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Knowledge Web(r) Document Display Page 1 o f 2 Diesel exhaust in the occupational setting. Current understanding of pulmonary health effects. Clin Lab Med 1998 Dec;18(4):767-79 (ISSN: 0272-2712) - Relevance to Query: Maximum Relevance: Comstock ML Health Services, Consolidated Rail Corporation, Philadelphia, Pennsylvania, USA. Doll's landmark 1959 study of the epidemiology of occupational lung cancer failed to find an increased risk in workers exposed to petrol fumes and emissions. In it, he pointed out a critical issue that is not resolved today. With theoretically increased risk based on biological plausibility but an absence of positive findings, epidemiologic methodology cannot reliably distinguishbetween no risk and very little risk. Despite the ensuing nearly 40 years of research, neither human epidemiologicstudies nor animal studies can support a causal relationship between either lung cancer or noncancer respiratory health effects at current levels of occupational exposure. Even with statistically significant but low relative risks, neither evidence of causality nor level of risk can be definitively established. Epidemiologic data suggest that an increased risk of lung cancer for diesel exhaust exposed workers may be comparable with that for environmental tobacco smoke. Monitoring and control of the particulate is necessary. Prudent policy dictates continued efforts to reduce emissions of soot from diesel engines and decrease occupational exposure as a matter of good health and safety practice. Improvements in engine design, soot filters, and fuel modification will provide the best approach to exposure control. Further research is also needed in the areas of carcinogenic mechanisms and development and validation of biomarkers of exposure before reliable estimates of risk of human health effects in the occupational setting can be made. r Include in Selection List? Related Searches Titles In: [MEDLmEl Authors In: [MEDLINEl Subjects In: JMEDLINEI I Major Subject Heading(s) Minor Subject Heading(s) Lung Diseases [chemically induced] Occupational Exposure 0 Vehicle Emissions [adverse effects] 0 Air Pollution 0 Environmental Monitoring 0 Lung Diseases [epidemiology] Lung Neoplasms [chemically induced] [epidemiology] Vehicle Emissions [analysis] CAS Registry / EC Numbers 0 (Vehicle Emissions) file://C:\WINDOWS\TEMP\KnowleWdgeeb(r) Document Display.htm 3/19/01 TOXICOLOGY 0272-2712/98 $8.00 + .OO DIESEL EXHAUST IN THE OCCUPATIONAL SETTING Current Understanding of Pulmonary Health Effects Marcia L. Comstock, MD, MPH Concern about potential carcinogenicity of diesel exhaust has existed for several decades. More recent widespread use of diesel equipment has intensified the debate about appropriate control of occupational exposure. Numerous cohort and case control studies of occupational exposure have been conducted over the past 20 years in industries with presumed high usage of diesel engines. In 1988 National Institute for Occupational Safety and Health (NIOSH) recommended that whole diesel exhaust be regarded as a potential occupational carcinogen based on an association in some animal studies, although epidemiologic data were weak.% In 1989, the International Agency for Research on Cancer (IARC) classified whole diesel exhaust in Group 2A, probably carcinogenic to humans, concluding that there was sufficient evidence in animals. In humans they believed information was credible; however, chance, bias, or confounding information have not been ruled outz3The US Environmental Protection Agency (USEPA) has classified it into the equivalent B-1 category. Many authorities believe these decisions were premature at best. Exposure criteria for diesel exhaust in the United States have not been defined. Establishing an exposure threshold presumes that investigators can define the level of human health hazard. Although a threshold limit value of 150 pg/m3 has been proposed for submicrometer particu- From Health Services, Consolidated Rail Corporation, Philadelphia, Pennsylvania CLINICS IN LABORATORY MEDICINE -VOLUME 18 NUMBER 4 * DECEMBER 1998 767 768 COMSTOCK late by the American Conference of Governmental Industrial Hygienists (ACGIH), there is much uncertainty in its basis.-` Particulate diesel exhaust, like particulate air pollution, has also been implicated in noncancer respiratory health effects. In 1993, USEPA established an inhalation reference concentration (RfC) of 5 pg/m3 for noncancer effects of diesel exhaust. This was intended to be an estimate of daily human exposure without risk of deleterious effects. The basis for this derivation has been criticized as inaccurate extrapolation. From the perspective of public health policy, there is a dilemma when facing the need to balance health concerns with the economic impact of regulations without proven scientific basis. Do investigators know enough about what is toxic and what causes health effects to properly regulate the matter? If not, premature action could have severe economic consequences. This article reviews the literature on pulmonary health effects of diesel exhaust, with particular reference to occupational exposure. Neither animal data nor epidemiology can accurately define the toxic potential of diesel engine fumes under human exposure conditions. GENERAL AIR POLLUTION Severe air pollution has been known to have adverse health effects. Studies have also reported weak, but statistically significant acute health effects of particulate air pollution, even below the current standard of 150 kg/m3 (24 hr). A 1995 review of the literature, however, concluded that studies are inconsistent, and the criteria for causality have not been met. Confounding by weather, other pollutants in the complex mixtures, or exposure misclassification could explain much of the positive association. Investigators do not yet know which constituents are most potent.I2 The association of ambient particulate matter with serious health effects, however, should not overly influence consideration of the question of diesel exhaust effects. These studies did not examine diesel exhaust; its contribution to particulates in the studies is unknown, and in many investigations, the source was known to be something else. COMPOSITION OF DIESEL EXHAUST Diesel emissions comprise a complex mixture that represents only a fraction of a broad array of air contaminants. Composition varies with fuel composition, engine type, operating conditions, and ambient air. Once emitted, transformation processes may alter the properties of the components, resulting in substances that may be more or less toxic than the original compound. Composition also varies with time of analysis. The chemical and physical composition of emissions has changed and will continue to do so with more stringent emission standards and evolving technology and fuel formulation.'" DIESEL FXFIAUST IN TNF OCCUPATIONAL, SETTING 769 The vapor phase contains gaseous components, such as oxides of carbon, sulfur, and nitrogen, and carcinogenic compounds, including benzene, formaldehyde, 1,3-butadiene, ethylene dibromide, and polycyclic aromatic hydrocarbons and derivatives. The carbon core of fine submicrometer particles is coated with adsorbed trace metals, nitrites, and sulfites, in addition to organic compounds, many of which are cytotoxic or classified as possible human carcinogens or mutagens. Particulate aggregates comprise 60% to 80% elemental carbon by weight. IN VITRO AND ANIMAL STUDIES Particulate and gaseous fractions of diesel fumes have demonstrated direct-acting mutagenic activity with Salnzonella. This is generally attributed to nitro polycyclic aromatic hydrocarbons.3oExtracts from diesel exhaust have considerable mutagenic activity without exogenous metabolic activation, unlike extracts of cigarette smoke. No quantitative relationship between mutagenicity in bacteria and carcinogenesis in humans, however, has been established. In a recent study, only the particle samples, not the semivolatile samples were mutagenic, and most of the mutagenicity was found in the polar fraction. The compounds causing mutagenesis are not polycyclic aromatic hydrocarbons because they require activation and are found in the aromatic, not the polar fraction.1s Inhalation of whole diesel exhaust results in DNA adduct formation in rats. Whole diesel exhaust and particles can also induce structural chromosome aberrations and sister chromatid exchange in cultured mammalian cells. These bioassays on the mutagenic effect of extracts of diesel exhaust are felt by Stobel and Abe140to be the only scientifically robust results supporting the conclusion that diesel exhaust is a borderline carcinogen by chemical carcinogenesis. Evidence from animal studies also indicate that organic extracts of diesel particulate are genotoxic and carcinogenic, Inhalation of whole diesel exhaust resulted in DNA adduct formation in rats. Diesel exhaust was classified by IARC as a probable human carcinogen based on these inhalation rat studies, which also showed an increase in benign and malignant tumors after 2 years. This study period is essentially equivalent to lifetime exposure to high (2-8 mg/m3) concentrations of unfiltered diesel exhaust.*' These results were not replicated in other animals. The phenomenon seems to be rat specific. The relationship between exposure levels and response is not clear cut. Data indicate that particle overload induces increased cell turnover, leading to inflammatory and proliferative changes that precede development of pulmonary tumors in rats. Chronic inhalation of high concentrations of whole diesel exhaust causes destruction of defensive pulmonary mechanisms, promoting development of primitive lung adenocarcinomas. Most studies support the observation 770 COMSTOCK that whole diesel exhaust is the culprit, and filtering exhaust minimizes risk. At lower exposure levels that do not reduce pulmonary clearance, diesel exhaust is not carcinogenic. This supports the notion that the mechanism of carcinogenic action is pulmonary overload and subsequent inflammation, not chemical carcinogenesis. The insoluble carbon core, specifically, is suspected because tumors of the lung have been experimentally induced following exposure to carbon black, which has the same carbonaceous core but no mutagenic adsorbates. Titanium dioxide, a chemically different but equally insoluble substance incapable of forming DNA adducts, also has provoked such tumors.21 Diesel particles also seem to be the main cause of noncancerous effects in animals. Concentrations at which effects are seen in these animal studies are orders of magnitude greater than those generally encountered in the workplace, but exposures shown to cause pulmonary injury in animals are lower than those that increase the incidence of tumors.26 Toxicity associated with acute exposure relates primarily to high concentrations of CO, NO2, and aliphatic aldehydes. With short-term exposure, there are some toxic effects from high concentrations of particulate, but minimal effects on pulmonary function. High concentrations over several months result in accumulation of particles and an increase in alveolar macrophages with aggregation. Decreased resistance to lung infection and behavioral, hematologic, and enzymatic changes, and reductions in growth rate have been noted with exposure of even longer duration. Histologic studies show that chronic exposure to high concentrations of diesel exhaust can cause changes in respiratory tract tissue. Pathologic effects are dependent on relative rates of pulmonary deposition and clearance. With concentrations above 1 mg/m3 and adequate duration of exposure, clearance is reduced because of impaired macrophage function.'l Data for animals other than rats are limited. EPIDEMIOLOGIC EVIDENCE Epidemiologic studies of human exposure are of limited value because of numerous methodologic flaws. Exposure assessment is crude and imprecise. It is not based on actual measurement, but rather is generally limited to few qualitative categories based on occupational features or duration of employment as a surrogate. Surrogates for exposure, however, do not permit estimates of dose-effect relationships or quantification of absolute risk. Confounding the studies by smoking, diet, and other lifestyle related factors or occupational exposures also seriously skews results. Inconsistencies in dose-effect relationships based on job category or duration of exposure are found in key studies. Preconceived bias for positive studies based on presumption of effect is common. Negative DIESEI EXHAUST IN THE OCCUPATIONAL SETTING 771 studies, however, frequently suffer from size limitations that result in lack of statistical power to detect difference or insufficient follow-up in view of disease laten~y.~" Earliest studies undertaken to evaluate the relationship between occupational exposure to diesel emissions and lung cancer were negative; however, none were scientifically rigorous. Studies of railroad workers" and dock workers15 found an association, but there was a definite suggestion that smoking confounded the results. A 1986 review by Steenland3yof 14 studies on lung cancer in truck drivers revealed that none had measured exposure and few adjusted for smoking habits or other potential confounders. He concluded that the studies did not produce a definitive answer. In 1992, MauderlyZs surveyed the literature on effects of diesel exhaust up to 1990 but did not critically analyze the studies. He recognized that the epidemiology was incomplete and contradictory. Up to 1986, none of the epidemiologic investigations published met the methodologic criteria for reliable studies. It has been suggested, too, that results from earlier studies may be less relevant than recent ones because improvements in engine design and emission control technology have altered the chemical composition of diesel exhaust. Mauderly concluded that weight of evidence suggested a possible, although small, carcinogenic effect. It is important to note that he was clearly influenced by investigations whose accuracy was subsequently ~hallenged.~ Only since 1987 have there been studies suggesting an association after adjustment for smoking. These studies too have serious flaws, including design,l0 other potential confounding occupational expos u r e ~ ,p' o~tential exclusion bias, and misclassification.6Case control studies in which smoking habits were carefully assessed and controlled for in the analysis demonstrated increased odds ratios only in the crude analysis and disappeared when smoking was accounted l6 The Garschick investigation of American railroad workers'* may be the best that exists of mortality studies evaluating the hypothesis of a causal link between diesel exhaust exposure and mortality from lung cancer. The investigation was previously thought to provide the most substantive evidence of a small but significant increase in lung cancer risk from diesel exhaust. Major concerns, however, relate to the classification of workers into exposed and unexposed and the methods used to evaluate and control for smoking, which were unsatisfactory based on established quality criteria. More importantly, a later reanalysis of the data requested by the Environmental Protection Agency (EPA) did not confirm the findings7 Two significant statistical anomalies were found. First, data from the cohort study were not compatible with a dose-effect relationship. Second, relative risk tended to decrease with increasing duration of exposure within exposed workers. It was also discovered that follow-up between 1978 and 1980, the last 3 years of the study, was inadequate, RISK ASSESSMENT I IIIESEI FXFIAUST IN THE OCCUI'ATIONAL SETTING 773 is likely nongenotoxic and related to a finite dose threshold.", Exposure scenarios and emission products differ between laboratory studies and human exposure. Data from animals suggest a threshold effect that may be caused by a volume of particulate matter that ultimately overwhelms the natural clearance defense mechanisms of the lung. High-dose to lowdose linear extrapolation ignores this threshold issue and is inappropriate." Some debate exists about whether or nut large species experience impairment of alveolar clearance, even with extremely large lung burdens, that nonetheless is unlikely to be replicated in occupational settings. Combined with cross-species extrapolation and what may be the unique sensitivity of the rat lung to inert particles, which cause chronic inflammation and alveolar epithelial cell proliferation, there is clear compromise of the use of animal results in drawing conclusions about human effects. Even the primary author of the rat studies has cautioned against their use in risk assessment for human pulmonary carcinogene- S~S.~~ Given all this uncertainty in extrapolation from animal studies, some investigators have attempted to base recommended unit risk on human epidemiology. As pointed out earlier, dose-response curves cannot be generated from available data; therefore, an acceptable risk estimate cannot be derived. This has been acknowledged by authors of key studies who admitted their original calculations were no longer valid.29 The Health Effects Institute concluded that lack of definitive exposure data for occupationally exposed populations precludes the use of the available epidemiologic data to develop quantitative estimates of cancer risk.20 NONCANCER HEALTH EFFECTS OF DIESEL EXHAUST In addition to concerns about carcinogenicity, `components of complete carbon combustion and incomplete combustion may be associated with other respiratory symptoms and health effects. The diesel particulate is also believed to be the main cause of noncancerous effects in animals. Concentrations at which effects are seen are orders of magnitude greater than those generally encountered in the workplace.27 Studies in humans have looked at symptoms, acute and chronic, pulmonary function tests, and radiograph evidence of pneumoconiosis, which has been described in workers exposed to carbon black, graphite, and similar materials. The studies are plagued by the same problems that impair evaluation of potential for carcinogenic effects: poor exposure characterization, thus misclassification; lack of control for confounding variables; and short duration with low intensity of exposure. Acute respiratory effects of diesel engine exhaust have been examined in studies of several occupationally exposed groups, including railroad yard workers, coal miners, salt miners, diesel bus garage me- 774 COMSTOCK chanics, and stevedores.', 3, 13, 36 Although no significant respiratory symptoms were noted, more than half reported eye irritation, apparently associated with measurable levels of NO, and particulate levels, but more likely caused by aldehydes, such as formaldehyde and acrolein, and phenols. The studies generally found no pattern or minimal changes in respiratory function over the course of a shift. When NOnr however, exceeds 5 ppm, a reduction in FEV, and FEFS0has been shown." In a salt miner study, however, it was later determined that before-to-after shift changes in pulmonary function only occurred in smokers. Pulmonary changes at NO, levels less than 5 ppm, the current OSHA standard, are minimal and similar in exposed and unexposed controls. Thus, it seems that acute symptoms, particularly eye irritation, are more reliable and sensitive indicators of exposure than acute changes in PFTs over the shift.13 There has been a suggestion that acute high-dose, long-duration exposure to diesel exhaust could result in persistent airflow o b s t r u ~ t i o n . ~ ~ As there are many components of diesel exhaust that could cause pulmonary irritation, such as aldehydes, carbonaceous particulate, or oxides of nitrogen or sulfur, it is not possible to know which components might be causative. The mechanism may be irritant or allergic. Most epidemiologic data do not demonstrate an increase in chronic respiratory disease. A few show higher prevalence of pulmonary symptoms, such as phlegm and persistent cough, not associated with definite functional decrements. No effects were attributable specifically to diesel exhaust, but many studies involved miners with confounding exposure to mine dust or A 1987 study of diesel bus garage employees using tenure as a surrogate for exposure showed dose-response relationships were inconsistent for various symptoms, but dyspnea showed a moderate association with employment. The study concluded that the potential for diesel engine exhaust to increase respiratory symptoms and reduce function is biologically plausible at some levels of exposure but revealed no convincing evidence of a causal relationship. Smoking was the strongest and most consistent risk factor for ~ymptorns.'~ Prevalence of pneumoconioses in several populations studied has been low and in all cases could be related to other exposures, such as coal dust or grinding dust.',13At the present time, epidemiologic studies do not provide solid evidence for noncancerous respiratory effects of diesel exhaust at occupational exposure levels. EXPOSURE MONITORING Because diesel exhaust is a very complex mixture of chemical compounds, there is considerable interest in identifying markers to monitor individual exposure and relate it to internal dose. An appropriate marker must be sufficiently specific and detectable I DIESEL TXHAUST IK THE OCCUI'ATIONAL StTTlNC 775 at low levels. The method used must be replicable, suitable for personal sampling, and practical for field use. Past studies have assessed gaseous and particulate fraction~.~Se?lection of the best marker requires careful review of the specific job tasks and exposures, including sources of emissions, to determine appropriate sensitivity and specificity.'" Attempts to assess gaseous components failed because oxides of sulfur or nitrogen cannot be reliably detected, and CO, cannot be used for breathing zone sampling. Because tumor induction in animals is associated with unfiltered exhaust, a measure of exposure to the carbonaceous aerosols in the particulate fraction is most relevant.34 Several strategies have been used to select out the nonrelevant components of particulate soot to provide a more accurate measure of exposure to diesel exhaust.174,3, 44 Size selective sampling for total respirable particulate matter (RSP) Elimination of contribution of environmental tobacco smoke (ETS) to obtain the adjusted respirable particulate (ARP) Determination of the mass extractable in dichloromethane to elimi- nate inorganic respirable aerosol and produce the adjusted extractable mass (AEM) Other methods of exposure monitoring focus on more specific measurement of carbon components. Use of total carbon, elemental plus organic, results in tobacco smoke bias. Determination of submicrometer elemental carbon using thermal-optical analysis is an excellent indicator of exposure, with high sensitivity, specificity and precision, permitting identification of organic and elemental carbon at environmental background levels. In most workplaces the diesel engne is the only significant source of elemental carbon. The method, generally using open-face cassettes for routine monitoring and evaluation of control technology, is inexpensive and practical. In at least one study there was a highly significant relationship between elemental carbon and respirable dust, with elemental carbon averaging slightly less than 20% of corresponding respirable dust level.4s Efforts to use a chemical component, such as one of the polycyclic aromatic hydrocarbons as a marker of exposure requires that it be present at levels detectable by routine analysis and that there not be other sources for the compound. Phenanthrene was found promising as a marker for diesel exhaust because it is the PAH found in the highest concentration in diesel exhaust. It correlated with known exposure by job grouping. The study found phenanthrene concentrations near the limit of detection, but a fairly constant ratio of phenanthrene to respirable particulate concentration on samples, suggesting the compound should be pursued as a possible marker of exposure.'R BIOLOGICAL MONITORING In addition to being flawed by exposure estimates that are imprecise, epidemiologic studies of diesel exhaust also suffer from failure to SUMMARY References 778 COMSTOCK 2. Ames RG, Reger RB, Hall DS: Chronic respiratory effects of exposure to diesel emissions in coal mines. Arch Env Hlth 39:6, 1984 3. Battigelli MC, Mannella RJ, Hatch TF: Environmental and clinical investigation of workmen exposed to diesel exhaust in railroad enginehouses. Industrial Medicine and Surgery 121-124, 1964 4. Birch ME, Cary RA: Elemental carbon-based method for occupational monitoring of particulate diesel exhaust: methodology and exposure issues. Analyst 121:1183-1190, 1996 5. Boffetta P, Harris RE, Wynder EL: Case control study on occupational exposure to diesel exhaust and lung cancer risk. Am J Ind Med 17577-591, 1990 6. Boffetta P, Stellman SD, Garfinkel L Diesel exhaust exposure and mortality among males in the American Cancer Society Prospective Study. Am J Ind Med 14:403415, 1988 7. Crump KS: Assessment of risk from exposure to diesel engine emissions. Prepared under contract for US Environmental Protection Agency, July 1991 8. Doll R Occupational lung cancer: A review. Br J Ind Med 16:181-190, 1959 9. El Gazzar Rh4, Abdel Hamid HA, Shamy MY Biological monitoring or occupational exposure to electrophilic compounds. J Environ Path Tox Oncol 13:19-23, 1994 10. Emmelin A, Nystrom L, Wall S Diesel exhaust exposure and smokmg: a case-referent study of lung cancer among Swedish dock workers. Epidemiology 4:237-244, 1993 11. Gamble J, Jones WG: Chronic health effects of exposure to diesel emissions among salt miners. Ann Am Conf Ind Hyg 473-83, 1983 12. Gamble JF, Lewis RJ: Health and respirable particulate (PMIO) air pollution: A causal or statistical association? Environmental Health Perspectives 104:838-850, 1996 13. Gamble J, Jones WG, Minshall S: Epidemiological-environmental study of diesel bus garage workers: Acute effects of NO2 and respirable particulate on the respiratory system. Environmental Research 42:201-214, 1987 14. Garshick E, Munoz A, Schenker MB, et al: A retrospective cohort study of lung cancer and diesel exhaust exposure in railroad workers. Am Rev Resp Dis 137820-825, 1988 15. Gustafsson L, Wall S, Larsson LG, et al: Mortality and cancer incidence among Swedish dock workers-A retrospective cohort study. Scand J Work Environ Health 12122-26, 1986 16. Hall NEL, Wynder EL: Diesel exhaust exposure and lung cancer: a case-control study. Environ Res 34:77-86, 1984 17. Hammond SK, Smith TJ, Woskie SR, et al: Markers of exposure to diesel exhaust and cigarette smoke in railroad workers. Am Ind Hyg Assoc J 49(10):516-522, 1988 18. Hammond KS, Smith TJ, Woskie SR, et al: Railroad diesel exhaust: Concentration and mutagenicity. Appl Occup Environ Hyg 8:955-963, 1993 19. Hayes RB, Thomas T, Silverman DT: Lung cancer in motor exhaust-related occupations. Am J Ind Med 16:685-695, 1989 20. Health Effects Institute: Diesel exhaust: A critical analysis of emissions, exposure, and health effects. A special report of the institute's diesel working group. April, 1995 21. Heinrich U, Fuhst R, Rittinghausen S, et al: Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel engine exhaust, carbon black, and titanium dioxide. Inhalation Toxic01 7:533-556, 1995 22. Howe GR, Fraser D, Lindsay J, et al: Cancer mortality (1965-1977) in relation to diesel fume and coal exposure in a cohort of retired railway workers. J Natl Ca Inst 70:1015-1019, 1983 23. IARC: IARC Monographs on the evaluation of carcinogenic risks to humans. Diesel and gasoline engine exhausts and some nitroarenes. Volume 46, Lyon, 1989 24. Kanoh T, Fukuda M, Onozuka H, et al: Urinary 1-hydroxypyrene as a marker of exposure to polycyclic hydrocarbons in environment. Environmental Research 62:230241, 1993 25. Mauderly J L Diesel exhaust. Itz Lippmann M (ed): Environmental Toxicants; Human Exposures and Their Health Effects. Van Nostrand Reingold, New York, 1992, pp 119162 26. Mauderiy JL: Toxicological and epidemiological evidence for health risks from inhaled engine emissions. Environ Health Perspect 102(4):165-171, 1994 DIESEL EXHAUST IN THE OCCUPATIONAL SETTING, 779 27. Mauderly JC, Jones RK, Griffin WC, et al: Diesel exhaust is a pulmonary carcinogen in rats exposed chronica. Toxicological and epidemiological evidence for health risks from inhaled engine emissions. Environ Health Perspect 102(4):165-171, 1994 28. McClellan RO: Health effects of exposure to diesel exhaust particles. Ann Rev Pharmacol Toxicol 27279-300, 1987 29. McClellan RO: Letter to the Air Resources Board, June 30, 1997 30. McClellan RO: Health effects of diesel exhaust: a case study in risk assessment. Am Ind Hyg Assoc J 471-13, 1986 31. Morrow PE: Possible mechanisms to explain dust overloading of the lungs. Fund Appl Toxicol 10:369-384, 1988 32. Muscat JE, Wynder EL: Diesel engine exhaust and lung cancer: An unproven associa- tion. Environ Health Perspect 103:812-818, 1995 33. Nielson PS, Andreassen A, Farmer PB, et al: Biomonitoring of diesel-exhaust exposed workers. DNA and hemoglobin adducts and urinary I-hydroxypyrene as markers of exposure. Toxicology Letters 86:27-37, 1996 34. NIOSH Current Intelligence Bulletin 50. Carcinogenic effects of exposure to diesel exhaust. USDHHS, PHS, CDC, NIOSH, US Government Printing Office, Washington DC 1988 35. Pepelco WE, Chen C: Quantitative assessment of cancer risk from exposure to diesel emissions. Regul Toxicol Pharmacol 175245, 1993 36. Purdham JT, Holness DFL, Pilger C W Environmental and medical assessment of stevedores employed in ferry operations. Appl Ind Hyg 2:133-139, 1987 37. Schenker MB, Kado NY, Hammond K, et al: Urinary mutagenic activity in workers exposed to diesel exhaust. Environmental Research 5713S148, 1992 38. Schenker MB, Samuels SJ, Kado NY, et al: Markers of exposure to diesel exhaust in railroad workers. Res Rep Health Effects Inst 33:l-51, 1990 39. Steenland K: Lung cancer and diesel exhaust: A review. Am J Ind Med 10:177-189,1986 40. Stobel W, Abel U R Lung cancer due to diesel soot particles in ambient air? A critical appraisal of epidemiological studies addressing this question. Int Arch Occup Environ Health 68:SS-S61, 1996 41. Valberg PA, Watson AY: Analysis of diesel-exhaust unit-risk estimates derived from animal bioassays. Regulatory Toxicology and Pharmacology 2430-44, 1996 42. Wade F,Newman LS: Diesel asthma. Reactive airway disease following overexposure to locomotive exhaust. JOM 35:149-154, 1993 43. Woskie SR, Smith TJ, Hammond SK, et al: Estimation of the diesel exhaust exposures of railroad workers: I. Current exposures. Am J Ind Med 13:381-394, 1988 44. Woskie SR, Smith TJ, Hammond SK, et a1 Estimation of the diesel exhaust exposures of railroad workers: 11. National and historical exposures. Am J Ind Med 13:395-404, 1988 45. Zaebst DD, Clapp DE, Blade LM, et al: Quantitative determination of trucking industry workers' exposures to diesel exhaust particles. Am Ind Hyg Assoc J 52:529-541, 1991 Address reprirzt requests to Marcia L. Comstock, MD, MPH 1157 Lafayette Road Wayne, PA 19087-2110