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 (Weiß et al. 2010; Henschler et al. 2012). Within technical PAH mixtures (DGUV 2011) and tobacco smoke (Weiß et al. 2010; Plöttner 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. Dörrenhaus et al. (2007) found this expression increased in human exfoliated urothelial cells of cigarette smokers, compared to non-smokers. Plöttner 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 induction of CYP1A1 by benzo[a]pyrene was enhanced, which was confirmed by Western blot data. A similar combination effect was seen for COX-2 and UGT1. Together with the data of Verma et al. (2012) of a concentration of benzo[a]pyrene in urinary bladder cells, this points to a biologically significant multiplicative combination effect of carcinogenic polycyclic aromatic hydrocarbons and carcinogenic aromatic amines on the epithelium of the urinary bladder. From a mechanistic angle, this is in line with the recent epidemiological meta-analysis by Rota et al. (2014). Therefore, it appears not plausible that the increased risks found associated with specific occupations are only caused by bias or confounders.

Another highly relevant cause of human urothelial cancer, for which combination effects with other toxicants are of scientific concern, is arsenic (Golka et al. 2010; Bolt 2012, 2013). In a recent review, Bustaffa et al. (2014) have summarised the genetic and epigenetic mechanisms in arsenic carcinogenicity. Both mechanistic pathways are interacting and relevant for arsenic carcinogenesis. Specifically for the urinary bladder, a recent study by Wang et al. (2014) used human urothelial cells in vitro and showed that sustained low-dose arsenic exposure resulted in epigenetic changes via lipocalin-2 promoter hypomethylation and overexpression, which was seen connected with carcinogenicity. Thus, the essential implication of epigenetic mechanisms in arsenic carcinogenesis evolves as an important point for risk management, because it could allow the derivation of health-based limit values.

Taken together, there are challenging new data on both endogenous (genetic) and exogenous (toxicological) factors connected with the origin of human urothelial cancer. A central topic for future research will be interaction(s) of these factors. Inter-disciplinary research in this field is highly encouraged, as well as its timely publication in our journal!