Document dYyNZQ9MygEb7b8oN9kpKRmpQ

News Special Report: Policy A review of human carcinogens--Part F: Chemical agents and related occupations In October, 2009, 23 scientists from six countries met at the International Agency for Research on Cancer (IARC) to reassessthe carcinogenicityofseveral chemical and occupational exposure circumstances previously classified as "carcinogenic to humans" (Group 1) and to identify additional tumour sites and mechanisms of carcinogenesis (table). These assessments will be published as the sixth and last part of Volume 100 of the IARC Monographs.1 Four aromatic amines and two related industrial processes were re affirmed as Group-1 carcinogens based on sufficient evidence that they cause urinary bladder cancer in humans. The Group-1 classification of dyes metabolised to benzidine and of 4,4'-methylenebis(2-chloroaniline) was based on sufficient evidence in animal models and strong mechanistic evidence.2 Exposure to polycyclic aromatic hydrocarbons (PAHs) causes cancers of the skin and lung in humans. Various PAH-related industries and PAHcontaining complex mixtures were confirmed as Group-1 carcinogens. Although there are no epidemiological studies of benzo[a]pyrene, carcino genicity in many animal species and strong mechanistic evidence justified its classification in Group 1.3 The carcinogenicity to humans of other chemicals and exposure scenarios was reaffirmed (table). For ethylene oxide, the epidemiological evidence was limited, but there is sufficient evidence for its carcinogenicity in rodents. Additionally, ethylene oxide is genotoxic and mutagenic in many in-vitro tests and in-vivo studies in animals, and its cytogenetic effects in lymphocytes of exposed workers provided strong support for its classification in Group 1.4 Workers in the rubber-manufactur ing industry have an increased risk for leukaemia, lymphoma, and cancers of the urinary bladder, lung, and stomach. Due to the diversity and complexity of the exposures in this industry, it is difficult to identify causative agents, but there is strong evidence of genotoxic effects in these workers.5 The Working Group reviewed more than 100 epidemiological studies of benzene and confirmed its carcino genicity, with sufficient evidence for ANLL, and limited evidence for ALL, CLL, MM, and NHL (for abbreviations, see table footnote). The Working Group also found limited evidence of an association between maternal ex posure to painting--before and during pregnancy--and an increased risk of childhood leukaemia in the offspring. Dioxin (2,3,7,8-tetrachlorodibenzopara-dioxin, TCDD) was classified in Group 1 in 1997, based on limited evidence of carcinogenicity in humans, For more on the IARC Monographs see http:// monographs.iarc.fr Tumour sites or types with sufficient evidence in humans Aromatic amines 4-Aminobiphenyl Urinary bladder Benzidine Urinary bladder Dyes metabolised to benzidine 4,4'-Methylenebis(2-chloroaniline) 2-Naphthylamine Urinary bladder Ortho-toluidine Urinary bladder Auramine production Urinary bladder Magenta production Urinary bladder PAH-related exposures Benzo[a]pyrene Soot (chimney sweeping) Skin, lung Coal gasification Coal-tar distillation Coke production Coal-tar pitches (paving, roofing) Lung Skin Lung Lung Aluminium production Lung, urinary bladder Other chemicals Aflatoxins Benzene Bis(chloromethyl)ether/chloromethyl methylether 1,3-Butadiene Hepatocellular carcinoma ANLL Lung Haematolymphatic organs Dioxin (2,3,7,8-TCDD) 2,3,4,7,8-Pentachlorodibenzofuran All cancers combined** 3,3',4,4',5-Pentachlorobiphenyl (PCB-126) Ethylene oxide Formaldehyde Sulfur mustard Vinyl chloride Nasopharynx Leukaemia^** Lung Hepatic angiosarcoma, hepatocellular carcinoma Tumour sites or types with limited evidence in humans Evidence of genotoxicity as the main mechanism Strong Strong Strong* Strong* Strong Moderate Weak/lack of datat Weak/lack of datat Urinary bladder Urinary bladder Strong* Moderate Strong Strong Strong Strong Weak/moderatet* ALL**, CLL**, MM**, NHL** Strong Strong Moderate/strong Lung, STS, NHL Strong See text Seetext* Lymphoid tumours (NHL, MM, CLL), breast Seetext* Strong* Sinonasal cancer Strong Moderate Larynx Strong Strong (Continues on next page) www.thelancet.com/oncology Vol 10 December 2009 1143 News (Continued from previous page) Other complex exposures Iron and steel founding Isopropyl alcohol manufacture using strong acids Mineral oils Occupational exposure as a painter Rubber-manufacturing industry Shale oils Strong inorganic acid mists Tumour sites or types with sufficient evidence in humans Tumour sites or types with limited evidence in humans Evidence of genotoxicity as the main mechanism Lung Weak/moderate Nasal cavity Weak/lack of data Skin Weak/lack of data Lung, urinary bladder, pleural mesothelioma Childhood leukaemia|| Strong* Leukaemia, lymphoma**, urinary Prostate, larynx, oesophagus Strong* bladder, lung**, stomach** Skin Larynx Lung Weak/lack of data Weak/lack of data ANLL=acute non-lymphocytic leukaemia. ALL=acute lymphocytic leukaemia. CLL=chronic lymphocytic leukaemia. MM=multiple myeloma. NHL=non-Hodgkin lymphoma. STS=soft-tissue sarcoma.*Agents classified in Group 1 on the basis of mechanistic information. tWeak evidence in workers, but strong evidence for some chemicals in this industry. *Due to the diversity and complexity of these exposures, other mechanisms may also be relevant. Strong evidence for an aryl hydrocarbon receptor (AhR)-mediated mechanism. ^Particularly myeloid leukaemia. ||After maternal exposure (before or during pregnancy, or both). **New epidemiological findings. Table: Evidence for carcinogenicity in humans and for genotoxicity as the main mechanism of the Group-1 agents assessed Monograph Working Group Members H Vainio-Co-Chair (Finland), M Kogevinas-Co-Chair (Spain), C J Portier-Co-Chair (USA); M Ghanei (Iran); H Kromhout (Netherlands); P Gustavsson (Sweden); L Beane-Freeman,J A Bond, T Carreon-Valencia, M R Elwell, M Friesen, B D Goldstein, J D Groopman, R B Hayes, R A Herbert, C WJameson, R Melnick, S Nesnow, N Rothman, A M Ruder, D A Savitz, M T Smith, M A Toraason (USA) Conflicts ofinterest BDG is a consultant on toxic tort cases involving benzene. MTS has received consulting and expert testimony fees from law firms representing both plantiffs and defendants in cases involving exposure to benzene and consulting fees from government agencies assessing the health risks associated with benzene exposure. The other Monograph Working Group Members declared no conflicts of interest. Invited Specialists None sufficient evidence in rodents, and strong evidence in humans and animals for a mechanism via initial binding to the aryl hydrocarbon receptor (AhR), which leads to changes in gene expression, cell replication, and apoptosis.6 There is now sufficient epidemiological evidence for all cancers combined, making TCDD the first agent classified initially in Group 1 based on sufficient animal data and mechanisms, to be later confirmed by increased cancer incidence in humans. This highlights the ability of mechanistic information to provide robust evidence of carcinogenicity. Like TCDD, 2,3,4,7,8-pentachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl (PCB-126) are complete carcinogens in experimental animals,7,8 and there is extensive evidence that they act through the same AhRmediated mechanism. The Working Group classified these two chemicals in Group 1. The Working Group unanimously reaffirmed the classification of formal dehyde in Group 1, based on sufficient evidence in humans of nasopharyngeal cancer. A possible association with leukaemia was previously considered "strong but not sufficient",9 because of the lack of a plausible mechanism. The epidemiological evidence has become stronger: a recent study10 found that embalming was significantly associ ated with an increased risk for myeloid leukaemia, with significant trends for cumulative years of embalming (ptrend=0-020) and for increasing peak formaldehyde exposure (ptrend=0-036). In addition, a recent study11 of a small group of exposed workers showed numerical chromosomal aberrations in myeloid progenitor cells (chromosome 7 monosomy, chromosome 8 trisomy) consistent with myeloid leukaemia, and haematological changes in peripheral blood that are indicative of effects on the bone marrow. The Working Group concluded that, overall, there is sufficient evidence for leukaemia, particularly myeloid leukaemia. Robert Baan, Yann Grosse, Kurt Straif, Beatrice Secretan, Fatiha El Ghissassi, Veronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Crystal Freeman, Laurent Galichet, Vincent Cogliano, on behalfofthe WHO International Agency for Research on Cancer Monograph Working Group International Agency for Research on Cancer, Lyon, France The IARC authors declared no conflicts of interests. Attending the meeting as Representatives were E Pasquier (French Agency for Environmental and Occupational Health and Safety [AFSSET]), A Huici-Montagud (European Commission Directorate General for Employment, Social Affairs and Equal Opportunities), and D DeVoney (US Environmental Protection Agency). Attending the meeting as Observers were M G Bird (ExxonMobil Corp, USA), A Bracco (European Tyre and Rubber Manufacturers' Association, Belgium), J Collins (Formaldehyde Council, USA), P Crosignani (International Society of Doctors for the Environment, Switzerland), S Gabriel (German Social Accident Insurance BGIA, Germany), P Gelbke (European Chemical Industry Council CEFIC, Belgium), P Infante (private consultant, USA), R J Lewis (International Institute of Synthetic Rubber Producers, USA), K Mundt (International Paint and Printing Ink Council, USA), and G Swaen (American Chemistry Council and American Petroleum Institute, USA; CONCAWE and ECETOC, Belgium). 1 Grosse Y, Baan R, Straif K, et al. A review of human carcinogens-Part A: pharmaceuticals. Lancet Oncol 2009; 10: 13-14. 2 Baan R, Straif K, Grosse Y, et al. Carcinogenicity of some aromatic amines, organic dyes, and related exposures. Lancet Oncol 2008; 9: 322-23. 3 Xue W, Warshawsky D. Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review. Toxicol Appl Pharmacol 2005; 206: 73-93. 4 IARC. 1,3-Butadiene, ethylene oxide and vinyl halides (vinyl fluoride, vinyl chloride and vinyl bromide). IARC Monogr Eval Carcinog Risks Hum 2008; 97: 185-309. 5 Somorovska M, Szabova E, Vodicka P, et al. Biomonitoring of genotoxic risk in workers in a rubber factory: comparison of the Comet assay with cytogenetic methods and immunology. Mutat Res 1999; 445: 181-92. 6 Nebert DW, Roe AL, Dieter MZ, et al. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol 2000; 59: 65-85. 7 National Toxicology Program. NTP toxicology and carcinogenesis studies of 2,3,4,7,8- pentachlorodibenzofuran (PeCDF) (CAS No. 57117-31-4) in female Harlan Sprague-Dawley rats (gavage studies). Natl Toxicol Program Tech Rep Ser 2006; 525: 1-202. 8 National Toxicology Program. NTP toxicology and carcinogenesis studies of 3,3',4,4',5- pentachlorobiphenyl (PCB 126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (gavage studies). Natl Toxicol Program Tech Rep Ser 2006; 520: 1-253. 9 IARC. Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropan-2-ol. IARC Monogr Eval Carcinog Risks Hum 2006; 88: 39-325. 10 Hauptmann M, Stewart PA, Lubin JH, et al. Mortality from lymphohematopoietic malignancies and brain cancer among embalmers exposed to formaldehyde. J Natl Cancer Inst 2009; in press. 11 Zhang L, Tang X, Rothman N, et al. Occupational exposure to formaldehyde, hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells. Cancer Epidemiol Biomarkers Prev 2009; in press. 1144 www.thelancet.com/oncology Vol 10 December 2009