Laurent Galichet

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 classifi ed 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. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect, res pectively, over 300 million and 170 million people worldwide, mainly in Asia and Africa. Chronic infection with these viruses is known to cause hepatocellular carcinoma. Suffi cient evidence is available to conclude that chronic infection with HCV can also cause non-Hodgkin lymphoma, especially B-cell lymphoma. In an inter vention study, patients with HCV infection and splenic lymphoma who were given the antiviral agent, interferon, showed regression of the lymphoma. Epstein–Barr virus (EBV) infects almost everyone and causes several 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. EBV-positive gastric carcinoma develops early in life and has distinct histopathology, therefore it might belong to a separate clinical entity. 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. 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. Evidence is suffi cient to show that KSHV causes primary eff usion 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 eff usion 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. 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. 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 classifi ed in

A review of human carcinogens--Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish.

www.thelancet.com/oncology Vol 10 November 2009 1033 In October, 2009, 30 scientists from 10 countries met at the International Agency for Research on Cancer (IARC) to reassess the carcinogenicity of tobacco, areca nut, alcohol, coal smoke, and saltpreserved fi sh, and to identify additional tumour sites (table) and mechanisms of carcinogenesis. These assessments will be published as part E of Volume 100 of the IARC Monographs. Tobacco smoking is the single largest cause of cancer worldwide. More than 1 billion people around the world are current smokers. New evidence con tinues to add to the extensive list of tobacco-related cancers (table); there is now suffi cient evidence that tobacco smoking causes cancer of the colon and of the ovary. More than 150 epi demiological studies of tobacco smoking and breast cancer were reviewed. Large cohort studies published since 2002 consistently show a small positive association (relative risks 1·1–1·3). Many chemicals in tobacco smoke cause mammarygland tumours in animals, and these carcinogens are stored in breast adipose tissue in women; therefore, the Working Group concluded that there is limited evidence that tobacco smoking causes breast cancer. A causal link between parental smoking and childhood cancers has been established. Four recent studies showed that children born of parents who smoke (father, mother, or both, including the preconception period and pregnancy) are at signifi cantly higher risk of hepatoblastoma, a rare embryonic cancer. The UK Childhood Cancer Study reported a relative risk of 1·86 for paternal smoking only and 2·02 for maternal smoking only, increasing to 4·74 (95% CI 1·68–13·35) when both parents smoke. For childhood leukaemia, a meta-analysis reported an associ ation with paternal smoking before pregnancy (summary relative risk 1·12, 1·04–1·21). Second-hand smoke causes lung cancer. There is now limited evidence for an association with cancers of the larynx and the pharynx, whereas evidence for female breast cancer remains inconclusive. Since secondhand smoke contains most of the constituents of mainstream smoke, it might also be associated with other cancer sites. Many types of smokeless tobacco are marketed and all contain nicotine and nitrosamines. Hundreds of millions of people use smokeless tobacco, mainly in India and southeast Asia, but also in Sweden and the USA. Earlier fi ndings showed a causal association between use of smokeless tobacco and cancers of the oral cavity and pancreas, and there is now suffi cient evidence for cancer of the oesophagus. All of the forms of tobacco discussed above induce malignant tumours in laboratory animals. Among the many carcinogens present in tobacco are nitrosamines, including the tobaccospecifi c nitrosamines 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone Special Report: Policy A review of human carcinogens—Part E: tobacco, areca nut, alcohol, coal smoke, and salted fi sh

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. 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). 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. 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). 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. Current evidence adds to the list of tumours caused by x-rays and gamma-rays (table), and also establishes that in-utero exposure increases the risk of cancer at multiple sites. 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

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 fi bres previously classifi ed 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 pro duction, wood preservation, glass manu facturing, 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). Epidemiological studies have shown that exposure to arsenic through inhalation or drinking-water 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 diffi cult 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 classifi ed 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 suffi cient evidence of cancer caused by DMA in experimental animals, and because MMA is extensively metabolised to DMA, both compounds are classifi ed as “possibly carcinogenic to humans” (Group 2B). Arsenobetaine and other organic arsenic compounds that are not metabolised in humans are “not classifi able” (Group 3). The Working Group reaffi rmed the classifi cation 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. 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. 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 fi bres carried home on the clothing of asbestos workers. Upcoming meetings June 2–9, 2009 Radiation

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 reassess the carcinogenicity of several chemical and occupational exposure circumstances previously classifi ed 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. Four aromatic amines and two related industrial processes were reaffi rmed as Group-1 carcinogens based on suffi cient evidence that they cause urinary bladder cancer in humans. The Group-1 classifi cation of dyes metabolised to benzidine and of 4,4’-methylenebis(2-chloroaniline) was based on suffi cient evidence in animal models and strong mechanistic evidence. Exposure to polycyclic aromatic hydro carbons (PAHs) causes cancers of the skin and lung in humans. Various PAH-related industries and PAHcontaining complex mixtures were confi rmed as Group-1 carcinogens. Although there are no epidemiological studies of benzo[a]pyrene, carcinogenicity in many animal species and strong mechanistic evidence justifi ed its classifi cation in Group 1. The carcinogenicity to humans of other chemicals and exposure scenarios was reaffi rmed (table). For ethylene oxide, the epidemiological evidence was limited, but there is suffi cient 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 eff ects in lymphocytes of exposed workers provided strong support for its classifi cation in Group 1. Workers in the rubber-manufacturing industry have an increased risk for leukaemia, lymphoma, and cancers of the urinary bladder, lung, and stomach. Due to the diversity and com plexity of the exposures in this industry, it is diffi cult to identify causative agents, but there is strong evidence of genotoxic eff ects in these workers. The Working Group reviewed more than 100 epidemiological studies of benzene and confi rmed its carcinogenicity, with suffi cient 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 exposure to painting—before and during pregnancy—and an increased risk of childhood leukaemia in the off spring. Dioxin (2,3,7,8-tetrachlorodibenzopara-dioxin, TCDD) was classifi ed in Group 1 in 1997, based on limited evidence of carcinogenicity in humans, For more on the IARC Monographs see http:// monographs.iarc.fr

Carcinogenicity of radiofrequency electromagnetic fields

Robert Baan a, Yann Grosse a, Beatrice Lauby-Secretan a, Fatiha El Ghissassi a, Veronique Bouvard a, Lamia Benbrahim-Tallaa a, Neela Guha a, Farhad Islami a, Laurent Galichet a, Kurt Straif a, on behalf of the WHO International Agency for Research on Cancer Monograph Working Group In May, 2011, 30 scientists from 14 countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to assess the carcinogenicity of radiofrequency electromagnetic fields (RF-EMF). These assessments will be published as Volume 102 of the IARC Monographs.1

Preventable Exposures Associated With Human Cancers

Information on the causes of cancer at specific sites is important to cancer control planners, cancer researchers, cancer patients, and the general public. The International Agency for Research on Cancer (IARC) Monograph series, which has classified human carcinogens for more than 40 years, recently completed a review to provide up-to-date information on the cancer sites associated with more than 100 carcinogenic agents. Based on IARCs review, we listed the cancer sites associated with each agent and then rearranged this information to list the known and suspected causes of cancer at each site. We also summarized the rationale for classifications that were based on mechanistic data. This information, based on the forthcoming IARC Monographs Volume 100, offers insights into the current state-of-the-science of carcinogen identification. Use of mechanistic data to identify carcinogens is increasing, and epidemiological research is identifying additional carcinogens and cancer sites or confirming carcinogenic potential under conditions of lower exposure. Nevertheless, some common human cancers still have few (or no) identified causal agents.

Carcinogenicity of chemicals in industrial and consumer products, food contaminants and flavourings, and water chlorination byproducts

In October, 2009, the International Agency for Research on Cancer (IARC) completed a review of the more than 100 agents classifi ed as “carcinogenic to humans” (Group 1). These assessments will be published in six parts as Volume 100 of the IARC Monographs (Volumes 100A–F). The IARC Monographs Programme has now resumed its regular schedule and in February, 2011, 18 scientists from eight countries met to assess the carcinogenicity of 18 chemicals present in industrial and consumer products or food—as natural con stituents, contaminants, or fla vourings—or occur ring as water chlorination by products (table). Some of these agents are discussed in more detail below. These assessments will be published as Volume 101 of the IARC Monographs. For most of the substances reviewed, there were many sources of exposure, including complex mixtures at the workplace, food, drinking water, consumer products, and the environment. For example, diethanolamine is one of many constituents of metalworking fl uids to which workers are exposed, and bromochloroacetic acid, dibromoacetic acid, and dibromoacetonitrile are three of the many chlorination byproducts present in drinking water and swimming pools. For this reason, there were no or very few epidemiological studies assessing agent-specifi c exposure. In view of the limited agent-specifi c information from epidemiological studies, our assessments relied mainly on carcinogenicity bioassays. The relevance to humans of the tumours reported in these studies was discussed with regard to mechanisms of carcinogenesis—eg, genotoxicity or other eff ects, such as peroxisome proliferation and PPARalpha activation, alpha2u-globulin nephropathy, and metabolism via CYP2F enzymes. For several of the compounds, similar tumour types, with low spontaneous incidences, were observed. For all 18 agents, the Working Group concluded that there was “suffi cient evidence of carcinogenicity in experimental animals”, leading to an overall evaluation—in the absence of adequate epidemiological information—of “possibly carcinogenic to humans” (Group 2B). The only exception was 2-nitrotoluene (Group 2A). Occupational exposure to 2-nitrotoluene occurs during production of dyes, rubber chemicals, agricultural chemicals, and explosives. In a Good Laboratory Practice (GLP) feeding study, 2-nitrotoluene caused an unusually high incidence of tumours in rats, including fi brosarcomas of the skin, malignant mesotheliomas, mammary gland fi broadenomas (also in male rats), and cholangiocarcinomas. Even short exposures of 13 or 26 weeks caused cancer in rats. In mice, unusually high incidences of carcinomas of the caecum and haemangiosarcomas were noted. In rodents, metabolism of 2-nitrotoluene results in formation of an electrophilic DNA-reactive compound that forms adducts in the liver. A similar pathway is likely to exist in humans. Indeed, workers exposed to a mixture of nitrotoluenes, including 2-nitrotoluene, had muta genic urine and increased levels of chromosome aberrations in circulating blood lymphocytes. The adduct 2-methylaniline-haemoglobin (specifi c for 2-nitrotoluene exposure) was also found in exposed workers. In rats, this biomarker correlated with liver–DNA adducts. Moreover, mutations were found in Catnb, p53, and K-Ras in tumours of the caecum For more on the IARC Monographs see http://monographs.iarc.fr

Bitumens and bitumen emissions, and some heterocyclic polycyclic aromatic hydrocarbons.

1190 www.thelancet.com/oncology Vol 12 December 2011 In October, 2011, 16 experts from nine countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to reassess the carcinogenicity of bitumens and their emissions, and of some N-heterocyclic and S-heterocyclic polycyclic aromatic hydrocarbons (PAHs). These assessments will be published as Volume 103 of the IARC Monographs. Bitumens are produced by distillation of crude oil during petroleum refi ning, and also occur naturally. Bitumens can be divided into six broad classes according to their physical properties and specifi cations required for diff erent applications (webappendix p 1). The main use (about 80%) of bitumens is for road paving; other uses include roofi ng, waterproofi ng, sealing, and painting. The term bitumen should not be confused with asphalt, which refers to the mixture of bitumen (4–10% by weight), small stones, sand, and fi ller used for road paving. Four major occupational exposures to bitumens and bitumen emissions have been evaluated for cancer risks in epidemiological studies: roofi ng, road paving, mastic asphalt work, and other occupations such as manufacturing of bitumen products and asphalt mixing. Roofers are often exposed to relatively high levels of bitumen emissions, due to high application temperatures (webappendix p 1). A meta-analysis of seven studies published before 1994 reported an increased risk for lung cancer (relative risk 1·78 [95% CI 1·50–2·10]), with risk estimates similar for cohort and case–control studies, the latter being adjusted for smoking. A subsequent Euro pean cohort study among workers exposed to bitumens reported an increas ed risk for lung cancer among roof ers and waterproofi ng workers (standardised mortality ratio [SMR] 1·33 [95% CI 0·73–2·23]). However, roofers can also be exposed to other lung carcinogens, such as coal tar from removing old roofs, and potential confounding is diffi cult to rule out. Four cohort studies reported increased risks for cancers of the upper aerodigestive tract, but potential confounding by tobacco smoking, alcoholic beverages, or other occupational exposures could not be excluded. A meta-analysis of four studies of road pavers reported no increase in lung cancer risk. The European cohort study, the largest study of road pavers published subsequently, reported a small increase in lung cancer mortality among road pavers compared with the general population (SMR 1·17 [95% CI 1·04–1·30]); however, the eff ect was attenuated when other construction workers were used as internal referents. Of the quantitative estimates of exposure to bitumen emissions modelled (cumulative, average, and duration of exposure), average exposure was signifi cantly associated with lung cancer mortality. In a nested case–control study that excluded pavers who were likely to have been exposed to coal tar and higher levels of bitumen, there was no suggestion of an increase in lung cancer risk with various metrics of bitumen exposure. Overall, the evidence for lung cancer risk among road pavers and road maintenance workers exposed to bitumens is inconsistent. Additionally, potential confounding by exposures to other carcinogens such as coal tar, diesel engine exhausts, or silica dust could not be ruled out. Work with mastic asphalt involves exposure to the highest reported levels of bitumen emissions, because of its use at high temperatures (webappendix p 1). Two studies investigated cancer risks associated with exposure to bitumens during mastic asphalt work, and both showed an increased risk for lung cancer. All informative studies of carcinogenicity of bitumens in experimental animals have been done in mice (apart from one inhalation study in rats), with bitumen applied dermally either neat, in a solvent (benzene, acetone, toluene, mineral spirits, mineral oil), or as a condensate of emissions generated from the bitumens. One of three studies with oxidised bitumens (Class 2) and all four studies with their fume condensates showed an increased risk for skin tumours (webappendix p 2). By contrast, none of the studies with straight-run bitumens (Class 1) or their fume condensates, including the inhalation study in rats, showed an increased risk. Of the two studies that investigated cut-back bitumens (Class 3), the initiation-promotion study showed evidence of a promoting eff ect on skin tumours. Bitumens of Bitumens and bitumen emissions, and some heterocyclic polycyclic aromatic hydrocarbons

Abstract 869: The IARC Monographs Vol. 100. A critical review and update on human carcinogens

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The IARC Monographs have been published continuously since 1971. For the 100th Vol. of the programme the evidence on all human carcinogens that have been identified to date has been updated. 147 experts from 28 countries contributed to the Vol. 100 series which was developed in six meetings from Oct 2008 to Oct 2009 (A. Pharmaceuticals, 23 agents; B. Biological agents, 11 agents; C. Metals, particles and fibres, 14 agents; D. Radiation, 14 agents; E. Lifestyle factors, 11 agents; F. Chemicals and related occupations, 34 agents). For each agent evaluations of the evidence in humans and in experimental animals and an overall evaluation of the human carcinogenicity have been developed and tumour sites with sufficient evidence of carcinogenicity as well as tumour sites that are strongly suspected and plausible mechanisms have been identified. All Group 1 carcinogens have been re-affirmed, several new Group 1 carcinogens and additional tumour sites for Group 1 carcinogens have been identified. Cancers of the colon, rectum and ovaries (mucinous type) have been added to the long list of tobacco smoking-related cancers, and parental smoking causes hepatoblastoma in the offspring and probably childhood leukemia. Acetaldehyde associated with alcohol consumption is carcinogenic to humans and causes cancers of the oesophagus, and head and neck. Based on sufficient evidence in humans for cutaneous and ocular melanoma, use of UV emitting tanning devices is now classified as “carcinogenic to humans”. In addition to lung cancer and mesothelioma, asbestos has now been linked with cancers of the larynx and ovaries, and leather dust has been identified as causing cancers of the nasal cavity and paranasal sinuses. There is now sufficient epidemiological evidence for TCDD exposure and 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. Like TCDD, 2,3,4,7,8-pentachlordibenzofuran and 3,3’,4,4’, 5-pentachlorobiphenyl are complete carcinogens in experimental animals, and there is extensive evidence that they act through the same AhR-mediated mechanism. The Working Group classified these two chemicals in Group 1. The Working Group unanimously reaffirmed the classification of formaldehyde in Group 1, based on sufficient evidence in humans of nasopharyngeal cancer and concluded that, overall, there is sufficient evidence for leukaemia, particularly myeloid leukaemia. The re-affirmation of all group 1 carcinogens underlines the robust procedures and criteria for human carcinogen identification employed in the IARC Monographs Programme. Two additional Working Groups will be convened to develop scientific publications that build on the data that have been summarized in Volume 100: 1) Tumour-site concordance between humans and experimental animals; 2) Mechanisms involved in human carcinogenesis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 869.