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The purpose of this bulletin is to disseminate recent information on the potential carcinogenicity of diesel exhaust. In March 1986, niosh issued a document entitled "Evaluation of the Potential Health Effects of Occupational Exposure to Diesel Exhaust in Underground Coal Mines." This document stated that workers exposed to diesel exhaust experienced eye irritation and reversible decrements in pulmonary function. In the document, niosh concluded that no causal relationship had been established between exposure to whole diesel exhaust and cancer, but that such a relationship was plausible on the basis of animal studies in which extracts of diesel exhaust were used. Since the release of that document, reports of studies in animals have confirmed the potential carcinogenicity of whole diesel exhaust.
On the basis of the results of these studies, niosh recommends that whole diesel exhaust be regarded as "a potential occupational carcinogen," as defined in the Cancer Policy of the Occupational Safety and Health Administration (OSHA) ("Identification, Classification, and Regulation of Potential Occupational Carcinogens," 29 CFR 1990). This recommendation is based on findings of carcinogenic and tumorigenic responses in rats and mice exposed to whole diesel exhaust. Though the excess risk of cancer in diesel-exhaust-exposed workers has not been quantitatively estimated, it is logical to assume that reductions in exposure to diesel exhaust in the workplace would reduce the excess risk.
Diesel exhaust is a complex mixture of compounds, and its composition varies greatly with fuel and engine type, load cycle, engine maintenance, tuning, and exhaust gas treatment. This complexity is compounded by a multitude of environmental settings in which diesel-powered equipment is operated. Because of limitations in currently available technology and test methods, niosh cannot at this time confidently offer recommendations for environmental monitoring of exposures to diesel exhaust, or for generally applicable control measures that would assure adequate reduction of the carcinogenic risks associated with occupational exposure to diesel engine emissions. Continued investigation of these issues is clearly essential.
niosh recommends that producers of diesel engines disseminate this current information to their customers, and that users of diesel-powered equipment disseminate this current information to their workers. niosh also recommends that professional and trade associations and unions inform their members of the new findings of potential carcinogenic hazards of exposure to diesel engine emissions, and that all available preventive efforts (including available engineering controls and work practices) be vigorously implemented to minimize exposure of workers to diesel exhaust. Readers seeking more detailed information on the studies cited this bulletin are urged to consult the original publications.
[signature] J. Donald Millar, M.D., D.T.P.H. (Lond.) Assistant Surgeon General Director, National Institute for Occupational Safety and Health Centers for Disease Control |
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William J. Moorman
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Laurence J. Doemeny, Ph.D.
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John F. Gamble, Ph.D.
Michael A. McCawley, Ph.D.
Rebecca Stanevich
William Wallace, Ph.D.
Division of Respiratory Disease Studies
Nancy J. Bollinger
Division of Safety Research
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Howard R. Ludwig
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Division of Standards Development and Technology Transfer
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Division of Surveillance, Hazard Evaluation, and Field Studies
Walter M. Haag, Jr.
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Naylor Dana Institute for Disease Prevention
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Chemical Industry Institute of Toxicology
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The emissions from diesel engines consist of both gaseous and particulate fractions. The gaseous constituents include carbon dioxide, carbon monoxide, nitric oxide, nitrogen dioxide, oxides of sulfur, and hydrocarbons (e.g., ethylene, formaldehyde, methane, benzene, phenol, 1,3-butadiene, acrolein, and polynuclear aromatic hydrocarbons) [Linnell and Scott 1962; Environmental Health Associates 1978; Schenker 1980; Travis and Munro 1983]. Particulates (soot) in diesel exhaust are composed of solid carbon cores that are produced during the combustion process and that tend to form chain or cluster aggregates. More than 95% of these particulates are less than 1 micrometer in size [Travis and Munro 1983; Vostal 1980; McCawley and Cocalis 1986]. Estimates indicate that as many as 18,000 different substances from the combustion process can be adsorbed onto diesel exhaust particulates [Weisenberger 1984]. The adsorbed material constitutes 15% to 65% of the total particulate mass and includes such compounds as polynuclear aromatic hydrocarbons (PAHs) [Travis and Munro 1983; Cuddihy et al. 1984].
OSHA, MSHA, and niosh exposure limits relevant to the particulate fraction of diesel engine emissions are listed in Table 2. Because diesel emission particulates are of respirable size, the presence of diesel equipment contributes to the total burden of respirable dust present in an occupational environment. Existing limits for occupational exposures to other respirable dusts also limit exposures to the particulate fraction of diesel emissions.
As much as 15% to 65% of the mass of particulate emissions (soot) of diesel engines is made up of organic compounds adsorbed onto the surface of the particulates [Travis and Munro 1983; Cuddihy et al. 1984]. Among these organic compounds is a group of compounds known as polynuclear aromatic hydrocarbons (PAHs), several of which are carcinogens [IARC 1983]. PAHs are produced as pyrolytic products during the combustion of any fossil fuel, including diesel fuel. Some readily condense onto the surface of the soot being expelled from diesel engines. Concentrations of PAHs can be determined by using solvents such as benzene or cyclohexane to extract these and other compounds from particulate samples. This analysis yields the solvent-soluble portion of the particulates (often referred to as coal tar pitch volatiles, or cyclohexane- or benzene-solubles), which can be further fractionated.
Limits for Occupational Exposure to Selected Components of the Gaseous Fraction of Diesel Exhaust; OSHA, MSHA, niosh Compared
MSHA PELs* | ||||
Component | OSHA PEL |
Underground coal mines |
Metal and nonmetal mines |
niosh REL |
Carbon dioxide (CO2) | 5,000 ppm (9,000 mg/m3), 8-hr TWA |
5,000 ppm (9,000 mg/m3), 8-hr TWA; 30,000 ppm (54,000 mg/m3), STEL§ |
5,000 ppm (9,000 mg/m3), 8-hr TWA; 15,000 ppm (27,000 mg/m3), STEL |
10,000 ppm (18,000 mg/m3), 8-hr TWA; 30,000 ppm (54,000 mg/m3), 10-min ceiling |
Carbon monoxide (CO) | 50 ppm (55 mg/m3), 8-hr TWA |
50 ppm (55 mg/m3), 8-hr TWA; 400 ppm (440 mg/m3), STEL |
50 ppm (55 mg/m3), 8-hr TWA; 400 ppm (440 mg/m3), STEL |
35 ppm (40 mg/m3), 8-hr TWA; 200 ppm (230 mg/m3), ceiling (no minimum time) |
Formaldehyde |
1 ppm, 8-hr TWA; 2 ppm, 15-minute STEL |
1 ppm (1.5 mg/m3), 8-hr TWA; 2 ppm (3 mg/m3), STEL |
2 ppm (3 mg/m3), ceiling |
0.016 ppm (0.020 mg/m3), 8-hr TWA; 0.1 ppm (0.12 mg/m3), 15-min ceiling |
Nitrogen dioxide (NO2) | 5 ppm (9 mg/m3), ceiling |
3 ppm (6 mg/m3), 8-hr TWA; 5 ppm (10 mg/m3), STEL |
5 ppm (9mg/m3), ceiling | 1 ppm (1.8 mg/m3), 15-min ceiling |
Nitric oxide (NO) | 25 ppm (30 mg/m3), 8-hr TWA | 25 ppm (30 mg/m3), 8-hr TWA | 25 ppm (30 mg/m3), 8-hr TWA; 37.5 ppm (46 mg/m3), STEL | 25 ppm (30 mg/m3), 10-hr TWA |
Sulfur dioxide (SO2) | 5 ppm (13 mg/m3), 8-hr TWA |
2 ppm (5 mg/m3), 8-hr TWA; 5 ppm (10 mg/m3), STEL |
5 ppm (13 mg/m3), 8-hr TWA; 20 ppm (52 mg/m3), STEL (5 min) |
0.5 ppm (1.3 mg/m3), 10-hr TWA |
OSHA, MSHA, and niosh Limits Relevant to Occupational Exposure to the Particulate Fraction of Diesel Exhaust
MSHA PELs | ||||
Component | OSHA PEL |
Underground coal mines |
Metal and nonmetal mines |
niosh REL |
Respirable dust* | 5 mg/m3 | 2 mg/m3 | No Limit | No REL |
Respirable dust when quartz content is more than 5% of total* |
10 mg/m3 % SiO2 +2 |
10 mg/m3 % quartz |
10 mg/m3§ % quartz+2 |
REL is specific to quartz |
Coal tar pitch volatiles (CTPV) | Not applicable to diesel emissions | Not considered relevant | Not considered relevant |
0.1 mg/m3, 10-hr TWA (cyclohexane-extractables) |
Polynuclear aromatic hydrocarbons | No PEL | No PEL | No PEL | No REL |
A stationary 1.6-liter diesel engine operated according to EPA's US-72 driving cycle was used to generate the exhaust. The diesel fuel used was a European reference fuel with a sulfur content of 0.36%. The exhaust was diluted with filtered air to a volume rate of 1:17 (diesel exhaust/air) and was then directed into an exposure chamber. At this dilution rate, the measured concentration of the particulate fraction of diesel exhaust was approximately 4 mg/m3. To remove particulates from the exhaust, the diesel emissions were passed through a centrifugal separator and/or a particle filter. The concentrations of exhaust components in the inhalation chambers for both filtered and unfiltered exhaust are shown in Table 4.
Characteristics of recent studies* of
carcinogenicity in animals
exposed to diesel exhaust by inhalation
Study | Type of engine | Nature of exhaust | Animal species | Exposure time |
Particulate exposure concentrations(mg/m3) |
Findings |
Heinrich et al. [1986] | 1.6-liter Volkswagen | Unfiltered | Female Wistar rats | 19 hr/day, 5 days/week, max. of 140 weeks | 4 | Significantly increased incidence of adenomas, benign squamous cell cysts, and squamous cell carcinoma of the lung when compared with controls. |
Filtered | Female Wistar rats | 19 hr/day, 5 days/week, max. of 140 weeks | ---- | No significant differences in histopathological findings compared with controls. | ||
Unfiltered | Female NMRI mice | 19 hr/day, 5 days/week, max. of 120 weeks | 4 | Statistically significant increase in malignant and total lung tumors (because of increases in adenocarcinomas) when compared with controls. | ||
Filtered | Female NMRI mice | 19 hr/day, 5 days/week, max. of 120 | ---- | Statistically significant increase in malignant and total lung tumors (because of increases in adenocarcinomas) when compared with controls. | ||
Unfiltered | Male and female Syrian golden hamsters | 19 hr/day, 5 days/week, max. of 120 weeks | 4 | No significant differences in histopathological findings compared with controls | ||
Filtered | Male and female Syrian golden hamsters | 19 hr/day, 5 days/week, max. of 120 weeks | ---- | No significant differences in histopathological findings compared with controls. | ||
Mauderly et al. [1987] | 5.7-liter Oldsmobile | Unfiltered | Male and female F344 rats | 7 hr/day, 5 days/week, max. 30 months |
0.35 3.5 7.0 |
High exposure led to statistically significant increases in benign squamous cysts and malignant tumors (adenocarcinomas and squamous carcinomas) compared with controls. Intermediate exposure led to a statistically significant increase in adenomas and total tumors when compared with controls. There were no statistically significant increases in benign or malignant tumors in low-exposure animals. |
Brightwell et al. [1986] | 1.5-liter Volkswagen | Unfiltered | Male and female F344 rats | 16 hr/day, 5 days/week, 2 years |
0.7 2.2 6.6 |
Statistically significant increase in undefined tumors in both male and female high-exposure animals compared with controls. Statistically significant increase in undefined tumors in female intermediate-exposure animals compared with controls. |
Filtered | Male and female F344 rats | 16 hr/day, 5 days/week, 2 years | Below the limit of detection | No increase in tumor incidence in any exposure group when compared with controls. | ||
Unfiltered | Male and female syrian hamsters | 16 hr/day, 5 days/week, 2 years |
0.7 2.2 6.6 |
No increase in tumor incidence in any exposure group when compared wth controls. | ||
Filtered | Male and female Syrian hamsters | 16 hr/day, 5 days/week, 2 years | Below the limit of detection | No increase in tumor incidence in any exposure group when compared with controls. | ||
Ishinishi et al. [1986] | Light-duty, 1.8-liter, 4-cylinder, swirl chamber | Unfiltered | Male and female F344 rats | 16 hr/day, 6 days/week, max. 30 months |
0.1 0.4 1 2 |
No statistically significant increase in lung tumors. Increase in hyperplasia, squamous hyperplasia, interstitial fibrosis, hyperplastic lesions. |
Heavy-duty, 11-liter, 6-cylinder, direct injection | Unfiltered | Male and female F344 rats | 16 hr/day, 6 days/week, max. 30 months |
0.4 1 2 4 |
Statistically significant increase in lung tumors (adenoma, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma) in the high-exposure group compared to controls. | |
Filtered | Male and female F344 rats | 16 hr/day, 6 days/week, max. 30 months |
0.005 0.019 |
No statistically significant increase in lung tumors. Increase in hyperplasia, squamous hyperplasia, interstitial fibrosis, hyperplastic lesions. | ||
Iwai et al., 1986 | 2.4-liter | Unfiltered | Female F344 rats | 8 hr/day, 7 days/week, 24 months§ | 4.9 | Statistically significant increase in total lung tumors (adenomas, adenocarcinoma, adenosquamous carcinomas, squamous carcinoma, and large cell carcinoma) compared with controls. Statistically significant increase in splenic malignant lymphoma compared with controls. Increased incidence of tumors other than lung, and multiplicity of tumors. |
Filtered | Female F344 rats | 8 hr/day, 7 days/week, 24 months§ | ---- | Minimal histopathologic changes. Statistically significant increase in splenic malignant lymphoma compared with controls. Increased incidence of tumors other than lung, and multiplicity of tumors |
In addition, some diesel-particle-associated PAHs were measured in the unfiltered exhaust. Concentrations of 13 ng/m3 of benzo(a)pyrene, 21 ng/m3 of benzo(e)pyrene, and 51 ng/m3 of a mixture of benzofluoranthenes were measured in batched samples. The authors did not specify the number of samples or the analytical method used to determine these concentrations. Interpretation of the hamster data is complicated by the fact that the animals were treated with antibiotics for several months during the study. Control hamsters were also treated with antibiotics. No significant differences in body weight developed between control and exposed hamsters over the entire length of the study. In contrast, mice and rats exposed to unfiltered diesel exhaust showed decrements in body weight after approximately 480 days. The median survival time of animals was not affected by exposure. Tissues from the nasal cavity, sinuses, larynx, trachea, esophagus, lungs, forestomach, glandular stomach, liver, kidneys, adrenals, and urinary bladder were subjected to histopathologic examination. In some cases, the salivary glands, thyroid, thymus, aorta, heart, spleen, lymph nodes, and ovaries were also subjected to histopathologic examination.
Histopathology of hamsters exposed to diesel exhaust failed to demonstrate the induction of tumors in the lung or upper respiratory tract. Significant deposits of soot particles were evident in the hamsters exposed to unfiltered diesel exhaust. The lungs of these animals exhibited an increased incidence (measured qualitatively) of thickened septa, bronchioalveolar hyperplasia, and emphysema compared with controls. No significant differences were found between the controls and the animals exposed to filtered diesel exhaust.
Mice exposed to filtered or unfiltered diesel exhaust showed a 2.5-fold increase in lung tumor incidence compared with controls. Combined benign and malignant tumor incidences were as follows: 13% in the control group at the end of the study; 31% in the group exposed to filtered diesel exhaust; and 32% in the group exposed to unfiltered diesel exhaust. This increase was predominantly due to the induction of adenocarcinomas. Bronchioalveolar hyperplasia was more frequent (64%) in the group of mice exposed to unfiltered diesel exhaust than in mice exposed to filtered diesel exhaust (15%) and controls (5%). Furthermore, multifocal alveolar lipoproteinosis was found in 71% of the mice exposed to unfiltered diesel exhaust compared with 3% for filtered diesel exhaust and 4% for controls. Similar results were obtained for interstitial fibrosis that occurred almost exclusively in the mice exposed to unfiltered diesel exhaust.
Of the 95 rats exposed to unfiltered diesel exhaust, 15 exhibited a total of 17 lung tumors. These tumors were classified as 8 bronchiolo-alveolar adenomas and 9 squamous cell tumors (8 benign keratinizing cysts and 1 squamous cell carcinoma). Hyperplasia was seen in the lungs of 94 of the 95 rats exposed to unfiltered diesel exhaust, and metaplasia occurred in 62 of these animals. Other severe inflammatory changes such as thickened septa, foci of macrophages, and cholesterol crystals were found in the lungs of rats exposed to unfiltered diesel exhaust. No changes were seen in the control animals or in those exposed to filtered diesel exhaust. No exposure-related changes were observed in the upper respiratory tracts of the rats exposed to unfiltered diesel exhaust.
Exposure to filtered and unfiltered diesel exhaust resulted in a statistically significant increase in the incidence of lung adenocarcinomas in female NMRI mice. In hamsters, long-term exposure to unfiltered diesel exhaust led to broncho-alveolar hyperplasia and emphysematous lesions in the respiratory tract, but it did not produce tumors. In rats, long-term exposure to unfiltered diesel exhaust led to extensive hyperplasia and metaplasia of the broncho-alveolar epithelium and to a significantly increased incidence of adenomas and squamous cell tumors of the lung compared with controls.
Concentrations of Exhaust Components for Filtered and Unfiltered
Diesel Exhaust Measured in
the Exposure Chambers
(mean ± standard deviation)
(Adapted from Heinrich et al., 1986)
Component | Control (clean air) |
Filtered exhaust | Unfiltered exhaust |
Carbon monoxide (ppm) | 0.16 ± 0.27 | 11.1 ± 1.92 | 12.5 ± 2.18 |
Carbon dioxide (vol.%) | 0.10 ± 0.01 | 0.35 ± 0.05 | 0.38 ± 0.05 |
Sulfur dioxide (ppm) | ---- | 1.02 ± 0.62 | 1.12 ± 0.89 |
Oxides of nitrogen (ppm) | ---- | 9.9 ± 1.80 | 11.4 ± 2.09 |
Nitric oxide (ppm) | ---- | 8.7 ± 1.84 | 10.0 ± 2.09 |
Nitrogen dioxide (ppm) | ---- | 1.2 ± 0.26 | 1.5 ± 0.33 |
Alkanes (ppm) | 3.5 ± 0.29 | 5.2 ± 0.65 | 5.5 ± 0.69 |
Methane (ppm) | 2.3 ± 0.17 | 2.4 ± 0.20 | 2.6 ± 0.19 |
Alkanes without methane (ppm) | 1.3 ± 0.5 | 2.9 ± 0.50 | 3.1 ± 0.53 |
Particles (mg/m3) | ---- | ---- | 4.24 ± 1.42 |
Male and female F344 rats that were 15 weeks old were randomly divided by litter into four treatment groups. There were 365 rats in the control group, and 366, 367, and 364 rats in the low-, intermediate-, and high-exposure groups, respectively. Rats were added to all treatment groups during February 1981; a second group of rats was added to all treatment groups 1 year later. Both groups of rats were derived from the same breeding colony and were exposed in the same chambers. The two added groups of rats were treated as one study population since the groups showed no differences in body weights or survival times. All animals were exposed to unfiltered diesel exhaust for 7 hours per day, 5 days per week for up to 30 months.
All rats terminated for histopathology and all rats that died or were euthanized received a complete necropsy. All lesions except for soot macules and representative portions of each lung lobe were examined microscopically, as were samples of other respiratory tract tissues. Exposure to diesel exhaust did not cause overt signs of toxicity. No significant differences in body weight or life span were observed in either the males or females in the experimental groups compared with the controls. The physical condition of all groups of animals appeared to be similar.
Concentrations of Key Components of Exposure
Atmospheres*
(Adapted from Mauderly et al., 1987)
Component | Control | Low | Medium | High |
Particulate (mg/m3) | 0.010 (0.010) | 0.350 (0.070) | 3.470 (0.450) | 7.80 (0.810) |
Carbon monoxide (ppm) | 1 (1) | 3 (1) | 17 (7) | 30 (13) |
Nitric Oxide (ppm) | 0 | 0.6 (0.3) | 5.4 (1.5) | 10.0 (2.6) |
Nitrogen dioxide (ppm) | 0 | 0.1 (0.1) | 0.3 (0.2) | 0.7 (0.5) |
Hydrocarbons (ppm) | 3 (1) | 4 (1) | 9 (5) | 13 (8) |
Carbon dioxide (%) | 0.2 (0.04) | 0.2 (0.03) | 0.4 (0.06) | 0.7 (0.1) |
Soot accumulated progressively and significantly in the lungs of all exposed rats. After 24 months of exposure, the mean lung burden of diesel exhaust particulate per rat was reported to be 0.6 ± 0.02 mg for the low exposure, 11.5 ± 0.5 mg for the intermediate exposure, and 20.8 ± 0.8 for the high exposure. These calculations were made by measuring the amount of light absorbed by lung homogenates from exposed rats and comparing those values with standard curves constructed from measurements made from known amounts of soot deposited in the lungs of unexposed rats.
Changes in the epithelial lining of the air spaces and progressive fibrosis occurred in the areas of soot accumulation. Hyperplasia and squamous metaplasia were seen in broncho-alveolar spaces.
Broncho-alveolar adenomas, adenocarcinomas, benign squamous cysts, and squamous cell carcinomas were observed in the lungs of exposed rats. Rats exposed to the high concentration of diesel exhaust for up to 30 months experienced statistically significant increases in adenocarcinomas, benign squamous cell tumors, and squamous cell carcinomas in male and female rats. The increase in total tumor incidence for the high-exposure group was also statistically significant when compared with the control group. The percentages of rats with lung tumors (males and females combined) are listed by exposure group in Table 6.
Percentages of Rats (Male and Female Combined)
with Lung Tumors, by Exposure
Group
(Adapted from Mauderly et al., 1987)
Exposure group | Adenomas |
Adenocarcinomas and squamous cell carcinomas |
Squamous cysts only | All tumors |
High | 0.4 | 7.5* | 4.9* | 12.8* |
Medium | 2.3* | 0.5 | 0.9 | 3.6* |
Low | 0 | 1.3 | 0 | 1.3 |
Control | 0 | 0.9 | 0 | 0.9 |
A statistically significant increase in adenomas occurred in the intermediate-exposure group. One adenocarcinoma and two squamous cysts were also observed in female animals in that group. The increase in all tumors in the intermediate-exposure group was statistically significant when compared with the control group.
No statistically significant increases in tumor incidence occurred in the low-exposure animals. Squamous tumors were always associated with focal areas of engine soot retention, epithelial cell alterations, and fibrosis. They are thus likely to represent a progression of squamous metaplasia. These tumors may have resulted from a generalized response to the accumulation of relatively insoluble particles.
None of the lung tumors had metastasized to pulmonary lymph nodes or other organs. Increased numbers of adducts were found in DNA extracted from the lungs of rats exposed to the highest concentration of diesel exhaust for 30 months.
Diesel exhaust inhaled chronically at the intermediate and high concentrations in this study induced a significant number of benign and malignant pulmonary tumors in male and female rats. The increased numbers of DNA adducts suggest that tumor development may have been initiated by the interaction of reactive metabolites of soot-associated organic compounds with lung cell DNA. In this study, the relationship between lung burden of diesel exhaust particulates and tumor prevalence was progressive rather than linear with time, rising rapidly late in the exposure regimen.
The diesel exhaust emissions used in this study were generated by a 1.5-liter light-duty diesel engine. The emissions were diluted to yield particulate exposure concentrations of approximately 0.7, 2.2, and 6.6 mg/m3. The diesel emissions were either subjected to particle filtration or they were unaltered (unfiltered). Exposures were carried out overnight for 16 hours per day, 5 days per week.
The mean concentrations for carbon monoxide (CO) and nitrogen oxides (NOx) for both filtered and unfiltered diesel exhaust in the high-exposure groups were 32 and 8 parts per million (ppm), respectively. Concentrations of those contaminants for the controls were 1 ppm CO and 0.1 ppm NOx. No data were presented for the concentrations of these contaminants in the intermediate- and low-exposure chambers. Similarly, no data were presented for exposure concentrations of other exhaust components, although regular analyses were conducted for particle size distributions, aldehydes, phenols, PAHs, sulfates, and individual hydrocarbons.
Interim sacrifices of rats were conducted after 6, 12, 18, and 24 months of exposure, while hamsters had interim sacrifices at 6 and 16 months. All surviving hamsters were sacrificed at the end of 2 years of exposure. Rats that survived 2 years of exposure were maintained for up to 6 additional months without further exposure to exhaust.
Animals that died or were sacrificed were subjected to a full necropsy, and histopathology was carried out on the respiratory tracts (nasal passages, larynx, trachea, and lungs) of all animals in the high-exposure and control groups. Histologic examinations were also performed on the respiratory tracts of all animals in the groups with intermediate and low exposures to filtered and unfiltered diesel exhaust. Histopathology was carried out on all suspected tumors regardless of experimental treatment.
The major histopathologic finding in the study was an increase in the incidence of primary lung tumors in rats exposed to the intermediate and high concentrations of unfiltered diesel exhaust. Table 7 summarizes the histopathologic findings for primary benign and malignant lung tumors in rats exposed to unfiltered diesel exhaust and to air alone. The incidence of primary lung tumors was 2%, 1%, 4%, and 23% for male rats in the control, low-, intermediate-, and high-exposure groups, respectively. Lung tumor incidence in female rats was 1%, 0%, 15%, and 54% for control and for low-, intermediate-, and high-exposure groups, respectively. However, a later analysis of these data [Fouillet and Brightwell 1987] points out that tumor incidence was based on the total number of animals examined in each treatment group. Since this total included some animals sacrificed after 6, 12, 18, and 24 months of exposure, some of them clearly were not exposed long enough to induce recognizable lung tumors. When tumor incidence was recalculated using only the data for rats surviving beyond 24 months, 44% of male and 99% of female rats exposed to unfiltered diesel exhaust developed lung tumors.
Primary Benign and Malignant Lung Tumors in Rats
Exposed to Unfiltered Diesel
Exhaust*
(Adapted from Brightwell et al., 1986)
F344 rats that developed lung tumors | |||||
Exposure group | Particulate concentration (mg/m3) |
Males Number |
% | Females Number |
% |
High | 6.6 | 16/71 | 23 | 39/72 | 54 |
Intermediate | 2.2 | 3.72 | 4 | 11/72 | 15 |
Low | 0.03 | 1/72 | 1 | 0.72 | 0 |
Control | 0 | 3/140 | 2 | 1/142 | 1 |
No increase occurred in the incidence of primary lung tumors in any other treatment group. Respiratory tract tumors were rare in hamsters and were not attributed to treatment.
The pathology description in this report [Brightwell et al. 1986] is very limited. It contains no specific diagnoses of the lung tumors, and no data on whether the tumors were single, multiple, lethal, or incidental. Data on degree of invasion are also absent. No comment is made on pathology of the nasal passages, larynx, or trachea. There is no description or discussion of chronic toxicity, hyperplasia, or the relationship of hyperplasia to neoplasia. Although the investigators did not present the full spectrum of their bioassay data, the information presented justifies the conclusion that long-term exposure to high concentrations of unfiltered diesel exhaust leads to a significant increase in the incidence of benign and malignant lung tumors in male and female F344 rats.
For the carcinogenicity experiment, five groups of animals (each consisting of 64 male and 59 female rats) were exposed for 30 months to unfiltered heavy-duty engine exhaust at a given particulate concentration originally designed to be 0, 0.4, 1, 2, and 4 mg/m3 (see Table 8 for actual concentrations). Five additional groups (each consisting of 64 male and 54 female rats) were exposed for 30 months to unfiltered light-duty engine exhaust at a given particulate concentration originally designed to be 0, 0.1, 0.4, 1, and 2 mg/m3 (see Table 8 for actual concentrations).
Two additional groups of 64 male rats were exposed to filtered exhaust from the heavy-duty engines. The 0.4- and 4-mg/m3 concentrations were filtered so that the animals were exposed only to the gaseous fraction of the exhaust. For comparison, three additional groups of 64 male rats were exposed to the unfiltered diesel exhaust from the same source at particulate concentrations of 0, 0.4, and 4 mg/m3. Table 8 presents a summary of gas and particle concentrations for each exposure atmosphere.
A concentration-dependent decrease in body weight was observed, with the greatest effect observed in the 4-mg/m3 group exposed to exhaust from heavy-duty engines.
Summary of Gas and Particle Concentrations*
(Adapted from Ishinishi et al., 1986)
Gaseous Concentration | |||||||||||
Type of diesel exhaust (%) | Particle concentration (mg/m)3 |
NOx (ppm) | NO (ppm) | NO2 (ppm) | CO (ppm) | CO2 (%) | SO2 (ppm) | Formal- dehyde (ppm) |
SO4-2 | O2 (%) | Target | Actual |
Unfiltered exhaust from heavy duty engine | |||||||||||
4 | 3.72 | 37.45 | 34.45 | 3.00 | 12.91 | 0.360 | 4.57 | 0.29 | 361 | 20.4 | |
2 | 1.84 | 21.67 | 19.99 | 1.68 | 7.75 | 0.215 | 2.82 | 0.18 | 198 | 20.6 | |
1 | 0.96 | 13.13 | 12.11 | 1.02 | 4.85 | 0.140 | 1.79 | 0.11 | 111 | 20.7 | |
0.4 | 0.46 | 6.17 | 5.71 | 0.46 | 2.65 | 0.084 | 0.98 | 0.05 | 62.9 | 20.8 | |
0 | 0.002 | 0.061 | 0.042 | 0.021 | 0.63 | 0.035 | 0.06 | 0.003 | 0.49 | 20.8 | |
Filtered and unfiltered exhaust from heavy-duty engine | 4 (unfiltered) | 2.99 | 36.45 | 31.50 | 4.95 | 12.90 | 0.412 | 4.03 | 0.20 | 358 | 20.3 |
4 (filtered) | 0.019 | 36.76 | 32.81 | 3.96 | 13.00 | 0.391 | 4.50 | 0.24 | 1.61 | 20.4 | |
0.4 (unfiltered) | 0.39 | 5381 | 5.37 | 0.44 | 2.50 | 0.084 | 0.98 | 0.04 | 57.7 | 20.7 | |
0.4 (filtered) | 0.005 | 5.58 | 5.16 | 0.472 | 2.54 | 0.083 | 0.96 | 0.04 | 1.43 | 20.7 | |
0 | 0.004 | 0.062 | 0.040 | 0.024 | 0.06 | 0.068 | 0.03 | 0.003 | 0.35 | 20.8 | |
Unfiltered exhaust from light-duty engine | 2 | 2.32 | 20.34 | 18.93 | 1.41 | 7.10 | 0.418 | 4.70 | 0.13 | 315 | 20.3 |
1 | 1.08 | 10.14 | 9.44 | 0.70 | 3.96 | 0.219 | 2.42 | 0.07 | 151 | 20.5 | |
0.4 | 0.41 | 4.06 | 3.81 | 0.26 | 2.12 | 0.105 | 1.06 | 0.03 | 62.4 | 20.7 | |
0.1 | 0.11 | 1.24 | 1.16 | 0.08 | 1.23 | 0.050 | 0.38 | 0.01 | 18.8 | 20.8 |
After 6 months of exposure, "anthracosis"* was observed in all groups exposed to particle-containing exhausts. Severity was proportional to concentration and duration of exposure. Hyperplasia of type II epithelial cells and bronchiolar epithelium associated with anthracosis was observed after 18 months in the groups exposed to the higher particle concentrations. The extent of these conditions depended on exposure. Squamous metaplasia with focal interstitial fibrosis was often observed in hyperplastic lesions of the subpleural zone. Scanning electron microscopy revealed irregularity, shortening, and absence of cilia in the mucosal epithelia of the trachea and main bronchi. These lesions were also observed in rats exposed only to the gaseous components of the exhaust; the severity of the lesions increased in proportion to exhaust concentration and duration of exposure.
A statistically significant increase occurred in the incidence of lung tumors in rats (male and female combined) exposed for 30 months to heavy-duty diesel engine exhaust with particulate concentrations of 4 mg/m3 compared with controls. Tumor incidence was 6.5% (8/124) for exposed rats and 0.8% (1/123) for controls. The majority of tumors were squamous cell carcinomas, adenosquamous carcinomas, and adenocarcinomas.
After 6 months of exposure to unfiltered diesel exhaust, phagocytotic macrophages filled with black particles were distributed in an irregular pattern in the lungs. Areas where macrophages were gathered showed proliferations of Type II alveolar epithelial cells showing adenomatous metaplasia. More lesions were found after 1 year of exposure, but no neoplastic lesions were observed. Two adenomas were found in one of five rats kept in clean air for 3 months after 1 year of exposure to unfiltered exhaust. After 2 years of exposure, the number of particles in the macrophages increased markedly. Fibrous thickening of alveolar walls was observed, and mast cell infiltration was found with epithelial hyperplasia where macrophages gathered. Neoplastic changes were observed after 2 years of exposure; some of these showed intra-lymphatic invasion indicative of malignant transformation. Two types of lung carcinoma (adenocarcinoma and squamous or adenosquamous carcinoma) were observed.
In the rats exposed to filtered diesel exhaust, histologic changes were minimal, and no heterotrophic hyperplasia was observed in the alveolar walls. Quantitative analysis of epithelial proliferative changes in the lung indicated an increase in affected areas that was associated with the length of exposure to unfiltered exhaust.
Rats exposed to unfiltered exhaust had a statistically significant increase in lung tumor incidence compared with controls. After 24 months of exposure, 4/14 rats had tumors, 2 of which were malignant. After an additional 6 months in clean air, four of the five remaining rats had tumors, three of which were malignant. The combined incidence of tumors was 42% (8/19) in rats exposed to unfiltered diesel exhaust compared with 0% (0/16) in rats exposed to filtered exhausts and 4.5% (1/22) in the controls. The distribution of tumor types found in rats exposed to unfiltered diesel exhaust was as follows:
Adenomas | 3 rats |
Adenocarcinoma | 3 rats |
Adenosquamous carcinomas | 2 rats |
Squamous carcinoma | 1 rat |
Large cell carcinoma | 1 rat |
The tumor found in the control rat was an adenoma. The authors concluded that the significantly higher incidence of lung tumors in the unfiltered exhaust exposure group could be attributed to the inhalation of particles.
Another important observation in this study was a statistically significant increase in the incidence of splenic malignant lymphoma, with or without leukemia. After 24 months, the incidence rate was 25.0% (6/24) for rats exposed to unfiltered diesel exhaust, 37.3% (9/24) for rats exposed to filtered diesel exhaust, and 8.2% (2/24) for controls. The incidence of tumors in other organs also increased in rats exposed to filtered exhaust (25%, or 6/24) and unfiltered exhaust (29%, or 7/24) compared with controls (8.2%, or 2/24). The multiplicity of tumors increased both in rats exposed to unfiltered exhaust and in those exposed to filtered exhaust, with a quadrupled incidence of tumors noted only in the unfiltered exhaust group.
Since the release of that document [niosh 1986], the final results of three epidemiologic studies have been released [Edling et al. 1987; Garshick et al. 1987a; Garshick et al. 1988]. Preliminary reports of data from each of these studies were discussed in the niosh document [niosh 1986]. Two of these recently released final reports [Garshick et al. 1987a; Garshick et al. 1988] have indicated an increased risk of death from lung cancer among railroad workers exposed to diesel engine emissions. These studies are summarized in Table 9 and discussed more fully in this section. The validity of the results obtained in the study by Edling et al. [1987] was questionable because of the small size of the cohort analyzed (694 male employees of five different bus companies), and because no exposure measurements were taken (exposures were estimated by job title). For these reasons, the study by Edling et al. [1987] will not be discussed in detail in this bulletin.
Work histories were determined from yearly job reports filed with the U.S. Railroad Retirement Board. These reports were used to classify workers as exposed or unexposed to diesel exhaust. The classifications were confirmed by measuring current exposures to respirable particulate matter for workers in selected jobs. Respirable particulate matter was chosen as a marker for exposure to the particulate fraction of diesel exhaust. The respirable particulate fraction was sampled because it included all of the diesel exhaust particulates and excluded some of the larger nondiesel particulates. Respirable dust exposures were corrected for cigarette smoke particulates by analyzing the nicotine content of composite samples [Woskie et al. 1988a; Woskie et al. 1988b]. An adjusted respirable particulate concentration was then calculated for each job group by subtracting the applicable average fraction of cigarette smoke from each railroad's average respirable particulate concentration. Personal exposure to respirable particulate matter was measured for 39 common jobs in four U.S. railroads over a 3-year period.
Characteristics of Epidemiologic Studies of Exposure to
Diesel Exhaust and Carcinogenicity, Published Since 1986
Investigator | Population studied | Observation period | Findings | Comments |
Garshick et al. 1987a | U.S. railroad workers born in 1900 or later with 10 or more years of service | 1959-81 for diesel exhaust exposure; deaths that occured between March 1, 1981, and February 28, 1982. | Workers exposed occupationally to diesel exhaust for 20 years had a significantly increased relative odds ratio (1.41, 95% CI*=1.06, 1.88) of lung cancer | Population-based, case-control study that included industrial hygiene characterization of exposures and multiple conditional logistic regression analysis to adjust for confounders such as smoking and asbestos exposures. Only 87% of death certificates were collected. |
Garshick et al. 1988 | U.S. railroad workers aged 40 to 64 in 1959 who started railroad service 10 to 20 years earlier | 1959-1980 for diesel exposure; deaths that occurred before December 31, 1980 | Workers aged 40-44 in 1959 had a significantly increased relative risk (1.45, 95% CI=1.11, 1.89) of lung cancer | Retrospective cohort study. Only 88% of death certificates were collected. Effects of smoking could not be eliminated. The effect of asbestos exposures was addressed by considering diesel-exposed workers separately from asbestos-exposed workers using a proportional hazards regression model. |
According to the authors, diesel locomotives replaced steam locomotives over a short period (from 14% diesel use in 1947 to 95% in 1959). Thus the year 1959 was chosen as the effective beginning of diesel exhaust exposure for this study. Workers who retired before that year were classified as unexposed to diesel exhaust. The authors acknowledged that some workers had additional earlier years of diesel exhaust exposure. Smoking histories were obtained by questionnaires from the deceased workers' closest relatives or by direct telephone contact if there was no response to the questionnaire. Asbestos exposures in railroad workers occurred primarily in the steam engine era. Asbestos exposure for this study was therefore categorized by the job held in 1959 (the end of the steam locomotive era) or by the last job held if retirement occurred before 1959.
The relative hazard of lung cancer attributable to diesel exhaust exposure was calculated using a multiple conditional logistic regression to adjust for smoking and asbestos exposure. A statistically significant increase in relative odds (1.41, 95% CI=1.06-1.88) was found for lung cancer among workers aged 64 or younger at the time of death who had worked in a [diesel-exposed] job with diesel exposure for 20 years. No increase was found in workers aged 65 or older. The authors felt that this finding reflected the fact that many of these men retired shortly after the transition to diesel-powered locomotives.
To control for the confounding effects of asbestos exposures in the cohort, the relative risk of lung cancer was not considered for groups of workers with possible exposures to asbestos in the past (shop workers and hostlers). When this analysis was conducted, the relative risk for lung cancer remained elevated at 1.57 (95% CI=1.19-2.05) in the group aged 40 to 44 in 1959, and it was 1.34 (95% CI=1.02-1.76) in the workers aged 45 to 49 in 1959. These results confirmed those obtained with the proportional hazards regression model.
The effects of cigarette smoking could not be eliminated because of the retrospective nature of the study. However, the prevalence of cigarette smoking was the same for workers with and without potential diesel exhaust exposure in a group of 517 current railroad workers who were surveyed in 1982 regarding past asbestos exposure [Garshick et al. 1987b].
Epidemiologic studies of lung cancer risk in diesel-exposed workers are inherently problematic because of (1) the difficulty in defining and quantifying exposure, (2) the relatively short time between initial exposures and analysis of risk in some studies, and (3) the need to control for cigarette smoking. The reports by Garshick et al. [1987a; 1988] are the most thorough epidemiologic studies conducted to date. Data on cigarette smoking were collected in the case-control study. An attempt was made to control for the confounding exposure to asbestos. Attempts were also made to characterize exposures to diesel exhaust through the collection of industrial hygiene data. The period between the first diesel exposure and data analysis was adequate to allow the observation of exposure-related cancer for some age groups of the cohort. The fact that the findings of the two studies were both independent (the two studies based their analyses on different lung cancer deaths) and consistent fortifies the conclusion that occupational exposure to diesel exhaust is associated with an increased risk of lung cancer.
The studies of Garshick et al. [1987a; 1988] are subject to a number of limitations, some of them inherent, that preclude them from providing definitive evidence that diesel exhaust is an occupational carcinogen. Ascertainment of death certificates was incomplete in both studies (87% in the case-control study, and 88% in the retrospective cohort study). In both reports of final data, the authors presented data on lung cancer risk only for separate-age subcohorts within the study population. Though there is merit in the authors' rationale for splitting the groups by age, the risk analysis should have considered diesel exposure for the combined cohort also. The investigators attempted to characterize exposures to diesel exhaust by collecting industrial hygiene data, but they were forced to use an experimental approach to collect them. Exposure to diesel exhaust is difficult to measure because of the complex nature of the exhaust. Measuring exposure to respirable particulate matter as a surrogate for diesel exhaust allows for a substantial error in classification of exposures, as there is no way to define the source of the particulates. Adjusting the measurements to exclude the contribution of cigarette smoke particulates eliminates only one extraneous source of respirable particulates. The classification of exposed and unexposed workers is particularly important to the outcome of the case-control study because the unexposed workers were used as the referent population. Furthermore, no attempts were made to control for potentially confounding exposures to pyrolysis products of fuels that were used to power locomotives before the use of diesel fuel.
The excess cancer risk for workers exposed to diesel exhaust has not yet been quantified, but the probability of developing cancer should be decreased by minimizing exposure. As prudent public health policy, employers should assess the conditions under which workers may be exposed to diesel exhaust and reduce exposures to the lowest feasible limits. Although a substantial amount of information suggests that some component (or combination of components) of the particulate fraction of diesel exhaust is associated with tumor initiation, the relative roles of the particulate and gaseous phases of emissions need further characterization.
Engineering control techniques can be effective in reducing the production or toxicity of diesel engine emissions. Fuel and engine modifications and exhaust treatment all have been investigated, and each approach entails costs as well as benefits. No technique effectively reduces or controls all components of diesel exhaust. Research is needed to improve the efficacy of known engineering controls, to develop additional techniques, to evaluate the combined effects of engineering controls, and to identify which controls are most appropriate for various uses of diesel-powered equipment. A preferred engineering control technique is substitution (replacing a hazardous material or process with an alternative that has a lower health risk). However, the health and safety implications of any proposed alternatives to diesel power require careful evaluation before implementation.
Diesel exhaust is a very complex mixture, and its composition varies greatly with fuel and engine type, load cycle, maintenance, tuning, and exhaust gas treatment. This complexity is compounded by the multitude of environmental backgrounds in which diesel-powered equipment is operated. Gases and particulates found in the workplace may emanate from a number of sources, including diesel engines. Methods have been developed and used for apportioning the contribution of highway vehicle emissions from various sources [Hampton et al. 1983] and for apportioning sources of occupational exposure to engine exhaust [Currie et al. 1981; Johnson et al. 1981; Cantrell et al. 1986]. Although niosh-validated sampling and analytical methods exist for components of diesel exhaust, none of these methods can be used to apportion sources of exposure. Quantitative risk estimates are yet to be developed for workers exposed to diesel exhaust. Studies involving measurement or careful estimation of the extent of exposure to diesel exhaust are urgently needed.
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