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Fuel Processing Technology 6566 2000. 5567 www.elsevier.

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Fine particulate matter and cardiovascular disease


Lucas M. Neas
) Epidemiology and Biomarkers Branch, Human Studies Diision, National Health and Enironmental Effects Research Laboratory, US Enironmental Protection Agency, Research Triangle Park, NC 27711, USA Received 7 December 1998; accepted 10 May 1999

Abstract The 1996 EPA Air Quality Criteria for Particulate Matter relied in large part upon epidemiologic studies of the short-term acute. effects of inhalable particulate matter PM. exposures on all-cause mortality and hospitalizations with very limited experimental evidence from toxicology or clinical studies. Recent research has identified several plausible biological mechanisms for both the initial pulmonary injury and the consequent systemic effects. Current epidemiologic research interests include the components. of PM which are responsible for the initial pulmonary injury, the effects of co-pollutants such as ozone, and the pathophysiological mechanisms for PM-induced acute health effects. Published by Elseveir Science B.V.
Keywords: Particulate matter; Cardiovascular disease; Co-pollutants

1. Introduction the 1996 Air Quality Criteria for Particulate Matter The US Environmental Protection Agencys 1996 Air Quality Criteria for Particulate Matter w1x reviewed the physiologic, toxicologic, and epidemiologic studies related to the inhalation, deposition and health effects of particulate matter PM. exposures. In numerous epidemiologic studies, PM exposure was adversely associated with various indicators of respiratory health. In adults, PM exposure was associated with increased incidence of respiratory symptoms, transient decrements in pulmonary function levels, and the onset of chronic pulmonary disease in adults. However, the findings of most concern were the association of PM exposures with mortality and hospital admissions. PMs association with all-cause mortality was examined in 38 longitudinal studies of the daily variation in mortality within unenumerated open cohorts commonly referred to as time series studies.. Most of these studies relied on measurements of total suspended
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particulates, a measurement that includes particles too large to enter the lower respiratory tract. However, in 14 studies, the investigators had size-specific measurements of PM less than 10 m m in aerodynamic diameter PM 10 .. With one exception, a 50 m grm3 increment in PM 10 was associated with a 29% increase in the daily number of deaths due to natural causes. The single exception was a slightly protective effect in Topeka, KS, where PM 10 contains a significant proportion of coarse particles between 2.5 and 10 m m. that are largely of crustal origin. The consistency was restored when Topeka and five other US cities were reanalyzed using measurements of PM less than 2.5 m m in diameter PM 2.5 . w2x. Cause-specific mortality associations were reported for several epidemiologic studies. In the Harvard Six-City Study, a 10 m grm3 increment in PM 2.5 was associated with increased mortality from pneumonia q4%., chronic obstructive pulmonary disease q3%., and ischemic heart disease q2%.. While public attention has focused on pulmonary mortality, these respiratory causes accounted for only 6% of all deaths due to natural causes and about 16% of the PM-related mortality. Ischemic heart disease deaths accounted for 32% of deaths due to natural causes and about 44% of the PM-related mortality. Studies of hospitalization rates were coherent with those for all-cause mortality w3x. Fourteen longitudinal studies found a consistent association between PM exposures and hospitalizations for respiratory disease with relative risks for a 50 m grm3 increment in PM 10 ranging from a 3% to a 25% increase in the daily number of hospitalizations. Hospital admissions for heart disease showed an association with PM exposures in two studies. Joel Schwartz and Robert Morris assembled data for approximately 517,000 admissions of elderly patients over 65 years of age to all hospitals in the Detroit, MI metropolitan statistical area from 1986 to 1989. They found ischemic heart disease admissions increased by 2% for a 32 m grm3 increment in PM 10 w4x. In a study of 168 hospitals in Ontario, Canada, from 1983 to 1988, Richard Burnett and colleagues w5x found a 3% increase in cardiac admissions with a 13 m grm3 increment in fine sulfate particles. The authors of both studies controlled for the effects of trend, season, temperature, and ozone on hospital admissions. In the Ontario study, the effect of a 13 m grm3 increment in fine sulfate particles was greater among cardiac patients over 65 years of age q3.5%., but still elevated among cardiac patients under age 65 q2.5%.. The longitudinal open cohort studies were supported by two large, prospective studies of closed cohorts of adults with individual level information on potential confounders. In the Harvard Six-City Study, Douglas Dockery and colleagues followed 8111 adults over a 14- to 16-year period in six US cities. They found that cardiopulmonary mortality was associated with the city-specific annual average concentrations of fine PM rate ratio RR. s 1.37 for an 18.6 m grm3 increment in PM 2.5 .. Arden Pope w6x and colleagues also examined cardiopulmonary mortality in a much larger study of 552,138 adults in 151 US metropolitan areas using data assembled by the American Cancer Society. In the period 19821989, they found that cardiopulmonary mortality was associated with the city-specific annual average concentrations of fine PM RR s 1.31 for a 24.5 m grm3 increment in PM 2.5 .. These closed cohort studies were able to overcome many of the objections to the open cohort studies by having individual information on alternative risk factors includ-

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ing age, sex, race, cigarette smoking, exposure to passive cigarette smoke, body mass index, alcohol consumption, education, and occupational exposure to dusts and fumes. These closed cohort studies still were criticized for a lack of information on individual exposures and their failure to control for city differences in cardiovascular risk factors such as diet and exercise w7,8x. Thus, the 1997 National Ambient Air Quality Standards for Particulate Matter relied in large part on epidemiologic studies with limited experimental evidence from toxicology or clinical studies on the pathophysiologic mechanisms underlying the PM-induced health effects.

2. Research priorities for PM epidemiology In response to concerns regarding the 1997 National Ambient Air Quality Standards for Particulate Matter, Congress mandated the creation of an independent scientific advisory committee under the auspices of the National Research Council. In March 1998, the Councils Committee on Research Priorities for Airborne Particulate Matter recommended a comprehensive program of research directed towards resolving scientific uncertainties regarding the health effects of PM exposure w9x. The Committee identified 10 research topics related to source-exposure relationships NAS topics 14., exposureresponse associations NAS topics 59., and statistical methods NAS topic 10.. The use of central-site PM measurements as a surrogate for personal exposures NAS topic 1. and the modeling of the health effects of combined exposures to PM and gaseous co-pollutants NAS topic 7. were frequent criticisms of the epidemiologic studies. Several exposure studies are currently directed towards assessing the personal PM exposures for patients with chronic respiratory and cardiac disease. EPAs Epidemiology and Biomarkers Branch has provided supplemental funds to support limited health measurements in conjunction with several of these personal exposure studies. Current epidemiologic study designs routinely include extensive measurements of numerous co-pollutants and, wherever practical, the measurement of indoor or personal PM exposures in a sample of the subjects. The identification of susceptible sub-populations for the health effects of PM exposure NAS topic 8. constitutes an important area of epidemiologic research with important policy implications. If the susceptible sub-population is limited to persons with severe acute illness or with end-stage chronic disease, then exposure to PM may advance mortality by only a few days. However, if the susceptible sub-population includes groups such as the active elderly with early coronary heart disease, then exposure to PM may advance mortality by several years. The identification and characterization of the toxic components of fine PM NAS topics 2 and 5. that are responsible for the initial pulmonary insult have become the goal of numerous toxicological and epidemiological studies. Most current epidemiologic study designs provide for the measurement of many physical and chemical constituents of fine PM including particle mass, size, number and concentrations of sulfates, nitrates, organic carbon, elemental carbon, and metal ions.

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However, many PM constituents are emitted from the same source and have similar atmospheric distributions. Observational studies will not be able to distinguish between the health effects of PM constituents that are correlated over both time and space. Instead of specific PM constituents, the development and application of source-receptor models NAS topics 3 and 4. will facilitate the epidemiologic studies of the health effects of distinct sources of fine PM. The proposed search for the toxic components of fine PM will not be a simple task. Several investigators have proposed various hypotheses regarding the mechanisms responsible for the initial pulmonary injury, the acute health effects produced by this initial insult, and the chronic health effects of long-term exposure. 3. Mechanisms of PM-induced acute pulmonary injury Recent research has identified several plausible biological mechanisms for both the initial pulmonary injury and the consequent systemic effects following PM exposure. The initial pulmonary injury may be related to one or more properties of PM and its constituents including physical, chemical and biological characteristics w10x. Physical characteristics include gravimetric mass, particle number, particle size, and particle surface area. In the ultrafine hypothesis, Gunter Oberdorster and colleagues suggested that particles smaller than 0.02 m m elicited a strong and persistent pulmonary inflammation w11,12x. Some epidemiological studies have found a stronger association with counts of the number of ultrafine particles w13x, but clinical studies have suggested that surface properties w14x and chemical composition w15,16x may be more important factors in the toxicity of ultrafine particles. Chemical characteristics involve the direct action of an agent in a process that consumes that agent. In the acid hypothesis, Mort Lippmann w17x proposed that the acidity delivered to the airways and alveoli through the deposition of particles was responsible for the observed health effects. Other chemical agents include hydrogen peroxides w18x, nitrates, sulfates, organic carbon and acid aldehydes. Catalytic characteristics transition metal hypothesis. are a special category of chemical characteristics that involve processes by which reactive metal ions produce an oxidative lung injury due to the formation of reactive oxygen andror reactive nitrogen species w19,20x. Various scientists have suggested that nickel w21x, vanadium, and copper w22x might play an important role in PM-induced acute cardio-pulmonary toxicity. Biological characteristics endotoxin hypothesis. may involve an immunological reaction to a biological constituent of PM such as bacterial endotoxins. Endotoxin exposures are known to cause respiratory problems in certain industries w23,24x, but their role in environmental disease has been questioned w25x. Other bioaerosols include allergens such as fungal spore fragments, pollen grains and antigens associated with house dust mites, cockroaches, and animal danders w26x. 4. Mechanisms of PM-induced acute health events Several hypotheses have been proposed to explain the pathophysiology of PM-induced health effects. The most obvious mechanism involves the reduction in pulmonary

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function in response to the pulmonary inflammation. In the hypoxia hypothesis, the susceptible population consists of individuals with severe respiratory disease whose pulmonary reserve capacity is already near the minimum compatible with life. Exposure to PM further lowers their pulmonary function levels and results in emergency hospitalization and death. Direct mechanisms involve the penetration of PM constituents through the lung into the circulation and their subsequent effects on distal organs such as the heart. In the ultrafine hypothesis, Gunter Oberdorster suggested that ultrafine particles penetrated into the blood, deposited in cardiac tissue, and caused cardiac arrhythmia and death w12x. Immunological mechanisms cytokine hypothesis. involve the release of secondary messengers cytokines. into the circulation by various pulmonary cells w10,27x. Alveolar macrophages, lymphocytes, and neutrophils can be stimulated to release a variety of cytokines including platelet activating factor and tumor necrosis factor w2830x. Airway epithelial cells have been shown to act directly as immune effector cells by releasing cytokines, such as interleukin-8 w31,32x, granulocytemacrophage colony stimulating factor w33,34x, and platelet activating factor w35x. Cytokines, including tumor necrosis factor and interleukins, have been linked to cardiac arrhythmias w36,37x and platelet activating factor has been implicated in atherosclerosis and cardiac thrombosis w38x. The principal objection to the cytokine hypothesis is the short half-lives of cytokines in the blood. Neural mechanisms vagal nerve hypothesis. involve the response of the autonomic nervous system to pulmonary irritants. The C-fibers in the lung and other receptors detect the initial irritation of airways and alveoli by PM and the signal is transmitted by the afferent arm of the Vagus nerve to the respiratory centers w39x. This signal stimulates the sympathetic nervous system and inhibits the parasympathetic nervous system. A decrease in the efferent arm of the Vagus nerve is associated with a decrease in heart rate variability, especially high frequency variability, and an increase in heart rate. Measures of autonomic dysfunction, such as increased heart rate and decreased heart rate variability, have been associated with the incidence of adverse coronary events and death. In the Framingham Heart Study, investigators enrolled 5070 subjects who were free of cardiovascular disease in 1948. After 30 years of follow-up, higher resting heart rates were associated with increased rates of coronary heart disease mortality especially sudden cardiac deaths w40x. Among 2501 subjects who were free of clinically apparent cardiac disease in 1983, 2-h measure of ambulatory heart rate variability was associated with coronary events w41x and mortality w42x over 4 years of follow-up.

5. Mechanisms of PM-induced chronic disease The chronic effects of PM exposures observed in the prospective studies of closed cohorts w5,6x appear to be greater than simply the accumulation of the acute effects of PM exposures observed in the longitudinal studies of open cohorts w2x. Some multi-stage process must be involved that increases the size of the susceptible population as well as causing illness and mortality within this susceptible population. One possible pathophysiological mechanism for PM-induced chronic disease involves hematological

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changes such as increased platelet activation and plasma viscosity w43x. These hematological changes may lead to the induction of atherosclerosis.

6. Recent toxicology studies Research on the health effects of PM exposure requires both observational studies of real-world exposures among free-living subjects epidemiology. and experimental studies of controlled exposures of well-characterized subjects toxicology and clinical research.. While most of the PM-related health effects were first demonstrated by epidemiologic studies, recent experimental studies have both complemented and extended these studies to new areas of research. A common thread to both strands of research is an increasing emphasis on the cardiac effects of PM exposures w44x. A principal difficulty with experimental studies has been the inability to generate a fine particle with the same physical, chemical and health properties as ambient fine particles. The intratracheal instillation of residual oil fly ash in rats does produce cardiac arrhythmias w45x, but this exposure does not mimic real-world particle exposures. Recently a particle concentrator was developed that concentrates fine ambient air particles ranging in size from 0.15 to 2.5 m m w46x. In the concentrator, ambient air is drawn at 5000 lrmin through an inlet with a 2.5-m m cut-point and then through a series of virtual impactors. At each stage, the gasses and ultrafine particles are drawn off while the fine particles are propelled by their inertial mass through an orifice to the next stage. This process can produce a 26-fold concentration of fine particles without altering the concentrations of gaseous co-pollutants such as ozone, carbon monoxide, and nitrogen dioxide. The particle concentrator has been used in a series of toxicology studies by Godleski and colleagues at the Harvard School of Public Health. Preliminary reports at scientific conferences have indicated that concentrated air particles induce pulmonary inflammation w47x, alter pulmonary function w48x, and cause death w49x in rat models of chronic bronchitis and pulmonary hypertension. The cardiac effects of PM exposure also have been reported by Godleski and colleagues at recent scientific conferences. Healthy dogs exposed to a fine particle aerosol generated from residual oil fly ash showed cardiac arrhythmias including T-wave alternans and ST segment elevation w50x. Preliminary reports of recent experiments using the virtual impactor have shown that exposure to fine concentrated air particles was associated with substantial electrocardial changes in dogs w51,52x.

7. Epidemiology of acute PM-health effects Epidemiologic research on the acute health effects of PM exposures continues with additional longitudinal studies of the daily variation in mortality and hospitalizations. Previous longitudinal studies were restricted to those few locations that had daily data on size-fractionated PM. The new nationwide PM monitoring network to be established under the auspices of EPAs Office of Air Quality Planning and Standards will provide

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daily size-fractionated gravimetric PM mass at 100 sites. Further speciation of selected PM constituents will be performed every third day at 40 additional sites. In four to eight super-sites, a comprehensive battery of PM monitors will provide daily information on every measurable constituent of PM. The Health Effects Institute has funded the National Morbidity and Mortality Air Pollution Study, a comprehensive longitudinal analysis of the association of fine PM exposures with mortality in 100 US cities and with hospital admissions in 40 US cities w53x. While the scope of these longitudinal studies has been greatly expanded, the problems regarding the lack of personal exposure information and a well characterized study population still remain. Panel studies of closed cohorts can address these issues, but with considerable loss of power to detect PM-induced health effects for relatively rare life-events such as hospitalization or death. To maintain adequate statistical power, panel studies generally focus on physiologic parameters that may be measured repeatedly in the same individuals as these subjects are exposed to varying levels of PM. The most common repeated measures design has been the measurement of pulmonary function levels in small cohorts of children. In collaboration with the National Institutes of Health and the Inner City Asthma Study investigators, the EPA Epidemiology and Biomarkers Branch will conduct a seven-city study of PM-induced health effects among 1022 inner-city children with moderate to severe asthma w54x. Daily information on pulmonary function levels will be compared with outdoor measurements of PM supplemented by indoor PM measurements in 25% of the homes. This study will be the largest investigation ever conducted of the exacerbation of asthma by PM. Over the last few years, panel studies have moved beyond measures of the initial pulmonary insult, such as pulmonary function levels, to measures of the systemic health effects of PM exposures. The first such study was conducted in Utah Valley among retired faculty and staff of Brigham Young University. Reasoning that PM-induced inflammation should decrease pulmonary diffusing capacity, Arden Pope and colleagues w55x used a pulse oximeter to measure the degree of oxygen saturation in the peripheral blood. They found that the daily variation in PM exposure was not consistently associated with hypoxia, but was associated with increased pulse rate. Increased pulse rate is an indicator of an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system and has been associated with cardiovascular mortality in prospective studies of clinically normal adults w40x. These findings have apparently been confirmed by several studies presented at recent scientific conferences. In Boston, Dr. Diane Gold and colleagues examined 21 active elderly aged 5387 years and found that PM 2.5 levels in the 2 h before the examination was associated with decreased heart rate variability w56x. In their 1997 Baltimore study of 26 nonsmoking, active elderly, Dr. Liao and colleagues w57x at the EPA Epidemiology and Biomarkers Branch found that PM 2.5 levels were associated with decreased heart rate variability and increased heart rate, but not with decrements in lung function or oxygen saturation. Heart rate variability is an important indicator of the proper function of the parasympathetic arm of the autonomic nervous system w58x. In these studies, electrocardiographs ECG. are filtered to exclude missing data, noise effects, ectopic beats a beat that begins at a point other than the sinoatrial node., and arrhythmic events that do not result

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from normal sinus node depolarizations. From the filtered ECG, the instantaneous heart rate is computed for each interval between normal beats. Heart rate variability is computed from the variation in this instantaneous heart rate. Using a Fourier transformation, heart rate variability may be separated into the high frequency variation, that is heart rate changes over a 1- to 4-beat period, and a series of lower frequency signals. High frequency heart rate variation is controlled by the Vagus nerve, part of the parasympathetic arm of the autonomic nervous system. The Vagus nerve also innervates pulmonary C-fibers and pulmonary neuroepithelial bodies in the airways and alveoli w59x. Vagal pulmonary C-fibers are stimulated by inhaled wood smoke in rats w60x and stimulation of pulmonary C-fibers produces the rapid, shallow breathing associated with the typical pulmonary response to inhaled irritants w61x. Decreased high frequency heart rate variability has long been recognized as an important indicator of mortality among recent heart attack survivors w62x. Recent work suggests that decreased heart rate variability may be the most important predictor of arrhythmic events and sudden death after an acute myocardial infarction w63x. Decreased heart rate variability also is an indicator of the progression of congestive heart failure and is an indicator of the extent of left ventricular dysfunction w64x. Among clinically normal adults, the Framingham Heart Study showed that decreased high-frequency heart rate variability was associated with long-term mortality w65x. The EPA Epidemiology and Biomarkers Branch has repeated the Baltimore study design over 4 weeks in the summer of 1998 during a period of higher ozone among a cohort of 57 active elderly residents of a retirement community. Along with a complete battery of outdoor, indoor and personal PM measurements, investigators measured heart rate, heart rate variability, supine and standing blood pressure, peak expiratory flow rate every other day w66x. Hematologic parameters were measured weekly and a carotid ultrasound was performed once to assess degree of atherosclerosis. These physiologic parameters will be measured in a new cohort of active elderly residents of a retirement community in Fresno, CA, during the winter and spring of 1999. Both of these studies should be completed prior to the drafting of the next Air Quality Criteria for Particulate Matter. Case-crossover analysis of the timing of coronary events permits the identification of short-term risk factors for coronary events w67,68x even for environmental factors with significant time trends w69x. Short-term pulmonary inflammation produced by acute respiratory tract infection was associated with first-time acute myocardial infarctions in a recent case-crossover study w70x. Investigators at the University of Washington w71x, the Harvard School of Public Health, and elsewhere are independently working to apply this technique to study the impact of recent PM exposures on the timing of acute myocardial events and sudden death.

8. Epidemiology of chronic PM-health effects The National Research Councils Committee on Research Priorities for Airborne Particulate Matter has recommended that the epidemiology of chronic health endpoints should be postponed pending the improvement of toxicological information on the

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effects of the various constituents of PM. Once the toxic constituents of PM have been further characterized by animal experiments and controlled clinical studies the epidemiology of PM-induced chronic health effects will recommence. The two major alternative epidemiologic designs for chronic disease endpoints are the retrospective analysis of existing adult cohorts using imputed PM exposures and the prospective study of new cohorts using concurrent measurements of PM exposures. In a retrospective study, researchers would identify elderly subjects and impute their of past exposures to specific constituents of PM from recent exposure measurements. The advantages to this design would include the enhanced power to detect the relatively rare event of PM-induced mortality using a case-control approach and the speed with which a study might be conducted using a retrospective cohort approach. The disadvantages would include the problems associated with imputing past PM exposures and the limited ability to control for potential confounders such as diet and exercise. In a prospective study, researchers would enroll a panel of middle-aged adults and measure their current PM exposures. The advantages to this design would include the ability to fully characterize the subjects health status at enrollment, the ability to control for potential confounders, and the ability to accurately assess personal PM exposures. The disadvantages would include the large size of the cohort required to have sufficient power to detect the health effects and the long time required for the accumulation of a sufficiently large number of health events. Both designs would benefit from the measurement of physiologic parameters in addition to the more common counting of health events such as hospitalization and mortality. The studies should measure the development of early health endpoints such as the onset of atherosclerosis and hypertension and the age-related decline in pulmonary function. Pulmonary function has the advantage over all-cause mortality in that diet and exercise are relatively weak determinants of pulmonary function levels and are unlikely to be strong confounders of the PM-induced health effect. 9. Conclusions Recent longitudinal epidemiologic studies of PM-induced health effects have moved beyond the studies of mortality and hospitalization in open cohorts. The future of PM epidemiology lies in prospective studies with repeated measurements of physiologic parameters in well-characterized cohorts of active, elderly subjects and asthmatic children. Preliminary results of experimental and epidemiologic studies suggest that exposure to PM may have an impact on the autonomic nervous system with measurable changes in cardiac function. 10. Disclaimer The research described in this paper has been reviewed by the US Environmental Protection Agency. The contents do not necessarily reflect the views or policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

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