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Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons Paolo Boffetta, Nadia Jourenkova, and Per Gustavsson Epidemiologic evidence on the relationship between polycyclic aromatic hydrocarbons (PAH) and cancer is reviewed. High occupational exposure to PAHs occurs in several industries and occupations. Covered here are aluminum production, coal gasification, coke production, iron and steel foundries, tar distillation, shale oil extraction, wood impregnation, roofing, road paving, carbon black production, carbon electrode production, chimney sweeping, and calcium carbide production. In addition, workers exposed to diesel engine exhaust in the transport industry and in related occupations are exposed t o PAHs and nitro-PAHs. Heavy exposure t o PAHs entails a substantial risk of lung, skin, and bladder cancer, which is not likely to be due to other carcinogenic exposures present in the same industries. The lung seems to be the major target organ of PAH carcinogenicity and increased risk is present in most of the industries and occupations listed above. An increased risk of skin cancer follows high dermal exposure. An increase in bladder cancer risk is found mainly in industries with high exposure t o PAHs from coal tars and pitches. Increased risks have been reported for other organs, namely the larynx and the kidney; the availableevidence, however, is inconclusive. The results of studies addressing environmental PAH exposure are consistent with these conclusions. Cancer Causes and Control 1997,8,444-472 Key words: Bladder cancer, lung cancer, occupational exposures, polycyclic aromatic hydrocarbons, skin cancer. Introduction Polycyclic (`polynuclear') aromatic hydrocarbons (PAH) are present ubiquitously in the environment as pollutants, often in small quantities of the order of pg/kg or ng/m'. They are a family of lipophilic non-polar chemicals comprising two or more benzene rings, and are formed mainly as a result of pyrolytic processes, in particular the incomplete combustion of organic materials. Exposure to PAHs often entails exposure to heterocyclic aromatic compounds, such as acridine and carbazole, that are formed under similar circumstances. Several hundred PAHs have been characterized; the best known is benzo[a]pyrene, which is often used as a marker of PAH exposure. The chemistry and formation of PAHs is reviewed by the International Agency for Research on Cancer (IARC).' Humans are exposed to PAHs by inhalation, ingestion, and skin contact. Non-occupational respiratory exposure is mainly from tobacco smoke and urban air, while the major sources of ingested PAHs are drinking water and cooked food. The main route of occupational exposure is, in most industries, inhalation; in many cases; however, skin exposure represents an important route. The interpretation of the studies on cancer risk from PAH exposure in humans is complicated by several factors. PAHs occur invariably as mixtures, whose Dr Boffetta is with the Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France. Dr Jourenkova was with the Unit of Environmental Cancer Epidemiology, IARC, at the time of preparation of the review; she is currently .with the Department of Medical Statistics of the Institute Gustave-Roussy in Villejug France. Dr Gustavsson is with the Department of Occupational Health, Karolinska Hospital, Stockholm, Sweden. Address correspondence to Dr Boffetta, International Agency for Research on Cancer, 150 cours Albert Tbomas, 69372 Lyon cedex 08, France. 444 Cancer Causes and Control. Vol 8. 1997 01997 Rapid Science Publishers c < d c t i 4 < c c c 4 4 6 4 d 4 i 4 Cancer risk from PAHs composition depends mainly on the raw material and the combustion circumstances. The comparison of studies conducted in the same industry is complicated therefore by qualitative, in addition to quantitative, differences in exposure. In addition, it is practically impossible for epidemiology to disentangle the risk posed by each individual PAI-I. PAHs in occupational environments are often adsorbed to particles. Epidemiologic data are inadequate to evaluate the possible interaction between PAHs and particles in the induction of lung cancer in humans. Finally, exposure to PAHs is ubiquitous, and many nonoccupational sources of exposure exist, mainly tobacco smoke and diet; the comparison of occupationally exposed populations and `unexposed' reference populations therefore is biased to an unknown extent. The evidence of carcinogenicity of several PAHs, their mixtures and related occupational settings has been evaluated by IARC within the Monograph program' (Table I). This review focuses on several industries and occupational groups at high exposure to various mixtures of PAHs. Although, almost invariably, other carcinogens and in particular, other lung carcinogens such as crystal- line silica, metals, and asbestos - are present in these occupational settings, PAH mixtures represent the most significant exposure. The industries and occupations reviewed in detail include aluminum production, coal gasification, coke production, iron and steel foundries, and different groups of workers exposed to diesel engine exhaust, coal tars and related products, carbon blacks, and other mixtures of PAHs. The review in particular focuses on data accumulated after the Monograph evaluations (Table 1). Data on cancer risk from exposure to mineral oils (including data on workers exposed to lubricating oil, such as mule spinners in the textile industry) are reviewed elsewhere in this issue (see Tolbert). Most available information comes from industry-based cohort and nested case-control studies; in some instances, however, community-based studies, mainly of casecontrol design, have provided additional relevant results. However, a systematic review of community-based studies has been conducted only for cancer of the lung, larynx, skin, kidney, and urinary bladder. Results of cohort studies also have been reviewed systematically for risk of cancer of the same organs;" dose-response relationships have been given special attention whenever data were available. It should be noted, however, that the risk of skin cancer is difficult to assess in studies based on mortality. Epidemiologic or experimental indication of risk from PAH exposure is available for other cancer sites, such as colon3and e s o p h a g ~ s . ~ a The only exception are studies of diesel exhaust exposed workers, for whom only data on lung and bladder cancer risk have been systematically reviewed. A brief review of data on cancer risk from environmental exposure to PAHs is included, together with a discussion of some key issues in the interpretation of experimental studies on PAH carcinogenicity. Given the abundance of human studies, however, a detailed review of experimental studies was not considered as a priority. Apart from exposure to PAHs in tobacco smoke,' which is not reviewed in detail here, data from exposure to PAHs outside the workplace and the general environment are sparse. One exception is the use of coal tar containing ointments and pastes for the treatment of psoriasis and other dermatologic diseases and symptoms.6 Data on cancer risk among these patients, however, are of very limited use as for carcinogenicity of coal tar. In recent years, a number of biomarker-based studies have been published on individuals exposed to PAHs in the occupational and the general environment (see, for example, Schoket et ul' and van Schooten et uZ*). Although these studies are useful to investigate mechanisms of toxicity (and, in particular, carcinogenicity of PAHs) and to contribute to the identification of the biological activity of specific chemicals, they have not contributed thus far to the identification and quantification of risk. These studies therefore are not reviewed in detail. Aluminum production PAH exposure in the aluminum industry originates mainly from the evaporation of carbon electrode materials used in the electrolysis process, in which carbon anodes are suspended in a bath contained in a carbon-lined steel vessel.' Anodes and the lining materials usually are made from coal tar pitch and coke. PAH exposure is particularly high (typical benzo[a]pyrene levels in the range 1-10 mg/m3)' in the Soderberg electrolysis department, while substantial, although lower (typical benzo[u]pyrene range, 0.1-1 mg/m'),' exposure occurs in the other main type of electrolysis, prebake, and in other departments, such as the carbon plant, in which anodes are manufactured." Other potential exposures in this industry include asbestos, fluorides, sulfur dioxide, and magnetic fields. Large epidemiologic studies of aluminum workers have been conducted in Canada, Norway, France, and the United States (Table 2 ) . The risk of bladder cancer was increased, in particular among Soderberg workers, in all the adequate studies that have considered it. A casecontrol study nested in a large Canadian cohort2' was particularly informative: bladder cancer risk was associated with increased exposure to coal tar pitch volatiles, measured either as benzene soluble matter or as benzo[u]pyrene (Figure I), the latter being a better pre- dictor of risk in a linear model with IO years of lag. Under this model, the risk of bladder cancer increased by 1.7 Cancer Causes and Control. Vol 8. 1997 445 I! Boffeettu et a1 Table 1. Carcinogenicity of polycyclic aromatic hydrocarbons (PAH), their mixtures, and related exposure circumstances - evaluations made within the IARC Monograph program2 PAHs and groups of PAHs Anthanthrene Anthracene Benz[a]acridine Benz[c]acridine Benz[a]anthracene Benzo[b]fluoranthene Benzo~]fluoranthene Benzo[k]fluoranthene Benzo[ghi]fluoranthene Benzo[a]fluorene Benzo[b]fluorene Benzo[c]fluorene Benzo[ghi]perylene Benzo[c]phenathrene Benzo[a]pyrene Benzo[e]pyrene Carbazole Carbon-black extracts Carbon blacks Chrysene Coronene Cyclopenta[cd]pyrene Dibenz[a,blacridine Dibenz[a,]]acridine Dibenz[a, clanth racene Dibenz[a,h]anthracene Dibenz[a,]]anthracene 7H-Dibenzo[c,g]carbazole Dibenzo[a,e]fluoranthene Dibenzo[h,rstJpentaphene Dibenzo[a,e]pyrene Dibenzo[a,h]pyrene Dibenzo[a,~]pyrene Dibenzo[a,dpyrene 1,4-Dimethyiphenanthrene 1,3-Dinitropyrene 1,6-Dinitropyrene 1,8-Dinitropyrene 3,7-Dinitrofluoranthene 3,9-Dinitrofluoranthene 1,3-Dinitropyrene 1,6-Dinitropyrene 1,8-Dinitropyrene Fluoranthene Fluorene Indeno[1,2,3-cd]pyrene 1-Methylchrysene Evidence of carcinogenicityasb Human' Animal' Overallb Year of evaluation ND L 3 1987 ND I 3 1987 ND L 3 1987 ND L 3 1987 ND S 2A 1987 ND S 26 1987 ND S 26 1987 ND S 26 1987 ND I 3 1987 ND I 3 1987 ND I 3 1987 ND I 3 1987 ND I 3 1987 ND I 3 1987 ND S 2A 1987 ND I 3 1987 ND L -S 3 1987 - 1995 I S 26 1995 ND L 3 1987 ND I 3 1987 ND L . 3 1987 ND S 26 1987 ND S 26 1987 ND L 3 1987 ND S 2A 1987 ND L 3 1987 ND S 26 1987 ND L 3 1987 ND L 3 1987 ND S 28 1987 ND S 26 1987 ND S 26 1987 ND S 26 1987 ND I 3 1987 ND L 3 1988 ND S 26 1988 ND S 2 6 1988 I S 2 6 1995 I S 26 1995 ND L 2 6 1988 ND S 3 1988 ND S 26 1988 ND I 28 1987 ND I 3 1987 ND S 3 1987 ND I 26 1987 Continued 446 Cancer Causes and Control. Vola. 1997 Cancer risk from PAHs Table 1. Continued Evidence of Humana Animala Overallb Year of evaluation 2-Methylchrysene ND L 3 1987 3-Methylchrysene ND L 3 1987 4-Methylchrysene ND L 3 1987 5-Methylchrysene ND S 28 1987 6-Methylchrysene ND L 3 1987 2-Methylfluoranthene ND L 3 1987 3-Methylfluoranthene ND I 3 1987 1-Methylphenanthrene ND I 3 1987 6-Nitroacenaphtane ND S 28 1987 9-Nitroanthracene ND ND 3 1987 7-Nitrobenz[a]anthracene ND L 3 1988 6-Nitrobenzo[a]pyrene ND L 3 1988 6-Nitrochrysene ND S 28 1988 3-Nitrofluoranthene ND I 3 1987 2-Nitrofluorene ND S 28 1988 1-Nitronaphthalene ND I 3 1988 2-Nitronaphthalene ND I 3 1988 3-Nitroperylene ND I 3 1988 1-Nitropyrene ND S 28 1988 2-Nitropyrene ND I 3 1988 4-Nitropyrene ND S 2B 1988 Phenanthrene ND I 3 1987 Pyrene ND I 3 1987 Mixtures of PAHs Bitumens Extracts of steam-refined and air-refined bitumens Steam-refined and cracking-residue bitumens Air-refined bitumens I - 3 1987 - S 26 1987 - L 3 1987 - I 3 1987 Coal-tar pitches S S 1 1987 Coal-tars S S 1 1987 Creosotes -Diesel engine exhaust -Whole diesel engine exhaust - -Gas-phase diesel engine exhaust (with particles removed) - -Extracts of diesel engine exhaust particles -Engine exhaust (unspecified as from diesel or gasoline engines) L L L S 2A 1987 2A 1988 S - 1988 I 1988 S 1988 - 1988 Gasoline engine exhaust I - 2B 1988 Whole gasoline engine exhaust Condensate/extracts of gasoline engine exhaust - I - 1988 - S - 1988 Mineral oils, untreated and mildly-treated S S 1 1987 Mineral oils, highly-refined I I 3 1987 Shale-oils S S 1 1987 soots S I 1 1987 Exposure circumstances related to PAHs: Aluminum production Coal gasification Coke production Iron and steel foundry S - 1 1987 S - 1 1987 S - 1 1987 S - 1 1987 a Abbreviations: ND = no data; I = inadequate evidence; L = limited evidence; S = sufficient evidence of carcinogenicity. b 1 = carcinogenic to humans; 2A = probably carcinogenic to humans; 2B = possibly carcinogenic to humans; 3 = not classifiable as for carcinogenicity to humans (for details, see the Preamble of an IARC Monograph volume). Cancer Causes and Control. Vol 8. 1997 447 l? Boffetta et al d! rmo r N * r 448 Cancer Causes and Conrrol. Vol 8. 1997 m m4- Uc al 5 -E c 2 om ?cp KO$O zz om c7 p z bz ?l nz II F -i.Q" m c E II 54 Cancer risk from PAHs percent for each year of exposure to benzo[u]pyrene at a concentration of 1 pg/m'. The risk of lung cancer was increased in some of the cohort studies of aluminum workers, although the results were not consistent among studies, nor clearly linked with estimates of coal tar pitch or PAH exposure. In the most informative study, however, a case-control study nested in a large Canadian cohort," lung cancer risk was associated with employment in the Soderberg electrolysis department and in the carbon plant; a dose-response was found in this study between lung cancer risk and estimated exposure to benzene soluble matter as well as benzo[a]pyrene (Figure 2). Under a linear model, the estimated relative risk (RR) was 1.0034for 1 mg/m'-year of benzene soluble matter and 1.0028for 1ng/m'-year of benzo[u]pyrene. However, power curve models fitted the data better than linear models, suggesting a decreasing slope at high exposures. Coal gasification Exposure to PAHs was high among workers employed in the production of town gas and industrial gas from destructive distillation of coal, in particular among workers involved in coal distillation and purification using old types of gasifiers, such as horizontal, vertical and continuous vertical retorts (range of typical benzo[u]pyrene levels: 1-10n~g/rn')?P~AH exposure, however, also occurs in modern processes (e.g., fixed-bed, fluidized-bed, and entrained-bed).22In the older gas-making processes, gas and tars were produced by the destructive distillation of coal; in modern gasifiers, oxygen is introduced, resulting in partial combustion of the coal: in this case, all the coal is distilled into gas and no coke is produced. Workers employed in the destructive distillation of coal were among the occupational groups included in early studies which reported an increase in scrotal and other skin cancers linked to exposure to tar or pit~h.''-'E~arly reports of increase of lung cancer among gas workers include the study by Bruusgaard from Norway.26The first modern epidemiologic studies on gas workers (Table 3) were conducted by Doll and c o l l e a g ~ e s ~in~ e~ig~h~t 'g~as boards in the United Kingdom. A twofold increased risk of lung and bladder cancer was reported among workers employed in coal carbonization, while no such excess was reported among other groups of workers. The same tumors were increased among gas workers from Hamburg, Germany,**although the interpretation of this study is complicated by the poor reporting. In addition to a small Danish studyz9suggesting an increased mortality from lung cancer, a small cohort from Sweden" confirmed the increased risk of bladder cancer, but not that of lung cancer. Increased risk of cancer from other sites has been reported occasionally in these studies; the evidence re- garding skin cancer is weak mainly because most of the studies analyzed cancer mortality rather than incidence. PAHs from coal tar are the most plausible explanation for the increased risk of lung and bladder cancer among coal gasification workers, in particular, those employed when the older equipment was in use. Other exposures include heavy metals, silica, and aromatic amines. Coke production Substantial airborne exposure to PAHs has been measured in various occupations in coke production." Other agents, including heterocyclic and substituted aromatic compounds, also have been reported. Exposure to PAHs is highest in coke oven operations, in particular at the top of the oven. In studies done in eastern European countries, average benzo[a]pyrene concentrations were as high as 112 pg/~n','w~hereas measurements in western Europe and the US during the same period showed concentrations one order of magnitude 10wer.'~ The most important epidemiologic study to date on coke oven workers has been conducted since the 1960s in the US and Canada." A recent update of this cohort3* shows a twofold increased risk of lung cancer, that decreased during the follow-up (Table 4). An analysis of lung cancer risk according to cumulative exposure to coal-tar pitch volatiles, based on measurements taken in the plants of the study in the late 1960s, showed a monotonic, significant dose-response (Figure 3). In another large cohort study, from China," the risk of lung cancer was increased between two- and fourfold, according to the department in which the subject worked. Similar results'were obtained in two smaller studies from Italy45 and France: while the risk of lung cancer was increased only moderately (30 percent) in other studies from the Netherlands*` and Japan.40 In the study from the US and Canada, an excess risk of prostate and kidney cancer also was found, but not for risk for other types of tumor, including digestive cancers; excess of digestive cancers, on the other hand, were reported sporadically in other studies. No evidence of an increased risk of bladder cancer was present in any study. Iron and steel foundry Employment in iron and steel foundries entails exposure to PAHs: concentrations of benzo[a]pyrene in the range 0.1-1.1 pg/m3 have been reported.""* PAHs are formed during thermal decomposition of organic materials in the sand; the main sources of PAHs are organic binders, coal powder and other organic additives as well as engine exhaust. In particular, use of coal tar pitch as a binder may result in high PAH exposure: in one study: benzo[a]pyrene levels were higher in foundries using coal Cancer Causes and Control. Vol 8. 1997 449 I! Boffettu et a1 5 8 em 0 II c aa.:l_ nm&n sal r P 0 L C % E n Ee D Y II i II > 450 Cancer Causes and Control. Vol 8. 1997 la: la: n Figure 1. Bladder cancer risk among aluminum workers by benzene-soluble matter (BSM) exposure21 7. R:: 4. 3. 2- 1. 04 <I(R) 1- 10- 20- Cumulative BSM exposure (mg/m3x yr) R: referencecategory: RR: relative risk 30- Figure 2. Lung cancer risk among aluminum workers by benzene-soluble matter (BSM) e x p o ~ u r e ' ~ 3 ........................................................ ~ .... ............. 2.5 ................................................................................................... (R) 1- 10- 20- Cumulative BSM exposure (mg/m3x yr) R referencecategory. RR. relative risk 30- Figure 3. Lung cancer risk among coke oven workers by PAH exposure3' 4 -. ................................................................... . ~............ 3.5 . . . . . . . . . . . . . . . ........................ 3 ............................................................................ R 2.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . zR .................. ..........: .............~ . . . ............-............. 1.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .._........ .. >....................... I ./. ............. .: ........................................... 0.5 ~ . . Cancer risk from PAHs zg g 2 wN bo 3 z Cancer Causes and Control. Vol 8. 1997 451 I! Boffeetta et a1 tar pitch as molding sand additive than in foundries using coal powder. Iron and steel foundry workers, however, are exposed to several other classes of known and suspected carcinogens, including in particular crystalline silica and heavy metals. The contribution of PAHs to any increase in cancer risk in this group of workers is therefore particularly difficult to assess. An increased risk of lung cancer has been reported consistently in cohort studies conducted in Europe and North America (Table 5). The overall increase in risk was rather small in most studies, with RRs in the range 1.2 to 1.5, although a suggestion of a dose-response was found in some of the studies that addressed it. Several studies analyzed the risk of lung cancer by department; however, no clear pattern has emerged. The risk of bladder cancer was increased sporadically; the fact that no results on bladder cancer was presented in several studies suggests the possibility of selective report of positive findings. Similarly,an elevated risk of stomach and prostate cancer was reported in some studies. Workers exposed to diesel engine exhaust Diesel engine exhaust comprises a particulate and a gaseous phase, the former being important for a possible carcinogenic effect. Diesel particles comprise a carbon core with organic compounds adsorbed. Particulate extracts contain PAHs - in particular, nitro-PAHs such as nitro- and dinitro-pyrenes.68Diesel exhaust extracts are carcinogenic in experimental animals, as is whole engine exhaust in inhalation experiments (Table 1). Exposure to diesel engine emissions occurs in many occupational settings, and it is often difficult to separate this agent from other combustion fumes, notably gasoline engine emissions. Levels of PAHs are highest in emissions from heavy-duty diesel engines, lower (and comparable) in emissions from light-duty diesel engines and from gasoline engines without catalytic converters, and lowest in emissions from gasoline engines with catalytic converters. Diesel engines, however, emit at least IO times more nitro-PAHs than gasoline engines.68Therefore, although epidemiologic studies have been conducted on groups at relatively high and pure exposure to diesel exhaust, co-exposure to other PAH-rich mixtures is invariably present. Table 6 reports the results of the industry-based studies conducted among workers exposed to diesel exhaust. Although many types of cancer have been reported sporadically at increased risk among workers exposed to diesel exhaust, this review will focus on lung and bladder cancer, for which the suspicion of an association is strongest. Drivers are an important group of workers exposed to diesel exhaust. Results of studies on bus drivers do not consistently show an excess of lung and bladder cancer. 452 Cancer Causes and Control. Vol 8. 1997 The evidence in favor of an association, on the other hand, is strong for truck drivers; all available studies consistently showed an increased risk, which was significant in many investigations. Tobacco smoking was controlled for in several of these studies. The most informative study is the case-control study nested in a cohort of US team- sters," in which a dose-response was found for duration of employment as a long-haul driver and the risk of lung cancer was highest among drivers of diesel trucks only. These findings are reinforced by a few studies conducted on unspecified and mixed drivers, in which truck drivers were the largest group, that also found positive results. The evidence regarding taxi drivers is less compelling than the one on truck drivers; most of the available studies suggest the presence of an association similar to the one found for truck drivers. In only one study, however, was tobacco smoking controlled for. Railroad workers may be a particularly informative group since exposure to other carcinogens is more limited than in the case of other diesel exposed groups. However, these studies are limited to countries where diesel engines have been widely used. Two large studies have been conducted in Canadaa5and the US.86-I8n8 the Canadian study, a small overall increase in lung cancer risk was found, and a trend with estimated level of diesel fume exposure (RR = 1.2 for possible exposure and 1.4 for probable exposure, compared with no exposure, P < 0.01). In the American study, the risk of lung cancer was increased significantly among workers aged less than 65 (RR for one year of exposure to diesel = 1.0, P < 0.05), while no association was found in older workers (RR = 1.0, P = 0.9). Mortality from other cancers, and notably bladder cancer, is not increased in studies of railroad workers. Other groups of workers exposed to diesel engine exhaust, that have been studied mainly in North America and northern Europe, include heavy equipment opera- tors, dock workers, and crane workers. In most of these studies, an increased risk of lung cancer has been found. The most informative study has been conducted on dock workers from Sweden? where a dose-response was found according to estimated diesel exposure. Results on bladder cancer are less consistent and often not available, suggesting the possibility of report bias. A further occupational group for which several inves- tigations are available are garage mechanics and other maintenance workers in transport companies. Benzo[u]- pyrene levels in bus garages have been measured in the range of 1-20 For these workers, however, expo- sure to other carcinogens, such as mineral oils, is likely to occur, making the interpretation of the results prob- lematic. In particular, one studyy5attempted to address the effect of diesel exhaust exposure among workers in five bus garages in Stockholm, Sweden. Although based Cancer risk from PAHs 2 DE 3 P r. W D? mC -K .g- om 0 mc m 0 -N m c d Ill a ?i F L a a ? mL Z .ce- ?a W0 xeEp O ? 'Do m x zW In md ?? ;5Y 33 - --f m (v0) c Ill Cancer Causes and Control. Vol 8. 1997 453 u) uC) a I 0 b SI C 0aln nm ua) Im a: 4 454 Cancer Causes and Control. Vol 8. 1997 Cancer risk from PAHs a (I) 3 0 0 Cancer Causes and Control. Vol 8. 1997 455 f? Boffetta et a1 .5- I Le r z? I m 7 (u ? 0 m(0 r a ", Q 2 za k9 07 01 m 0) m a -1 -31 m E Z P0 m ;5 00 ?? gn 51 zg n ImI- I r4n CD 0 ?js 456 Cancer Causes and Control. Vol 8. 1997 -< 2 al .cf- 4 Cancer risk from PAHs Figure 4. Lung cancer risk by cumulative exposure to diesel exhaust among bus garage workersg6 R8 R 74 d 51 41 o I--- I I 0-IRI , 10- 20- 30- Diesel exhaust index* R referencecategory; RR- relative risk * Based on score (0,1 , 1.5.2.25 3.38. 5.06) x years of exposure on relatively few deaths, a dose-response was found with estimated cumulative diesel-exhaust exposure (Figure 4). In conclusion, different occupational groups at high exposure to diesel exhaust have been studied. An increased risk of lung cancer has been found quite consistently and the results were more consistent among studies conducted on workers with the highest exposure; the overall RR is in the order of 1.5 to 2.0, and dose- response analyses, in most cases, have shown a positive trend. Although a final conclusion cannot be reached, the increased risk does not seem to be due to tobacco smoking (which was controlled for in a number of the available investigations),nor to other extra-occupational confounders. The groups studied experienced exposures to other agents, including known or suspected carcinogens such as asbestos and mineral oils; however, different exposures occurred in the different industries, and a cautious interpretation of the body of evidence would identify diesel engine exhaust as the most likely cause of the increase. No pattern of excess of bladder cancer risk emerges from cohort studies of workers exposed to diesel engine exhaust. Workers exposed to coal tars and related products Exposure to coal tars, coal tar pitches, and related products occurs in a number of occupational environments. Groups of workers have been studied, for whom PAH exposure is mainly t o coal tar and related products. They include workers in tar distillation, shale oil extraction, and workers exposed to creosotes, mainly during wood impregnation. In addition, workers exposed to bitumen in roofing, road paving, and related industries may have substantial exposure to coal tar. Results of relevant cohort studies are summarized in Table 7. Tar distillation Crude coal tar is one of the main by-products of coal carbonization for coke production. Distillation is aimed to produce, from the different fractions of coal tar, different products such as creosote oils, fluxing oils, carbon black oils, and road t a x 6Tar distillation workers from the UK were found at higher risk of bladder cancer in a early mortality study.'"Results of two cohort studies are available, from the UK" and Francey8(Table 7). An increasewas found in lung and bladder cancer mortality in the UK but not in the French study. Shale oil extraction Shale oil is the product of thermal processing of raw oil shale; on average, crude shale oils have higher PAH content than crude petroleum oils. Shale oils have been used in the past as fuels and chemical plant feedstocks. They are used currently in only a few countries. Workers in shale oil extraction are exposed to PAHs in gas and vapor, as well as to crude and spent shale oil through dermal ont tact.'"^ (See Tolbert, this issue.) The carcinogenicity of shale oil was shown in the 1920s among workers from Scotland who experienced a high number of skin and, in particular, scrotal cancers.lobCohort studies conducted in this industry are summarized in Table 7. Excesses of skin cancer were confirmed in a study from Estoniaw and Scotland (only for workers employed before 1953), but not in a US study of 325 workers employed during 1948-69.'07 No increased risk of lung cancer was present in these investigations, nor in a population-based case-control studylo8conducted in seven parishes from an area in central Sweden where shale oil extraction used to be a major industry. Creosote exposed workers Creosotes are one of the main distillate fractions of coal tars and coal tar pitches. PAHs, mostly unsubstituted, generally account for at least 75 percent of creosotes.They have been used extensively as wood As for shale oil, during the first decades of the century, there were reports of skin cancer and, in particular, scrotal cancer among workers exposed to creosotes;2)''09these reports were confirmed by a mortality analysis of brickmakers from the UK? A study of wood impregnators exposed to creosotes from Norway'"' in which an in- creased incidence of lip and skin cancer - but no excess of lung cancer - was reported, is summarized in Table 7. A small study from Swedish wood impregnators reported no excess of lung cancer."" Creosote exposure was associated with increased risk of multiple myeloma in a casecontrol study from Sweden."' (See Dich et al, this issue.) Cancer Causes and Control. Vol8. 1997 457 I! Boffetta et al cv) 0a W g U -mc0) 2 U Cm -tij c m 0 0 c0 E a v) n0 xa, -ol .K- c0c al .-v) 0 cL va) .UK- av) 5.0- $ - $ 0 .K- ? U -8 n E E al +5 0 5 c .m- 0C ln c .a-l U wC 1 Y3 -a cIn c5 8 I; 0 6 F 458 Cancer Causes and Control. Vol 8. 1997 Cancer risk from PAHs Roofers and asphalt workers Roofers and asphalt workers are exposed to PAHs from fumes formed during heating of bitumen."' Groups of workers exposed to bitumen fumes include roofers, road pavers, asphalt mastic workers, highway maintenance workers, and other miscellaneous and unspecified groups. For example, roofers are exposed to PAH levels in the range 1-100 mg/m'."' Table 7 reports the results of two cohort studies of roofers and asphalt workers; other studies have been published based on routine statistics and record linkage studies. The risk of cancer in these occupational groups has recently been re~iewed;"a~n increased risk of lung (aggregated RR = 1.2, 95 percent confidence interval [CI] = 1.1-1.3) and skin cancer (RR = 1.7, CI = 1.1-2.7) emerges from such studies, while the risk of bladder cancer is less consistent (RR = 1.2, CI = 0.9-1.5). Roofers had, in general, higher cancer risk than other asphalt workers. It is not possible, however, on the basis of available studies, to disentangle the contribution of coal tar fumes from that of tar-free bitumen fumes. Carbon black manufacture Carbon black is a commercial product of fine particulate soot which is manufactured mainly by gas combustion and principally used for printing inks, rubber.products, paints, and in photocopying machines. Carbon black is lower in content of PAHs than soot generated by combustion of fossil fuels or wood. Although most workers exposed to carbon blacks are in the application industries, levels of exposure are higher in the production industry. In this industry, earlier dust levels have been high, and sometimes very high."' Cohort studies of carbon black workers are summarized in Table 8. A study of carbon black workers in the US""."' showed no increased risk of death from respira- tory cancer, but the study has some methodologic problems.11'A nested case-referent study of cancer cases within the cohorttLd8id not show an association between cancer risk and exposure to carbon black. A small excess of lung cancers of borderline statistical significance and an excess of bladder cancer based on few deaths was reported among carbon-black production workers at five factories in the UK."' Carbon and graphite electrode manufacture Electrodes of carbon or graphite are used in the metal industry. Graphite is composed of crystalline carbon, which occurs naturally, and also is produced industrially from coke and pitch. Graphite dust is low in PAHs since the production process involves heating up to 2,8OO0C, but workers are exposed to considerable amounts of PAHs during the manufacturing."e Cohort studies of carbon and graphite electrode work- ers are summarized in Table s. A study at 11 US plants showed no excess of lung cancer that could be attributed to PAHs or carbon products."') There was no indication of an increased lung cancer risk at two French graphite and carbon electrode plants. However, a relatively large proportion (around IO percent) of the cohort was lost to follow-up."o A small study of Swedish graphite electrode workers"' showed no clear excess of respiratory cancer, but included few cancer cases. No conclusion therefore can be drawn at present on the presence of an increased risk of lung cancer in this industry. Results on bladder cancer risk are also inconclusive. Chimney sweeps Chimney sweeps are exposed to chimney soot that is rich in PAHs as well as metals such as arsenic, chromium, and nickel. They also may be exposed to asbestos, combustion gases such as sulphur dioxide and carbon monoxide, and to organic solvents used for degreasing.Industrial hygiene measures have been applied to a less extent to this group compared with other workers. Although cancer risk among chimney sweeps has a distinct place in the history of occupational epidemiology because of the report of scrotal cancer in this group of workers by P0tt,lZ4relatively few modern epidemiologic studies have been conducted to quantify the risk among currently employed workers. The most informative study, from Sweden,"' is summarized in Table 8. An increased risk of cancer of the lung, esophagus, liver, prostate, kidney, and skin was found. Smaller studies have been conducted in Denmark"' and former Yugos1avia;'zb in both, lung cancer risk was increased, although based o n small numbers. Calcium carbide production Calcium carbide is used in the production of acetylene and of calcium cyanamide, used as fertilizer, and in the pyrotechnics industry. Its production involves electrothermal reduction in arc furnaces with Soderberg electrodes. Elevated PAH exposure may occur intermittently in severaljobs. Workers from one Norwegian plant have been studiedl2' (Table 8). No excess of lung cancer was shown. Community-based studies Exposure to PAHs has been examined in detail in a casecontrol study conducted during 1982-87 in Montreal, Canada."' A total of 3,730 cases of cancer from 20 sites were administered a detailed occupational questionnaire; Cancer Causes and Control. Vol 8. 1997 459 . ._. ~ - . .. . .-... . - . . . . ..-. I! Boffeettu et a1 C Oln-W 460 Cancer Causes and Control. Vol 8. 1997 W E E P c II mo a their workplace exposure to 293 agents then was assessed by a team of chemists and industrial hygienists. The method resulted in a rather high proportion of study subjects being assessed as exposed to PAHs. In the analysis, cases of each cancer were compared with cases of all other cancers. Among the agents considered, there were several mixtures of PAHs (Table 9): the risk of lung cancer was increased among subjects exposed to PAHs from wood combustion but not to other groups of PAHs; results on bladder and kidney cancer did not show any pattern of risk. Exposure to carbon black in this study was analyzed more in detail.''# A nonsignificant risk of lung cancer was found among individuals with a high cumulative exposure to carbon black. Other community-based studies that have reported results for PAH exposure or employment in industries and occupations with high exposure are summarized in Tables 10 (lung cancer), 11 (bladder cancer), and 12 (laryngeal, skin, and renal cancers). In general, results on occupations entailing exposure to diesel exhaust (e.g., bus and truck drivers) have been reported more often than results on other occupations (e.g., steel foundry workers). This fact probably is due to a higher prevalence of employment in the transport industry in the populations where the studies have been conducted. The possibility of publication bias (ie., selective reporting of positive or significant results) has to be considered seriously in the case of industries and occupations for which results were presented in few studies. On the other hand, the low prevalence of exposure contributes to the lack of statistical significance reached by many studies addressing rare occupations. Results on lung cancer (Table 10) are similar to those found in cohort studies of corresponding groups of workers: adjustment for smoking did not modify substantially the results of most studies, suggesting that confounding by tobacco smoking is not an important confounder in cohort studies. In only one study - in addition to the one from Montreal described above - was PAH exposure estimated vza a job-exposure matrix:'" this study suggested a small increase in lung cancer risk only in the highest exposure group. Case-control studies of bladder cancer (Table 11)tend to report positive results for exposure to PAHs, although statistical significance is rarely reached, given the small number of cases in the different exposure categories. In the two studies that addressed PAH exposure from any occupational s o ~ r c e , ' ~ *af.t'e~r~controlling for aromatic amine exposure, an increased risk was found in the highest category of exposure. Results from case-control studies of laryngeal, skin, and renal cancer (Table 12) are sparse, and the few strongly positive results reported should be considered with care given the possibility of reporting bias. Environmental exposure Urban air pollution is a complex mixture of chemical compounds, partly adsorbed to particles. PAHs in urban air occur both in the gaseous and particle phase, and originate mainly from residential heating and vehiclefuels. I n d o o r a i r s o u r c e s of PAH e x p o s u r e i n c l u d e environmental tobacco smoke, fumes from open fires, kerosene heaters, and Exposure to environ- mental tobacco smoke is associated with an increased risk Table 9. Results of the Montreal (Canada) multisite case-control study on polycyclic aromatic hydrocarbon (PAH) exposure by Siemiatyckii2' Exposure % EXD Luna cancer Bladder cancer Carbon black Diesel engine emission Coal comb. products Wood comb. products soot Cutting fluids, pre-1955 Asphalt Coal tar, pitch PAH from coal PAH from petroleum PAH from wood PAH from other sources PAH from any source Benzo[a]pyrene 5 15 5 4 9 7 3 2 8 62 4 20 64 22 Exp cases 5 73 19 15 27 20 13 12 35 394 15 74 79 39 OR (90% CI) 1.7 (0.5-5.7) 1.2 (0.9-1.7) 1.1 (0.6-1.9) 1.9 (1 .O-3.9) 1.6 (0.9-2.6) 1.O (0.6-1.6) 0.7 (0.4-1.4) 0.7 (0.4-1.5) 1.0 (0.7-1.5) 1.1 (0.9-1.3) 1.9 (1.0-3.9) 0.9 (0.7-1.1) 1.1 (0.8-1.4) 1.O (0.7-1.5) Exp cases 3 32 4 8 4 13 0 6 12 190 8 46 29 9 OR (90% CI) 1.1 (0.4-3.2) 1.O (0.7-1.4) 0.3 (0.1-0.8) 1.3 (0.7-2.7) 0.4 (0.2-1.O) 1.3 (0.8-2.3) 1.1 (0.5-2.1) 1.6 (0.7-3.7) 0.7 (0.4-1.1) 0.9 (0.8-1.1) 1.3 (0.7-2.7) 1.1 (0.8-1.5) 0.7 (0.5-1.1) 0.5 (0.3-0.9) Abbreviations: Exp = exposed; OR = odds ratio; CI = confidence interval. Kidnev cancer Exp cases OR (90% CI) 1 0.9 (0.2-4.9) 14 1.3 (0.8-2.0) 3 1.1 (0.4-2.9) 0 0 (0.0-1.7) 3 1.1 (0.4-3.1) 4 1.1 (0.5-2.7) 1 0.4 (0.1-2.2) 1 0.6 (0.1-3.5) 5 1.O (0.4-2.1) 68 1.1 (0.8-15) 0 0 (0.0-1.7) 15 1.O (0.6-1.6) 8 0.8 (0.4-1.4) 7 1.3 (0.7-2.6) I I I!I jjl i;li 'I' I! Bofferru et a1 .- F --r 0 O 0n 0n I aa a r0 0 a 462 Cancer Causes and Control. Vol 8. 1997 L O L O 9 C ? t o! 0 - .-.-N 0 'Lo t N . - Y- -Owb 0 O- WmN w N N- bb b 2 Ya, ;$ UC m 2 Y E C 0 2 17 - -4 N 0 '4 0 m E ga, - m I K -L Ia a- b 9- z.;f ..- cu 0 7- m N.;r U r' I - +LL H m0 .- I! Boffettu et a1 al 1s! auCl) a m p! b J m 8 A P c? 7 01 N al v0 .5I v E c z0 e a .- b I aaaa -d- 0 0y - d mz W 7 >%%HI L+ L U+ >HZ Lal 0c m0 -c 0 o0 xI1 o-v.)^ 0 cL c I8 L al V II I II 464 Cancer Causes and Control. Vol 8. 1997 0 c a L 0 2 Cancer risk from PAHs c 0 f II z ,.C Imnou Cancer Causes and Control. Vol 8. 1997 465 Table 13. Estimates, from selected studies, of lung cancer risk following lifelong exposure to 1 ng/m3 of benzo[a]pyrene Author (ref.) Year Country W H ~ ~ ~ Euro~pe 1987 pottlg8 1985 EPA"' 1984 ''Armstrong et a/ 1994 Germany USA Canada Risk of lung cancer1100,000 9 5 0.1-1.4 1.o Notes Based on results of study of coke oven workers from the USA by Redmond,'" assuming 0.71% benzo[a]pyrene in benzene soluble coke oven emissions Based on exposure to benzo[a]pyrene of German coke oven workers Based on different models on results of studies of coke oven workers Based on risk among aluminum workers of lung cancer,'" and PAHs are likely to be among the while motor exhausts play a major r01e.190-192 agents responsible for it. In conclusion, exposure to urban airpollution, of which There are a number of cohort and case referent studies PAHs are one constituent, seems to be associated with showing an increased lung cancer risk in urban areas; they an increased risk of lung cancer in humans. It is not known have been reviewed recently by Pershagen and Si- to what extent this excess can be attributed to exposure r n ~ n a t o "a~nd by Hemminki and Pershagen.'" Tobacco to PAHs, to related heterocyclic compounds, to other smoking has been accounted for either by direct or indi- organic or inorganic compounds, to fine particles, o r to rect data. A recent and large cohort study of 151 US a combination of these. Very high levels of PAHs have metropolitan areas indicated that the lung cancer risk been demonstrated from burning of smoky coal in correlated with sulfate levels but not with levels of Chinese homes. These studies add to the evidence that medium fine particles.'" Sulfates make up a large propor- combustion products from burning of fossil fuels is tion of particles in the submicron range. The relevance of these findings in relation to PAH carcinogenicity is debatable. Findings from animal inha- associated with an increased cancer risk but cannot be used for evaluation of effects of PAHs, neither as a group nor for specific PAHs. lation studies indicate that particles in the submicron range are potent in inducing lung cancer, and that adsorbed PAHs play little role for the carcinogenic Animal experimental data effect.181"8I2t is not known if this also pertains to lung cancer development in humans. Epidemiologic data are inadequate to separate the effects of particles and PAHs since both occur concurrently in most situations. In Xuan Wei county in China, the lung cancer rate among women is among the highest in the country. Three types of cooking and heating fuels are used in this area: smoky coal, smokeless coal, and wood. The excess of lung cancer was correlated strongly with the use of smoky Historical observations of increased risk of skin cancer among chimney sweeps and workers exposed to shale oil and tar pitch were reported already in the 18th and 19th centuries. The first instance in which cancer was induced in experimental animals was in 1912 when Yamagiwa and I ~ h i k a w a ' ~de' monstrated development of skin cancer in rabbits after repeated applications of coal tar. Later, a number of experiments were performed, demonstrating development of skin cancer in mice after dermal applica- coal.'*' The levels of combustion products, including tion of coal tar products.' Subsequent work was aimed at PAHs, in homes using smoky coal are high, of the same identifying the chemical composition of coal tar and which magnitude as in highly polluted occupational environ- substances might be involved in the carcinogenk process. ments."* Investigations from China also suggest that In the beginning of the 1930s, Cook and colleagues dem- fumes from cooking, particularly from rape seed oil, may onstrated a carcinogenic activity of a specific constituent contribute to an increased risk of lung ~ a n c e r . ' ~ ~A~ ' * ' of coal tar, benzo[u]pyrene.''' Subsequent research was case-referent study of risk factors for lung cancer among focused on benzo[a]pyrene, but it later was found to be women in Los Angeles, California (US),""showed a posi- only one of several carcinogenic PAHs in coal tar and tive association with coal burning in the home during that it was a poor indicator of the carcinogenic activity childhood. For a review of cancer risk from indoor air of coal tar, soot, and combustion product^.^^*^'^^ A number pollution, see Simonato and Pershagen.'*' of specific PAHs have been tested in animal experimental Residential wood combustion accounts for a large part systems, as well as in short-term mutagenicity tests. The of PAHs emitted to the environment in the US, but only evidence for carcinogenicity of individual PAHs from for a minor part of the calculated carcinogenic activity, animal experiments is summarized in Table I. 466 Cancer Causes and Control. Vol 8. 1997 , Cancer risk from PAHs Conclusions Heavy occupational exposure to mixtures of PAHs entails a substantial risk of lung, skin, or bladder cancer. The lung is the major target site of the carcinogenic effect of PAH mixtures and an increased risk of lung cancer is present in most of the industries and occupations reviewed here. The increased risk of skin cancer is restricted to settings entailing substantial dermal exposure. The increase in bladder cancer risk is less consistent, although a pattern may be identified, pointing toward positive results in industries with high PAH exposure from coal tar and pitch, such as aluminum production, coal gasification, and tar distillation. In addition, truck drivers are likely to be at increased risk of bladder cancer. Results on laryngeal and renal cancer are likely to suffer from reporting bias; however, a risk of the latter type of cancer is present in some studies. A number of PAH mixtures and of industries in which PAH exposure in the past has been high have been classified by IARC as human carcinogens (Table 1). Recent papers on the effects on workers exposed to high levels in the past have provided useful information on the quantification of the r i ~ k . ' ~ ~V'a.r'io~u~s estimates of risk of lung, bladder, and total cancers have been proposed. They usually are based on linear non-threshold models and quantify the risk of lifetime exposure (ie.,40 years' workplace exposure, 40 h per week) to 1 ng/m' benzo[u]pyrene o r 1 pg/m3 of benzene soluble compounds and are based o n the results of studies o n occupationally exposed populations. An important assumption is, therefore, that benzo[a]pyrene o r benzene soluble compounds are regarded as an index of exposure to PAH mixtures, which may be valid in some situations (e.g., coke oven emissions) but not in others (e.g., diesel engine exhaust). Table 13summarizes some risk estimates from exposure to 1ng/m3benzo[a]pyrene: these estimates fall within a range of two orders of magnitude and should be interpreted with caution given the strong dependence on the assumptions on which different models are based. The same populations of workers studied for cancer risk may provide useful data on biomarker-based studies on mechanisms of PAH carcinogenesis in humans.2w From the public health perspective, whenever a carcinogenic risk attributable to PAHs has been shown, exposure to this class of compounds should be carefully controlled; and this still may not be the case, in particular in developing countries.2o' The most important current research question, however, is the identification and the quantification of the risk - mainly of lung cancer - from mixtures with relatively low PAH content, such as bitumen fumes and diesel engine exhaust.192In these instances, the available epidemiologic evidence is not able to identify with certainty, nor to quantify, a carcinogenic risk, which in any case is expected to be rather low. Future epidemiologic studies need to be larger and less prone to exposure misclassification. 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