Causation of human urothelial cancer: there are challenging new data!

Abstract

2011) and tobacco smoke (Weis et al. 2010; Plottner et al. 2012), the contents of carcinogenic aromatic amines are usually small. Therefore, the role of PAH as a specific reason for human urinary bladder cancer requires (re-) consideration. In this context, relevant contributions have appeared in Archives of Toxicology in recent years. Verma et al. (2012) exposed primary porcine urothelial cells (PUBEC) in culture to benzo[a]pyrene and found a high intracellular accumulation, leading to concentrations ranging from 7.3 to 35.7 μM within cells exposed to 0.5 μM benzo[a]pyrene. Srivastava et al. (2008) demonstrated that the exon 3 His genotype of the microsomal epoxide hydrolase was more prone to the risk of sporadic bladder cancer in North India. Thus, from entirely different perspectives, experimental and epidemiological data point to some specific role of PAH in the induction of human urothelial cancer. For the bioactivation of both PAH and aromatic amines, a key process is the local expression of CYP1A1. Dorrenhaus et al. (2007) found this expression increased in human exfoliated urothelial cells of cigarette smokers, compared to non-smokers. Plottner et al. (2009), using the PUBEC model, observed a strong, concentration-dependent CYP1A1 induction in a “responsive” sub-population of urothelial cells with benzo[a]pyrene in a concentration of 1 to 10 μM. By contrast, no such induction was seen in a “non-responsive” subpopulation of cells , up to the highest tested concentration of 100 μM. Having this in mind, Borza et al. (2008) studied the interaction between the aromatic amine 4-aminobiphenyl (1–50 μM) and benzo[a]pyrene (1 μM) in the PUBEC model. As expected, benzo[a]pyrene increased mrNA expression of CYP1A1, whereas 4-aminobiphenyl alone had no such effect. However, upon co-exposure with 4-aminobiphenyl (or alternatively 2-naphthylamine), the Very recently, the following aspects regarding causes of human urinary bladder cancer were addressed in this journal: (1) genome-wide association studies have identified a multitude of single nucleotide polymorphisms (SNPs) associated with moderate bladder cancer risks (Selinski 2014). It appears likely that such “wimp SNPs” collectively have a strong influence on cancer development, because of their high numbers (Golka et al. 2011). At this time, it can be predicted that many SNPs relevant for human bladder cancer are remaining undetected. (2) rota et al. (2014) presented an updated meta-analysis of epidemiological studies on workers in aluminium production industries, iron/steel industries, asphalt workers and carbon black production, which in total confirmed increased risks of bladder cancer in occupations with exposures to polycyclic aromatic hydrocarbons (PAH). However, because for all industries reviewed the excess risks were modest, influences of possible bias or residual confounders could not be ruled out. For occupational induction of urothelial cancer of the urinary bladder, aromatic amines are viewed as the most relevant cause (Golka et al. 2003; Kim et al. 2007). At the same time, the most important non-occupational causality of urinary bladder cancer is smoking (IArC 2004). Chemical exposures to carcinogens, both occupational and by smoking, are complex. Within this complexity, the role of carcinogenic aromatic amines is a matter of discussion, which is partly driven by practical matters of legal compensation of occupational diseases (Weis et al. 2010; Henschler et al. 2012). Within technical PAH mixtures (DGUV