part 1. PART 1

concordance between cancer in humans and in experimental CHAPTER 7 animals

chapter 7. Polycyclic aromatic hydrocarbons and associated occupational exposures Charles William Jameson

Properties of PAHs this makes them more readily uptake or degradation, which means available for biological uptake and that their persistence in the environ- Most polycyclic aromatic hydrocar- degradation (Mackay and Callcott, ment is increased (Johnsen et al., bons (PAHs) with potential biolog- 1998; Choi et al., 2010). Furthermore, 2005; Haritash and Kaushik, 2009). ical activity have been determined two- to four-ring PAHs volatilize The properties that influence the to have a molecular structure that sufficiently to appear in the atmo- biological activity of PAHs include ranges in size from two to six fused sphere predominantly in gaseous their vapour pressure, their adsorp- aromatic rings (IARC, 2010). The form, although the physical state of tion on surfaces of solid carrier par- physicochemical properties of four-ring PAHs can depend on tem- ticles, their absorption into liquid these PAHs that are critical to their perature (Atkinson and Arey, 1994; carriers, their lipid–water partition biological activity vary greatly, be- Srogi, 2007). coefficient in tissues, and their limits cause their molecular weights cover In contrast, PAHs with five or of solubility in the lipid and aqueous a vast range. more rings have low solubility in wa- phases of tissues. These properties Aqueous solubility of PAHs de- ter and low volatility. They therefore are linked with the metabolic activa- creases approximately logarith- occur predominantly in solid form, tion of PAHs, as well as their deposi- mically with increasing molecular bound to particulates in polluted air, tion and disposition. mass (Johnsen et al., 2005). Two- soil, or sediment (Choi et al., 2010). PAHs share a similar mecha- ring PAHs, and, to a lesser extent, In the solid state, these compounds nism of carcinogenic action in both three-ring PAHs, dissolve in water; are less accessible for biological humans and experimental animals.

Part 1 • Chapter 7. Polycyclic aromatic hydrocarbons and associated occupational exposures 59 This includes metabolic conversion PAH body burdens among exposed critical for determining the over- to oxides and dihydrodiols, which in workers that are considerably higher all evaluation for each one (IARC, turn are oxidized to diol epoxides. than those in the general population. 2010). These oxides and diol epoxides are There is growing awareness that The remaining 45 PAHs reviewed the ultimate DNA-reactive metabo- by IARC were acenaphthene, ace- uptake of PAHs through the skin is lites of PAHs. The oxides form stable pyrene (3,4-dihydrocyclopenta[cd] substantial (Jongeneelen, 2001). DNA adducts, and the diol epoxides pyrene), anthanthrene, anthracene, Dermal uptake has been shown to form stable adducts but also unsta- 11H-benz[bc]aceanthrylene, benz[l] contribute to the internal exposure ble adducts (so-called depurinating aceanthrylene, benzo[b]chrysene, adducts) with DNA through formation of workers to PAHs; a study in the benzo[g]chrysene, benzo[a]fluoran- of electrophilic carbonium ions. creosote industry found that the total thene, benzo[ghi]fluoranthene, benzo internal dose of PAHs did not neces- [a]fluorene, benzo[b]fluorene, ben- Occupational exposure to sarily correlate with levels of inhala- zo[c]fluorene, benzo[ghi]perylene, PAHs tion exposure alone, and that dermal benzo[e]pyrene, coronene, 4H-cyclo-­ penta[def]chrysene, 5,6-cyclopen- exposure contributed significantly Occupational exposure to PAHs oc- teno-1,2-benzanthracene, dibenz (Vanrooij et al., 1992). curs predominantly through inhala- [a,c]anthracene, dibenz[a,j]anthra- tion and dermal contact. Industrial Classification of PAHs cene, dibenzo[a,e]fluoranthene, processes that involve the pyroly- 13H-dibenzo[a,g]fluorene, dibenzo sis or combustion of coal and the The IARC Monographs Programme [h,rst]pentaphene, dibenzo[a,e]py- production and use of coal-derived rene, dibenzo[e,l]pyrene, 1,2-dihy- has reviewed experimental data for products, including coal tar and droaceanthrylene, 1,4-dimethylphen­ 60 individual PAHs (IARC, 2010). coal tar-derived products, are major anthrene, fluoranthene, fluorene, Of these 60 PAHs, one, benzo[a] sources of occupational exposure to 1-methylchrysene, 2-methylchry- PAHs. Workers at coal-tar produc- pyrene, is classified as carcino- sene, 3-methylchrysene, 4-methyl­ tion plants, coking plants, bitumen genic to humans (Group 1). Other chrysene, 6-methylchrysene, production plants, coal-gasification PAHs reviewed by IARC include 2-methyl­fluoranthene, 3-methylflu- sites, smokehouses, aluminium pro- cyclopenta[cd]pyrene, dibenz[a,h] oranthene, 1-methylphenanthrene, duction plants, coal-tarring facilities, anthracene, and dibenzo[a,l] naphtho[1,2-b]fluoranthene, naph- and municipal waste incinerators are pyrene, which are classified as tho[2,1-a]fluoranthene, naphtho exposed to PAHs. Exposure may [2,3-e]pyrene, perylene, phenan- probably carcinogenic to humans also result from inhalation of engine threne, picene, pyrene, and triphen- (Group 2A), and benz[ j]aceanthry- exhaust and from use of products ylene. These compounds were de- lene, benz[a]anthracene, benzo[b] that contain PAHs in a variety of termined to be not classifiable as fluoranthene, benzo[ j]fluoranthene, other industries, such as mining, oil to their carcinogenicity to humans refining, metalworking, chemical pro- benzo[k]fluoranthene, benzo[c] (Group 3), because of limited or in- duction, transportation, and the elec- phenanthre­ ne,­ chrysene, dibenzo adequate experimental evidence trical industry (Vanrooij et al., 1992). [a,h]pyrene, dibenzo[a,i]pyrene, in- (IARC, 2010). Studies in Germany measured deno[1,2,3-cd]pyrene, and 5-methyl- As noted above, benzo[a]pyrene concentrations of PAHs in the chrysene, which are classified as is the only PAH classified by IARC breathing zone of chimney sweeps possibly carcinogenic to humans in Group 1. A review of the data during “black work”; the PAHs in available for this PAH indicates that (Group 2B). It should be noted that in the air samples varied depending the complete sequence of steps in the evaluations of benz[ j]aceanthry- on the type of fuel burned (oil, oil/ the metabolic activation pathway lene, benzo[c]phenanthrene, benzo solid, or solid) (Knecht et al., 1989). of benzo[a]pyrene to mutagenic Concentrations of PAHs in coal-tar [a]pyrene, cyclopenta[cd]pyrene, and carcinogenic diol epoxides has products may range from less than dibenzo[a,h]anthracene, and diben- been demonstrated in humans, in 1% to 70% or more (ATSDR, 2002). zo[a,l]pyrene, the mechanistic data human tissues, and in experimental Occupational exposure can lead to available for these compounds were animals. After exposure, humans

60 Table 7.1. Group 1 agents associated with dermal exposures to polycyclic aromatic hydrocarbons (PAHs) that cause squamous cell carcinoma of the skin in humans and in rodents

Agent Target organ PART 1 CHAPTER 7

Humans Mice Rats

Benzo[a]pyrene No data Skin Skin Chimney sweep soots Skin, including scrotum Skin No data Coal tar Skin, including scrotum Skin No data Coal-tar pitch Skin, including scrotum Skin No data Mineral oils, untreated and mildly treated Skin, including scrotum Skin No data Shale oils Skin, including scrotum Skin No data

metabolically activate benzo[a]py- mechanistic evidence from studies potential chemical interactions and rene to benzo[a]pyrene diol epox- in exposed humans and in experi- the presence of other carcinogenic ides that form DNA adducts. The mentally exposed animals, and from substances. anti-benzo[a]pyrene-7,8-diol-9,10- in vitro studies in human and animal Certain occupations associated oxide–deoxyguanosine adduct has with high exposure to PAHs have tissues and cells, provides biologi- been measured in populations (e.g. been classified by IARC as carci- cal plausibility to support the overall coke-oven workers and chimney nogenic to humans (Group 1); these classification of benzo[a]pyrene as sweeps) exposed to PAH mixtures include coal gasification, coke pro- that contain benzo[a]pyrene. The carcinogenic to humans (Group 1) duction, coal-tar distillation, chimney reactive anti-benzo[a]pyrene-7,8-di- (IARC, 2010, 2012). sweeping, paving and roofing with ol-9,10-oxide induces mutations in coal-tar pitch, and work involving rodent and human cells. Mutations Studies of cancer in humans mineral oils, shale-oil production, (G → T transversions) in the K-ras and aluminium production. In most There are no epidemiological stud- proto-oncogene in lung tumours from cases the classification is based on mice treated with benzo[a]pyrene are ies on human exposure to individu- epidemiological studies of increased associated with anti-benzo[a]pyrene- al PAHs, because these chemicals cancer incidence without reference 7,8-diol-9,10-oxide–deoxyguanosine never occur in isolation in the envi- to supporting evidence from bio- adducts. Similar mutations in the ronment but are present as compo- assays in experimental animals. KRAS proto-oncogene and muta- nents of complex chemical mixtures. The roles of individual PAHs in the tions in the tumour suppressor gene PAHs are very widespread environ- genesis of cancer observed in these TP53 were found in lung tumours mental contaminants, because they occupations could not be defined from non-smokers exposed to PAH- (IARC, 2010). rich products of coal combustion that are formed during incomplete com- are known to contain benzo[a]pyrene bustion of materials such as coal, Tumour site concordance (as well as many other PAHs). In an oil, gas, wood, or waste, or during in vitro study, the codons in TP53 pyrolysis of other organic materials, There are six IARC Group 1 agents that are most frequently mutated in such as tobacco. Data on the carci- that cause non-melanoma tumours lung cancer in humans were shown nogenicity of PAHs to humans are of the skin (Rice, 2005). Five of to be targets for DNA adduct forma- these are related to occupations available primarily from studies in tion and mutation induced by ben- where PAH exposures are high and occupational settings where workers zo[a]pyrene. The strong and exten- are believed to be the causative sive experimental evidence for the are exposed to mixtures containing agents (Table 7.1). There is a precise carcinogenicity of benzo[a]pyrene PAHs. It is difficult to ascertain the correlation between carcinogeni- in many animal species, support- carcinogenicity of the component city to human skin and carcinogen- ed by the consistent and coherent PAHs in these mixtures, because of icity to mouse skin for these five

Part 1 • Chapter 7. Polycyclic aromatic hydrocarbons and associated occupational exposures 61 Table 7.2. Group 1 carcinogens associated with inhalation exposures to polycyclic aromatic hydrocarbons (PAHs) that cause lung cancer in humans and in rodents

Agent Target organ Route/target organ

Humans Mice Rats

Benzo[a]pyrene No data Intraperitoneal injection of and Intratracheal and intrapulmonary oral exposure to soot extracts/ instillation of soot extracts/lung lung Chimney sweep soots Lung No data Intratracheal instillation of soot extracts/ lung Coal-tar vapours from Lung Inhalation/lung Inhalation/lung coke ovens Soots and vapours from Lung, bladder No data No data aluminium production

PAH-associated exposures when by an appropriate route (Table 7.2). abolically active cell types include the complex mixtures isolated from Both mice and rats developed lung pulmonary macrophages as well as the occupational environment are tumours after inhalation of coal-tar epithelial cells. applied topically. vapours from coke ovens. Soot ex- Benzo[a]pyrene is the only PAH In 1775, Pott made the pioneering tracts caused lung tumours in rats that has been classified by IARC as observation that cancer of the scro- after intratracheal instillation. There carcinogenic to humans (Group 1). tum in chimney sweeps was an occu- appears to be a good correlation be- As indicated above, the basis for pational disease resulting from direct tween lung cancer in humans and in this classification is the extensive contact with soot (Pott, 1775). All five rodents for these two mixtures when knowledge of the mechanism of car- established PAH-based chemical studied by an appropriate route in cinogenic action of benzo[a]pyrene carcinogens for human skin to which mice and rats. All these complex exposures occur by direct dermal mixtures have genotoxic activity, in humans and experimental ani- contact are complex mixtures: coal which is recognized to underlie their mals. None of the many remaining tar, coal-tar pitch, untreated and carcinogenic activity in the lung. In PAHs shown to be carcinogens in mildly treated mineral oils, shale oils, summary, many of the individual animals have been classified as an and soots. Because these mixtures PAHs in these complex mixtures that IARC Group 1 carcinogen, most like- contain PAHs, all have a genotoxic have been classified by IARC as ei- ly because much less mechanistic component to their mode of action in ther probably carcinogenic or possi- information is available for these rodents. Most of the individual PAHs bly carcinogenic to humans are also agents than for benzo[a]pyrene. classified by IARC as either probably genotoxic and have been shown to These other PAHs are classified as carcinogenic to humans (Group 2A) cause lung tumours in rodents when either probably carcinogenic to hu- or possibly carcinogenic to humans administered by an appropriate route mans (Group 2A) or possibly carci- (Group 2B) (listed above) are geno- (IARC, 2010). nogenic to humans (Group 2B). Most toxic and have been shown to cause The various tissue compartments marked human occupational expo- skin cancer and/or be initiators of of the respiratory tract are meta- sure to these compounds involves skin cancer in rodents (IARC, 1983, bolically active towards exogenous complex mixtures that contain more 2010). chemicals in both humans and ex- Soots and vapours from coke pro- perimental animals and are clear- than one of these PAHs and that of- duction, aluminium production, and ly capable of transforming many ten contain other, non-PAH carcin- related industries also cause lung metabolism-dependent chemicals, ogens. Therefore, the carcinogenic cancer in humans, but only extracts including carcinogenic PAHs, to activity of these mixtures cannot of soot and vapours from coke pro- their chemically reactive metabo- confidently be ascribed to any one of duction have been tested in rodents lites (Rice, 2005). In the lung, met- their individual components.

62 References PART 1 CHAPTER 7

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