Seminar article Bladder cancer risk from occupational and environmental exposures Kyle J. Kiriluk, M.D., Sandip M. Prasad, M.D., M.Phil., Amit R. Patel, M.D., Gary D. Steinberg, M.D., Norm D. Smith, M.D.* Section of Urology, University of Chicago Hospitals, Chicago, IL 60637, USA Abstract Approximately 50% of bladder cancer incidence in the United States has been attributed to known carcinogens, mainly from cigarette smoking. Following the identification of this important causative factor, many investigators have attempted to identify other major causes of bladder cancer in the environment. Genetic and epigenetic alterations related to carcinogenesis in the bladder have been linked to environmental and occupational factors unrelated to cigarette smoking and may account for a significant portion of bladder cancer cases in non-smokers. The interaction between genetics and exposures may modulate bladder cancer risk and influence the differing incidence, progression, and mortality of this disease in different genders and races. Comparative molecular studies are underway to measure the relative effects of environment and inheritance to account for observed differences in the epidemiology of bladder cancer. The use of geospatial tools and population-based data will offer further insight into the environmentally-linked causes of bladder cancer. © 2012 Elsevier Inc. All rights reserved. Keywords: bladder cancer; environment; risk factors; etiology; epidemiology Introduction In 2011, it is estimated that 69,250 individuals living in the U.S. will develop bladder cancer, and 14,990 will die of the disease [1]. In developed countries, approximately 90% of bladder cancers are urothelial cancers, with the remainder consisting typically of squamous cell carcinoma and adeno- carcinoma [2]. The development of these malignancies has long been connected with exposure to environmental car- cinogens. In 1895, Ludwig Rehn, a German physician, first noted that a significant number of dye workers developed bladder cancer theorizing that aniline was the responsible agent [3]. In prior observational studies, a directly inherited link to bladder cancer had also been proposed [4–6]. How- ever, many of these studies failed to adequately account for the effects of smoking and other possible environmental exposures. Moreover, multiple large scale epidemiologic investigations have found no association between bladder cancer incidence within first degree relatives and argue strongly against a straightforward genetic mechanism [7–9]. Currently, many believe that the environment plays a pri- mary role in the development of bladder cancer, while inherited factors alter the phenotype and clinical presenta- tion of the disease [10,11]. In spite of the numerous clinical observations, epidemi- ologic investigations, and experimental animal studies that have elucidated environmental carcinogens responsible for bladder cancer, many cases still appear to be sporadic with patients having no known risk factors. Identification of causative agents can be problematic as exposures may occur by inhalation, ingestion, and skin contact both in occupa- tional and non-occupational settings. Discovering new risk factors and confirming suspicions are difficult as there is typically a long latency period from time to exposure to the development of cancer and environmental carcinogens may occur together, limiting the ability to identify the risk posed by each individual exposure. Determining the level of risk associated with each carcinogen is further complicated as both the amount and duration of exposure affect the poten- tial to develop cancer in the future. A summary of environ- mental factors associated with bladder cancer can be found in Table 1. This article will review current knowledge of these factors and discuss the role of novel technologies in identifying new environmental risk factors that may be responsible for the development of bladder cancer. * Corresponding author. Tel.: +1-773-702-6105; fax: +1-773-702- 1001. E-mail address: nsmith1@surgery.bsd.uchicago.edu (N.D. Smith). Urologic Oncology: Seminars and Original Investigations 30 (2012) 199 –211 1078-1439/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2011.10.010