News www.thelancet.com/oncology Vol 14 August 2013 807 Carcinogenicity of some drugs and herbal products In June, 2013, 23 experts from nine countries met at the International Agency for Research on Cancer (IARC), Lyon, France, to assess the carcinogenicity of 14 drugs and herbal products (table). Some agents are discussed in more detail because of data complexity or the extent of human exposure. These assessments will be published as volume 108 of the IARC Monographs. 1 Thiazolidinediones (eg, pioglitazone and rosiglitazone) have been used for the treatment of type 2 diabetes. Many patients might have received both drugs sequentially. Among ever-users of rosiglitazone, relative risks (RRs) of bladder cancer from two case–control studies and two cohort studies were close to null in all except for one study from the UK. Pioglitazone was assessed in an analysis of one large randomised controlled trial, four cohort studies, and three case–control studies. Ever- use of pioglitazone was associated with an increased risk of bladder cancer in all except for one case– control study from Taiwan, and across all study designs and geographical regions, with RRs ranging from 1·2 in the observational studies to almost 3 in the randomised controlled trial. Dose–response associations were assessed in five studies, three of which were high-quality population-based studies. Increased risks were reported with higher dosage or longer use in one case–control study 2 and in one cohort study. 3 However, the Working Group was unable to consistently rule out confounding and bias related to disease severity and detection. Notably, pioglitazone induced an increased incidence of urinary bladder transitional cell carcinoma 4 or papilloma in male rats in two individual gavage studies. Urolithiasis or peroxisome proliferator-activated receptor-mediated effects seemed to be the most likely mechanisms of carcinogenesis. 5,6 Pioglitazone was classified as probably carcinogenic to humans (group 2A), on the basis of limited evidence in humans that it causes urinary bladder cancer, and sufficient evidence in experimental animals. Rosiglitazone was assessed as not classifiable as to its carcinogenicity to humans (group 3), on the basis of inadequate evidence in humans and limited evidence in experimental animals. Digoxin, a widely prescribed drug that is extracted from the digitalis plant, shares structural homology with steroid hormones. An association with breast cancer was investigated in four case–control studies (including two studies in men) undertaken in Scandinavia, France, and Switzerland; in a nationwide records-based cohort study of women in Denmark; and in two cohort studies in the USA and Norway. All four case–control studies reported significant increases in the incidence of breast cancer; odds ratios were 1·3 in women and 2–4 in men. The largest study, which included all women using digitalis drugs in Denmark, reported an increased risk for current users only (hazard ratio 1·39, 95% CI 1·32–1·46). 7 Although no clear effects of duration or dose were recorded, detection of incident tumours decreased after cessation of exposure, which is consistent with a possible promoting effect of digoxin. The association was stronger for oestrogen receptor (ER)- positive than for ER-negative breast tumours. Moreover, the incidence of cancers of the uterus was increased in current users in the cohort study in Denmark, and the risk of prostate cancer, another steroid hormone- related cancer, was reduced in one high-quality cohort study from the USA. 8 However, one cohort study reported a positive association (RR 1·25) for prostate cancer. Excess risk for male breast cancer provides further support for the association reported in women. Nonetheless, the record linkage studies that provided key evidence could not adjust for many of the recognised risk factors for female breast cancer, notably obesity and alcohol consumption. No carcinogenicity studies were done in experimental animals and only a few studies supported an ER- mediated mechanism. Digoxin was Published Online July 5, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70329-2 For more on the IARC Monographs see http:// monographs.iarc.fr/ Upcoming meetings Oct 8–15, 2013 Volume 109: Ambient air pollution Monograph Working Group Members B W Stewart (Australia)–Chair; R J Biggar (Australia); D W Lachenmeier (Germany); S Singh (unable to attend; India); H Tsuda (Japan); B Baguley (New Zealand); M M Marques (Portugal); C-H Tseng (Taiwan, China); T L Knight (UK); F A Beland, J M Betz, E J Carcache de Blanco, M L Cunningham, J K Dunnick, L Guo, C W Jameson, M Karagas, R M Lunn, D L McCormick, S Singh, K L Witt (unable to attend), S Zhou (USA) Therapeutic or other use Group Pioglitazone Rosiglitazone Type 2 diabetes 2A 3 Digoxin Chronic heart failure and irregular heart rhythm 2B Hydrochlorothiazide* Hypertension, by diuresis 2B Triamterene Hypertension, by diuresis (combined with other drugs, including hydrochlorothiazide) 2B Sulfasalazine Autoimmune arthritis; inflammatory bowel disease 2B Pentosan polysulfate sodium Prevention of blood clots; interstitial cystitis 2B Primidone Essential tremor 2B Methylene blue Nitrate and cyanide poisoning antidote; methaemoglobinaemia; psychiatric disorders; disinfectant; microscopic staining agent 3 Whole leaf extract of Aloe vera Laxative (latex component); food flavouring; in beverages and dietary supplements; cosmetics 2B Ginkgo biloba extract Food flavouring; in dietary supplements; medicinal products (peripheral arterial diseases and cerebral insufficiency) 2B Goldenseal root powder Prevention and reduction of inflammation and related diseases 2B Kava extract In beverages and dietary supplements; cosmetics; medicinal products (anxiety or insomnia) 2B Pulegone Component of pennyroyal oils (used to treat dyspepsia and menstrual disorders); and several species of mint (used in foods and beverages) 2B *Previously assessed as “not classifiable as to its carcinogenicity to humans” (group 3). Table: Agents assessed by the IARC Monograph Working Group