Document M477mVLXr7RQG7Rj3agoqVDL9

Policy Watch Carcinogenicity of carbon black, titanium dioxide, and talc Robert Baan, Kurt Straif Yarn Grasse, Beatrice SeCretan, Fatiha El Ghissassi, Vincent Cogliano, on behalf of the WHO International Agency for Research on Cancer Monograph Working Group In February, 2006, 19 scientists from eight countries met atthe International Agency for Research on Cancer (IARC), Lyon, France, to reassess the carcino genicity of carbon black, titanium dioxide, and non-asbestiform talc. These assessments will be published as volume 93 of the IARC Monographs,1 and are the first assessments since the IARC Monograph preamble was amended.1 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, inflammatory response, production of reactive oxygen species, cell injury, cell proli feration, fibrosis, induction of mutations, and, ultimately, cancer. Because many of these steps arise in people who work in dusty environ ments (eg, coal miners),3'4 data on cancer in animals obtained in conditions of impaired lung clearance could be relevant to human beings. Furthermore, impaired lung clearance and adverse effects in the lungs of rats that have been exposed to ultrafine particles (<100 nm) occur at much lower mass concentrations than in rats exposed to fine particles (<10 pm), 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 aggre gates (ie, particle size, 5 0 -6 0 0 nm) and agglomerates (227 pm). Most types of carbon black have small quantities (ie, <1%) of organic compounds, including polycyclic aromatic hydrocarbons, adsorbed onto their surface. The highest exposuresto carbon black arise during its manufacturing. Exposure in industries that use carbon black is difficult to assess because data are scarce. No substantial exposure to carbon black isthoughtto occurwhen it is bound to other materials such as rubber, printing ink, or paint. Workers who produced carbon black in Germany5and the UK6had an excess risk of lung cancer. Confoun ding 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 study7 of workers in carbon black production found no excess risk of lung cancer, but no data according to level of exposure were reported. A study8 of workers in the rubber industry in Germany who were exposed to carbon black showed no significant excess risk of lung cancer after adjustmentforpotential confounding by asbestos and talc. The working group concluded that the epide miological 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 sufficient evidence in laboratory animals for the carcinogenicity of carbon black and carbon-black extracts. The working group classified 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. Ultrafine grades of titanium dioxide (ie, 10-50 nm) are used in sunscreens and plastics to block ultraviolet light, and in catalysts. Highest exposures occur in titanium-dioxide production during packing, milling, site cleaning, and maintenance. Exposure data for industries that use titanium dioxide are scarce. The largest epidemiological cohort study9 considered included workers in the titanium dioxide production industry in six European countries, and showed a small but significant 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 under taken 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 epide miological studies on titanium dioxide provide inadequate evidence of carcinogenicity. Pigment-grade titanium dioxide and ultrafine titanium dioxide have been tested in rats, mice, and hamsters by various routes of administration. Overall, results from studies of inhalati on and intrat racheal instillation provided sufficient evid ence in animals for the carcino genicity of titanium dioxide. The working group classified 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 June 14-21,2006 Ingested nitrates and nitrites, and blue-green aigae toxins, including microcystin-LR and nodularin Oct 10-17 2006 Indoor air pollution from household combustion and heating http://monographs.iarc.fr http://oncology.thelancet.com Vol 7 A pril 2 0 0 6 295 Policy Watch occurs naturally in a platy (flat) form, but also as asbestiform fibres; it is generally associated with other minerals, for instance, quartz and occasionally asbestos. Asbestiform talc should not be confused with talc that contains asbestos. Talc is used in agricultural products, ceramics, cosmetics, paint and other coatings, paper, pharmaceuticals, plastics, roofing materials, rubber, and for waste treatment. Occupational exposure to talc arises during mining, milling, and industrial use. Consumers are exposed during the use of loose talc-based powders--eg, baby powders and body powders used by women on the perineum or genital area. Cohort studies from various countries of talc miners and millers were available for assessment. In US miners,10an excess risk of lung cancer was noted, but this risk could have Monograph Working Group Members P A Demers,J Siemiatyckl-Chair (Canada); J Olsen (Denmark); U Heinrich; R Schins (Germany); HTsuda (Japan); E Weiderpass-Vainio (Norway); IJ Yu (Republic of Korea); been due to exposure to radon and quartz. The other cohort studies did not report an increased cancer risk. A nested case-control study of cohorts in France and Austria11found no higher risk of lung cancer with increasing cumulative exposure to talc dust. A Mvan Tongeren (UK); V Antony, J A Bond, J S Brown, D Costa, S Hankinson, E D Kuempel, A GWylie (USA) study12 of women working in the Norwegian pulp and paper industry noted an increased risk of ovarian Conflictsofinterest cancer, but this risk was attributed to The working group declares no conflicts of interest. Invited Specialists L Levy (UK);TJunghans, S Olin (USA) asbestos exposure. The working group concluded that the epidemiological studies provided inadequate evidence for the carcinogenicity of inhaled talc Conflicts ofinterest LL is scientific advisor to the International Carbon Black Association, USA Representatives of health agencies A Ullrich (WHO, Switzerland); CW Jameson (NIEHS, USA) Observers P Morfeld, K Mundt (International Carbon Black Association, USA); NJehan (University of Peshawar, Pakistan); J Hoskins (CEFIC, Belgium); JE Muscat, G Oberdorster (Industrial Minerals Associations o f Europe, Belgium, and of North America, USA); DB Warheit (American Chemistry Council, USA) that does not contain asbestos or asbestiform fibres. Talc has been tested in rats, mice, and hamsters by various routes of administration. Along-term inhalation study" showed increased incidences of alveolar or bronchiolar carcinoma in female rats and adrenal pheochromocytoma in rats of both sexes. This increase in incidence provided limited evidence for carcinogenicity in animals. Overall, the working group concluded that inhaled talc that does not contain asbestos or asbestiform fibres is not classifiable as to its carcinogenicity (ie, group 3)- Particular attention was paid to epidemiological data from a prospective cohort study14 and from 19 case-control studies on the association between use of talc-based body powder and risk of ovarian cancer. Although the cohort study14 did not lend supportto an association, the case-control studies showed a high degree of consistency: the eight m o re -in fo rm a tiv e s tu d ie s 1S22reported a 30-60% increase in risk, and most of the other studies noted similar relative risks. Only two studies18'20 suggested that women with the highest exposure had the highest risk. The case-control studies could have been affected by recall bias, if women with ovarian cancer were more likely to over-report bodypowder use. These powders generally contain quartz. Furthermore, low concentrations of asbestos were occasionally present In these powders before the mid-1970s, but the available information is sparse and poorly reported, and analyses were often inadequate to identify the fibres detected. After careful assessment of the biases and possible confounding factors, the working group concluded that the epide miological studies provided limited evidence for the carcinogenicity of perineal use of talc-based body powder, and classified this use as possibly carcinogenic to human beings (ie, group 2B). The authors declare no conflicts of interest. 1 IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Volume 93Carbon black, titanium dioxide, talc. Lyon: International Agency for Research on Cancer (in press). 2 IARC. Pream bletothe IARC monographs on the evaluation o f carcinogenic risks to humans, http://monographs.iarc.fr/monoeval/ preamble-new-06.pdf (accessed March 6, 2006). 3 Kuempel ED, O'Flaherty EJ, Stayner LT, et al. A biomathematical model o f particle clearance and retention in the lungs o f coal miners. Regul Toxicol Pharmacol 2001; 34- 6 9 -8 7 . 4 Soutar CA, Hurley JF, Miller BG, et al. Dust concentrations and respiratory risks in coal miners: key risk estimates from the British pneumoconiosis field research. Occup Environ Med 2004; 6 1 :4 7 7 -8 1 . 5 Wellmann j, Weiland SK, Neiteler G, et al. Cancer mortality in German carbon black workers 1 9 7 6 -1 9 9 8 . Occup Environ Med 2006; published online Feb 23,001:10.1136/ oem .2 0 0 6.0 26 5 2 6. 6 SorahanT, Ham ilton L, van Tongeren M, et al. A cohort mortality study of UK carbon black workers, 1951-1996. Am J Ind Med 2001; 39:158-70. 7 Dell LD, Mundt KA, Luippold RS, et al. A cohort mortality study of employees in the United States carbon black industry.) Occup Environ Med 20 06 (in press). 8 Straif K, Keil U.Taeger D, et al. Exposure to nitrosamines, carbon black, asbestos, and talc and mortality from stomach, lung, and larygea! cancer in a cohort of rubber workers. Am J Epidemiol 2000; 1 5 2:2 9 7 -3 0 6 . 9 Boffetta P, Soutar A, Cherrie JW, et al. Mortality am ong workers employed in the titanium dioxide production industry in Europe. Cancer Causes Control 2004; 1 5 :6 9 7 -7 0 6 . 10 Seievan SG, Dement JM, Wagoner JK, Froines JR. Mortality patterns among miners and millers of non-asbestiformtalc: preliminary report. J Environ Pathol Toxicol 1979; 2:273-84- 11 Wild P. Lung cancer risk and talc not containing asbestiform fibres: a review of the epidemiological evidence. Occup Environ Med 2006; 63:4-9. 12 Langseth H, Kjaerheim K. Ovarian cancer and occupational exposure among pulp and paper employees in Norway. ScandJ Work Environ Health 2 0 0 4 ;3 0 :3 5 6 -6 1 . 13 US National Toxicology Program. Toxicology and carcinogenesis studies of talc (CAS No 14807-96-6) in F344/N rats and B6C3F1mice (inhalation studies). Bethesda: National Institutes of Health, 1993- 1 4 Gertig DM, Hunter DJ, Cramer DW, et al. Prospective study o f talc use and ovarian cancer.) Natl Cancer Inst 2000; 9 2 :2 4 9 -5 2 . 15 Chang S, Risch HA. Perineal talc exposure and risk o f ovarian carcinoma. Cancerl997; 79:2396-401. 16 Cook LS, Kamb ML, Weiss NS. Perineal powder exposure and the risk of ovarian cancer. Am ) Epidemiol 1997; 1 4 5 :4 5 9 -6 5 - 17 Cramer DW, Welch WR, Scully RE, Wojciechowski CA. Ovarian cancer and talc: a case-control study. Cancer 1982; 5 0: 3 7 2 -7 6 . 18 Cramer DW, Liberman RF,Titus-ErnstoffL, et al. Genital talc exposure and risk of ovarian cancer. Int) Cancer 19 99 ; 8 1 :3 5 1 -5 6 . 19 Harlow BL, Cramer DW, Bell DA, Welch WR. Perineal exposure totale and ovarian cancer risk. Obstet Gynecol 1992; 8 0 :1 9 -2 6 . 20 Ness RB, GrissoJA, Cottreau C, et al. Factors related to inflammation of the ovarian epithelium and risk o f ovarian cancer. Epidemiology 2000; 1 1 :1 1 1 -1 7 21 Purdie D, Green A, Bain C, et al. Reproductive and other factors and risk of epithelial ovarian cancer: an Australian case-control study, int) Cancer 1995; 6 2 :6 7 8 -8 4 - 22 W hittemore AS, Wu ML, Paffenbarger RSJr, et al. Personal and environmental characteristics related to epithelial ovarian cancer. IL Exposures to talcum powder, tobacco, alcohol, and coffee. A m J Epidemiol 1988; 128:1228-40. 296 http://oncology.thelancet.com V 0I 7 A pril 2 0 0 6