The Toxicity of Diesel Exhaust: Implications for Primary Care

Diesel Exhaust Composition

There are many components of diesel exhaust, including (1) carbon monoxide and carbon dioxide; (2) nitrogen oxides; (3) sulfur oxides; (4) hydrocarbons; (5) unburned carbon particles (soot); and (6) water.² Exhaust from diesel engines is considered to contribute to more than 50% of ambient particulate matter with a mass median aerodynamic diameter less than 10 μm (PM10), greatly contributing to overall air pollution. For fine particulate matter with a diameter below 2.5 μm (PM2.5) and ultra-fine particles with a diameter below 0.1 μm, this contribution is even higher.¹ These carbon particles are small enough to be inhaled and deposited in the lungs but have a large surface area. Organic compounds from diesel exhaust with known toxic and carcinogenic properties, such as polycyclic aromatic hydrocarbons (PAH), adhere easily to the surface of the carbon particles and are carried deep into the lungs.⁴ The majority of these particles tend to be found in the greatest concentration within the immediate vicinity of busy streets or highways.^7,8 Diesel engines emit other toxic compounds in disproportionately higher concentrations than gasoline engines, including nitrogen oxides, sulfur oxides, ozone, formaldehyde, benzene, and smaller organic molecules. Diesel engines also produce 26% of the total nitrogen oxides in outdoor air. Nitrogen oxides are a major contributor to ozone production and smog. More attention has been focused on the hundreds of different types of organic molecules created from the high-compression ratios of diesel engines because many are highly toxic.¹ A summary of the composition of diesel exhaust and its biological effects are detailed in Table 2.

Cardiac Effects

Acute coronary syndrome (ACS) and other thrombotic effects have been associated with acute exposure to diesel exhaust.^9,10 A recent study by Mills and associates evaluated men with previous myocardial infarction who were exposed to diesel exhaust during moderate exercise. Significant ST-segment depression was noted, as well as diminished release of endothelial tissue plasminogen activator.¹¹ Possible mechanisms to explain these results include diesel exhaust-induced coronary vasoconstriction, transient thrombus formation, carbon monoxide exposure, and altered myocardial energetics.¹² Another recent study of 1816 postmenopausal women with long-term exposure to air pollution, of which diesel exhaust represented a significant proportion, concluded there was an increased risk of cardiovascular disease and death proportional to the level of exposure.¹³ One European study group examined the association between exposure to diesel exhaust and hospital admission for ischemic heart disease in 8 cities and found that patients 65 years and older had a significantly increased risk of ACS after exposure to diesel pollution.¹⁴ In a study performed in a major European city, Peters et al determined that exposure to traffic, with its high levels of diesel exhaust, was associated with the onset of myocardial infarction within 1 hour. They concluded the time spent in traffic was consistently linked with an increased risk of myocardial infarction.¹⁵

Diesel exhaust particles (DEPs) have been shown to be cardiotoxic in animal studies. Minami and colleagues demonstrated in a guinea pig model that DEPs had a negative inotropic effect, induced arrhythmias, and caused sudden cardiac death.¹⁶ Another animal study by Sakakibara et al determined that DEP-induced cardiotoxicity could not be prevented with propranolol, atropine, verapamil, diltiazem, diphenhydramine, indomethacin, superoxide dismutase, or catalase.¹⁷ Diesel exhaust induces heart rate variability, ventricular arrhythmia, a significant decrease in left-ventricular systolic pressure, and an increase in left-ventricular end-diastolic pressure in animal models.^18,19 It is postulated that DEP produces superoxide radicals, which cause irreversible myocardial damage leading to cardiac arrest.²⁰

DEPs also have been shown to induce immunoglobulin E synthesis and cause histamine release.²¹ Histamine is a potent coronary vasoconstrictor and platelet and thrombin activator, and it up-regulates P-selectin on endothelial cell surfaces.²² A high incidence of serious cardiac arrhythmias was noted in patients with implanted cardioverter defibrillators who had significant exposure to air pollution.²³ Zanobetti and Schwartz reported that diabetics have twice the risk of ACS-related admission because of particulate air pollution exposure.²⁴ Another study from Finland found that patients undergoing serial cardiac exercise testing had a higher incidence of ST-segment depression during days of high particulate air pollution.²⁵ Progression of atherosclerosis has also been linked to air pollution exposure.²⁶

Occupational hazards may also be a factor in development of coronary artery disease. Finkelstein et al, after controlling for smoking, reported higher incidence of ischemic heart disease in heavy equipment operators chronically exposed to DEPs.²⁷ It may then be important for primary care physicians to inquire about occupational or environmental exposure to diesel exhaust from patients presenting with chest pain and dyspnea. For patients whose ACS was indeed precipitated by acute exposure to diesel exhaust, it will be important to counsel them about avoiding diesel fumes in the future.

Pulmonary Effects

DEPs have been demonstrated to increase the production of inflammatory cytokines such as interleukin 1β, interleukin 8, and granulocyte-macrophage colony-stimulating factor from cyclo-oxygenase stimulation in bronchial epithelial cells.²⁸ This in turn results in decreased adhesion between cells, reduction of structural integrity, and inhibited repair. Pulmonary damage incurred from DEP exposure may resemble that caused by bacterial endotoxin.²⁹ Asphyxiation from diesel exhaust is more likely to be caused by acute lung injury from soot particles, nitrogen dioxide, and sulfur dioxide than by carbon monoxide. This is different from gasoline exhaust, which contains 28 times more carbon monoxide than diesel exhaust.³⁰ Nevertheless, in patients with significant acute and/or chronic diesel exhaust exposure, carbon monoxide levels should be checked. In the absence of deliberate exposure, elevated carbon monoxide levels may represent a marker for serious exposure to diesel exhaust and should be further investigated. Patients with reactive and/or obstructive airway diseases such as asthma and emphysema may have their underlying disease exacerbated as a result of exposure to diesel exhaust.^31–33 Visits to the emergency department for pulmonary complaints have been shown to increase during periods of severe air pollution.³⁴ One possible explanation is DEPs combining with atmospheric allergenic molecules to create even more inflammatory allergens.³⁵ Admission rates for pediatric asthma exacerbation have been shown to be higher in areas with greater-than-average diesel emissions.³⁶ DEPs have been shown to directly induce degranulation of mast cells with subsequent histamine release.³⁷ Histamine release-induced by exposure to DEPs may result in allergic conjunctivitis, rhinosinusitis, pharyngitis, laryngitis, and chronic cough.³⁸ Macrophages, the first line of immunologic defense within the lung, are severely impaired from exposure to high concentrations of DEPs, resulting in an increased risk of bacterial and viral bronchitis and pneumonia.³⁹ Although no relevant clinical studies have been published, primary care physicians may consider the inclusion of antihistamines in addition to β-agonists and corticosteroids for the care of patients with acute exacerbation of reactive airway disease precipitated by diesel exhaust exposure.

Many substances in diesel exhaust, such as ozone, can contribute to lung tissue destruction. Ozone is formed from nitrogen oxides, which diesel engines emit in disproportionately higher amounts compared with catalytic converter-equipped gasoline engines. Many of the hydrocarbon molecules emitted by diesel engines, such as PAH, are quite toxic to the lung. Living in areas with high DEPs accelerates pulmonary disease. Chronic exposure to DEPs is associated with an increased risk for the development of asthma. Churg et al compared postmortem lung histology of nonsmoking inhabitants of Mexico City, Mexico, with those of Vancouver, British Columbia, Canada.⁴⁰ The lungs of the Mexico City inhabitants were significantly more diseased, with smaller airways consistent with an obstructive pattern and ultra-fine particles embedded in the airway mucosa. A similar study comparing young, recently deceased patients in Los Angeles and Miami found higher levels of pulmonary centriacinar inflammation in the Los Angeles residents.⁴¹ A large study of children demonstrated a significant decrease in the forced expiratory volume in 1 second (FEV1) in those patients living in areas with high concentrations of DEPs.⁴² Another pediatric study concluded a dose-dependent inverse association exists between the carbon content of airway macrophages and FEV1 for children living in urban areas with significant diesel exhaust exposure.⁴³ Workers in enclosed spaces such as mines and ships are especially at risk from DEP-induced pulmonary disease. Jorgensen and Svensson reported that underground miners had productive cough and frequent respiratory infections,⁴⁴ and Wade and Newman attributed asthma in train crews to diesel exhaust.⁴⁵

Cancer

In 1989, the International Agency for Research on Cancer concluded that there is sufficient evidence for the carcinogenicity of diesel exhaust in experimental animals but limited evidence for carcinogenicity in humans. In 1990, California identified diesel exhaust as a substance known to cause cancer. Diesel exhaust particles have been shown to directly damage DNA and result in carcinogenesis in several animal lung studies.⁴⁶ Diesel exhaust particles have been shown to generate reactive oxygen species, which lead to oxidative stress and DNA damage. PAH associated with diesel exhaust are genotoxic, forming PAH-DNA adducts and resulting in mutation and DNA strand breakage.⁴⁷ Occupational studies of railroad workers, heavy equipment operators, and truck drivers have demonstrated a significantly higher-than-normal incidence of death from lung cancer.^48,49 A more recent case-control study of occupational diesel exhaust exposure in Montreal, Quebec, Canada found a limited association with lung cancer in both smokers and nonsmokers.⁵⁰ Gustavsson et al reported that workers exposed to combustion products had a higher incidence of esophageal cancer.⁵¹ In a study by Guo et al, human exposure to DEPs was associated with a higher risk of ovarian cancer but not with esophageal, testicular, or urinary tract cancers or leukemia.⁵² A possible causal relationship between DEPs and multiple myeloma was reported by Lee et al.⁵³

Hypertension

A link between hypertension and diesel exhaust exposure seems to exist, based on several studies.^54–57 Transient hypertension has been associated with brief periods of severe pollution and is possibly related to the effect of DEPs on cardiovascular autonomic control. This sudden increase in blood pressure may be a cofactor in the development of myocardial ischemia precipitated by diesel exhaust exposure. At levels encountered in an urban environment, inhalation of dilute diesel exhaust impairs regulation of vascular tone and endogenous fibrinolysis.⁵⁸

Neurotoxicity

Volatile hydrocarbons such as PAH attach to DEPs and are rapidly absorbed through the lungs into the central nervous system. A possible association between chronic DEP exposure and Parkinson's disease has been explored because DEPs have been shown to decrease the number of dopaminergic neurons in the brain tissue of mice.⁵⁹ Another study group demonstrated that brain inflammation induced by DEPs resulted in histopathologic changes similar to those seen in patients with Alzheimer's disease.⁶⁰ The result of chronic DEP exposure may affect learning ability, coordination, memory, and judgment in both children and adults.⁶¹ Kilburn demonstrated slowness of response, memory loss, and disordered sleep suggestive of neurobehavioral impairment in workers whose occupations involved significant indoor diesel exhaust exposure. Abnormalities such as visual field defects, delayed blink reflex latency, and balance impairment, as well as impaired recall memory, problem solving, and perceptual motor speed tests were also detected.⁶²

Perinatal Health and Infertility

Several worldwide studies have linked diesel exhaust exposure to low birth weight in infants, premature births, congenital abnormalities, and elevated infant mortality rate.^63–66 DEPs caused a significant decrease in adult sperm production and a diminished number of Sertoli cells in an animal model.⁶⁷ Other studies have shown aberration of sex hormone production and effect in chronically exposed female rats, with increased levels of testosterone and subsequent masculinization.⁶⁸ Pregnant rats exposed to DEPs had higher rates of spontaneous abortions. There are few human epidemiologic studies, but one study demonstrated a negative effect of DEPs on human sperm motility.⁶⁹ Another compound isolated from DEPs, 4-nitrophenol (PNP), has been identified as a vasodilator. One study group demonstrated that PNP has estrogenic and antiandrogenic activities in vivo, leading to sterility.⁷⁰ The accumulation of PNP in air, water, and soil may be one factor in the increasing incidence of sterility in humans and animals, but epidemiologic studies are pending.

The Future

In 2001 the Environmental Protection Agency proposed the Heavy-Duty Engine and Vehicle Standards and Highway Diesel Fuel Sulfur Control Requirements, to be implemented by 2008.¹ The production and distribution of low (<30 parts per million) sulfur content diesel fuel, which is widely available in Europe, is one of the most significant changes in policy. This cleaner diesel fuel is viewed as being essential to reducing tailpipe emissions from large trucks and buses; the current sulfur content prevents pollution control equipment from working properly.⁷¹ After-treatment devices such as diesel particulate filters, traps, and nitrogen oxide-reducing catalysts are also being implemented. One study found that buses using diesel and compressed natural gas as well as clean diesel fuel and particulate traps were superior to standard diesel buses with regard to emissions.⁷² A new generation of diesel engines developed for Europe should become available in the United States in the near future. The Environmental Protection Agency has issued a Notice of Proposed Rulemaking to implement onboard diagnostic systems to monitor diesel exhaust emissions on heavy-duty engines used in highway vehicles over 14,000 pounds by 2010. Individual states are also implementing “No Idling” policies with regard to diesel-powered vehicles that are not in active use.

Conclusions

As populations continue to grow worldwide, the expansion of mass transportation and the construction of new buildings for housing and commerce will occur concomitantly. Until alternative energy sources are fully developed and implemented, reliance on diesel fuel will increase. Acute and chronic exposure to diesel exhaust will continue to be a problem in the United States. This will ultimately increase the number of patients presenting to urban primary care clinics and emergency departments with cardiopulmonary disease, neurological disorders, and adverse perinatal events. If new regulations and technology to reduce DEP emissions are fully implemented and prove to be effective, this outcome may be averted. The omnipresence of diesel exhaust in urban areas may lead the clinician to preclude its query in the patient's history. A plethora of unexplained signs and symptoms may be caused by diesel exposure (Table 3). Although no specific screening guidelines exist, primary care physicians should question patients about potential exposure to diesel exhaust and be familiar with its myriad deleterious health effects.