Vincent Cogliano

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

Carcinogenicity of shift-work, painting, and fire-fighting

In October, 2007, 24 scientists from ten countries met at the International Agency for Research on Cancer (IARC), Lyon, France, to assess the carcinogenicity of shift-work, painting, and fi re-fi ghting. These assessments will be published as volume 98 of the IARC Monographs. About 15–20% of the working population in Europe and the USA is engaged in shift-work that involves nightwork, which is most prevalent (above 30%) in the health-care, industrial manufactur ing, mining, transport, communication, leisure, and hospitality sectors. Among the many diff erent patterns of shiftwork, those including nightwork are the most disruptive for the circadian clock. Six of eight epidemiological studies from various geographical regions, most notably two independent cohort studies of nurses engaged in shiftwork at night, have noted a modestly increased risk of breast cancer in long-term employees compared with those who are not engaged in shiftwork at night. These studies are limited by potential confounding and inconsistent defi nitions of shiftwork, with several focused on a single profession. The incidence of breast cancer was also modestly increased in most cohorts of female fl ight attendants, who also experience circadian disruption by frequently crossing time zones. Limitations of studies in these fl ight attendants include the potential for detection bias, proxy measures of exposure, and potential uncontrolled confounding by reproductive factors and cosmic radiation. Several diff erent rodent models have been used to test the eff ect of disruption of the circadian system on tumour development. More than 20 studies investigated the eff ect of constant light, dim light at night, simulated chronic jet lag, or circadian timing of carcinogens, and most showed a major increase in tumour incidence. No clear eff ect was seen for light pulses at night or constant darkness. A similar number of studies investigated the eff ect of reduced nocturnal melatonin concentrations or removal of the pineal gland (where melatonin is produced) in tumour development and most showed increases in the incidence or growth of tumours. Exposure to light at night disturbs the circadian system with alterations of sleep-activity patterns, suppression of melatonin production, and de regul ation of circadian genes involved in cancer-related pathways. Inactivation of the circadian Period gene, Per2, promotes tumour develop ment in mice, and in human breast and endo metrial tumours, the expression of PERIOD genes is inhibited. In animals, melatonin suppression can lead to changes in the gonadotrophin axis. In humans, sleep deprivation and the ensuing melatonin suppression lead to immunodefi ciency. For example, sleep deprivation suppresses natural killer-cell activity and changes the T-helper 1/T-helper 2 cytokine balance, reducing cellular immune defence and surveillance. On the basis of “limited evidence in humans for the carcinogenicity of shift-work that involves nightwork”, and “suffi cient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)”, the Working Group concluded that “shift-work that involves circadian disruption is probably carcinogenic to humans” (Group 2A). Painters are potentially exposed to many chemicals used as pigments, extenders, binders, solvents, and additives. Painters can also be exposed to other workplace hazards, such as asbestos or crystalline silica. Cohort and linkage studies of painters have shown consistent and signifi cant increases in lung cancer compared with the general population. No information on tobacco smoking was available in the cohort studies; however, the increases are comparable to results from many case–control studies that controlled for smoking. A meta-analysis by the Working Group of all independent studies, including two recent large studies, showed a signifi cant excess risk of about 20% overall, and of 50% when the analysis was restricted to smoking-adjusted estimates from population-based case–control studies. Increased mortality from mesothelioma was consistently noted. Similarly, cohort and linkage studies showed consistent 20–25% increases in the occurrence of urinary bladder cancer in painters, and similar increases were noted in case– control studies that controlled for smoking. Although fi ndings for lymphatic and haemopoietic cancers in painters were inconsistent, four of fi ve case– control studies reported signifi cant increases in childhood leukaemia associated with maternal exposure to paint. The risks tended to be greater when mothers were exposed before or during, rather than after, pregnancy, and two studies showed some evidence of an increasing risk with increasing exposure. Upcoming meetings February 5–12, 2008 Industrial and cosmetic dyes and related exposuresIn October, 2007, 24 scientists from ten countries met at the International Agency for Research on Cancer (IARC), Lyon, France, to assess the carcinogenicity of shift-work, painting, and fi re-fi ghting. These assessments will be published as volume 98 of the IARC Monographs. About 15–20% of the working population in Europe and the USA is engaged in shift-work that involves nightwork, which is most prevalent (above 30%) in the health-care, industrial manufactur ing, mining, transport, communication, leisure, and hospitality sectors. Among the many diff erent patterns of shiftwork, those including nightwork are the most disruptive for the circadian clock. Six of eight epidemiological studies from various geographical regions, most notably two independent cohort studies of nurses engaged in shiftwork at night, have noted a modestly increased risk of breast cancer in long-term employees compared with those who are not engaged in shiftwork at night. These studies are limited by potential confounding and inconsistent defi nitions of shiftwork, with several focused on a single profession. The incidence of breast cancer was also modestly increased in most cohorts of female fl ight attendants, who also experience circadian disruption by frequently crossing time zones. Limitations of studies in these fl ight attendants include the potential for detection bias, proxy measures of exposure, and potential uncontrolled confounding by reproductive factors and cosmic radiation. Several diff erent rodent models have been used to test the eff ect of disruption of the circadian system on tumour development. More than 20 studies investigated the eff ect of constant light, dim light at night, simulated chronic jet lag, or circadian timing of carcinogens, and most showed a major increase in tumour incidence. No clear eff ect was seen for light pulses at night or constant darkness. A similar number of studies investigated the eff ect of reduced nocturnal melatonin concentrations or removal of the pineal gland (where melatonin is produced) in tumour development and most showed increases in the incidence or growth of tumours. Exposure to light at night disturbs the circadian system with alterations of sleep-activity patterns, suppression of melatonin production, and de regul ation of circadian genes involved in cancer-related pathways. Inactivation of the circadian Period gene, Per2, promotes tumour develop ment in mice, and in human breast and endo metrial tumours, the expression of PERIOD genes is inhibited. In animals, melatonin suppression can lead to changes in the gonadotrophin axis. In humans, sleep deprivation and the ensuing melatonin suppression lead to immunodefi ciency. For example, sleep deprivation suppresses natural killer-cell activity and changes the T-helper 1/T-helper 2 cytokine balance, reducing cellular immune defence and surveillance. On the basis of “limited evidence in humans for the carcinogenicity of shift-work that involves nightwork”, and “suffi cient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)”, the Working Group concluded that “shift-work that involves circadian disruption is probably carcinogenic to humans” (Group 2A). Painters are potentially exposed to many chemicals used as pigments, extenders, binders, solvents, and additives. Painters can also be exposed to other workplace hazards, such as asbestos or crystalline silica. Cohort and linkage studies of painters have shown consistent and signifi cant increases in lung cancer compared with the general population. No information on tobacco smoking was available in the cohort studies; however, the increases are comparable to results from many case–control studies that controlled for smoking. A meta-analysis by the Working Group of all independent studies, including two recent large studies, showed a signifi cant excess risk of about 20% overall, and of 50% when the analysis was restricted to smoking-adjusted estimates from population-based case–control studies. Increased mortality from mesothelioma was consistently noted. Similarly, cohort and linkage studies showed consistent 20–25% increases in the occurrence of urinary bladder cancer in painters, and similar increases were noted in case– control studies that controlled for smoking. Although fi ndings for lymphatic and haemopoietic cancers in painters were inconsistent, four of fi ve case– control studies reported signifi cant increases in childhood leukaemia associated with maternal exposure to paint. The risks tended to be greater when mothers were exposed before or during, rather than after, pregnancy, and two studies showed some evidence of an increasing risk with increasing exposure. Upcoming meetings February 5–12, 2008 Industrial and cosmetic dyes and related exposures

Carcinogenicity of alcoholic beverages

In February, 2007, 26 scientists from 15 countries met at the International Agency for Research on Cancer (IARC) in Lyon, France, to reassess the carcino-genicity of alcoholic beverages and of ethyl carbamate (urethane), a frequent contaminant of fermented foods and beverages. These assessments will be published as volume 96 of the IARC Monographs.

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

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.

Meeting report: summary of IARC monographs on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol.

An international, interdisciplinary working group of expert scientists met in June 2004 to develop IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans (IARC Monographs) on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol. Each IARC Monograph includes a critical review of the pertinent scientific literature and an evaluation of an agent’s potential to cause cancer in humans. After a thorough discussion of the epidemiologic, experimental, and other relevant data, the working group concluded that formaldehyde is carcinogenic to humans, based on sufficient evidence in humans and in experimental animals. In the epidemiologic studies, there was sufficient evidence that formaldehyde causes nasopharyngeal cancer, “strong but not sufficient” evidence of leukemia, and limited evidence of sinonasal cancer. The working group also concluded that 2-butoxyethanol and 1-tert-butoxy-2-propanol are not classifiable as to their carcinogenicity to humans, each having limited evidence in experimental animals and inadequate evidence in humans. These three evaluations and the supporting data will be-published as Volume 88 of the IARC Monographs.

Carcinogenicity of carbon black, titanium dioxide, and talc

In February, 2006, 19 scientists from eight countries met at the International Agency for Research on Cancer (IARC), Lyon, France, to reassess the carcinogenicity of carbon black, titanium dioxide, and non-asbestiform talc. These assessments will be published as volume 93 of the IARC Monographs, and are the fi rst assessments since the IARC Monograph preamble was amended. All three of the above agents are poorly soluble particles that are weakly toxic, and were chosen for assessment because evidence suggests that they cause cancer in the respiratory tract of rats through similar mechanisms: after exposure to high concentrations of these agents, deposition of particles onto the respiratory epithelium can lead to enhanced particle retention, impaired lung clearance, infl ammatory response, production of reactive oxygen species, cell injury, cell proliferation, fi brosis, induction of mutations, and, ultimately, cancer. Because many of these steps arise in people who work in dusty environments (eg, coal miners), data on cancer in animals obtained in conditions of impaired lung clearance could be relevant to human beings. Furthermore, impaired lung clearance and adverse eff ects in the lungs of rats that have been exposed to ultrafi ne particles (<100 nm) occur at much lower mass concentrations than in rats exposed to fi ne particles (<10 μm), increasing the potential relevance to human beings. Carbon black is a particulate form of elemental carbon. About 90% of carbon black is used in rubber products, mainly tyres. Carbon black is also used as a pigment in inks, paints and coatings, and in plastics. Exposure to carbon-black particles occurs mainly in the form of aggregates (ie, particle size, 50−600 nm) and agglomerates (227 μm). Most types of carbon black have small quantities (ie, <1%) of organic compounds, including polycyclic aromatic hydrocarbons, adsorbed onto their surface. The highest exposures to carbon black arise during its manufacturing. Exposure in industries that use carbon black is diffi cult to assess because data are scarce. No substantial exposure to carbon black is thought to occur when it is bound to other materials such as rubber, printing ink, or paint. Workers who produced carbon black in Germany and the UK had an excess risk of lung cancer. Confounding by smoking was unlikely to explain the entire excess risk, but no clear dose-response relation between exposure to carbon black and lung cancer was noted. A US study of workers in carbon black production found no excess risk of lung cancer, but no data according to level of exposure were reported. A study of workers in the rubber industry in Germany who were exposed to carbon black showed no signifi cant excess risk of lung cancer after adjustment for potential confounding by asbestos and talc. The working group concluded that the epidemiological studies of carbon black provided inadequate evidence of carcinogenicity. Carbon black and its extracts have been tested in rats and mice by inhalation, intratracheal instillation, dermal application, and subcutaneous injection. The overall results provided suffi cient evidence in laboratory animals for the carcinogenicity of carbon black and carbon-black extracts. The working group classifi ed carbon black as possibly carcinogenic to human beings (ie, group 2B). Titanium dioxide accounts for 70% of the total production volume of pigments worldwide. The primary particles are typically 200–300 nm in diameter, but larger aggregates and agglomerates are formed readily. Ultrafi ne grades of titanium dioxide (ie, 10–50 nm) are used in sunscreens and plastics to block ultraviolet light, and in catalysts. Highest expo sures occur in titanium-dioxide produc tion during packing, milling, site cleaning, and maintenance. Exposure data for industries that use titanium dioxide are scarce. The largest epidemiological cohort study considered included workers in the titanium dioxide production industry in six European countries, and showed a small but signifi cant increase in risk of lung cancer compared with that for the general population; however, the data did not suggest an exposure-response relation. Two cohort studies undertaken in the USA did not report excess risks of lung cancer, neither did a Canadian population-based casecontrol study. Overall, the working group concluded that the epidemiological studies on titanium dioxide provide inadequate evidence of carcinogenicity. Pigment-grade titanium dioxide and ultrafi ne titanium dioxide have been tested in rats, mice, and hamsters by various routes of administration. Overall, results from studies of inhalation and intratracheal instillation provided suffi cient evidence in animals for the carcinogenicity of titanium dioxide. The working group classifi ed titanium dioxide as possibly carcinogenic to human beings (ie, group 2B). Talc refers to both mineral talc and industrial products that contain 35% to >95% mineral talc. Mineral talc Upcoming meetings