together departments that wouldn't normally have natural affinity. The center provides an infrastructure to support and nurture those interactions."
The Six Cities Study
|
A home at Harvard. Located at the Harvard School of Public Health, the Kresge Center is the longest continually awarded grant in NIEHS history.
Photo: Harvard School of Public Health |
The Kresge Center has made some of its strongest contributions to understanding urban environmental health problems through its studies in air pollution. A series of important revelations in urban air composition began in 1974 with the Six Cities Study, which looked at the effects of sulfur oxides and particulate matter in six major U.S. cities with significant fossil fuel air pollution.
Using data from questionnaires and periodic measures of lung function, the Six Cities Study showed that particulate matter had important health effects never before considered. Subsequent studies at the Kresge Center and a number of other centers demonstrated that there was a strong positive correlation between particulate matter and mortality. The relationship has been shown to exist not just in the United States, but in cities in South America, China, and Eastern Europe.
Following the release of the study's results in 1993, recalls David Dockery, an associate professor of environmental science and epidemiology, the American Lung Association brought suit against the EPA to tighten its standards on particulate matter pollution. The resulting Clean Air Act Amendments passed by Congress in 1993 and the EPA staff paper on particulate matter, which will be used to develop new exposure standards, are replete with data from the Six Cities Study.
"The quality and quantity of the data were both very impressive," says Mort Lippmann, a New York University Medical Center professor of environmental science who served on the EPA's Clean Air Scientific Advisory Committee. "This was the largest epidemiologic study of the effect of pollution on individuals that was available. It was done very carefully over a long period of time, and it had to be taken very seriously."
Six Cities Study data were also cited in the EPA's standards for nitrous oxide and ozone. Numerous foreign countries have consulted the study when reviewing their limits for particulate matter pollution.
The Kresge Center followed the Six Cities Study with more large epidemiological investigations of air pollution and public health. The Twenty-four Cities Study, completed in 1992, looked at the effects of acid aerosols on chronic respiratory symptoms in 4th- and 5th-graders, while the Five Cities Study, underway since 1992, is studying the effects of acid aerosols and ozone on schoolchildren in urban areas.
In addition, Brain points out, center researchers have also devised animal models that mimic various respiratory diseases, such as an animal treated with sulfur dioxide that suffers from chronic bronchitis. Using a particulate matter concentrator that suspends particulates from the air around the center for use in the laboratory, researchers can continue to study the effects of these pollutants.
"The hallmark of the center has been the interdisciplinary approach to health assessment," says Dockery. "We have strong exposure assessment and analytic capabilities with biostatistics and epidemiology. The center makes all this possible."
Upstream Epidemiology
Increased awareness of the dangers of particulate matter led to interest in exactly how these pollutants create disease. One line of inquiry has been through the use of biomarkers that signal the early onset of inflammation in response to toxic substances before any clinical changes take place.
"The most common criticism of epidemiology," Christiani says, "is that we arrive on the scene to count the bodies. This so-called 'upstream approach' allows us to look at small physiologic changes and see whether cytokines are being expressed that indicate the beginnings of inflammation and disease."
Samples are being experimentally collected via nasal lavage and assessed for the presence of biomarkers. As Christiani points out, there is very little difference between the nasal and bronchial epithelia, so changes in one should reflect changes in the other. Currently, a respiratory and occupational collaborative group in the center is simultaneously performing nasal lavage and lung washes on workers exposed to fuel ash in a local power plant in order to correlate results of the two assessments. Urine is also collected in order to determine the internal dose.
Using an inductive coupled plasma mass spectrometer, Joe Paulauskis, an assistant professor of molecular biology, can determine whether the cytokine interleukin-8 has been switched on--an early sign of inflammation--in samples taken from workers. Investigations such as these may lead to less expensive, more sensitive measures of worker dose and sensitivity to pollutants.
"As fuel burning becomes more and more efficient," Christiani says, "we're seeing a steady increase in the amount and fineness of particulate matter in the atmosphere and in its metallic content. While the health effects of these materials are not fully understood, it's pretty clear that they are dangerous."
An interdisciplinary program headed by Richard Monson, a professor of epidemiology and director of the center's occupational health core, recently received major support from the NIEHS Superfund Program to identify biomarkers of exposure to lead, vanadium, PCBs, and arsenic--all Superfund target chemicals. A common genetic polymorphism in the delta-aminolevulinate dehydratase (ALAD) gene has been associated with elevated lead levels in children. The ALAD gene may provide a useful biomarker for the effectiveness of treatments for lead poisoning. Christiani is also leading a four-year effort, supported by the National Cancer Institute and the NIEHS, to identify genes that can be used as biomarkers for susceptibility to lung cancer. "The center provides infrastructure that allows us to give a thorough look at some very important questions," he says. "As a result, we have a record of turning small pilot investigations into some broad-reaching projects."
Induced Genomic Instability
|
John B. Little
Photo: Harvard School of Public Health |
One of the first steps in preventing cancer is determining the processes that lead to carcinogenesis. Since he was charged with developing the radiobiology and experimental carcinogenesis core in 1965, Little has been working to determine how and why radiation causes cancer.
One line of inquiry that has recently borne fruit is the study of induced genetic instability. Little and his colleagues have discovered that some cells, when exposed to radiation, do not immediately experience cancerous mutations. However, the progeny of these seemingly unaffected cells appear to be at increased risk for mutagenesis--in some cases even 40 and 50 cell divisions later. "These findings may have implications for understanding why there is often such a long period between exposure to a carcinogen and cancer induction," Little observes. "We still don't know why, 40 years later, cancers still arise in people who were exposed to radiation from the atom bomb. Induced genomic instability, if we can figure out what it is, may provide the explanation."
Important studies on basic cancer processes are also ongoing in the toxicology core. Leona Samson, a professor of toxicology, has been looking at alkylation damage to DNA and how that damage is enzymatically repaired. Samson recently cloned the gene for ADA, a protein that appears to perform an important DNA repair function in bone marrow. Damage to marrow is frequently the limiting factor in cancer radiation treatment and chemotherapy. Further research on this protein may allow clinicians to protect bone marrow and thus use stronger anticancer measures.
"There is a bidirectional flow of information that occurs under the center that wouldn't occur if it wasn't there," says Armen Tashjian, Jr., a professor of toxicology and director of the center's biochemical and environmental toxicology core. "It brings together different kinds of people doing different kinds of things, and that's a distinct advantage of the center philosophy."
John F. Lauerman
Last Update: July 31, 1997