Document NEdKba9OoQo1zvOY0dOeBBqDR

Toxicological and Epidemiological Evidencefor Health Risks from Inhaled Engine Emissions Joe L. Mauderly InhalationToxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico !nfamation from toxicological and epidemiologicalstudies of the cancer and noncancer health risks from inhaled diesel engine exhaust (DE) and engine exhaust (GE) was reviewed. The toxicological database is more extensive for DE than for GE. Animal studies have shown that hemvy, chronic exposures to both DE and GE can cause lung pathology and associated physiologicaleffects. Inhaled GE has not been shown to be Csrcinogenic in animals. Chronically inhaled DE at high concentrations is a pulmonary carcinogen in rats, but the response is questionablein mice ad negative in Syrian hamsters. The response in rats is probably not attributable to the DE soot-associated organic compounds, as previously sauned, and the usefulness of the rat data for predicting risk in humans is uncertain. Experimentalhuman exposures to DE show that lung inflam- naOry and other cellular effects can occur after single exposures, and sparse data suggest that occupational exposures might affect respiratory 'ufuXb and symptoms. Epidemiology suggests that heavy occupationalexposures to exhaust probably increase the risks for mortality from both J18cancer and noncancer pulmonarydisease. The small magnitudes of the increasesin these risks makethe studies very sensitive to confounding 'anors and uncertainties of exposure; thus, it may not be possible to resolve exposureresponse relationships conclusively by epidemiology. Our JsJent knowledgesuggests that heavy occupationalexposures to DE and GE are hazardousbut does not allow quantitativeestimates of risk with a -phdegree ofcertainty. Environ Health Perspect 102(Suppl4):165-171 (1994). *wwds: automotive emissions, air pollution, diesal exhaust, epidemiology. gasoline exhaust, inhalation, inhalationtoxicology, lung cancer, lung isease. rat Mmduction ibL paper provides an overview of informaon from toxicological studies in aninab urd experimental and epidemiological ndits in humans of the cancer and non- pulmonary effects of inhaling gasoengine exhaust (GE) and diesel engine h i s t (DE). This review focuses on the tfms of inhaled whole, diluted exhaust, aher than on individual exhaust con- 'Ituents or reaction products. Because of of this paper, published informa- on is only summarized; original reports lould be consulted for details. Recent vamsare noted, and information not mdY reviewed is treated in more detail. health effects of DE were recently (1,2)b,ut there is no good recent -.-c '' Was presented at the Symposium on Risk of Urban Air: Emissions. Exposure, Risk * 'm and Risk Ouantitation held 31 May-3 inS m m , Sweden. ." 'Wbw was prepared with support from the af H W h and Environmental Research, US. ~f new,u b r m t r a c t no. DE-ACW Evp1013.The toxicological research on inhaled %I and carbon Mack reportedfrom this ''bM,msrrppoRed bv the above contract and bv fens Institute under agreement no. 8 8 2 *US. Meritof ~nergy. 4ddreW correspondence to Joe Mauderly. ~ ~ ~ Reseabrch Instigtute. Lovvelace m.and EnvironmentalResearch Institute. ) eQ, Albuquerque. NM 87185. Telephone '%1169. Fax (5051845-1198. summary on GE. The 1989 monograph on engine exhaust by the International Agency for Research on Cancer (3)is another key information source. Lung Cancer from Engine Exhaust TdwlogicalEvidence: c;lsolineEng-inelkhaust There have been few cancer bioassays of animals exposed chronically to GE, but there is little evidence that GE causes lung cancer in animals. In 1936, Campbell ( 4 ) reported exps- ing groups of 75 mice, males and females, strain unspecified, 7 hrlday, 5 dayslweek for 750 days to exhaust from either a 1.0-L engine burning "ordinary petrol" or a 3.0L engine burning leaded gasoline. The carbon monoxide (CO) concentration in the statically operated chambers varied from 6 to 12%. A slight, but questionably significant, increase in lung tumor incidence resulted from both exposures with a greater incidence for leaded than for unleaded GE. The microbial status of the exposed or control mouse lungs was nor indicated. In 1978, Hyde et al. (5)reported the pdmonary histopathology of dogs exposed, beginning in the mid-I96Os, in the study conduaed by the U.S. Nauod Air PoUuuon Control Administration, often called the "Cincinnati Beagle study." Groups of 12 female Beagles were examined 32 to 36 months after the end of exposures 16 hrlday, 7 dayslweek for 68 months to exhaust from a 2.3-L engine burning leaded gasoline and operated on an urban cycle to produce chamber concentrationsof approxi- mately 110 pprn CO (6).Although the small group sizes preclude a good test of car- cinogenicity, no lung tumors were observed in the dogs. In 1981, Roggendorf et al. (7)reported exposing 100 Wistar rats (both sexes) 8 hrlday, 5 dayslweek for up to 28 months to exhaust from an idling engine that was diluted to 90 ppm CO. Inflammation, pneumonia, and emphysema of the lungs were attributed to infectionsin both control and exposed rats, but no lung tumors were described. Heinrich et al. (8)srposed groups of 80 female Wistar rats and 80 Syrian hamsters 19 hrlday, 5 dayslweek for 24 months to exhaust from a 1.6-Lengine burning laded fuel and operated on an urban cydc to produce chamber concentrations of either 112 pprn CO (1:61 ddution) or 207 pprn Co (1:27 dilution). The pacfide concentrations at these dilutions were approximately 0.05 and 0.10 mg/m3, respectively. No hueax in lung tumor incidence was observed Brightwell et al. (9)exposed groups of 144 F344 rats or 312 Syrian hamstas ( d e s and females) 16 hrlday, 5 dayslweek for 24 months to exhaust from 1.6-L engines oper- tal Health Perspectrves t J. L. MAUDERLY ated on an urban cyde and burning unleaded fuel, either with or without an exhaust catalytic converter. Exhaust was diluted to 1:29 or 1:83 to produce CO concentrations of 6 to 21 ppm (catalyst) and 67 to 224 ppm (noncatalyst). No increase in lung tumors was observed in either species. T4mIogid Evidene Did w e Exhaust The extensive data from cancer bioassays of DE in rats, Syrian hamsters, and mice were reviewed recently ( 2 ) ,and the most recent studies, noted below, have reproduced these findings. There is clear evidence of the pulmonary carcinogenicity of DE in rats. Studies by several laboratories in four countries dearly demonstrated by the mid-1980s that repeated exposure of rats for 24 months or longer to whole, diluted DE at soot concentrationsof 3.5 mg/m3 or greater increases the incidence of lung tumors. Studies by Brightwell et al. (9)and Heinrich et al. (IO), using filtered and unfiltered DE, demonstrated that the carcinogenicity of DE in rats requires the presence of soot. Although few studies have been done, there is some evidence that inhalation of DE might act as a co-carcinogen by increasing the lung tumor response of rats to chemical carcinogens (I). There is no evidence for carcinogenicity of DE in Syrian hamsters from five studies conducted in four laboratories, including three studies in which hamsters were exposed for 24 months or longer. There is mixed evidence for the carcinogenicity of DE in mice. Pepelko and Peirano ( I I ) found increased lung tumors in female S7trdoanygslAweaenkdtoSeDncEaramt i6cetoexp1o2smedg8shoroltdlamy3 for 7.5 to 15 months. These mouse strains are particularly sensitive to cancer induction. Heinrich et al. (IO)found DE to be carcinogenic in female NMRI (Swiss) mice exposed 19 hrlday, 5 da s/week for 28 months at 4.2 mg soot/m< however, both filtered and unfiltered DE caused tumors in mice, unlike rats. Because of these con& ing results and the fact that other studies found no lung tumor induction in mice, the carcinogenicity of DE in mice is questionable. The few studies that have been done do not suggest that DE is a co-carcinogen in mice or hamsters (I). Several questions remain unanswered concerning the interpretation of the carcinogenicity of DE in rats and its implication for human health risk. Concern for DE carcinogenesis originated because of the mutagenic and carcinogenic organic compounds adsdrbed to DE soot. Increased levels of lung-DNA adducts in exposed rats support- ed the view that the tumors were caused by chemical carcinogenesis via DNA adduction (2). Further, unit lung cancer risks derived from the rat data are generally similar to those predicted earlier by comparing the bacterial mutagenic potency of DE soot extract to those of known human carcinogens (2). These facts led some to propose extrapolation of human unit risks for DEinduced lung cancer from the rat carcinogenesis data on the basis of the delivered doseof soot-awciated organic compounds. Other facts suggested that DE-induced lung cancer in rats might occur by mechanisms that may not be directly applicable to human risk Statistidly significant increases in lung cancer incidence have been observed only in rats exposed sufficiently to cause an overloading of particle clearance from the deep lung by macrophages, which results in a progressive sequestration of soot in the lung. This increasing lung burden of soot is accompanied by chronic inflammation, alveolar epithelial hyperplasia, and multifocal fibrosis. Slight increases in lung tumor incidence have occurred in rats exposed to lower DE concentrations that do not cause the proliferative and fibrotic changes, but the group sizes (up to approximately 200) have not allowed the significance of the smaller increases to be evaluated with confidence. It also has become apparent that the inhalation or instillation of high doses of a wide range of poorly soluble particles without mutagenic chemical compounds can c a w a syndrome of particle sequestration, inflammation, cell proliferation, fibrosis, and tumors in rat lungs indistinguishable, as of yet, from that caused by DE (12,13). Further, although DE soot particles accumulate in lungs of mice and hamsters as they do in rats, those species do not characteristically respond by developing lung tumors. These facts suggested that the tumor response of rats to inhaled DE may not be very specific to the chemical nature of DE soot. It is not known whether the response of human lungs to DE might be more like that of rats or like that of mice and hamsters. The differences among species, however, suggest the possibility that tumors rmght occur in rats by mechanisms that might not occur in humans. Two laboratories, the Fraunhofer Institute in Hannover, Germany, and the Inhalation Toxicology Research Institute (ITRI) in Albuquerque, New Mexico, have recently completed similar studies of the importance of the soot-associated mutagenic organic compounds in the lung tumor response of ran to DE. Both laboratories compared the pulmonary carcinogenicityin rats of DE and icarbon black (CB),which simulated particles Withour the mutagenic 0% tion. Although the studies varied and neither has been M y publish4 time, preliminary information india the findings of the studies are consj their major points, and that t h m have important implications for in - the earlier carcinogenicitydata (24-fi At ITRI, groups of apprc male and 100 female F344 exposed 16 hrlday, 5 dayslweek months to whole DE at 6.5 or soot/m3, to CB at the same concent or to clean air as controls. The [ generated by 1988 model General 6.2-L engines burning EPA cenii fuel and operated on the FTP urt# cycle. Cabot Elftex-12 CB, whid particle size and specific surface a r q to that of DE soot, was aerosolh air jet mill. Approximately 8% of; soot mass consisted of solvent-c organic material having a bacter ~ genic potential similar to that ofj previous studies. Only appro 0.04% of the CB was extractabk.4 extract was not mutagenic. In ac carcinogenesis, lung burdens of clearance of radiolabeled tracer bronchoalveolar lavage fluid (BA cators of inflammation, and histq were evaluated serially. The DE exposures at ITRI re the findings of previous studies. exposures also caused an overloadi ticle clearance; progressive accumr particles in the lungs; and in& proliferative, and fibrotic changc because of differences in the pa distributions of the two materi; burdens of DE soot were higher 1: of CB, and the noncancer effects greater in DE-exposed rats. At si ticle exposure levels, DE and C nearly identical prevalences of I and benign lung tumors amonp; or sacrificed for observation dur I throughout the study. The types' caused by DE and CB were the, identical to those observed in p* ies. Because the lung burdens d lower than those of DE soot, & to CB was actually greater response to DE per unit of acc partide lung burden. The results of the recent DE d ies suggest that the soot-asociated organic compounds are not ii DE-induced lung cancer in rats. r] suggest that extrapolation to hur risks derived from the rat stu 1CC Environmental Health k bu;s of the delivered dose of soot-associated miners who worked in mines where diesel epic material is not warranted. Follow- equipment was operated. Garshick et al. up r w c h is examining the role of lung conducted a retrospective study of U.S. DNA &duction in the tumor response, the railroad workers by inferring exposure from d t i o m k p between epithelial proliferation job title, assuming that workers with the md m o r formation, and whether or not greatest DE exposures were the youngest at differencesexist at the gene level between the time railroads were converted to diesel [he DE- and CB-induced rumors. O f engines and judging that smoking preva- Course, it is possible that soot-associated lence was the same among workers in rela- organic compounds or their metabolites tively exposed and unexposed jobs. might affect organs other than the lung. Garshick et al. calculated a RR for lung &re is epidemiological evidence suggest- cancer of 1.5 for the group which was ing a siight increase in risk for bladder can- youngest at the time of diesel conversion cer among workers with heavy occupational and calculated lower RR values for groups aposures to DE, but there is little toxico- older at that time. logid evidence for effects of inhaled DE in Fourteen case-control studies were organs other than the lung (2). reported between 1976 and 1990. The ~~1 'calEvidence: Gasoline PndDidL number of cases ranged from 376 to 6434, typically with the same or greater numbers of controls. The study periods ranged from The epidemiological evidence for human 1 to 10 years. Notabky, all but two of these lung cancer from exposures to engine studies used some form of control for smok- ahaust is taken from a recent review (2)of ing. The RR for lung cancer among these 30published studies. The 15 cohort studies, studies ranged from less than 1.0 to 2.4 for 14 caseanuol studies, and one combined exhaust-exposed groups. Twelve of the 14 analysis of 12 studies focused on DE expc- studies reported a RR of 1.2 or greater. sures, but many of the occupations also The two most robust case-control studies involved substantial exposures to GE. were probably also those of Boffetta et al. Importantly, no study to date has included (19)and Garshick et al. (20). In 1987, aaual measurements of the exposures of the Garshick et al. studied 1256 cases of lung NbjaD studied. Two studies estimated pre- cancer and 2512 controls among railroad GOUSexposures from measurements in con- workers dying during a 1-year period in 1~~~ workplaces, and three questioned 1981 to 1982. DE exposure was inferred the subject or immediate family directly from job title. Afier adjusting for smoking about DE exposure. Exposure classification and asbestos exposure, they calculated a In other studies was based on job history, RR for cancer of 1.4 among 251 cases and enmloccupation, or union membership. 496 controls under 64 years of age (with Fourteen retrospective and one prospective cohort study were reported between '957 md 1988. Cohon sizes ranged from '00 to 477,000,and the study periods longer DE exposures than older workers) and a RR of 1.6 for workers with 20 years or more of exposure. In 1990, Boffetta et al. conducted a hospital-based study of from 3 months to 32 years. Notably, two of these studies attempted controls 'or smoking as a confounding variable. The r d a k risks (RR)for lung cancer for specific 'krt~among these studies ranged from less 2584 lung cancer cases and 5099 controls divided into occupations with different exposures to DE. They analyzed separately a subgroup of 477 cases and 946 controls entered after subjects began to be ques- 1.0 to 2.7. Ten of the 15 studies tioned directly about DE exposure. The ' w dat least one exposed subcohort with smoking-adjusted RR for lung cancer for a R R fbr cancer of 1.2 or greater. self-reported exposure was 1.3 and that for the most robust of the cohort self-reported exposures of 31 years or 'tudiWaere those of Boffetta et al. (17) longer was 2.4. ud U c k et al. (le),both published in Dubrow and Wegman (21)performed a 1988* bffettaet al. reported the results of combined analysis of 12 epidemiological Ibc fint two years of follow-up in the studies in a manner that gave equal weight- ' W w mortality study of U.S. males ing from each study to the combined RR L o dbuy the American Cancer Society. for occupations thought to have the greatest .'bBtion, DE exposure, and smoking '?q-re obtained interviewing living *during enrollment. They calculated for lung cancer among DE-exposed Of 1.6 for railroad workers, 2.6 for -9' operators, and 2.7 for exposures. They calculated a combined RR of 1.3 for heavy equipment operators and truck drivers and 1.2 for professional drivers of buses, taxis, and other motor vehicles. The weight of the above epidemiological evidence suggests that heavy occupational exposure to DE probably increases the RR for lung cancer in the range of 1.2 to 2.0. In considering this information, it is important to keep three ficts in mind. First, the database contains no individual studies that cannot be sharply criticized in terms of exposure discrimination and potential confounding fictors. Second, becaw the lower limit of the 95% confidence intervals for many of the elevated risk ratios overlapped 1.O, the possibility of increased risk was precluded for many groups. Third, because elevations of risk in the range of 20 to 50% (RR of 1.2 to 1.5) are at the approximate lower limit of practical detectability by epidemiology, it may be that the true human lung cancer riik from DE will never be resolved conclusively. Summary of Evidence br Erhaust-inducadLung Can- Epidemiology suggests that past long-term occupational exposures to DE have slightly increased the risk fix lung cancer. It is plausible that GE also contributed to this effect, but present information does not allow partitioning of the effect between the two materials. It is dear that inhaled DE can act as a pulmonary carcinogen in rats, but it is uncertain that other species, including humans, respond similarly. The mechanism of the effect in rats is unknown, but it does not appear to require the soot-associated mutagenic organic compounds that were the original agent of concern. It is not presently clear how, or if, the cancer results from rats can be used to estimate cancer risk for humans. There is no good toxicological evidence for the carcinogenicity of inhaled GE. NoncarcinogenicPulmonary Effects of Engine Exhaust T&cdogid Evidence: GasolineExhaust Perhaps the study with the most direct relevance to the long-term, noncancer effects of GE in humans is the Cincinnati Beagle study mentioned above. This is because the dog has a lower airway structure more simiiar than rodents to that of humans, the exposures of this long-lived species were longer than those of other species, the detailed serial physiological evaluations were performed during and after the exposures,and the final evaluations occurred at a considerable time after exposures ceased. Female Beagles were exposed to GE as described above (6)for over 5 years. Respiratory function was evaluated extensively throughout exposure (22).After exposures, the dogs were transferred to the University of California, Davis, where more '%, supplement 4, October 1994 167 r J. L MAUNRLY extensive functional evaluations were per- humans, the EPA exposed male cats 8 formed [(23);]. Gillespie, personal commu- hr/day, 5 daydweek to DE from a 3.2-L nication], followed by detailed histopatho- engine operated on an urban cycle diluted to logical evaluations at 32 to 36 months after 6 mg soot/m3 for 61 weeks, then 12 mg the end of exposure (5). soot/m3 for the remainder of 27 months Little effect on respiratory function was ( II ). A restrictive respiratory function observed during exposure (22). Subsequent impairment with nonuniform gas distribu- tests revealed increases in lung volumes, tion was observed at the end of exposure deadspace ventilation, and dynamic lung (27). Accompanying histopathology campliance, and a decrease in alveolar-cap- included peribronchiolar fibrosis and illary gas exchange efficiency ( 2 3 ) . epithelial metaplasia in terminal and respi- Distinct, although not severe, histopatholo- ratory bronchioles (28). Interestingly, the gy included squamous metaplasia and some epithelial changes lessened, but the fibrosis loss of cilia in large airways, epithelial worsened during 6 months after exposure hyperplasia in small bronchioles, and ended. emphysema in proximal alveoli (5). These There are extensive data on noncancer findings indicated that, in lungs morpho- pulmonary effects of DE in rodents, but logically similar to those of humans, long- most are from heavily exposed animals, and term DE exposure induced functional and the majority are from rats. In all species, structural changes in airways and alveoli most soot deposited in alveoli is phagocy- that persisted after exposures ceased. tized by macrophages that, at low exposure The most extensive study of the noncancer rates, remain largely unaggregated and clear pulmonary effccn of GE on lungs of rodents most of the soot from the lung. In rats was that of Heinrich et al. [ (8);personal exposed repeatedly at a high rate, the communicaaon)who arposod rats and Syrian macrophages become loaded with soot and hamsters for 24 months to GE diluted 1:27 tend to f o m aggregates in alveoli instead of or 1:61 as described above. Evaluations clearing fiom the lung. Under these condi- included respiratory Function, airway reactivi- tions,macrophage-mediatedparticle clearance ty to acetylcholine, chemistry of BALF,dear- fiom alveoli is slowed, although mucociliary ance of inhaled Lrric oxide (59Fe,03) parti- clearance in ainvays is not (29).The p e d cles, and histopathology. GE did not cause phenomenon of overwhelnung macrophage- any substantial histopathology or alterations mediated clearance by high rates of particle of lavage fluid chemistry in either species. deposition is not specific to DE soot, and has The higher concentration of GE increased been termed dust overload (30). This term lung weight, retarded particle clearance, is sometimes wrongly used to include the reduced dynamic lung compliance, and other functional and morphological (includ- increased acetyicholiiesensitivity in rats. No ing cancer)abnormalities that are characteris- s i i c a n t functional changes were found in tic for rats with continued macrophage over- rats at the lower concentration or in hamsters loading c a d by chronic exposwe. at either concentration. The time course and exposure-response Other toxicological data on the non- relationshipsof the DE-indud, noncarcino- cancer effects of GE are sparse. The cancer genic changes in animals, particularly at early study by Brightwell et al. (9) of rats and times and low exposures, are not well- hamsters exposed to GE, mentioned above, defined. White and Garg (31)otposed F344 also included limited evaluationsof respira- rats 20 hr/day, 5.5 daydweek to DE f b m a tory h c t i o n (24)b,ut no significant alter- 5.7-L engine operated at constant load at 6 ations were observed. In 1966, Hueter et mg sootlm3 and examined lungs serially. al. (25) reported limited measurements of Afier only one orposure, soot was found in the respiratory function of guinea pigs dur- epithelial cells as well as macrophages, and ing 20 months of exposure to GE at 100 the number of Type I1 cells was slightly ppm CO, but found no significant effects. increased. By 3 days of exposure, soot was In 1979, Pepelko et al. (26) reported in peribronchiolar and mediastinal lym- exposing rats 16 hr/day for 90 days to GE phoid tissue, and Type I1 cell hyperplasia at a dilution of 1:lO. They observed alveo- was evident. Afier 2 weeks of exposure, litis and increases in lung volume and macrophage aggregates, an influx of weight in both exposed and control rats; inflammatory cells, and some alveolar septal thus, the results are inconclusive. thickening were seen. Several studies have TmicOogid J%i&cc of diadExhalwt shown that, with long-term exposure of rats, many of thesc aggregates become the focus of progressive Type I1 cell hyperpla- In the only DE study involving animals sia, squamous epithelial metaplasia, and with airway morphology similar to that of fibrosii. The lowest chronic exposure rate for which soot lung burdens had 4measured in rats was that of the in which F344 rats were exposed 5 daydweek to DE from a 5.7-L4 operated on an urban cycle at I soot/m3. Soot accumulated prq in the rat lungs at that exposure ionly reached 0.6 mg/lung after 24 of exposure (29).At that expoo\r few macrophage aggregates wert and no significant inflammatory ,. ticle clearance (29),respiratory ~ (33),pulmonary immune functioa or morphological changes (32) Heavier exposures of rats caw s abnormalities which have been rq several laboratories. These e f f m sented by the results of the abovr study which also included rats 3.5 and 7.1 mg soot/m3. These caused a dose-related overload macrophage-mediated particle cle (29) and a progressive accum soot, reaching lung burd 20.5 mg/lung (32). Serial demonstrated a progressive and cytotoxic response, increases in lung weight, lung gen, and histological multifo (32). A progressive restrictive function impairment with gas and gas exchange abnormalities accompanied the lung patholo Although soot also accumulate lung-associated lymph nodes, the responses in these nodes to intra instilled pmiculate antigen were IN (34). Thus, chronic lung dia induced in rats by chronic arposu and 7.1 but not at 0.35 mg soot4 not known if there is a threshold effects. It is of interest to compare the nod responses of rats to DE to responses (1 species. At ITRI, CD-1 (Swiss) I were exposed 7 hr/day135dayslwed 3.5,or 7.1 mg sootlm . Lung Wci burdens of soot, BALF chemistry a ogy, and lung tissue collagen, a teinase, reduced g"lutathion histopathology were evaluated pt up to 18 months. The lung b -per-gram of lung was sligh mice than in rats (32),&&sa although particle clearance was I sured in mice, it was probably sla was in rats. Less of the retained contained in macrophage a g g r q more was in s q l e macrophages in 1 in rats. Except fix glutathione, rb muons of cells, enzymes, and p m ~ BALF of mice were increased p q TOXKxlLoGYAND EHDEEMNKOOY OF ENGINE EXHAUST but increased only slightly glutathione in lung tissue rmI) d#nzsed by exposure in mice but in a dose-related manner in -I~ p s e collagen was not increased i, y in nts,and only occasional colla- aggregation, no depletion /*glutathione, and little fibrosis in -be also are data for noncancer effects 4DE in Chinese and Syrian hamsters. *I&$, Emironmental Protection Agency measurements of the of Chinese hamsters ons of soot-laden mpiratory function of Syrian I_.fter exposure 16 hrlday, 5 16 months to DE at 6.6 mg no significant abnormalities Nontumor histopathology ibed. The Heinrich et al. em d.y evaluated lung weight, Bn, and BALF chemistry IOfSyrian hamsters exposed 19 W k for 2 years to DE at dm', I- or .to_filtered DE. Lung ), and the clear- 1 Of "Fe 0 , was increased --mt)d e r 1 year of expo- BALF parameters reflected -matory and cytotoxic griticant effects on respira- observed after 2 years of @&010gy included bron- W i d hyperplasia, alveolar b and emphysema. there is little information f acute low-level exposures 'OJL Repeated exposure of animals to DE at high concentrations causes a slowing of macrophage-mediated particle clearance and persistent inflammation. Continued exposure causes epithelial hyperplasia and fibrosis, which may vary in degree among species. Present data suggest that the rat, and possibly the Chinese hamster, might be more prone to developing focal proliferative and fibrotic changes than the other species. hperimental and Epidemiological Evidencefrom Humans There are few reports of experimental expo- sures of humans to DE and no reports of experimental GE exposures. In 1965, Battigelli (35) reported exposing 13 sub- jects for up to 1 hr to DE from a 7 hp sin- gle-cylinder engine. Soot concentrations were not reported, but the highest of three DE concentrations included 55 ppm CO, 4.2 ppm NO,, and 1 ppm SO,. No effect was found on pulmonary flow resistance measured during exposure. In 1987, Ulfvarson et al. (36)reported exposing six subjects for 3.7 hr to DE at 0.6 mg soot/m3 generated by a 2.4-L engine o p t e d at con- stant speed at 0.6 mg s o o t h . No s*- cant changes were found in forced exhalation and single-breath nitrogen washout parame- ters. Rudell, Sandstrom, and colleagues in U m d have done the most recent studies. In 1990, Rudell et al. (37)reported exposing eight nonsmoking subjects for 1 hr to DE from an i d h i t 1 mg soodm r uck (4.3 exng1in0e6 at approximately particleslcm3 ). The cytology of BALF and in vitro phagocy- tosis of opsonized yeast by macrophages obtained by lavage were measured before and 18 hr after exposure. The DE exposure increased BALF neutrophils, decreased mast cells, increased the T-helper and suppressor lymphocyte ratio,and depressed macrophage phagocytosis. There are a few data on workshift changes in respiratory function in occupations with heavy exhaust exposures. In 1982, Ames et al. (38)reported that the workshift decre- ment in forced expiratory function did not di&r stgruficanty between workers in mines where DE was present or absent. In 1987, Ulfvarson et al. (36)reported studies of workshift decrements in forced expiratory function of workers with heavy exhaust expo- sures. They found slgNficant decrements in roll-on, roll-off ship W O I ~ C Sduring loading and unloading operations in which the pri- mary exposure was DE at 0.13 to 0.59 mg sooth3, but no sigmficantdecrements in bus garage or car ferry workers exposed to both GE and DE at 0.10 to 0.46 mg soot/m3. A few studies have examined longer term effects of heavy exhaust exposures on -piratory function and respiratory symptoms. In 1984, Ames et al. (39)reported that the maximal expiratory flow-rate at 50% of forced vita capacity was lower in workers in mines using diesel engines but found no differences in other forced expiratory parameters or in symptoms. In 1987, Gamble et al. (40)reported that bus garage workers had a higher age and smoking-adjusted incidence of cough,phlegm, and wheezing than controls, but found no association between symptoms and length of employment and no differences in respiratory function. Also in 1987, Purdham et al. (42) reported comparing the respiratory function and symptoms of 17 stevedores exposed to exhaust at 0.06 to 1.72 mg soot/m3 to those of 11 office worker controls. After adjusting for smoking, they found that the forced expiratory function of the stevedores was lower than that of the controls, but that there was no difference in symptoms. Three of the epidemiological studies of lung cancer reviewed above also evaluated mortality from noncarcinogenic chronic respiratory disease (CRD). In their caseantrol study of railroad workers, Garshicket al. (42)found 575 cases of CRD mortality among exposed workers and calculated a RR of 1.2 for workers exposed 5 years or longer. In their retrospective cohort study, the same group (43)calculated a RR of 1.6 for CRD mortality among railroad workers aged 40 to 49 in 1959 (those with the longest DE exposures). In their prospective mortality study of 476,648 U.S. males, Boffetta et al. (44) observed 1242 noncancer respiratory deaths during 1983 to 1984, and calculated RRs for DE-arpod subjects of 1.2 for emphysema, 1.2 for other chronic obstructive lung disease, and 1.7 for pneumonia and influenza. Summary OfEvidence krExhaustinduced NoncancerLung Disespe The experimental and epidemiological data base giving evidence for noncancer pulmonary effects of exhaust exposure in humans is small, but it suggests that heavy exposures probably afFect respiratory funaion and contribute to symptoms and development of CRD. Experimental exposures have shown that a siigle expowe can cause lung inflammation and other cellular changes. Repeated exposures might therefore be expected to a&ct lung h a i o n , symptoms, and disease, and the plausibility of these effectr is supported by the toxicological data. An impairment of partide clearance and sig- 169 J. L MAUDERLY nificant noncancer histopathology can occur in a n i d s with repeated exposures, and the histopathology is reflected by impairments of respiratory hnction. Present information suggests that the effects in humans have small magnirudes; however, the data do not lend themselves to accurate quantitative estimates of risk. Conclusions Other than studies of individual exhaust components such as CO, nitrogen oxides (NOx),etc., most attention to health riiks from inhaled exhaust has been given to i a potential for causing cancer. For this reason, DE exhaust has been given greater attention than GE. There is a very large toxicological data base on the cancer and noncancer effects of DE and much less information on GE. Animal studies have shown that heavy chronic exposures to DE cause cancer and noncancer lung disease in rats, but the exposure conditions in these studies and the potential uniqueness of the lung tissue responses of this species make derivation of human risk factors from these data highly questionable. Data from humans suggest that heavy occupational exposures to DE can cause acure inflammation and other cellular effects and that chronic exposures probably incur small increases of similar magnitude in the risks for lung cancer and other chronic lung disease. At present, the toxicological data demonstrate that engine exhaust can present a health hazard and support the plausibility of both cancer and nonca monary effects in humans. of these effects are such that of exhaust as a single material primarily for occupational ex present, quantitative estimates for exhaust-induced cancer an disease are difficult to make degree of confidence. Our leaves little doubt, however, tha exposures to high concentr exhaust are hazardous and mized. Engine exhaust is a and a ubiquitous component of pollution; thus, it undoubtedly to the adverse health eff'ects of the mixture. REFERENCES 1. Mauderly JL, Grifith WC, Henderson RF, Jones RK, McClellan RO. Evidence from animal studies for the carcinogenicity of inhaled diesel exhaust. In: Nitroarenes (Howard PC, ed). New York:Plenum Press, 1990;13. 2. Mauderly JL. Diesel exhaust. In: Environmental Toxicants - Human Exposures and Their Health Effects, Chap 5 (Lippmann M, ed). 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