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
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)
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.
The authors declare no conﬂicts of interest. 1
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