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Special Report: Policy A review of human carcinogens—Part A: pharmaceuticals
In October, 2008, 21 scientists from nine countries met at the International Agency for Research on Cancer (IARC) and reaffirmed the Group 1 classification “carcinogenic to humans” of 20 pharmaceutical agents (tables 1 and 2). IARC is compiling a review of the more than 100 Group 1 agents, many of which were assessed more than 20 years ago, before mechanistic studies were prominent tools in assessments. Furthermore, additional tumour sites and exposure scenarios might be identified in the new review. For example, tobacco was first identified as a cause of lung cancer in smokers, and has since been shown to cause cancer at more than a dozen sites, through smoking and smokeless forms. The assessments will be published as Volume 100 of the IARC Monographs, to be developed in six parts. Volume 100 will include information on tumour sites and mechanisms of carcinogenesis, although this does not preclude the possibility that an agent might cause cancer at other sites or by other mechanisms. Volume 100 will provide information for two subsequent publications: Tumour Site Concordance between Humans and Animals and
Group 1 agent Diethylstilbestrol

Mechanisms Involved in Human Carcinogenesis. The major findings of Volume 100 will also become the first entries of an enhanced electronic database of Monograph findings. Five hormonal treatments were reassessed (table 1), two of which increase cancer risk at some sites and decrease risk at others, acting through receptor-mediated events and genotoxic mechanisms. The Working Group concluded that there is sufficient evidence that oestrogen-only menopausal therapy increases the risk for ovarian cancer, whereas no definite association was identified in the IARC 1999 evaluation.1 Two meta-analyses published since then reported an increased risk for ovarian cancer among women who used oestrogen-only therapy: the relative risks (RRs) for ever use were significant and ranged from 1·19 to 1·51.2,3 Furthermore, a dosedependent increase in risk was noted per year of use of oestrogen-only therapy (RR 1·07 [95% CI 1·06–1·08]).3 The Working Group also highlighted the decrease in breast cancer incidence after the widespread reduction in the use of combined oestrogen-progestagen menopausal therapy since 2003.4 Additionally, the Group confirmed that

combined oestrogen-progestagen oral contraceptives increase the risk for hepatocellular carcinoma,5 stressing that in populations where hepatitis B virus (HBV) infection is endemic, the risk is presumably masked by the higher risk associated with HBV infection. A further 15 agents were reassessed, including some mixtures (table 2). The Working Group identified the specific component most likely to be responsible for cancer risk in three mixtures, although it is not an expressed intent of Volume 100 to identify new carcinogenic agents. The Working Group reaffirmed the Group 1 classification of analgesic mixtures containing phenacetin, and further classified phenacetin itself in Group 1 (previously classified as “probably carcinogenic to humans” Group 2A, in 1987). The Group reached this decision because increased risks for cancers of the renal pelvis and the ureter could not be explained by other components of the analgesic mixtures (ie, aspirin, codeine phosphate, and caffeine) and noted that phenazone (sometimes added to these mixtures) was not a component of those mixtures assessed in an influential study.6 When reviewing antineoplastic drugs, the Working Group noted that
Other likely mechanistic events Epigenetic programming

Published Online December 1, 2008 DOI:10.1016/S14702045(08)70286-9

Upcoming meetings February 24–March 3, 2009 Biological Agents March 17–24, 2009 Metals, Particles, and Fibres June 2–9, 2009 Radiation September 29–October 6, 2009 Lifestyle Factors October 20–27, 2009 Chemical Agents and Related Occupations http://monographs.iarc.fr/

Cancer on which sufficient evidence in humans is based Breast (exposure during pregnancy), vagina and cervix (exposure in utero) Limited evidence: testis (exposure in utero), endometrium Endometrium, ovary Limited evidence: breast

Sites where cancer Established mechanistic risk is reduced events ·· Oestrogen receptormediated events (vagina, cervix), genotoxicity Oestrogen receptormediated events Receptor-mediated events Receptor-mediated events

Oestrogen-only menopausal therapy

·· ·· Endometrium, ovary

Genotoxicity Oestrogen genotoxicity Oestrogen genotoxicity, hormone-stimulated expression of human papillomavirus genes ··

Combined oestrogen– Endometrium (risk decreases with number progestagen menopausal therapy of days/month of progestogen use), breast Combined oestrogen– progestagen oral contraceptives Breast, cervix, liver

Tamoxifen

Endometrium

Breast

Oestrogen receptormediated events, genotoxicity xx

Table 1: Hormonal treatments assessed by the IARC Monograph Working Group

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Group 1 agent Busulfan Chlorambucil Cyclophosphamide Melphalan Semustine (methyl-CCNU) Thiotepa Treosulfan MOPP combined chemotherapy

Cancer on which sufficient evidence in humans is based Acute myeloid leukaemia Acute myeloid leukaemia Acute myeloid leukaemia, bladder Acute myeloid leukaemia Acute myeloid leukaemia Leukaemia Acute myeloid leukaemia

Established mechanistic events Genotoxicity (alkylating agent) Genotoxicity (alkylating agent) Genotoxicity (metabolism to alkylating agents) Genotoxicity (alkylating agent) Genotoxicity (alkylating agent) Genotoxicity (alkylating agent) Genotoxicity (alkylating agent)

This shows how mechanistic data can help identify carcinogenic hazards. It is encouraging to think that other environmental or occupational cancers might be investigated and resolved with similar confidence.

Acute myeloid leukaemia, lung Genotoxicity Genotoxicity; translocations involving MLL gene (etoposide) Genotoxicity, translocations involving MLL gene Genotoxicity (alkylating agent, metabolism to 2-naphthylamine derivatives) Genotoxicity, immunosuppression

Etoposide in combination Acute myeloid leukaemia with cisplatin and bleomycin Etoposide (Group 2A in 2000) Chlornaphazine ·· Bladder

Yann Grosse, Robert Baan, Kurt Straif, Béatrice Secretan, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Laurent Galichet, Vincent Cogliano, on behalf of the 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 interest. 1 IARC. IARC Monographs on the evaluation of carcinogenic risks to humans. Volume 72. Hormonal contraception and post-menopausal hormonal therapy. Lyon: International Agency for Research on Cancer 1999. Zhou B, Sun Q, Cong R, et al. Hormone replacement therapy and ovarian cancer risk: a meta-analysis. Gynecol Oncol 2008; 108: 641–51. Greiser CM, Greiser EM, Dören M. Menopausal hormone therapy and risk of ovarian cancer: systematic review and meta-analysis. Hum Reprod Update 2007; 13: 453–63. Jemal A, Ward E, Thun MJ. Recent trends in breast cancer incidence rates by age and tumor characteristics among U.S. women. Breast Cancer Res 2007; 9: R28. IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91. Combined estrogen-progestogen contraceptives and combined estrogen-progestogen menopausal therapy. Lyon: International Agency for Research on Cancer 2007. McCredie M, Stewart JH, Day NE. Different roles for phenacetin and paracetamol in cancer of the kidney and renal pelvis. Int J Cancer 1993; 53: 245–49. Pedersen-Bjergaard J, Christiansen DH, Desta F, et al. Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2006; 11: 1943–49. WHO classification of tumours of haematopoietic and lymphoid tissues. Swerdlow SH, Campo E, Harris NL, et al, eds. Lyon: WHO Press, 2008. Lord GM, Hollstein M, Arlt VM, et al. DNA adducts and p53 mutations in a patient with aristolochic acid-associated nephropathy. Am J Kidney Dis 2004; 43: e11–17. Grollman AP, Shibutani S, Moriya M, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci USA 2007; 93: 12129–34. Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000; 342: 1686–92.

Azathioprine
Monograph Working Group Members A B Miller—Co-Chair (Canada), D H Phillips—Co-Chair (UK); J Kaldor (Australia); J H Olsen (Denmark); M R Berger, H H Schmeiser (Germany); H Tsuda (Japan); S H Kim (unable to attend, Republic of Korea); B C Baguley (New Zealand); M Marques (Portugal); P Karran (UK); E Barrett-Connor, F A Beland, J L Bolton (unable to attend), M C Bosland, J F Buell, D Eastmond, C J Jameson, D G Kaufman, A A Molinolo, C A Schiffer, L Titus-Ernstoff, D B Thomas (USA) Conflicts of interest DE has previously received funding from, and acted as consultant to, Johnson & Johnson. He currently receives funding from Pfizer. Both of these companies manufacture hormone-based contraceptives. JK is deputy director of the Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Australia, which receives partial funding from Hoffman-La Roche, Bristol-Myers Squibb, Pfizer, and Johnson & Johnson. All of these companies manufacture drugs, or alternatives to drugs, mentioned in this article Invited Specialists None Representatives None Observers M G Bird (ExxonMobil Corp, USA)

Non-Hodgkin lymphoma, skin

Ciclosporin Methoxsalen+ultraviolet light Plants containing aristolochic acid Aristolochic acid (Group 2A in 2002)

Non-Hodgkin lymphoma, skin, Immunosuppression multiple other sites Skin Renal pelvis, ureter Genotoxicity following photo-activation Genotoxicity, DNA adducts in humans, A:T→T:A transversions in TP53 in human tumours Genotoxicity, DNA adducts in animals are the same as those found in humans exposed to plants, A:T→T:A transversions in TP53, RAS activation (See phenacetin) Genotoxicity, cell proliferation 5 2

3

··

4

Analgesic mixtures containing phenacetin Phenacetin (Group 2A in 1987)

Renal pelvis, ureter Renal pelvis, ureter

MOPP=chlormethine (mechlorethamine), vincristine (oncovin), procarbazine, and prednisone

Table 2: Antineoplastic drugs and other drugs evaluated by the IARC Monograph Working Group

6

acute myeloid leukaemia induced by alkylating agents, such as busulfan, frequently exhibits clonal loss (partial or total) of either chromosome 5 or 7, thereby distinguishing it from acute myeloid leukaemia induced by topoisomerase II inhibitors, such as etoposide. The latter shows clonal balanced translocations involving the MLL gene on chromosome 11 (11q23).7,8 Following this line of reasoning, the Working Group classified etoposide itself in Group 1 (previously classified in Group 2A, in 2000). When reviewing plants containing aristolochic acid, the Working Group reviewed new evidence that DNA

adducts and A:T→T:A transversions in TP53 induced by aristolochic acid were found in patients with nephropathy or urothelial tumours after ingestion of material from Aristolochia plant species.9,10 As a result, aristolochic acid was classified in Group 1 (previously classified in Group 2A, in 2002). In just 6 years, mechanistic studies convincingly showed that aristolochic acid was responsible for the high risk for cancer and nephropathy in individuals who ingested material from Aristolochia plants—in the form of weight-loss pills in Belgium and from cereal fields in the Balkans where Aristolochia plants were growing as weeds.10,11

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Special Report: Policy A review of human carcinogens—Part B: biological agents
In February, 2009, 36 scientists from 16 countries met at the International Agency for Research on Cancer (IARC) to reassess the carcinogenicity of the biological agents classified as “carcinogenic to humans” (Group 1) and to identify additional tumour sites and mechanisms of carcinogenesis (tables 1 and 2). These assessments will be published as part B of Volume 100 of the IARC Monographs.1 Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect, respectively, over 300 million and 170 million people worldwide, mainly in Asia and Africa. Chronic infection with these viruses is known to cause hepatocellular carcinoma.2 Sufficient evidence is available to conclude that chronic infection with HCV can also cause non-Hodgkin lymphoma, especially B-cell lymphoma. In an intervention study, patients with HCV infection and splenic lymphoma who were given the antiviral agent, interferon, showed regression of the lymphoma.3 Epstein–Barr virus (EBV) infects almost everyone and causes several
Group 1 agent Epstein–Barr virus (EBV)

types of cancer, including nasopharyngeal carcinoma, one of the most common cancers in southeastern Asia, and Burkitt’s lymphoma in children in Africa. New evidence points to a role for EBV in 5–10% of gastric carcinomas worldwide.4 EBV-positive gastric carcinoma develops early in life and has distinct histopathology, therefore it might belong to a separate clinical entity.5 In this subset of gastric tumours, presence of the viral genome in a monoclonal form and expression of EBV-transforming proteins are strong evidence for the involvement of EBV.6 Data from 22 cohort studies and 80 case–control studies show an association between Kaposi’s sarcoma herpes virus (KSHV) and Kaposi’s sarcoma, with relative risks higher than 10. Most studies are of transplant recipients and people infected with HIV-1. In both patients who are and are not infected with HIV-1, risk of Kaposi’s sarcoma increases relative to increasing titre of antibodies directed against KSHV, which are markers of the viral load.7,8 Evidence is sufficient to show

that KSHV causes primary effusion lymphoma, a rare subgroup of B-cell non-Hodgkin lymphoma. Mechanistic data support an oncogenic role for KSHV in Kaposi’s sarcoma and in primary effusion lymphoma—in individuals who are immunocompromised and in those apparently immunocompetent. KSHV is also associated with multicentric Castleman’s disease. Individuals who are infected with HIV-1 have a high risk of cancer. HIV-1 infection, mainly through immunosuppression, leads to increased replication of oncogenic viruses such as EBV and KSHV. Although antiretroviral therapy lowers the risk of many cancers associated with HIV-1, risks remain high.9 Cervical cancer is caused by types of human papillomavirus (HPV) that belong to a few phylogenetically related “high-risk” species (alpha-5, 6, 7, 9, 11) of the mucosotropic alpha genus.10,11 The types found most frequently in cervical cancer (HPV-16, 18, 31, 33, 35, 45, 52, 58) and four types less constantly found (HPV-39, 51, 56, 59) were classified in

See From the Archives page 430 Upcoming meetings June 2–9, 2009 Radiation September 29–October 6, 2009 Lifestyle Factors October 20–27, 2009 Chemical Agents and Related Occupations http://monographs.iarc.fr/

Cancers for which there is sufficient evidence in humans Other sites with limited evidence in humans Nasopharyngeal carcinoma, Burkitt’s lymphoma, immune- Gastric carcinoma,* lympho-epithelioma-like suppression-related non-Hodgkin lymphoma, extranodal carcinoma* NK/T-cell lymphoma (nasal type), Hodgkin’s lymphoma Hepatocellular carcinoma Hepatocellular carcinoma, non-Hodgkin lymphoma* Kaposi’s sarcoma,* primary effusion lymphoma* Kaposi’s sarcoma, non-Hodgkin lymphoma, Hodgkin’s lymphoma,* cancer of the cervix,* anus,* conjunctiva* Carcinoma of the cervix, vulva, vagina, penis, anus, oral cavity, and oropharynx and tonsil Cholangiocarcinoma* multicentric Castleman’s disease* Cancer of the vulva,* vagina,* penis,* nonmelanoma skin cancer,* hepatocellular carcinoma* Cancer of the larynx .. .. .. .. ..

Established mechanistic events Cell proliferation, inhibition of apoptosis, genomic instability, cell migration

Hepatitis B virus (HBV) Hepatitis C virus (HCV) Kaposi‘s sarcoma herpes virus (KSHV) Human immunodeficiency virus, type 1 (HIV-1) Human papillomavirus type 16 (HPV-16)†

Cholangiocarcinoma,* non-Hodgkin lymphoma* Inflammation, liver cirrhosis, chronic hepatitis Inflammation, liver cirrhosis, liver fibrosis Cell proliferation, inhibition of apoptosis, genomic instability, cell migration Immunosuppression (indirect action)

Immortalisation, genomic instability, inhibition of DNA damage response, anti-apoptotic activity Immortalisation and transformation of T cells Inflammation, oxidative stress, altered cellular turnover and gene expression, methylation, mutation .. Inflammation, oxidative stress, cell proliferation Inflammation, oxidative stress

Human T-cell lymphotrophic Adult T-cell leukaemia and lymphoma virus, type-1 (HTLV-1) Helicobacter pylori Clonorchis sinensis Opisthorchis viverrini Schistosoma haematobium Non-cardia gastric carcinoma, low-grade B-cell mucosaassociated lymphoid tissue (MALT) gastric lymphoma* Cholangiocarcinoma* Cholangiocarcinoma Urinary bladder cancer

*Newly identified link between virus and cancer. †For other types, see table 2.

Table 1: Biological agents assessed by the IARC Monograph Working Group

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Group HPV types Alpha HPV types 1 1 2A 2B 2B 3 2B 3 16 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 68 26, 53, 66, 67, 70, 73, 82 30, 34, 69, 85, 97 6, 11 5 and 8 Other beta and gamma types

Comments

International Agency for Research on Cancer, Lyon, France
The IARC authors declared no conflicts of interest. D Blair attended as a Representative of the US National Cancer Institute (Bethesda, MD, USA). F Buonaguro (NCI, Napoli, Italy) and A Fiander (Cardiff University, Cardiff, UK) attended as Observers. 1 Grosse Y, Baan R, Straif K, et al. A review of human carcinogens—Part A: pharmaceuticals. Lancet Oncol 2009; 10: 13–14. IARC. Hepatitis viruses. IARC Monogr Eval Carcinog Risks Hum 1994; 59: 1–255. Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002; 347: 89–94. Zur Hausen H. Infections causing human cancer. 2006. Weinheim: Wiley-VCH; Chichester: John Wiley. Fukayama M, Hino R, Uozaki H. Epstein-Barr virus and gastric carcinoma: virus-host interactions leading to carcinoma. Cancer Sci 2008; 99: 1726–33. Hino R, Uozaki H, Inoue Y, et al. Survival advantage of EBV-associated gastric carcinoma: surviving up-regulation by viral latent membrane protein 2A. Cancer Res 2008; 68: 1427–35. Sitas F, Carrara H, Beral V, et al. Antibodies against human herpesvirus 8 in black South African patients with cancer. N Engl J Med 1999; 340: 1863–71. Newton R, Ziegler J, Bourboulia D, et al. The seroepidemiology of Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) in adults with cancer in Uganda. Int J Cancer 2003; 103: 226–32. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 2000; 92: 1823–30. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hansen. Classification of papillomaviruses. Virology 2004; 324: 17–27. IARC. Human papillomaviruses. IARC Monogr Eval Carcinog Risks Hum 2007; 90: 1–636. IARC. Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the evaluation of carcinogenic risks to humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum 1994; 61: 1–241. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001; 49: 347–53. Wundisch T, Thiede C, Morgner A, et al. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol 2005; 23: 8018–24. Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prev Res (Phila Pa) 2008; 1: 329–38. Honjo S, Srivatanakul P, Sriplung H, et al. Genetic and environmental determinants of risk for cholangiocarcinoma via Opisthorchis viverrini in a densely infested area in Nakhon Phanom, northeast Thailand. Int J Cancer 2005; 117: 854–60. Choi D, Lim JH, Lee KT, et al. Cholangiocarcinoma and Clonorchis sinensis infection: a case-control study in Korea. J Hepatol 2006; 44: 1066–73.

Most potent HPV type, known to cause cancer at several sites Sufficient evidence for cervical cancer Limited evidence in humans and strong mechanistic evidence for cervical cancer Limited evidence in humans for cervical cancer Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in humans ··

Beta HPV types Limited evidence for skin cancer in patients with epidermodysplasia verruciformis ··

2 3

Table 2: Human papillomavirus (HPV) types assessed by the IARC Monograph Working Group 4
Monograph Working Group Members T F Schulz—Co-Chair (Germany), N Mueller—Co-Chair (USA); A Grulich, F Sitas (Australia); K Polman (Belgium); C J Chen, Y Y Fang (China); R Herrero (Costa Rica); B J Vennervald (Denmark); R Mahieux, F Mégraud, F Zoulim (France); H Blum, H zur Hausen (both unable to attend) (Germany); L Banks, A Carbone, D Serraino (Italy); M Matsuoka (Japan); S T Hong (South Korea); M C Kew (South Africa); S de Sanjosé (Spain); I Ernberg (Sweden); B Sripa (Thailand); A Hall, D Forman, R Newton (UK); E Cesarman, D Dittmer, E T H Fontham, P F Lambert, S Moss, E Murphy, M Schiffman, S Stuver, D Whitby (USA) Conflicts of interest SDS receives funding from Merck and Sanofi-Pasteur. AG has received funding from and is an advisor for CSL. RM has acted as a consultant for MP Biomedicals. SM served on a speaker’s bureau for Otsuka Pharmaceuticals and was a consultant for Altana. NuM is a member of steering committees and a speaker’s bureau for Merck and SanofiPasteur. EM owns stock in Genentech. CJC received funding from Bristol-Myer-Squibb. Invited Specialists N Muñoz (IARC, France; retired)

Group 1 (table 2). The risk of cancer may be an order of magnitude higher for HPV-16 infection than for other highrisk HPV types. HPV-68 was classified as “probably carcinogenic to humans” (Group 2A) with limited evidence in humans and strong mechanistic evidence. The remaining types of HPV in the high-risk alpha species were classified as “possibly carcinogenic” (Group 2B; table 2). Finally, HPV-6 and HPV-11, which belong to the alpha10 species, were “not classifiable as to its carcinogenicity to humans” (Group 3) on the basis of inadequate epidemiological evidence and absence of carcinogenic potential in mechanistic studies. The Working Group recognises the need for further research of cutaneous HPV types of the beta and gamma genera. These widespread HPV types were classified in Group 3 on the basis of inconclusive evidence of causing skin cancer in humans and limited mechanistic data. Exceptions were the beta types HPV-5 and HPV-8, which are “possibly carcinogenic” in patients with epidermodysplasia verruciformis (Group 2B). Helicobacter pylori infection is associated with gastric cancer,12 one of the most prevalent cancers worldwide. Prospective epidemiological studies and eradication trials show that H pylori infection causes non-cardia gastric cancer.13 H pylori infection also causes B-cell mucosa-associated lymphoid tissue (MALT) gastric

lymphoma; eradication treatment leads to remission of these low-grade lymphomas.14 Several studies show that individuals with H pylori infection have a reduced risk of oesophageal adenocarcinoma compared with those without the infection.15 Opisthorchis viverrini and Clonorchis sinensis, two liver flukes of the genus Opisthorchis, are endemic in northeastern Thailand and many areas of southeastern Asia, respectively. In particular areas, prevalence of infection with liver flukes correlates with incidence of cholangiocarcinoma, and several case–control studies showed a high risk for this cancer.16,17 Therefore, infections with O viverrini or with C sinensis were both classified in Group 1. Schistosoma haematobium is endemic in most countries in Africa and the eastern Mediterranean region; infection with this worm, which causes urinary bladder cancer, is classified in Group 1. The proportion of cancers caused by infectious agents was recently estimated to be more than 20%.4 The identification of new cancer sites attributed to these agents means that more cancers are potentially preventable.

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Véronique Bouvard, Robert Baan, Kurt Straif, Yann Grosse, Béatrice Secretan, Fatiha El Ghissassi, Lamia Benbrahim-Tallaa, Neela Guha, Crystal Freeman, Laurent Galichet, Vincent Cogliano, on behalf of the WHO International Agency for Research on Cancer Monograph Working Group

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Special Report: Policy A review of human carcinogens—Part C: metals, arsenic, dusts, and fibres
In March, 2009, 27 scientists from eight countries met at the International Agency for Research on Cancer (IARC) to reassess the carcinogenicity of metals, arsenic, dusts, and fibres 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 part C of Volume 100 of the IARC Monographs. Inhalation is the primary route of exposure to arsenic in the workplace and happens in industries such as nonferrous smelting, arsenic production, wood preservation, glass manufacturing, production and application of arsenic-based pesticides, and electronics. Non-occupational exposure to arsenic is mainly through food, except in areas with high levels of arsenic in the drinking water—eg, Taiwan, Bangladesh, West Bengal (India), northern Chile, and Cordoba Province (Argentina).1 Epidemiological studies have shown that exposure to arsenic through inhalation or drinking-water
Group 1 agent

causes cancer of the lung, skin, and urinary bladder. Evidence suggests an association between exposure to arsenic in drinking water and the development of tumours at several other sites; however, various factors prevent a conclusion. Analytical studies have provided only limited information to support an association with kidney cancer, causes of liver cancer can be difficult to elucidate in groups that are high-risk for hepatitis B, and data on prostate cancer and arsenic exposure are not consistent between countries. Overall, the Working Group classified arsenic and inorganic arsenic compounds as “carcinogenic to humans” (Group 1). The organic arsenicals monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) are the active ingredients of some herbicides and are metabolites of inorganic arsenic. On the basis of sufficient evidence of cancer caused by DMA in experimental animals, and because MMA is extensively metabolised to DMA, both compounds are classified as “possibly carcinogenic

to humans” (Group 2B). Arsenobetaine and other organic arsenic compounds that are not metabolised in humans are “not classifiable” (Group 3). The Working Group reaffirmed the classification of beryllium and its compounds, cadmium and its compounds, chromium (VI) compounds, and nickel compounds as “carcinogenic to humans” (Group 1). Studies involved complex occupational exposures to a metal and its compounds, making it impossible to separately assess their carcinogenicity. Globally, an estimated 125 million people are still exposed to asbestos in the workplace.2 Although asbestos has been banned or restricted in most of the industrialised world, its use is increasing in parts of Asia, South America, and the former Soviet Union.3 Naturally occurring sources of asbestos, its use in brake linings, and deterioration of asbestos-containing products all contribute to environmental exposure worldwide. Exposure may also come from fibres carried home on the clothing of asbestos workers.4

Upcoming meetings June 2–9, 2009 Radiation September 29–October 6, 2009 Lifestyle Factors October 20–27, 2009 Chemical Agents and Related Occupations http://monographs.iarc.fr/

Tumour sites (or types) for which Other sites with limited evidence there is sufficient evidence in in humans humans Lung, skin, urinary bladder Kidney, liver, prostate ·· Prostate, kidney Nasal cavity and paranasal sinuses ··

Established mechanistic events

Arsenic and inorganic arsenic compounds

Oxidative DNA damage, genomic instability, aneuploidy, gene amplification, epigenetic effects, DNA-repair inhibition leading to mutagenesis Chromosome aberrations, aneuploidy, DNA damage DNA-repair inhibition, disturbance of tumour-suppressor proteins leading to genomic instability Direct DNA damage after intracellular reduction to Cr(III), mutation, genomic instability, aneuploidy, cell transformation DNA damage, chromosome aberrations, genomic instability, micronuclei, DNA-repair inhibition, alteration of DNA methylation, histone modification Impaired fibre clearance leading to macrophage activation, inflammation, generation of reactive oxygen and nitrogen species, tissue injury, genotoxicity, aneuploidy and polyploidy, epigenetic alteration, activation of signalling pathways, resistance to apoptosis Genotoxicity Impaired particle clearance leading to macrophage activation and persistent inflammation ·· ··

Beryllium and beryllium compounds Lung Cadmium and cadmium compounds Lung Chromium (VI) compounds Nickel compounds Asbestos (chrysotile, crocidolite, amosite, tremolite, actinolite, and anthophyllite) Erionite Silica dust, crystalline in the form of quartz or crystobalite Leather dust Wood dust Lung Lung, nasal cavity, and paranasal sinuses

Lung, mesothelioma, larynx, ovary Colorectum, pharynx, stomach Mesothelioma Lung Nasal cavity and paranasal sinuses ·· ·· ··

Nasal cavity and paranasal sinuses, ·· nasopharynx

Table: Metals, arsenic, dusts, and fibres assessed by the IARC Monograph Working Group

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Monograph Working Group Members U Heinrich—Co-Chair (Germany), J Samet—Co-Chair (USA); P A Demers, M Gérin, J Siemiatycki (Canada); P Grandjean (Denmark); A Aitio, T Kauppinen (Finland); M Goldberg (France); A Hartwig, H Muhle (Germany); B Fubini, F Merletti (Italy); M Ikeda (Japan); M D Attfield, K P Cantor, B A Fowler, R Henderson, P F Infante, AB Kane, P J Landrigan, R Lunn, T G Rossman, L Stayner, M P Waalkes, E M Ward, J M Ward (USA) Conflicts of interest RH served as chair of the US EPA Clean Air Seminar Advisory Committee from 2004 to 2008, which reviews US air standards for noxious gases and particulate matter. ABK is a member of the Science Advisory Board for the US EPA and served as chair of their Working Group on Asbestos in 2008. Invited Specialists None

Epidemiological evidence has increasingly shown an association of all forms of asbestos (chrysotile, crocidolite, amosite, tremolite, actinolite, and anthophyllite) with an increased risk of lung cancer and mesothelioma. Although the potency differences with respect to lung cancer or mesothelioma for fibres of various types and dimensions are debated, the fundamental conclusion is that all forms of asbestos are “carcinogenic to humans” (Group 1). Mineral substances (eg, talc or vermiculite) that contain asbestos should also be regarded as “carcinogenic to humans”. Sufficient evidence is now available to show that asbestos also causes cancer of the larynx and of the ovary. A meta-analysis of cohort studies reported a relative risk of cancer of the larynx of 1·4 (95% CI 1·2–1·6) for “any” exposure to asbestos. With different exposure metrics, the relative risk for “high” exposure versus “none” was at least 2·0 (1·6–2·5).5 Cohort studies of women who were heavily exposed to asbestos in the workplace consistently report increased risks of ovarian cancer, as in a study of women in the UK who manufactured gas masks during World War II.6 Studies suggest that asbestos can accumulate in the ovaries of women who are exposed to it.7 The Working Group classified the evidence for an association between asbestos and colorectal cancer as “limited”, although members were evenly divided as to whetherx the evidence was strong enough to warrant classification as “sufficient”. Further, there is “limited” evidence in humans for cancers of the pharynx and of the stomach. The mechanism of the carcinogenicity of asbestos fibres involves a complex interaction between the crystalline mineral fibres and target cells. The physicochemical properties of asbestos fibres that are most relevant to pathogenicity are surface chemistry and reactivity, surface area, fibre dimensions, and biopersistence. Direct and indirect mechanisms have been

proposed on the basis of in-vitro cellular assays and acute and subchronic animal bioassays (table). Respiratory responses to inhalation of asbestos fibres are substantially different between species, and the biological mechanisms responsible for these differences are unknown. The Working Group reaffirmed the carcinogenicity of crystalline silica dust as Group 1. An increased risk of lung cancer was observed across various industries and processes.8 The Working Group reviewed evidence of epidemiological studies of boot and shoe manufacture and repair, and found that sinonasal cancers can result from exposure to leather dust and leukaemias from exposure to benzene. A particularly high risk of sinonasal adenocarcinoma was noted among workers with the highest exposure to leather dust.9 Leather dust was classified as “carcinogenic to humans” (Group 1). Epidemiological studies report a strong association between exposure to wood dust and development of sinonasal cancer.10 Only a few studies included details of tumour histology and substantial risks for sinonasal adenocarcinoma were noted. The few studies that assessed exposure to specific wood types found strong evidence of carcinogenicity for hardwood dusts. Case–control studies that investigated exposure to softwood dust observed a consistent but smaller risk, compared with hardwood dust, mainly for squamous-cell carcinoma. For cancer of the nasopharynx, exposure to formaldehyde is unlikely to be responsible for the increased risks (compared with the reference population) that were reported in most case–control studies and in the pooled reanalysis of cohort studies.11 Wood dust was reaffirmed as “carcinogenic to humans”.

International Agency for Research on Cancer Monograph Working Group.
International Agency for Research on Cancer, Lyon, France
The IARC authors declared no conflicts of interest. Attending the meeting as Representatives of their respective health agencies were P B Larsen (Danish Environmental Protection Agency), A Huici-Montagud (European Commission Directorate General for Employment, Social Affairs and Equal Opportunities), T Bateson and R Sams (US Environmental Protection Agency), and F Rice and M Schubauer-Berigan (US National Institute for Occupational Safety and Health). Attending the meeting as Observers sponsored by various organisations were J Addison (RT Vanderbilt Co, USA), D Bernstein and J Hoskins (American Forest and Paper Association), M G Bird (ExxonMobil Corp, USA), F Bochmann (German Social Accident Insurance), G Bromfield (Canadian Cancer Society), P Crosignani (International Society of Doctors for the Environment, Switzerland), D Deubner (Brush Wellman Inc, USA), M Eldan (Methanearsonic Acid Research Task Force, USA), J Gamble (National Stone, Sand and Gravel Association, USA), J Goodman (Eurometaux, Belgium), TK Grimsrud (Cancer Registry of Norway), E Kovalevskiy (Russian Academy of Medical Sciences), R A Lemen (private consultant, USA), P Morfeld and G Oberdörster (EUROSIL, Belgium; EUROTALC, Belgium; Industrial Minerals Association, North America, USA), L Neumeister (International Social Security Association, Germany), and A Oller (Nickel Producers Environmental Research Association Inc, USA). 1 IARC. Some drinking-water disinfectants and contaminants, including arsenic. IARC Monogr Eval Carcinog Risks Hum 2004; 84: 1–477. WHO. Elimination of asbestos-related diseases. http://whqlibdoc.who.int/hq/2006/WHO_SDE_ OEH_06.03_eng.pdf (accessed April 9, 2009). LaDou J. The asbestos cancer epidemic. Environ Health Perspect 2004; 112: 285–90. Anderson HA, Lilis R, Daum SM, Selikoff IJ. Asbestosis among household contacts of asbestos factory workers. Ann N Y Acad Sci 1979; 330: 387–99. Institute of Medicine, Committee on Asbestos. Selected health effects. Asbestos: selected cancers. Washington, DC: National Academies Press, 2006. Acheson ED, Gardner MJ, Pippard EC, Grime LP. Mortality of two groups of women who manufactured gas masks from chrysotile and crocidolite asbestos: a 40-year follow-up. Br J Ind Med 1982; 39: 344–48. Heller DS, Gordon RE, Westhoff C, Gerber S. Asbestos exposure and ovarian fiber burden. Am J Ind Med 1996; 29: 435–39. Steenland K, Mannetje A, Boffetta P, et al. Pooled exposure-response analyses and risk assessment for lung cancer in 10 cohorts of silica-exposed workers: an IARC multicentre study. Cancer Causes Control 2001; 12: 773–84. ‘tMannetje A., Kogevinas M, Luce D, et al. Sinonasal cancer, occupation, and tobacco smoking in European women and men. Am J Ind Med 1999; 36: 101–07. Demers PA, Boffetta P, Kogevinas M, et al. Pooled reanalysis of cancer mortality among five cohorts of workers in wood-related industries. Scand J Work Environ Health 21: 1995; 179–90.

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Special Report: Policy A review of human carcinogens—Part D: radiation
In June 2009, 20 scientists from nine countries met at the International Agency for Research on Cancer (IARC) to reassess the carcinogenicity of the types of radiation previously classified as “carcinogenic to humans” (Group 1) and to identify additional tumour sites and mechanisms of carcinogenesis (table and panel). These assessments will be published as part D of Volume 100 of the IARC Monographs.1 Alpha particles, consisting of two protons and two neutrons, are a densely ionising type of radiation with low capacity to penetrate living tissue (less than 0·1 mm). Beta particles are electrons or positrons that are less ionising, but more penetrating (up to a few milimetres). The health hazards resulting from radionuclides that emit these particles largely occur after internal deposition. Epidemiological evidence shows a number of radionuclides that emit alpha or beta particles increase cancer risks at several anatomical sites (table). The Working Group reaffirmed the carcinogenicity of internally deposited radionuclides that emit alpha or beta particles (Group 1).
Radiation type Alpha-particle and beta-particle emitters Radon-222 and decay products Radium-224 and decay products Radium-226, radium-228, and decay products Thorium-232 and decay products Plutonium Phosphorus-32 Fission products, including strontium-90 Radioiodines, including iodine-131 X-radiation or gamma-radiation General population (residential exposure), underground miners Medical patients Radium-dial painters Medical patients Plutonium-production workers Medical patients General population, following nuclear reactor accident Children and adolescents, following nuclear reactor accident Atomic-bomb survivors, medical patients; in-utero exposure (offspring of pregnant medical patients and of atomic-bomb survivors) Lung Bone Bone, paranasal sinus and mastoid process (radium-226 only) Liver, extrahepatic bile ducts, gall bladder, leukaemia (excluding CLL) Lung, liver, bone Acute leukaemia Solid cancers, leukaemia Thyroid Salivary gland, oesophagus, stomach, colon, lung, bone, skin (BCC), female breast, urinary bladder, brain and CNS, leukaemia (excluding CLL), thyroid, kidney (atomic-bomb survivors, medical patients); multiple sites (in-utero exposure) Skin (BCC, SCC, melanoma) Skin (melanoma), eye (melanoma, particularly choroid and ciliary body)

After the Chernobyl accident, a sharp increase in the risk of thyroid cancer was found with exposure to radioiodines, particularly iodine-131, during childhood and adolescence.2,3 This increased risk might be due to higher milk intake per unit of body weight among children; a higher thyroid dose per unit of iodine-131 intake from milk; a higher susceptibility per unit of thyroid dose; or a combination of these. Radon exposure occurs mainly through contamination of indoor air by radon released from soil and building materials. Combined analyses of case–control studies now estimate that residential exposure to radon gas is the leading cause of lung cancer after tobacco smoke (8–15% attributable risk in Europe and North America).4,5 X-rays and gamma-rays are sparsely ionising electromagnetic radiation that penetrate living tissue, typically producing fast electrons that deposit energy, resulting in tissue damage. Extensive study of atomicbomb survivors shows increased cancer risks at multiple anatomical sites.6 Current evidence adds to the list of tumours caused by x-rays
Major study populations

and gamma-rays (table), and also establishes that in-utero exposure increases the risk of cancer at multiple sites.7,8 The Working Group reaffirmed the carcinogenicity of x-radiation and gamma-radiation (Group 1). Neutrons are produced by nuclear reactions and are a main component of cosmic radiation. They are highly penetrating and interact with the traversed tissue, producing protons, other charged particles, and gamma-radiation. Epidemiological evidence is inadequate to assess the carcinogenicity of neutrons, because of co-exposures to other types of radiation. However, the evidence of cancer in experimental animals is sufficient, and mechanistic data show that neutrons transfer their energy in clusters of ionising events— resulting in similar, but more severe, local damage than that induced by x-rays or gamma-rays. On the basis of this evidence, the Working Group reaffirmed the carcinogenicity of neutron radiation (Group 1). Each type of ionising radiation (panel) transfers energy in the form of highly structured tracks of

Upcoming meetings Sept 29–Oct 6, 2009 Lifestyle Factors Oct 20–27, 2009 Chemical Agents and Related Occupations http://monographs.iarc.fr/

Tumour sites (and types) on which sufficient evidence is based

Solar radiation UV-emitting tanning devices

General population General population

CLL=chronic lymphocytic leukaemia. BCC=basal-cell carcinoma. SCC=squamous-cell carcinoma.

Table: Radiation exposures with sufficient evidence in humans

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Monograph Working Group Members B Armstrong–Co-Chair (Australia), E Cardis–Co-Chair (Spain); A Green (Australia); D Krewski, R Mitchel, N Priest (Canada); L Tomašek (Czech Republic); K Baverstock (Finland); J-F Doré, J Hall, L Sabatier (France); M Sokolnikov (Russian Federation); M Hill, M Little, M Marshall, C Muirhead, A Riddell (UK); D Brenner [unable to attend], R Guilmette, D Hoel, D Richardson, R Ullrich (USA) Conflicts of interest NP works for, and RM is a consultant to, Atomic Energy of Canada Ltd. CM receives funding from the UK Ministry of Defence. JH receives funding from Electricité de France. AG receives funding from L’Oreal Recherche. Invited Specialists None

Panel: Types of radiation classified in Group 1 • Ionising radiation • Alpha-particle emitters • Beta-particle emitters • X-rays and gamma-rays • Neutron radiation • Solar radiation • Ultraviolet radiation (wavelengths 100–400 nm, encompassing UVA, UVB, and UVC)

ionisation and excitation events that can produce a variety of molecular lesions and clustered, complex DNA damage.9 Subsequent processing of this damage induces many responses (eg, cell killing, chromosomal aberrations, mutations, genomic instability, cell transformation, and bystander effects) that contribute to carcinogenesis. Based on these mechanistic considerations, all types of ionising radiation were classified by the Working Group as “carcinogenic to humans” (Group 1). Solar radiation is the main source of human exposure to ultraviolet (UV) radiation, which is further subdivided into UVA, UVB, and UVC. The ultraviolet component that reaches the earth’s surface comprises around 95% UVA and 5% UVB; UVC is blocked by stratospheric ozone. Epidemiological studies have established a causal association between exposure to solar radiation and all major types of skin cancer (table). The Working Group reaffirmed the carcinogenicity of solar radiation (Group 1). Exposure to solar radiation causes a specific mutation fingerprint (cytidine to thymidine transition), as a result of cyclobutane pyrimidine dimers in DNA. This pattern had long been attributed to UVB.10 However, this same cytidine to thymidine transition has been detected in the skin of UVA-treated mice11 and in the Tp53 gene of UVA-induced or UVB-induced skin tumours in hairless mice.10 In humans, this

transition has been seen in TP53 in premalignant solar keratosis and in malignant skin tumours.12 Based on these mechanistic data, the Working Group classified UV radiation as “carcinogenic to humans” (Group 1). The use of UV-emitting tanning devices is widespread in many developed countries, especially among young women. A comprehensive meta-analysis concluded that the risk of cutaneous melanoma is increased by 75% when use of tanning devices starts before 30 years of age.13 Additionally, several case–control studies provide consistent evidence of a positive association between the use of UV-emitting tanning devices and ocular melanoma.14,15 Therefore, the Working Group raised the classification of the use of UVemitting tanning devices to Group 1, “carcinogenic to humans”. While reviewing the studies of occupational UV exposure, the Working Group concluded that there is “sufficient evidence” for ocular melanoma in welders.16,17 However, because welders are also exposed to other harmful agents, this association could not be attributed specifically to UV radiation. A full review of the carcinogenic hazards of welding will be undertaken by IARC with high priority.

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Fatiha El Ghissassi, Robert Baan, Kurt Straif, Yann Grosse, Béatrice Secretan, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Crystal Freeman, Laurent Galichet, Vincent Cogliano, on behalf of the 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 interest. 1 Grosse Y, Baan R, Straif K, et al. A review of human carcinogens—part A: pharmaceuticals. Lancet Oncol 2009; 10: 13–14. UN Chernobyl Forum expert group “Health” (EGH). Health effects of the Chernobyl accident and special health care programmes. Geneva; 2006. http://whqlibdoc.who.int/publi cations/2006/9241594179_eng.pdf.

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Cardis E, Howe G, Ron E, et al. Cancer consequences of the Chernobyl accident: 20 years on. J Radiol Prot 2006; 26: 127–40. Darby S, Hill D, Auvinen A, et al. Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case–control studies. BMJ 2005; 330: 223. National Research Council, Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, Board on Radiation Effects, and Research Division on Earth and Life Studies. Health effects of exposure to radon: BEIR VI. Washington: National Academies Press; 1999. National Research Council, Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, Board on Radiation Effects, and Research Division on Earth and Life Studies. Health risks from exposure to low levels of ionizing radiation: BEIR VII, Phase 2. Washington: National Academies Press; 2006. Wakeford R, Little MP. Risk coefficients for childhood cancer after intrauterine irradiation: a review. Int J Radiat Biol 2003; 79: 293–309. Preston DL, Cullings H, Suyama A, et al. Solid cancer incidence in atomic bomb survivors exposed in utero or as young children. J Natl Cancer Inst 2008; 100: 428–36. Goodhead DT. Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol 1994; 65: 7–17. Runger TM, Kappes UP. Mechanisms of mutation formation with long-wave ultraviolet light (UVA). Photodermatol Photoimmunol Photomed 2008; 24: 2–10. Ikehata H, Kawai K, Komura J, et al. UVA1 genotoxicity is mediated not by oxidative damage but by cyclobutane pyrimidine dimers in normal mouse skin. J Invest Dermatol 2008; 128: 2289–96. Agar NS, Halliday GM, Barnetson RS, Ananthaswamy HN, Wheeler M, Jones AM. The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proc Natl Acad Sci USA 2004; 101: 4954–59. IARC Working Group. The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: a systematic review. Int J Cancer 2006; 120: 1116–22. Seddon JM, Gragoudas ES, Glynn RJ, Egan KM, Albert DM, Blitzer PH. Host factors, UV radiation, and risk of uveal melanoma: a case-control study. Arch Ophthalmol 1990; 108: 1274–80. Vajdic CM, Kricker A, Giblin M, et al. Artificial ultraviolet radiation and ocular melanoma in Australia. Int J Cancer 2004; 112: 896–900. Lutz JM, Cree I, Sabroe S, et al. Occupational risks for uveal melanoma results from a casecontrol study in nine European countries. Cancer Causes Control 2005; 16: 437–47. Shah CP, Weis E, Lajous M, Shields JA, Shields CL. Intermittent and chronic ultraviolet light exposure and uveal melanoma: a metaanalysis. Ophthalmology 2005; 112: 1599–607.

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