Cardiovascular diseases are the leading cause of death in the United States. Morbidity (other than hypertension) and death from cardiovascular disease occur after the age of 50. Death is due to coronary heart disease or cerebrovascular disease. Factors that contribute to increased risk of those diseases can be assumed to contribute either to chronic risk or to acute triggering of an event. Although dividing putative risk factors between chronic and acute effects is somewhat artificial, it is useful for the present review. If exposures that occurred in the Gulf War play a role in the onset of cardiovascular disorders, it is necessary to postulate that the exposures contribute to chronic processes, such as atherosclerosis. Those chronic processes are complex and multifactorial, eventually occur to some extent in nearly all adults, and are believed to begin in adolescence. There are many established risk factors for cardiovascular diseases, including smoking, male sex, diabetes, hypertension, family history, and blood lipid concentrations. Determining that a relatively brief exposure to combustion products in the Persian Gulf is associated with occurrence or acceleration of atherosclerotic cardiovascular disease—and results in increased incidence of disease years later—is a substantial challenge. Determining that such an effect occurs after an exposure-free period is even more difficult.
The vascular biology of ischemic heart disease and the effect of combustion products on the cardiovascular system are rapidly evolving subjects of scientific inquiry. Much additional information that will inform the toxicologic and epidemiologic database can be expected in the next 2–10 years.
As previously noted, the committee’s inclusion criteria require specificity of outcome, methodologic rigor, and some exposure information. Studies that meet the committee’s inclusion criteria are referred to as primary studies; ecologic and toxicologic studies, studies of self-reported exposure or multiple exposures, and studies of intermediate1 outcomes or with lack of specificity about outcomes, such as a broad range of International Classification of Diseases (ICD) codes, are considered support studies. For relevance to Gulf War veterans, the committee focused on long-term cardiovascular effects that persist after exposure ceases (see Chapter 2).
FUELS AND CARDIOVASCULAR DISEASE
Several studies (Huang 1986; Pollini et al. 1986, 1989; Van Peenen et al. 1985) have been conducted in the petroleum industry to identify and assess potential cardiovascular risk factors. However, the studies did not look specifically at whether exposure to petroleum products or fuels was associated with an increased risk of cardiovascular disease. Instead, they attempted to identify behavioral risk factors and potential screening tools that could form the basis of behavior-modification programs and health risk assessments among petroleum industry-workers.
In contrast, cohort mortality studies of petroleum-refinery workers (such as Christie et al. 1987; Dagg et al. 1992; Hanis et al. 1985; Kaplan 1986; Rushton and Alderson 1981; Tsai et al. 1992; Wong et al. 2001a, 2001b) have examined mortality due to cardiovascular and cerebrovascular diseases. The researches typically used job titles to assess exposure and this can lead to misclassification of exposures. The studies found no increased risk of cardiovascular or cerebrovascular diseases among petroleum-industry workers compared with the general population. In fact, in many studies, mortality was lower than expected. For example, in Wong et al. (2001b), ischemic heart disease had a standard mortality ratio (SMR) of 0.88, 95% confidence interval (CI) 0.77–0.99; chronic endocardial disease and other myocardial insufficiencies had an SMR of 0.08, 95% CI 0.00–0.46; and all other heart disease had an SMR of 0.64, 95% CI 0.43–0.92. As discussed previously, the “healthy-worker effect” probably contributed to those findings.
The committee is unable to draw a conclusion of association given the lack of studies that specifically examined the relationship between exposure to fuels and cardiovascular diseases and the large confounding role of hypertension, high blood pressure, smoking, diet and exercise—which are not often controlled for in cohort mortality studies—in the etiology of those diseases.
COMBUSTION PRODUCTS AND CARDIOVASCULAR DISEASE
The literature on combustion product exposure and cardiovascular disease is large and complex and the there have been recent publications that provide background for this burgeoning area of research (for example, Brook et al. 2004). However, a substantial portion of the literature concerns occupational cohorts in specific occupations (for example, vehicle drivers and tunnel workers) whose exposure is of uncertain relevance to the exposures in the Persian Gulf; such studies are nonetheless considered in this review. Another, larger group of studies, regarding acute exposure to particulate air pollution and cardiovascular events (morbidity and mortality), were not considered relevant to this review; these studies, typically time-series or case-crossover analyses, provide information on events that occurred within days of exposure and so are not relevant to Gulf War exposure and onset of cardiovascular effects long after return from the Gulf War. One useful background reference would be the recently published statement on air pollution and cardiovascular diseases from the American Heart Association.
A common difficulty in assessing the literature for this review is the lack of specificity of diagnoses reported in published articles. For example many articles treat “cardiopulmonary mortality” as one outcome. That provides some information on effects, but it is difficult to translate such a highly heterogeneous outcome into specific diagnoses to support conclusions on specific health outcomes.
This section covers the effect of exposure to combustion products on long-term cardiovascular outcomes, including ischemic heart disease, myocardial infarction, and
cerebrovascular disease. It is divided into studies of Gulf War veterans, air-pollution studies, and occupational studies. Each subsection begins with primary studies that had strong methods and exposure information, and then takes up support studies that are not as methodologically robust. If the support studies’ findings are consistent with those of the primary studies, they add weight to the primary evidence.
Gulf War Veteran Studies
In February 1991, retreating Iraqi forces set fire to more than 600 oil wells. Fires burned over a 10-month period, until November 1991, exposing thousands of US troops to combustion products. The two studies summarized below (Smith et al. 2002; Proctor et al, 1998) were the only well-designed Gulf War studies that examined cardiovascular effects expressly in relation to combustion-product exposure. The study of Smith et al (2002), the stronger of the two studies by virtue of its objectively documented exposures did not find a relationship; that finding is consistent with several studies of Gulf War veterans that are not reported here because they did not examine specific exposures in relation to symptoms. Another study (Kang et al. 2000), a large and representative, population-based study of 15,000 Gulf War veterans, did not find greater self-reporting of coronary heart disease among Gulf War veterans than among controls Similarly, mortality studies of Gulf War veterans have not found excess cardiovascular disease deaths.
Smith et al. (2002) examined hospitalization patterns of all active-duty personnel who were deployed to the Gulf War in 1991–1999 (n=405,142) and who were in the Persian Gulf during the oil-well fires. For each active-duty veteran (hospitalized and nonhospitalized alike), the study assigned an oil-smoke exposure by using National Oceanic and Atmospheric Administration modeling (Draxler et al. 1994; McQueen and Draxler 1994). Six exposure categories were created on the basis of average daily exposure and duration of exposure. The largest category of exposure to particulate matter (137,000 personnel) was 1–260 μg/m3 for 1–25 days; this was similar in dose but of much shorter duration than the exposure of those in the American Cancer Society (ACS) cohort (see below and Chapter 5). The study examined hospitalizations in relation to exposure. Hospitalizations were for any cause, for major diagnoses in International Classification of Diseases, 9th Edition-Clinical Modification, and for nine specific diagnoses potentially related to oil-well fires.2 A subject who had been hospitalized with one of the specific diagnoses before the war was excluded from further analysis. The study examined only hospitalizations in Department of Defence (DOD) hospitals because of the availability of data. It found decreased risk of ischemic heart disease among exposed than among nonexposed veterans (relative risk [RR] 0.82, 95% CI 0.68–0.99). One limitation of the study is that hospitalizations were captured only for DOD hospitals, which care for active-duty personnel or veterans with medical benefits. The authors pointed out, however that rates of service attrition were comparable across all exposure categories, including absence of exposure to smoke from oil-well fires.
Proctor et al. (1998) examined self-reported exposures in relation to the symptom experience of two cohorts of Gulf War veterans from Massachusetts (Ft. Devens) and New
Orleans. The study’s nearly 300 subjects made up a stratified random sample of 2,949 troops from Ft. Devens and 928 troops from New Orleans, both including active-duty, reserve, and National Guard troops. The response rate was 58–85% of those participating in an earlier study who could be contacted and located. The control group (n=50) was Gulf-era veterans deployed to Germany. Subjects were given symptom checklists (covering the previous 30 days), exposure questionnaires, and a neuropsychologic test battery; were interviewed about combat exposure; and underwent diagnostic interviews for posttraumatic stress disorder (PTSD). Each of the 52 symptoms on the symptom checklist was assigned by four independent judges to one of nine body systems, including one for “cardiac symptoms”, defined as irregular heartbeats (or “heart flutters”), chest pain, or racing heart. The exposure questionnaire, given only to Gulf War-deployed subjects, contained eight items, four of which were related to combustion products: “smoke from burning oil wells”, “vehicle exhaust”, “smoke from tent heaters”, “smoke from burning human waste”. In the Gulf War-deployed cohort, multiple regression adjusting for age, sex, education, and PTSD diagnosis was used to determine symptom-exposure relationships. Self-reported exposure to smoke from oil-well fires had no noteworthy associations, however, vehicle exhaust (p=0.026), smoke from burning human waste (p=0.001), and smoke from tent heaters (p<0.001) were associated with cardiac symptoms. But in a second set of multiple regression-analyses with exposures entered as independent variables, vehicle exhaust and smoke from burning human waste were no longer associated with those symptoms. The findings reported above were essentially unchanged when subjects who met criteria for PTSD were removed from analyses. The study limitations were self-reported symptoms and exposures, moderate to low response rate, and lack of representativeness of the entire Gulf War cohort.
Respiratory mortality findings have been reported from several large, longitudinal cohorts with long-term exposures, usually more than 5 years—ACS (Pope et al. 1995), Six-Cities (Dockery et al. 1993), Netherlands Cohort Study on Diet and Cancer (Hoek et al. 2002), and Seventh-Day Adventists (SDAs) (Abbey et al. 1999). All but the SDA study relied on a broad mortality category—cardiopulmonary. Two further analyses, however, provided greater specificity regarding mortality in the ACS and Six-Cities cohorts.
For the ACS cohort, Pope et al. (2004) undertook a more diagnosis-specific analysis with the same methods as their previous report (Pope et al. 2002). The analysis expanded on earlier findings, including 7–16 years of followup of people enrolled in 1982. Exposures to particulate matter were assigned to each participant on the basis of his or her ZIP code at the time of enrollment. For cardiovascular-disease mortality as a composite category, the study found increased RR of 1.12 (95% CI 1.08–1.15) per increase of 10 μg/m3 in PM2.5.3 Within that category, deaths from ischemic heart disease (ICD-9 codes 410–414) were increased (RR 1.18, 95% CI 1.14–1.23) even after adjustment for smoking. Deaths from dysrhythmias, heart failure, and cardiac arrest (ICD-9 codes 420–429) were also increased (RR 1.13, 95% CI 1.05–1.21).
A reanalysis of the Six-Cities cohort by Krewski et al. (2003) found that cardiovascular mortality—instead of the less-specific “cardiopulmonary” mortality—was increased (RR 1.41, 95% CI 1.13–1.76 per increase of 18.6 μg/m3 in PM2.5). The vast majority of cardiovascular mortality was from ischemic heart disease. Nevertheless, although the Six-Cities and ACS findings have been robust to intense scrutiny and reanalysis, the exposure-assessment scheme is
still far from definitive. The Netherlands Cohort Study on Diet and Cancer (Hoek et al. 2002), focusing on motor-vehicle exhaust as a source of air pollution, reported on one composite category covering over 50 ICD codes—cardiopulmonary mortality (most of which was from ischemic heart disease). The study had an improved assessment of exposure compared with the prior cohort studies. It found that living for up to 8 years near a major road had an RR of 1.95 (95% CI 1.09–3.51) for cardiopulmonary mortality (codes 400–440 or 460–519). It did not report on more-specific mortality categories, but most cardiopulmonary mortality was from ischemic heart disease.
The city of Rotorua, New Zealand, is above a geothermally active area with substantial hydrogen sulfide (H2S) exposures. About one-fourth of the population of 40,000 is regularly exposed to H2S exceeding 200 μg/m3 (143 ppb). A series of studies by Bates and co-workers investigated morbidity and mortality from the full range of diseases, including respiratory diseases (Bates et al. 1997, 1998, 2002). The mortality study (Bates et al. 1997), using census data, compared deaths in Rotorua with those in the rest of New Zealand (1981–1990). It found higher SMRs for hypertensive disease (codes 401–405: SMR 1.61, 95% CI 1.24–2.05, p<0.001) but lower SMR for ischemic heart disease (codes 410–414: SMR 0.95, 95% CI 0.89–1.01, p<0.10) and other heart disease (codes 420–429: SMR 0.70, 95% CI 0.58–0.84, p<0.001). The authors interpreted those findings as canceling one another, owing to differences in coding: the rest of New Zealand, unlike Rotorua, is more likely to classify heart disease as “other heart disease” rather than the more-specific hypertensive disease.
Bates et al. (2002) later used hospital-discharge data over a 3-year period (1993–1996) to calculate standardized incidence ratios (SIRs) for respiratory and other diseases (and subgroupings) for Rotorua residents. Exposures were assigned as high, medium, and low, on the basis of mapping of H2S with passive sampling in residential census-area units of 1,000–3,000 people. Exposure-response trends were found for circulatory-system diseases (ICD codes 390–459: p for trend=0.0001); for ischemic heart disease (codes 410–414: p for trend <0.02), cerebrovascular disease (codes 430–438: p for trend=0.01), and diseases of arteries, arterioles, and capillaries (codes 440–448, p for trend=0.002). The authors had no information on smoking and socioeconomic status (SES) as potential confounders and no information on residential histories or daily variations for work or study. The limited exposure-assessment information makes it difficult to interpret a dose-response relationship for cardiovascular disease.
In a third study, Bates et al. (1998) used hospital-discharge data over a decade (1981–1990) to calculate SIRs for cardiovascular disease (and subgroupings) for Rotorua residents. In contrast with the other incidence study (Bates et al. 2002), no exposure categories were assigned. The SIRs were slightly increased for cardiovascular disease (codes 390–459: SIR 1.05, 95% CI 1.02–1.07, p=0.001). But the overall figure masked a variety of lower risks of some minor disease groupings, and higher risks of others. Lower risks were those of diseases of pulmonary circulation (codes 415–417: SIR 0.72, 95% CI 0.54–0.93, p=0.01) and cerebrovascular disease (codes 430–438: SIR 0.85, 95% CI 0.79–0.91, p<0.001). Greater risks were those of hypertensive disease (codes 401–405: SIR 1.15, 95% CI 1.00–1.32, p=0.05), other heart disease (codes 420–429: SIR 1.06, 95% CI 1.00–1.13, p=0.04), and diseases of arteries, arterioles, and capillaries (codes 440–448: SIR 1.17, 95% CI 1.07–1.28; p=0.001). The Bates studies were the only epidemiologic studies of H2S found by the committee that examined long-term health outcomes. Due to the paucity of literature, the committee did not make a separate conclusion on H2S.
Gustavsson et al. (2001) conducted a case-control study of myocardial infarction among men and women (45–70 years old) in Stockholm, Sweden. Strict diagnostic criteria and a population-based design were used to identify the first, nonfatal myocardial infarction. A detailed occupational history was obtained with a questionnaire, which was followed by a sophisticated job-exposure matrix to provide quantitative exposure intensity of motor-vehicle exhaust as assessed with carbon monoxide (CO) and other combustion products as assessed with respirable particles. Exposures were expressed in terms of highest intensity during at least 1 year of work and cumulative exposure. Exposures were presumably higher in earlier decades, and time in occupation contributed to the cumulative-exposure estimate. Information on potential confounders (age, sex, smoking, hypertension, obesity, and diabetes), was obtained and incorporated into the analysis. It is not clear whether SES was used in the analysis, considering that referents were somewhat more likely to be of higher SES (25% of referents vs 19% of cases) and cases were substantially more likely to be manual workers (34% of cases vs 25% of referents). Fairly consistent effects were observed for combustion products, and there was evidence of a dose-response relationship. Myocardial infarction was, after adjustment, increased in the combustion-product group with high intensity during at least 1 year of occupational exposure (RR 2.11, 95% CI 1.23–3.60) and with intermediate intensity (RR 1.42, 95% CI 1.05–1.92). The analysis of the exposure-response trend generated an RR of 1.24, 95% CI 1.07–1.51. An exposure-response trend was also found for the other exposure category, cumulative exposure (in milligrams of respirable particles per cubic meter per year). The group with high cumulative exposure to combustion products had RR 1.35, 95% CI 1.02–1.79, and the group with intermediate cumulative exposure had RR 1.22, 95% CI 0.91–1.64. For the motor-vehicle exhaust group (which included many of the same subjects as the combustion-products group), myocardial infarction was not increased with high exposure (after adjustment), but was increased with intermediate exposure (RR 1.32, 95% CI 1.01–1.73). The trend analysis for the motor-vehicle exhaust group was not noteworthy. Examples of high combustion-product exposure referred to exposures at the threshold limit value. Examples of occupations with high combustion-product exposure were ship engine room crew, firefighters, engineers and technicians in energy production, chimney sweeps, and blacksmiths.
Mortality was studied in a subset of the large ACS cohort to assess occupational exposure to diesel exhaust (Boffetta et al. 1988). The study, initiated in 1984, enrolled 1.2 million people. The focus was on men (40–79 years old) and used a crude job-exposure matrix (based on 2-digit standard industrial classification codes) to determine exposure to diesel exhaust. Men with and without exposure to diesel exhaust were compared. Exposure was not associated with an increased risk of ischemic heart disease (RR 0.98) on the basis of 398 deaths, but there was an increased risk of cerebrovascular disease (codes 430–438: RR 1.61, p<0.05) on the basis of 62 deaths, and of “arteriosclerosis” a minor ICD category (code 440: RR 3.12, p<0.05) on the basis of 10 deaths. However, mortality attributed on death certificates to arteriosclerosis is nonspecific and thus difficult to interpret.
Alfredsson et al. (1993) performed an incidence and mortality study of myocardial infarction among bus drivers in Sweden over a 15-year period. It relied on two population-based registries—one of first acute myocardial-infarction hospitalizations and another of all deaths. Registries were linked to census records of occupation. Comparing male bus drivers with people in other occupations, the study found a higher incidence of myocardial infarction in bus drivers (RR 1.4, 95% CI 1.1–1.8, adjusted for age, calendar year, county, and SES); the effect appeared
to decline in retirement. The cohort-mortality study found a small excess of myocardial-infarction deaths and ischemic-heart-disease deaths in bus drivers (RR 1.1, 95% CI 1.0–1.3) with adjustment for age and county but not for smoking or SES. However, the increased mortality risk was unlikely to have been due to smoking inasmuch as lung-cancer mortality was not increased in those workers.
A cohort-mortality study compared 5,529 tunnel (high exhaust) and bridge (low exhaust) workers to the rest of the NYC during 1952–1981 (Stern et al. 1988). Although the focus of the study was on CO, there is no evidence that it was not a study of all combustion products. There was a substantial excess of deaths from atherosclerotic heart disease (ICD-9 codes 410–414). Bridge workers had an SMR for atherosclerotic heart disease of 0.85, and tunnel workers 1.35 (90% CI 1.09–1.68, p<0.05); the effect was much larger in tunnel workers who had more than 10 years on the job. Risk differences between tunnel and bridge workers decreased after separation from employment. No exposure assessment was conducted other than some representative CO monitoring. There was no control for confounders (SES, smoking, and so on), but the lack of excess lung-cancer or emphysema deaths and the identical smoking rates in tunnel and bridge workers suggest that the effect is unlikely to be related to smoking. Bridge and tunnel workers are drawn from the same applicant pool, so SES differences are less likely.
A mortality study in a cohort of Montreal bus drivers (Paradis et al. 1989) found an excess of death from circulatory system diseases (codes 390–458: SMR 122; 95% CI 105–140) and ischemic heart disease (codes 410–414: SMR 120, 95% CI 102–141) in bus drivers with less than 30 years of exposure. Deaths from circulatory system disease and ischemic heart disease were not increased, however, among those with more than 30 years of employment (SMRs 99 and 95, respectively) and there were no increased risks in those employed more than 5 years (circulatory disease SMR 109, 95% CI 99–119; ischemic heart disease SMR 106; 95% CI 95–118). The findings do not preclude a small effect, but there was no control for important confounders such as smoking.
Rushton et al. (1983) studied mortality in a cohort of bus maintenance workers in London was. When they compared those workers with the male population of England and Wales, they found a deficit of ischemic heart disease. However, there was no control for SES, smoking, or other confounders.
Several similar occupational mortality studies were difficult to interpret owing to lack of exposure data or lack of control for confounders (Borgia et al. 1994; Hansen 1989; Maizlish et al. 1988; Michaels and Zoloth 1991; Stern et al. 1981) or lack of control groups (Herbert et al. 2000).
Eight mortality studies were conducted in urban firefighters (Aronson et al. 1994; Beaumont et al. 1991; Burnett et al. 1994; Demers et al. 1992; Deschamps et al. 1995; Feuer and Rosenman 1986; Heyer et al. 1990; Musk et al. 1978) there was one cohort study of coronary heart disease incidence (Glueck et al. 1996), and one study of ischemic heart disease incidence among firefighters nested in a cohort study (Dibbs et al. 1982). Those studies share several features and collectively do not inform the committee’s evaluation of the relationship between combustion-product exposure in the Persian Gulf and cardiovascular disease, for the following reasons: all studies were of urban firefighters whose exposures are of uncertain relevance to fossil-fuel combustion-product exposure during the Gulf War; firefighters are typically screened for health problems, and those with health problems often leave the line of work earlier, so such studies are especially susceptible to the healthy-worker effect, which can strongly bias observed relationships, especially in the case of cardiovascular disease (Murray et al. 1979), making the
negative associations observed in the majority of the studies impossible to interpret; and firefighters probably differ from people in other occupations with regard to several potentially confounding factors that may influence the incidence of cardiovascular disease. Only the Dibbs et al. study, nested within the Normative Aging Study, has the capability to adjust for potential confounding factors, although the analysis is unclear as to whether the authors have done so.
There is relatively consistent epidemiologic evidence of the relation between ischemic heart disease (including myocardial infarction) and long-term exposure to fossil-fuel combustion products, including motor-vehicle exhaust and combustion-derived fine particulate matter. Several well-designed primary studies support an association (Dockery et al. 1993; Gustavsson et al. 2001; Hoek et al. 2002; Pope et al. 2004), as do several support studies (Alfredsson et al. 1993; Bates et al. 1997; Stern et al. 1988). However, the increased risk is small in absolute terms, and there is no adequate epidemiologic evidence to support the role of relatively short exposures (similar to that experienced in the Gulf War), followed by an exposure-free period, and then development of ischemic heart disease events. The committee recognizes that scientific inquiry in this subject is rapidly evolving, and that more definitive information may be available in the next several years.
The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between short-term exposure (less than 2 years) to combustion products and the development of ischemic heart disease after an exposure-free period of months to years.
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