Carcinogenicity of polycyclic aromatic hydrocarbons

Carcinogenicity of polycyclic aromatic hydrocarbons

Policy Watch Carcinogenicity of polycyclic aromatic hydrocarbons Kurt Straif, Robert Baan, Yann Grosse, Béatrice Secretan, Fatiha El Ghissassi, Vince...

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Policy Watch

Carcinogenicity of polycyclic aromatic hydrocarbons Kurt Straif, Robert Baan, Yann Grosse, Béatrice Secretan, Fatiha El Ghissassi, Vincent Cogliano, on behalf of the WHO International Agency for Research on Cancer Monograph Working Group

In October, 2005, 24 scientists from nine countries met at the International Agency for Research on Cancer, Lyon, France, to assess the potential carcinogenicity of 60 polycyclic aromatic hydrocarbons and several occupational exposures involving coal-derived polycyclic aromatic hydrocarbons. These assessments will be published as volume 92 of the IARC Monographs,1 the first of several volumes that will cover topics on air pollution. Polycyclic aromatic hydrocarbons are formed during the incomplete combustion of organic material. Environmental sources of polycyclic aromatic hydrocarbons include industrial air pollution, urban air pollution, tobacco smoke, and diet (which is commonly the main source of exposure in nonsmokers who are not exposed to such hydrocarbons through their occupations). High occupational exposure can arise during the conversion of coal to coke and coal tar, and during the processing and use of products derived from coal tar. Workplace concentrations of benzo(a)pyrene, a polycyclic aromatic hydrocarbon commonly used as a marker of exposure to polycyclic aromatic hydrocarbons, can be as high as 0·1 g/L compared with typical ambient air concentrations of less than 0·01 ng/L. The highest benzo(a)pyrene concentrations have been measured in the aluminium-production industry when the Söderberg process is used. After metabolic activation, many polycyclic aromatic hydrocarbons have been shown to induce lung tumours and skin tumours in animals. The main enzymes of activation (phase I) that catalyse the mono-oxygenation of these hydrocarbons to form epoxides are cytochromes P450 1A1, 1A2, and 1B1. Epoxide hydrolase forms intermediate transdihydrodiols, which are converted by specific cytochrome http://oncology.thelancet.com Vol 6 December 2005

isoenzymes to reactive diolepoxides that are one class of ultimate carcinogenic metabolites of polycyclic aromatic hydrocarbons.2,3 Cytochromes and peroxidases catalyse one-electron oxidation of some polycyclic aromatic hydrocarbons depending on their ionisation potential to form reactive radical cations.4 The intermediate transdihydrodiols can also be oxidised further by aldoketo reductase isoforms to generate reactive and redox-active polycyclic aromatic hydrocarbon orthoquinones.5 The main enzymes of detoxification (phase II) that conjugate metabolites of polycyclic aromatic hydrocarbons include the glutathione S-transferases GSTM1, GSTP1, and GSTT1; UDP-glucuronosyltransferases; and sulphotransferases. Polymorphisms in several of these enzymes have been identified in human beings, some of which could modulate cancer susceptibility.6,7 The working group discussed several mechanisms that could contribute to understanding the carcinogenesis of polycyclic aromatic hydrocarbons. The diolepoxide mechanism involves formation of stable and unstable DNA adducts, mainly at G and A, which can lead to mutations in proto-oncogenes (RAS) and tumour-suppressor genes (P53). Many polycyclic aromatic hydrocarbon diolepoxides and their precursor diols and epoxides are tumorigenic in animals.2,3,8 The radical cation mechanism involves generation of unstable adducts at G and A, leading to apurinic sites and mutations in HRAS.4 Orthoquinone formation could lead to stable and unstable DNA adducts and generation of reactive oxygen species, inducing mutations in P53.9 Arylhydrocarbon receptor mechanisms and immunological mechanisms were also discussed.

The most widely investigated polycyclic aromatic hydrocarbon is benzo(a)pyrene, which induces tumours in mice, rats, guineapigs, hamsters, rabbits, monkeys, newts, and ducks. In mice, strong evidence shows that benzo(a)pyrene causes lung tumours through the diolepoxide mechanism, and skin tumours through the diolepoxide and radical-cation mechanisms. Important steps of these mechanisms, including the complete activation pathways, have been reported in individuals exposed to polycyclic aromatic hydrocarbons. G to T transversions in the Kras proto-oncogene identified in lung tumours from mice treated with benzo(a)pyrene are causally associated with formation of DNA adducts derived from the diolepoxide.8 Human beings exposed to benzo(a)pyrene activate this molecule metabolically to diolepoxides that form DNA adducts. One of these adducts has been measured in chimney sweepers and coke-oven workers, who are frequently exposed to mixtures of polycyclic aromatic hydrocarbons that contain benzo(a)pyrene.10,11 Similar mutations in KRAS were found in lung tumours from nonsmokers exposed to coal combustion products rich in polycyclic aromatic hydrocarbons containing benzo(a)pyrene.12 The working group classified benzo(a)pyrene as carcinogenic to human beings (IARC group 1), based on sufficient evidence in animals and strong evidence that the mechanisms of carcinogenesis in animals also operate in exposed human beings. Use of mechanistic data to classify benzo(a)pyrene in group 1 indicates the increasing strength of mechanistic data to contribute to the identification of human carcinogens that cannot be studied as single agents in epidemiological studies.

Upcoming meetings Feb 7–14, 2006 Carbon black, titanium dioxide, non-asbestiform talc June 14–21, 2006 Ingested nitrates and nitrites, and blue–green algae toxins including microcystin-LR and nodularin Oct 10–17, 2006 Indoor air pollution from household combustion and heating http://monographs.iarc.fr

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Monograph Working Group Members D Krewski—Chair (Canada); T Partanen (Costa Rica); K Vähäkangas (Finland); I Stücker (France); J Borlak (Germany); V J Feron (Netherlands); M M Marques (Portugal); P Gerde, P Gustavsson (Sweden); T Fletcher (UK); J Arey, F A Beland, S Burchiel, L Flowers, R A Herbert, H Mukhtar, S Nesnow (USA); T M Penning, R Sinha (not present for evaluations; USA); T Shimada (unable to attend; USA) After the meeting, a member of the Working Group did not agree with the outcome and asked to be removed from any resulting publications. For this reason, the participant’s name is not included in the above list Conflict of interest The working group declares no conflicts of interest. Invited Specialists H Kromhout (Netherlands); R Herrick, T Junghans, S Olin (USA) Conflict of interest HK has received funding from the Dutch Pavers’ Association. RH has received funding from the National Asphalt Pavement Association, USA Representatives of health agencies C De Rosa (ATSDR, USA); J A Ross (EPA, USA); V Loch, A Ullrich (WHO, Switzerland) Observers G Granville (CONCAWE—the European oil companies’ association, Belgium); D L Williams (Michelin, France)

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The working group also classified cyclopenta(c,d)pyrene, dibenz(a,h)anthracene, and dibenzo(a,l)pyrene as probably carcinogenic to human beings (group 2A), on the basis of sufficient evidence in animals and strong mechanistic data. Several other polycyclic aromatic hydrocarbons were assessed as possibly carcinogenic to human beings (group 2B): benz(a)anthracene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)fluoranthene, chrysene, dibenzo(a,h)pyrene, dibenzo(a,i)pyrene, indeno(1,2,3-cd)pyrene, and 5-methylchrysene on the basis of sufficient evidence in animals; and benz(j)aceanthrylene and benzo(c)phenanthrene on the basis of limited evidence in animals and on strong mechanistic data. A few polycyclic aromatic hydrocarbons seem to be more potent carcinogens than benzo(a)pyrene. Of particular concern is dibenzo(a,l)pyrene, which seems to be more than ten times more potent than benzo(a)pyrene in rats.13,14 The Working Group recommended that this potent polycyclic aromatic hydrocarbon compound be measured routinely in the workplace and the environment. Another highly potent polycyclic aromatic hydrocarbon compound is dibenz(a,h)anthracene.15,16 On the basis of increased risks of lung cancer or skin cancer, the working group confirmed previous conclusions17–19 that occupational exposures during coal gasification, coke production, coal-tar distillation, paving and roofing, aluminium production, and chimney sweeping are carcinogenic to human beings (group 1), and that exposure to creosotes is probably carcinogenic to humans (group 2A). Occupational exposure during carbon-electrode manufacturing20,21 was assessed for the first time and classified as probably carcinogenic to human beings (group 2A). The working group also concluded that exposure to mixtures of coalderived polycyclic aromatic hydrocarbons in these industries contributed to increased cancer risks, but could not define the role of individual polycyclic aromatic hydrocarbons.

The working group assessed several new studies of dietary exposure to polycyclic aromatic hydrocarbons in human beings that suggest an association between consumption of polycyclic aromatic hydrocarbons in foods and increased risks of colorectal adenoma and pancreatic cancer.22,23 A substantial source of exposure to polycyclic aromatic hydrocarbons in non-smokers who are not exposed through their occupation is consumption of some foods, notably grain products and grilled meats. These foods contain measurable amounts of benzo(a)pyrene and other polycyclic aromatic hydrocarbons, which can induce tumours of the upper digestive tract in animals by ingestion. These new epidemiological studies, however, are restricted to the USA, and are too small to be conclusive. Large-scale, independent cohort studies are needed to investigate these associations more definitively.

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IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Volume 92. Some non-heterocyclic polycyclic aromatic hydrocarbons and some related exposures. Lyon: International Agency for Research on Cancer (in press). WHO. IPCS environmental health criteria 202, selected non-heterocyclic polycyclic aromatic hydrocarbons. Geneva: World Health Organization, 1998. Xue W, Warshawsky D. Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review. Toxicol Appl Pharmacol 2005; 206: 73–93. Cavalieri E, Rogan E. Mechanisms of tumour initiation by polycyclic aromatic hydrocarbons in mammals. In: Neilson AH (ed). The handbook of environmental chemistry, Volume 3J, PAHs and related compounds. Heidelberg: SpringerVerlag, 1998, 81–117. Penning TM, Burczynski ME, Hung C-F, et al. Dihydrodiol dehydrogenases and polycyclic aromatic hydrocarbon activation: generation of reactive and redox-active o-quinones. Chem Res Toxicol 1999; 12: 1–18. Bartsch H, Nair U, Risch A, et al. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobaccorelated cancers. Cancer Epidemiol Biomarkers Prev 2000; 9: 3–28. Nebert DW. Inter-individual susceptibility to environmental toxicants: a current assessment. Toxicol Appl Pharmacol 2005; 207 (suppl 2): 34–42. Ross JA, Nesnow S. Polycyclic aromatic hydrocarbons: correlations between DNA adducts and ras oncogene mutations. Mutat Res 1999; 424: 155–66.

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Yu D, Berlin JA, Penning TM, Field JM. Reactive oxygen species generated by PAH o-quinones cause change-in-function mutations in p53. Chem Res Toxicol 2002; 15: 832–42. Pavanello S, Favretto D, Brugnone F, et al. HPLC/fluorescence determination of anti-BPDEDNA adducts in mononuclear white blood cells from PAH-exposed humans. Carcinogenesis 1999; 20: 431–35. Casale GP, Singhal M, Bhattacharya S, et al. Detection and quantification of depurinated benzo[a]pyrene-adducted DNA bases in the urine of cigarette smokers and women exposed to household coal smoke. Chem Res Toxicol 2001; 14: 192–201. DeMarini DM, Landi S, Tian D, et al. Lung tumor KRAS and TP53 mutations in nonsmokers reflect exposure to PAH-rich coal combustion emissions. Cancer Res 2001; 61: 6679–81. Cavalieri EL, Rogan EG, Higginbotham S, et al. Tumour-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a]pyrenes: the very potent environmental carcinogen dibenzo[a,l]pyrene. J Cancer Res Clin Oncol 1989; 115: 67–72. Cavalieri EL, Higginbotham S, RamaKrishna NVS, et al. Comparative dose-response tumorigenicity studies of dibenzo[a,l]pyrene versus 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene and two dibenzo[a,l]pyrene dihydrodiols in mouse skin and rat mammary gland. Carcinogenesis 1991; 12: 1939–44. Platt KL, Pfeiffer E, Petrovic P, et al. Comparative tumorigenicity of picene and dibenz[a,h]anthracene in the mouse. Carcinogenesis 1990; 11: 1721–26 Ross JA, Nelson GB, Wilson KH, et al. Adenomas induced by polycyclic aromatic hydrocarbons in strain A/J mouse lung correlate with timeintegrated DNA adduct levels. Cancer Res 1995; 55: 1039–44. IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Volume 34. Polynuclear aromatic compounds—part 3: industrial exposures in aluminium production, coal gasification, coke production, and iron and steel founding. Lyon: International Agency for Research on Cancer, 1984. IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Volume 35. Polynuclear aromatic compounds— part 4: bitumens, coal-tars and derived products, shaleoils and soots. Lyon: International Agency for Research on Cancer, 1985. IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Suppl 7. Overall evaluations of carcinogenicity: an updating of IARC monographs volumes 1 to 46. Lyon: International Agency for Research on Cancer, 1987. Liu N, Wang Z et al. Cancer mortality among carbon workers in China: restrospective cohort study. J Occup Health 1997; 39: 325–30. Mori I. Cancer mortality among man-made graphite electrode manufacturing workers: results of a 38-year follow-up. Occup Environ Med 2002; 59: 473–80. Sinha R, Kulldorff M, Gunter MJ, et al. Dietary benzo[a]pyrene intake and risk of colorectal adenoma. Cancer Epidemiol Biomarkers Prev 2005; 14: 2030–34. Anderson KE, Sinha R, Kulldorff M, et al. Meat intake and cooking techniques: associations with pancreatic cancer. Mutat Res 2002; 506–07: 225–31.

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