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-methyl fluoranthene, 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- phen anthre 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.