Environmental non-occupational risk factors associated with bladder cancer | Actas Urológicas Españolas (English Edition)

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Ferrís, O. Berbel, J. Alonso-López, J. Garcia, J.A. Ortega" "autores" => array:5 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Ferrís" "email" => array:1 [ 0 => "ferris_jos@gva.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "O." "apellidos" => "Berbel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J." "apellidos" => "Alonso-López" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "J." "apellidos" => "Garcia" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "J.A." "apellidos" => "Ortega" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Unitat de Salut Mediambiental Pediàtrica, Unitat d‘Oncologia Pediàtrica, Hospital Universitari i Politècnic La Fe, València, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Facultad de Medicina, Universidad Católica de Valencia, Centre de Salut de Chella, Chella, València, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unitat de Neumologia i Al·lèrgia Pediàtrica, Hospital Universitari i Politècnic La Fe, València, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Secció d‘Anatomia Patològica, Hospital de Sagunt, València, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Unidad de Salud Medioambiental Pediátrica (www.pehsu.org), Hospital Materno-Infantil Universitario Virgen de la Arrixaca, Murcia, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Factores de riesgo ambientales no ocupacionales asociados al cáncer vesical" ] ] "textoCompleto" => "IntroductionIn Western countries, one in 26 men and one in 87 women will develop a bladder carcinoma (BC) over the course of their lifetime, especially in the last third.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> This significant morbidity, which generates a great emotional, physical and economic, highlights the transcendent personal and professional involvement of urologists to recognize, reduce or eliminate environmental risk factors (RF) associated to its etiopathogenesis with more or less evidence.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>In this paper we review the major non-occupational environmental RF associated with BC (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), completing our previous contribution.<a class="elsevierStyleCrossRef" href="#bib0015">3</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>SmokingSmoking is the main RF associated with the incidence and biological aggressiveness of BC. This factor has the largest scientific evidence.<a class="elsevierStyleCrossRefs" href="#bib0020">4–14</a> Until recent times smoking was associated with 50–60% of the BC in men and 20–30% in women. This difference was due in part to the traditional differences of consumption and the long latency periods of bladder carcinogenesis (≥30 years). Today, the risks are similar in both sexes and it is associated to 50% of BC, as smoking rates between men and women in Western countries are equal.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a>Numerous epidemiological case–control and cohort studies convincingly demonstrate the direct relationship between active smoking and BC.<a class="elsevierStyleCrossRefs" href="#bib0020">4,12</a> Except for neoplasms of the respiratory tract and oral cavity, the BC is the best smoking-related neoplasia documented.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> Overall, smokers have 2–3 times greater risk than non-smokers, being even up to 5 times for those consuming ≥1 pack daily.<a class="elsevierStyleCrossRefs" href="#bib0020">4,8</a> Similarly, patients who smoke have more infiltrating varieties and increased BC mortality compared to non-smokers.<a class="elsevierStyleCrossRefs" href="#bib0025">5,9,10,14</a>The risk increases with the intensity of smoking (number of cigarettes per day), with RR (relative risk) of 2.0–5.0 among moderate to heavy smokers compared to nonsmokers.<a class="elsevierStyleCrossRefs" href="#bib0020">4,6,9</a> The studies demonstrate a very convincing dose–response curve, although some researches show stabilization from moderate to severe consumptions, but they are attributed to confounding factors (recall bias, lower relative inhalation among large consumers, genetic polymorphisms, etc.).Another variable involved in the risk is the relationship with the years of exposure.<a class="elsevierStyleCrossRefs" href="#bib0020">4,6,8</a> The same applies to the depth of inhalation, which increases the risk 30–40% when compared to those who inhale very little or nothing.<a class="elsevierStyleCrossRefs" href="#bib0025">5,9</a> Studies conducted to compare gender differences in the risk of BC in smokers do not find differences between men and women when analyzing equivalent doses of intensity, duration, depth of inhalation and variety of tobacco consumed.The different varieties of cigarettes (filters, black, blond) have been also studied as well as the consumption without cigarettes (pipes, cigars and smokeless tobacco).<a class="elsevierStyleCrossRefs" href="#bib0020">4,9</a> The results on the effects of cigarette filters have been inconsistent. The black tobacco smokers have risks of 1.5–3 times higher than those who smoke blond tobacco. Pipe smokers have a RR of 1.3–3.9 with respect to non-smokers and cigar smokers have a RR of 1.3–1.6. The sniffers and tobacco chewers have been poorly evaluated to obtain valid results.In a hospital-based study conducted in Spain<a class="elsevierStyleCrossRef" href="#bib0060">12</a> 1219 BC patients and 1271 controls were analyzed in relation to the consumption of tobacco. Current smokers (men OR=7.4 [CI 95%: 5.3–10.4]/women OR=5.1 [CI 95%: 1.6–16.4]) and former smokers (men RR=3.8 [IC 95%: 2.8–5.3]/women RR=1.8 [95% CI: 0.5–7.2]) had higher risks, statistically significant, than never-smokers. Direct relationship between risk and the longer duration and intensity of consumption was observed. After adjusting the duration and amount, the risk was 40% higher in smokers of black tobacco compared to smokers of blond tobacco (OR=1.4 [95% CI: 0.98–2.0]). This difference may be due to higher concentrations of N-nitrosamines and 2-naphthylamines in black tobacco.<a class="elsevierStyleCrossRefs" href="#bib0020">4,8</a> The study also documented that deep inspiration increases the risk between 50 and 70% compared to those who hold the smoke in their mouth. The researchers found that snuff is responsible for 42% of BC in men and 13% in women. Finally, if the effect of tobacco was eliminated, the man/woman relation in the BC incidence decreased from 8.2 to 1.7, suggesting that the great gender difference in our country was due to the consumption of tobacco and its black variety.Smoking cessation is associated with a 30–60% reduction in BC risk in most studies; however, the pattern of change of risk in relation to the cessation period is not sufficiently established.<a class="elsevierStyleCrossRefs" href="#bib0045">9–11</a> However, the rapid decline of risk in the early years of the cessation suggests that tobacco smoke carcinogens play a role in the later stages of bladder carcinogenesis.Exposure to environmental tobacco smoke has also been associated with increased risk of BC, but the results are not unanimous. A large study documents increased risk in women exposed to tobacco during childhood and adulthood with OR=3.08 (IC 95%: 1.16–8.22)<a class="elsevierStyleCrossRef" href="#bib0045">9</a> (95% CI: 1.16–8.22).<a class="elsevierStyleCrossRef" href="#bib0045">9</a> The effect was greater especially in women who had never been smokers. The mechanisms underlying these gender differences are unknownThe mechanisms of action of the 62 carcinogens contained in snuff smoke are well established, but it is not clear how many of them, individually or in combination, are primarily responsible for the development of BC.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> As it can be seen in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, various aromatic amines such as 2-naphthylamine, 2-toluidine and 4-aminobiphenyl, numerous n-nitrosamines, polycyclic aromatic hydrocarbons such as benzo(a)pyrene and dibenzo(a,h)anthracene, aromatics hydrocarbons such as benzene and 1,3-butadiene, have proved decisive involvement bladder carcinogenesis. Curiously, from the seventh decade of the last century, the analyses of concentrations of these carcinogens in tobacco smoke are increasing and this partly explains the maintained persistence of cancers associated to them, such as BC, despite the decrease in the consumption of tobacco in Western countries.<a class="elsevierStyleCrossRef" href="#bib0040">8</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Dietary factors (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>)Water pollutantsArsenicWater intake with high concentrations (>0.2mg/l) of inorganic arsenic is well a documented cause of BC. Likewise, populations exposed to such use show an increase of mortality attributed to BC in cohort studies.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Carcinogenesis activity of arsenic on bladder mucosa is biologically demonstrated by the increase of chromosomal aberrations in exfoliated bladder cells of healthy people exposed, and by higher percentages of chromosomal deletions in bladder tumors associated with high levels of exposure.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Also a linear relationship between the concentrations of arsenic in water and increased risk of BC has been demonstrated. RRs were 1.9, 8.2 and 15.3 for concentrations of 10.1–50.0, 50.1–150.0 and >100mg/l.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Also, in populations exposed to high concentrations in the public water supply, the replacement for bottled water without arsenic has decreased the incidence of BC<a class="elsevierStyleCrossRef" href="#bib0075">15</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>By-products of water chlorinationThe chlorine, added to disinfect drinking water, reacts with organic matter generating the so-called chlorination byproducts (SPC). The most studied are trihalomethanes, iodomethanes, halonitromethanes and hidroxy-furanes. Numerous studies of control–cases with water intake with high concentrations of BPCs (∼50μg/l, levels observed in many western countries and regions), identified a 50% increased risk of BC with regarding consumption of dechlorinated water.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The risk is lower in populations where disinfection is done by ozone.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The exposure to BPCs through inhalation and transdermal absorption along with the intake are the routes that contribute to the total exposure to trihalomethanes, and it has been evaluated in an epidemiological study documenting an increased risk in showers, baths and swimming pools.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Hexavalent chromiumIt has also been suggested that the contamination of drinking water with hexavalent chromium derived from industrial activity and listed as a human carcinogen, is associated with an increased incidence, recurrence and mortality of BC.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Fluid intakeStudies comparing total fluid intake with the risk of BC have given mixed results.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> High consumptions of liquids have been associated with lower risk, higher risk and null effects. The disparity of results is subject to methodological flaws and logistical difficulties of these studies. We will highlight one of the best studies on a cohort of health professionals,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> which shows a protective effect of high intake, with a risk reduction of 7% for each 240cc of total liquid increase. This study also documents that the use of e ≥2.531 cc/day reduces the risk between 24–40% compared to those that ingest ≤1.290 cc/day. The assumptions underlying these results are that high intake dilutes urinary carcinogens and increased urinary frequency decreases contact time with the bladder mucosa.Intake of coffee, alcohol, tea and mateA direct association between coffee intake and increased risk of BC was published in 1971, with RR of 1.3 for men and 2.5 for women.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Numerous subsequent studies differ in results with respect to gender, but document RR ∼2.0. Listed by IARC in 1991 as 2B (possibly carcinogenic to the bladder). A meta-analysis published in 2001 documents OR=1<a class="elsevierStyleCrossRef" href="#bib0130">26</a> (95% CI:1.09–1, 46) for men and OR=1.08 (95% CI: 0.79–1.46) for women, and OR=1.18 (IC 95%: 1.01–1.38) 1.18 (95% CI: 1.01–1.38) for the 2 genres combined.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Regarding alcohol intake results are still mixed. A recent meta-analysis documents an increased risk but without statistical significance.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> The possible association with specific alcoholic beverages has been also studied, but the data are inconsistent.Regarding tea consumption, epidemiological studies control–cases, cohort and meta-analysis found no protective effects of tea polyphenols on bladder carcinogenesis. A recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0100">20</a> found that only the variety of green tea is associated with statistically significant lower risk with OR=0.814 (95% CI: 0.678–0.976).High and maintained intake of mate, infusion of the herb Ilex paraguariensis, popular in South American countries, increases the risk of BC.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>Artificial sweetenersSaccharin was suggested as RF by the results obtained in intrauterine exposure to high doses in rats, but not postnatally.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Numerous investigations performed on humans have ruled out the association.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Fruits and vegetablesAmong the dietary RF that have been evaluated with respect to the risk of BC, a wide scientific evidence shows that high consumption of fruits and vegetables has protective effects.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Numerous epidemiological studies show that consumption of natural fruits, juices and vegetables (carrots, cruciferous and dark-green leafy) decreases the risk of BC.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> A meta-analysis found that diets low in fruits increase the RR 1.4 (95% CI:1.1–1, 8) and in vegetables RR 1.2 (95% CI: 1.0–1.3).<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The role of specific micronutrients is less clear. In animal dietary supplements of natural or synthetic retinoids inhibit bladder carcinogenesis. In humans, some studies suggest that supplements of vitamin A, vitamin C, folate and carotenoids as well as vitamin E and selenium are protective, but most results are inconsistent.<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a>Other dietary factorsRisk increases have been associated with high intakes of meat, especially red meat, animal fats and cholesterol, fish, animal foods cooked at high temperatures, smoked and salted. Temperatures >200° generate the formation of heterocyclic amines, classified as probable human carcinogens.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5,22</a>Biological plausibility of dietary RF (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>) in the bladder carcinogenesis is based on: (a) the protective effect of fruits and vegetables is consistent and similar to that observed in other neoplasias; (b) the high consumption of red meat cooked at high temperatures is also associated with increased risks in other cancers, and elevates the levels of heterocyclic amines in urine; (c) flavonoids provided by many fruits and vegetables inhibit the mutagenicity of heterocyclic amines in cell cultures; and (d) experimentally, urinary acidity influences the metabolism of bladder carcinogens, increasing the formation of genetic alterations in bladder mucosa. Foods of animal origin generate acidic urine, while consumption of vegetables generates alkaline urine.Medicines/drugsAnalgesicsHigh consumption of phenacetin increased between 2–6 times the risk of BC.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a> This drug was banned for developing chronic interstitial nephropathy and it was replaced by acetaminophen paracetamol, aromatic amino metabolite of phenacetin, with no effects on the risk of BC in the short and medium term.NSAIDs, including acetylsalicylic acid, are associated with a lower risk of BC. The biological plausibility is supported by experimental evidence that NSAIDs are potent inhibitors of BC developed by chemical carcinogens.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>PhenobarbitalIts long-term use as anticonvulsant drug decreases up to 40% risk of BC.<a class="elsevierStyleCrossRefs" href="#bib0025">5,25</a> Apparently, both phenobarbital and phenytoin induce deactivation of bladder carcinogens, especially those contained in tobacco smoke.AntineoplasticAlkylating agentsAlkylating agents are a family of drugs used in the therapy of neoplastic and rheumatic diseases. Its side effects include second neoplasms, and therefore they are classified as human carcinogens. Only 2 of them, cyclophosphamide (CFM) and ifosfamide (IFM), are associated with the development of hemorrhagic cystitis and BC.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5,25</a> CFM and MFIs need to be metabolized in order to develop antineoplastic and carcinogenic actions. The major metabolite involved in bladder toxicity is acrolein. If uroprotector Mesna (2-mercaptoethane sulfonate) is not used concomitantly, the direct association between cumulative doses and risk of BC shows RR of 2.4, 6.0 and 14.5 in survivors with total doses of ≤20g, 20–49g and ≥50g, respectively.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> However, it is not entirely clear what role corresponds to acrolein and other metabolites in bladder carcinogenesis. Although concomitant use of Mesna is universal, all treated with CFM and IFM survivor should be monitored for BC.ChlornaphazineThis former antineoplastic drug was associated with increased risk of BC, but its therapeutic use was very limited.<a class="elsevierStyleCrossRefs" href="#bib0120">24,25</a>Other drugsPioglitazone, drug used in the treatment of diabetes mellitus type 2, increases the risk of BC.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>Isoniazid and some laxatives have been associated with an increased risk of BC, but with inconsistent results.<a class="elsevierStyleCrossRefs" href="#bib0020">4,27</a>Ionizing radiationConsistent evidence of an association between ionizing radiation (IR) and the BC exists. Numerous epidemiological studies have documented that people exposed to RI for medical reasons or because of nuclear accidents, nuclear plant workers and survivors of atomic explosions are associated with increased risk of BC with respect to that expected in the normal population.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>It has been demonstrated an excess RR of 1.02 per Sievert of exposure in the population cohorts exposed to atomic blasts of Hiroshima and Nagasaki.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> The underlying biological mechanisms are of two types: (a) the direct action on the DNA double helix and (b) indirect actions generated by oxygen free radicals.Hair dyesCertain hair dyes contain 4-aminobiphenyl, substance that is considered as occupational carcinogen of BC.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> People who use hair dyes usually excrete larger amounts of urine. Epidemiological studies at the end of the last century did not document any association. In 2001, a case–control study found that women population with regular use of hair dyes had a 70% higher risk of BC with respect to non-users.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> The risk was directly related to the time of use and the frequency of application. However, this association has not been subsequently replicated by other researchers.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Urologic diseasesUrinary tract infectionsPositive associations between bladder infections and increased risk of BC have been described in most case–control studies.<a class="elsevierStyleCrossRefs" href="#bib0020">4,25</a> A research carried out in U.S.A. has documented the direct relationship between cystitis and BC in both sexes, and that patients with ≥3 infectious episodes present a 2-fold increased risk of BC with respect to unaffected individuals.<a class="elsevierStyleCrossRefs" href="#bib0025">5,25</a> Furthermore, the squamous cell histological subtype is predominant among the BCs of people with a history of chronic cystitis (paraplegics, SCI patients carrying catheters). The mechanisms underlying the association cystitis-BC are: (a) chronic inflammatory phenomena (oxygen free radicals), (b) alteration of the mucosal barrier to urinary carcinogens and (c) the formation of N-nitroso compounds by bacterial growth.Infestation by the parasite Schistosoma haematobium is typically associated with the squamous cell variety. In countries where the parasite is endemic such as Egypt, more than 70% of BCs are squamous cell carcinoma, while in Western countries this type of cancer accounts for only 2%. Besides the underlying mechanisms discussed in the bacterial cystitis, egg deposits cause urinary bladder stasis, and parasitic antigens are immunosuppressive.<a class="elsevierStyleCrossRefs" href="#bib0020">4,25,32</a>Also papillomavirus (HPV) and polyomavirus (BKV and JVC) are associated with increased risk of BC, but the scientific evidence for this is less.<a class="elsevierStyleCrossRefs" href="#bib0025">5,25,33</a> High carcinogenic risk papillomavirus transfer to mucosal cells E6 and E7 genes, which encode oncoproteins that disrupt the cell cycle, the maintenance of telomerase and regulation of apoptosis. HPV-infected immunosuppressed patients provide more convincing data. Some meta-analysis find increases 2.3–2.8 times higher to submit BC in this group of patients.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> A recent meta-analysis documented a significantly increased risk of bladder cancer associated with HPV positivity overall (OR 2.84 [95% CI 1.39–5.80]); other factors influencing this increase were: the type of HPV, the region of study, DNA sample of the HPV and the detection method. The 5 most common types of HPV identified, in decreasing order of prevalence, were HPV-16, HPV-18, HPV-33, HPV-31 and HPV-5234.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>LithiasisThe urinary tract lithiasis, regardless of their association with local infections, increases the risk of BC. The most extensive study carried out up to date was conducted in a cohort of 61,144 patients hospitalized with kidney or ureteral stones and 25-years follow-up. A statistically significant increase in patients both with and without secondary infection was found.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Case–control studies have been less convincing.NeoplasiasSome studies in survivors of the renal pelvis carcinoma have greater RR of subsequently developing BC.<a class="elsevierStyleCrossRefs" href="#bib0180">36,37</a> The risk is inversely proportional to the time since diagnosis of kidney cancer, suggesting that the same RFs, such as smoking, are involved in the two locations.Higher risks have been also described after diagnoses of renal parenchyma, prostate, testes and even in non-melanocytic skin cancers.<a class="elsevierStyleCrossRefs" href="#bib0020">4,37,38</a> If we do not consider tobacco as common RF with renal parenchymal tumors and prostate cancer, the plausible hypotheses of the association are based on the effects of treatment, greater evolutionary control and other unknown effects.Bladder stasis and urinary pHUrine is the major route of elimination of soluble carcinogens, so the retention time increases contact with the bladder mucosa and may be associated with an increased risk of BC.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> Experimental and ecological studies attest that relationship. In humans only a case–control study with positive results has been published.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>Studies in vitro and in experimentation animals show that acid urine rapidly hydrolyze glucuronide conjugates of 4-aminobiphenyl and their nitro-hydroxylated derivative, and metabolize into active forms which produce injuries and forming adducts in the DNA of the bladder mucosa. In a recent study<a class="elsevierStyleCrossRef" href="#bib0200">40</a> conducted in Spain with 1219 patients and 1271 hospital controls urinary pH, smoking and the risk of BC were analyzed. The study documented that pH ≤ 6.0 was associated with increased risk of BC with OR=1.5 (IC 95%: 1.2–1.9). CI: 1.2–1.9). When comparing the BC risk with smoking intensity, the risk was higher in active smokers with acid urine (OR=8.8, 11.5 and 23.8) while the risk in smokers with basic urine (OR=4.3, 7.7 and 5.8)); the data relate to consumers of 1–19.20–29 and ≥ 30 cigarettes/day, respectively. These data suggest that urine pH is an important RF of BC.Finals remarksExposure to smoke of tobacco combustion is associated in both sexes with 50% of the BC and becomes the main RF of this neoplasm. For this reason we present the following comments. First, we must think about the importance of urologists in the primary prevention of BC, for recommending smoking cessation to smokers presenting any kind of disease.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Second, we have to assess their importance in tertiary prevention of BC, ordening to survivors of BC, who are active or passive smokers, to stop smoking, in order to decrease the likelihood of local recurrence.<a class="elsevierStyleCrossRefs" href="#bib0040">8–10</a> Third, it is important to emphasize the natural resilience of the bladder mucosa cell to the carcinogenic actions of numerous chemical substances that are contained in the combustion of tobacco.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Fourth, it is necessary to highlight the synergistic action of carcinogens that reach the bladder uroepithelium via the blood and urinary tract.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Among the remaining RF analyzed, urologists should advise all BC survivor relevant dietary modifications in order to increase plant-food intakes and to decrease animal-food ones, as well as to increase total fluid intake, mainly non-chlorinated water, and to avoid using hair dyes.Lastly, all the survivors of malignancies, both urological and any other location, who have been treated with CFM, MFIs and ionizing radiation, should be candidates for secondary prevention of BC.FundingThis review was made possible by the funding and support from: a Scientific Foundation of the AECC (Spanish Association Against Cancer) (Macape Research Project) and Mount Sinai International Exchange Program for Minority Students (MD001452, National Center on Mino-rity Health and Health Disparities, National Institutes of Health).Conflict of interestsThe authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:2 [ "identificador" => "xres289250" "titulo" => array:5 [ 0 => "Abstract" 1 => "Context" 2 => "Acquisition of evidence" 3 => "Synthesis of evidence" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec272691" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres289251" "titulo" => array:5 [ 0 => "Resumen" 1 => "Contexto" 2 => "Adquisición de evidencia" 3 => "Síntesis de evidencia" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec272692" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Smoking" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Dietary factors (Table 3)" "secciones" => array:8 [ 0 => array:3 [ "identificador" => "sec0020" "titulo" => "Water pollutants" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Arsenic" ] ] ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "By-products of water chlorination" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Hexavalent chromium" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Fluid intake" ] 4 => array:2 [ "identificador" => "sec0045" "titulo" => "Intake of coffee, alcohol, tea and mate" ] 5 => array:2 [ "identificador" => "sec0050" "titulo" => "Artificial sweeteners" ] 6 => array:2 [ "identificador" => "sec0055" "titulo" => "Fruits and vegetables" ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Other dietary factors" ] ] ] 7 => array:3 [ "identificador" => "sec0065" "titulo" => "Medicines/drugs" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Analgesics" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Phenobarbital" ] 2 => array:3 [ "identificador" => "sec0080" "titulo" => "Antineoplastic" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0085" "titulo" => "Alkylating agents" ] ] ] 3 => array:2 [ "identificador" => "sec0090" "titulo" => "Chlornaphazine" ] 4 => array:2 [ "identificador" => "sec0095" "titulo" => "Other drugs" ] ] ] 8 => array:2 [ "identificador" => "sec0100" "titulo" => "Ionizing radiation" ] 9 => array:2 [ "identificador" => "sec0105" "titulo" => "Hair dyes" ] 10 => array:3 [ "identificador" => "sec0110" "titulo" => "Urologic diseases" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0115" "titulo" => "Urinary tract infections" ] 1 => array:2 [ "identificador" => "sec0120" "titulo" => "Lithiasis" ] 2 => array:2 [ "identificador" => "sec0125" "titulo" => "Neoplasias" ] 3 => array:2 [ "identificador" => "sec0130" "titulo" => "Bladder stasis and urinary pH" ] ] ] 11 => array:2 [ "identificador" => "sec0135" "titulo" => "Finals remarks" ] 12 => array:2 [ "identificador" => "sec0140" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "sec0145" "titulo" => "Conflict of interests" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-02-12" "fechaAceptado" => "2013-02-14" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec272691" "palabras" => array:7 [ 0 => "Bladder cancer" 1 => "Epidemiology" 2 => "Risk factors" 3 => "Smoking" 4 => "Arsenic" 5 => "Chlorination by-products" 6 => "Schistosoma haematobium" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec272692" "palabras" => array:7 [ 0 => "Cáncer vesical" 1 => "Epidemiología" 2 => "Factores de riesgo" 3 => "Tabaquismo" 4 => "Arsénico" 5 => "Subproductos cloración" 6 => "Schistosoma haematobium" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "ContextBladder carcinoma (BC), due its high morbidity and relapsing course, generates significant economic and health care costs. Accordingly, we reviewed the environmental nonoccupational risk factors (RF), more or less evidence-based, in the etiology and pathogenesis of BC, because the involvement of urologists is essential for prevention. Acquisition of evidenceReview of the peer-reviewed literature (1987–2012) on nonoccupational environmental RF associated with BC retrieved from Medline, Embase and Science Citation Index. The search profiles have been “Risk factors/Epidemiology/Tobacco-smoking/Diet-nutrition-water-liquids/Radiation/Infectious/Farmacological drugs” and “Bladder cancer”. Synthesis of evidenceSmoking was associated with 50% of BC in both sexes. Smokers have a 2–5 times higher risk than nonsmokers, directly proportional to the amount and duration of addiction. Drinking water contaminated with arsenic and chromium chlorination byproducts increases the risk of BC. High consumption of red meat and saturated fat may increase the risk, while high intake of fruits and vegetables decreases it. Patients treated with cyclophosphamide, ifosfamide and ionizing radiation have an increased risk of BC. Frequent and prolonged use of hair dyes and Schistosoma haematobium infestation increases the risk of BC. ConclusionsThe reduction or the cessation of smoking decrease BC. The contaminant-free water consumption with the increase of vegetal foods favors BC prevention. Cancer survivors treated with cyclophosphamide, ifosfamide and radiation therapy should be monitored for early diagnosis of BC." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ContextoEl carcinoma vesical (CV), por su elevada morbilidad y evolución recidivante, genera importantes costes asistenciales y económicos. Por ello revisaremos los factores de riesgo (FR) ambientales no ocupacionales implicados, con mayor o menor evidencia científica, en la etiopatogenia del CV, pues la implicación de los urológos es fundamental para su prevención. Adquisición de evidenciaRevisión bibliográfica de los últimos 25 años de los mencionados FR asociados al CV, obtenida de MedLine, Science Citation Index y Embase. Los perfiles de búsqueda han sido Risk Factors/Epidemiology/Tobacco-smoking/Diet-nutrition-water-liquids/Infectious/Radiation/Farmacological drugs y Bladder cancer. Síntesis de evidenciaEl tabaquismo se asocia al 50% de los CV en ambos sexos. Los fumadores presentan riesgos 2–5 veces superiores, dependiendo de la intensidad y duración de la adicción. El agua potable contaminada con arsénico, subproductos de cloración y cromo, incrementa el riesgo de CV. Consumos altos de carne roja y grasa saturada posiblemente aumenten el riesgo, mientras la ingesta elevada de frutas y verduras lo disminuye. La administración de ciclofosfamida, ifosfamida y radioterapia incrementa el riesgo de CV. El uso frecuente y prolongado de tintes capilares y la infestación por Schistosoma haematobium se asocian a mayores riesgos. ConclusionesLa reducción o eliminación del tabaquismo disminuirá la prevalencia del CV. El consumo de agua sin contaminantes, con el incremento de alimentos vegetales favorece la prevención del CV. Los supervivientes de cánceres tratados con ciclofosfamida, ifosfamida y radioterapia deben ser monitorizados para el diagnóstico precoz del CV." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Ferrís J, Berbel O, Alonso-López J, Garcia J, Ortega J.A. Factores de riesgo ambientales no ocupacionales asociados al cáncer vesical. Actas Urol Esp. 2013;37:579–586." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dietary factors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Water pollutants \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arsenic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">By-products of water chlorination \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hexavalent chromium \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Liquid intake \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intake of coffee, alcohol, tea and mate \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Artificial Sweeteners \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fruits and vegetables \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other dietary factors \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Medicines/drugs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Analgesics \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phenobarbital \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antineoplastic \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alkylating agents \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chlornaphazine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other drugs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ionizing radiation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hair dyes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urologic diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urinary tract infections \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lithiasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neoplasias \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bladder stasis and urinary pH \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab421146.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Major non-occupational environmental RF associated with BC." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Chemical group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No. of carcinogens \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Representative carcinogens \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Polycyclic aromatic hydrocarbons and heterocyclic analogs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benzo(a)pyrene (BaP) Dibenzo(a,h) anthracene \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N-nitrosamines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) N′-nitrosonornicotine (NNN) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aromatics amines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4-Aminobiphenyl 2-naphthylamine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aldehydes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Formaldehyde acetaldehyde \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phenols \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Catechol caffeic acid \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Volatile hydrocarbons \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benzene1,3-ButadieneIsoprene \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other organics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ethylene oxideAcrylonitrile \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inorganic compounds \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CadmiumPolonio-210 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab421144.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Human carcinogens contained in tobacco smoke, classified by chemical groups and highlighting the most representative.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a>" ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Nutrients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Association \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vit. A, carotenoids, retinoids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dubious (possibly ↓ risk) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Selenium \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dubious (possibly ↓ risk) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vit. E \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dubious (possibly ↓ risk) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vit. C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dubious (possibly ↓ risk) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multivitamin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dubious (possibly ↓ risk) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Meat products \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increases risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fats \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increases risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fruits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decrease risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vegetables \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decrease risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Soy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dubious (possibly ↓ risk) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Water</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Overall liquid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dubious (possibly ↓ risk) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arsenic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increases risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">By-products of water chlorination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increases risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hexavalent chromium \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increases risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alcohol</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Coffee \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increases risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">? \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increases risk \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Artificial sweeteners \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab421145.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Dietary risk factors associated with bladder carcinoma.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5,15–23</a>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer Statistics, 2012" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => 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Environmental non-occupational risk factors associated with bladder cancer

Factores de riesgo ambientales no ocupacionales asociados al cáncer vesical

J. Ferrísa,

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ferris_jos@gva.es

Corresponding author.

, O. Berbelb, J. Alonso-Lópezc, J. Garciad, J.A. Ortegae

a Unitat de Salut Mediambiental Pediàtrica, Unitat d‘Oncologia Pediàtrica, Hospital Universitari i Politècnic La Fe, València, Spain

b Facultad de Medicina, Universidad Católica de Valencia, Centre de Salut de Chella, Chella, València, Spain

c Unitat de Neumologia i Al·lèrgia Pediàtrica, Hospital Universitari i Politècnic La Fe, València, Spain

d Secció d‘Anatomia Patològica, Hospital de Sagunt, València, Spain

e Unidad de Salud Medioambiental Pediátrica (www.pehsu.org), Hospital Materno-Infantil Universitario Virgen de la Arrixaca, Murcia, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In Western countries&#44; one in 26 men and one in 87 women will develop a bladder carcinoma &#40;BC&#41; over the course of their lifetime&#44; especially in the last third&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> This significant morbidity&#44; which generates a great emotional&#44; physical and economic&#44; highlights the transcendent personal and professional involvement of urologists to recognize&#44; reduce or eliminate environmental risk factors &#40;RF&#41; associated to its etiopathogenesis with more or less evidence&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In this paper we review the major non-occupational environmental RF associated with BC &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; completing our previous contribution&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Smoking</span><p id="par0015" class="elsevierStylePara elsevierViewall">Smoking is the main RF associated with the incidence and biological aggressiveness of BC&#46; This factor has the largest scientific evidence&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;14</span></a> Until recent times smoking was associated with 50&#8211;60&#37; of the BC in men and 20&#8211;30&#37; in women&#46; This difference was due in part to the traditional differences of consumption and the long latency periods of bladder carcinogenesis &#40;&#8805;30 years&#41;&#46; Today&#44; the risks are similar in both sexes and it is associated to 50&#37; of BC&#44; as smoking rates between men and women in Western countries are equal&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Numerous epidemiological case&#8211;control and cohort studies convincingly demonstrate the direct relationship between active smoking and BC&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;12</span></a> Except for neoplasms of the respiratory tract and oral cavity&#44; the BC is the best smoking-related neoplasia documented&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Overall&#44; smokers have 2&#8211;3 times greater risk than non-smokers&#44; being even up to 5 times for those consuming &#8805;1 pack daily&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;8</span></a> Similarly&#44; patients who smoke have more infiltrating varieties and increased BC mortality compared to non-smokers&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;9&#44;10&#44;14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The risk increases with the intensity of smoking &#40;number of cigarettes per day&#41;&#44; with RR &#40;relative risk&#41; of 2&#46;0&#8211;5&#46;0 among moderate to heavy smokers compared to nonsmokers&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;6&#44;9</span></a> The studies demonstrate a very convincing dose&#8211;response curve&#44; although some researches show stabilization from moderate to severe consumptions&#44; but they are attributed to confounding factors &#40;recall bias&#44; lower relative inhalation among large consumers&#44; genetic polymorphisms&#44; etc&#46;&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Another variable involved in the risk is the relationship with the years of exposure&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;6&#44;8</span></a> The same applies to the depth of inhalation&#44; which increases the risk 30&#8211;40&#37; when compared to those who inhale very little or nothing&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;9</span></a> Studies conducted to compare gender differences in the risk of BC in smokers do not find differences between men and women when analyzing equivalent doses of intensity&#44; duration&#44; depth of inhalation and variety of tobacco consumed&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The different varieties of cigarettes &#40;filters&#44; black&#44; blond&#41; have been also studied as well as the consumption without cigarettes &#40;pipes&#44; cigars and smokeless tobacco&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;9</span></a> The results on the effects of cigarette filters have been inconsistent&#46; The black tobacco smokers have risks of 1&#46;5&#8211;3 times higher than those who smoke blond tobacco&#46; Pipe smokers have a RR of 1&#46;3&#8211;3&#46;9 with respect to non-smokers and cigar smokers have a RR of 1&#46;3&#8211;1&#46;6&#46; The sniffers and tobacco chewers have been poorly evaluated to obtain valid results&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">In a hospital-based study conducted in Spain<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> 1219 BC patients and 1271 controls were analyzed in relation to the consumption of tobacco&#46; Current smokers &#40;men OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;4 &#91;CI 95&#37;&#58; 5&#46;3&#8211;10&#46;4&#93;&#47;women OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;1 &#91;CI 95&#37;&#58; 1&#46;6&#8211;16&#46;4&#93;&#41; and former smokers &#40;men RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;8 &#91;IC 95&#37;&#58; 2&#46;8&#8211;5&#46;3&#93;&#47;women RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;8 &#91;95&#37; CI&#58; 0&#46;5&#8211;7&#46;2&#93;&#41; had higher risks&#44; statistically significant&#44; than never-smokers&#46; Direct relationship between risk and the longer duration and intensity of consumption was observed&#46; After adjusting the duration and amount&#44; the risk was 40&#37; higher in smokers of black tobacco compared to smokers of blond tobacco &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;4 &#91;95&#37; CI&#58; 0&#46;98&#8211;2&#46;0&#93;&#41;&#46; This difference may be due to higher concentrations of N-nitrosamines and 2-naphthylamines in black tobacco&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;8</span></a> The study also documented that deep inspiration increases the risk between 50 and 70&#37; compared to those who hold the smoke in their mouth&#46; The researchers found that snuff is responsible for 42&#37; of BC in men and 13&#37; in women&#46; Finally&#44; if the effect of tobacco was eliminated&#44; the man&#47;woman relation in the BC incidence decreased from 8&#46;2 to 1&#46;7&#44; suggesting that the great gender difference in our country was due to the consumption of tobacco and its black variety&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Smoking cessation is associated with a 30&#8211;60&#37; reduction in BC risk in most studies&#59; however&#44; the pattern of change of risk in relation to the cessation period is not sufficiently established&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;11</span></a> However&#44; the rapid decline of risk in the early years of the cessation suggests that tobacco smoke carcinogens play a role in the later stages of bladder carcinogenesis&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Exposure to environmental tobacco smoke has also been associated with increased risk of BC&#44; but the results are not unanimous&#46; A large study documents increased risk in women exposed to tobacco during childhood and adulthood with OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;08 &#40;IC 95&#37;&#58; 1&#46;16&#8211;8&#46;22&#41;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> &#40;95&#37; CI&#58; 1&#46;16&#8211;8&#46;22&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The effect was greater especially in women who had never been smokers&#46; The mechanisms underlying these gender differences are unknown</p><p id="par0055" class="elsevierStylePara elsevierViewall">The mechanisms of action of the 62 carcinogens contained in snuff smoke are well established&#44; but it is not clear how many of them&#44; individually or in combination&#44; are primarily responsible for the development of BC&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> As it can be seen in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; various aromatic amines such as 2-naphthylamine&#44; 2-toluidine and 4-aminobiphenyl&#44; numerous n-nitrosamines&#44; polycyclic aromatic hydrocarbons such as benzo&#40;a&#41;pyrene and dibenzo&#40;a&#44;h&#41;anthracene&#44; aromatics hydrocarbons such as benzene and 1&#44;3-butadiene&#44; have proved decisive involvement bladder carcinogenesis&#46; Curiously&#44; from the seventh decade of the last century&#44; the analyses of concentrations of these carcinogens in tobacco smoke are increasing and this partly explains the maintained persistence of cancers associated to them&#44; such as BC&#44; despite the decrease in the consumption of tobacco in Western countries&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Dietary factors &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Water pollutants</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Arsenic</span><p id="par0060" class="elsevierStylePara elsevierViewall">Water intake with high concentrations &#40;&#62;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;l&#41; of inorganic arsenic is well a documented cause of BC&#46; Likewise&#44; populations exposed to such use show an increase of mortality attributed to BC in cohort studies&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Carcinogenesis activity of arsenic on bladder mucosa is biologically demonstrated by the increase of chromosomal aberrations in exfoliated bladder cells of healthy people exposed&#44; and by higher percentages of chromosomal deletions in bladder tumors associated with high levels of exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Also a linear relationship between the concentrations of arsenic in water and increased risk of BC has been demonstrated&#46; RRs were 1&#46;9&#44; 8&#46;2 and 15&#46;3 for concentrations of 10&#46;1&#8211;50&#46;0&#44; 50&#46;1&#8211;150&#46;0 and &#62;100<span class="elsevierStyleHsp" style=""></span>mg&#47;l&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Also&#44; in populations exposed to high concentrations in the public water supply&#44; the replacement for bottled water without arsenic has decreased the incidence of BC<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">By-products of water chlorination</span><p id="par0065" class="elsevierStylePara elsevierViewall">The chlorine&#44; added to disinfect drinking water&#44; reacts with organic matter generating the so-called chlorination byproducts &#40;SPC&#41;&#46; The most studied are trihalomethanes&#44; iodomethanes&#44; halonitromethanes and hidroxy-furanes&#46; Numerous studies of control&#8211;cases with water intake with high concentrations of BPCs &#40;&#8764;50<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;l&#44; levels observed in many western countries and regions&#41;&#44; identified a 50&#37; increased risk of BC with regarding consumption of dechlorinated water&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The risk is lower in populations where disinfection is done by ozone&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The exposure to BPCs through inhalation and transdermal absorption along with the intake are the routes that contribute to the total exposure to trihalomethanes&#44; and it has been evaluated in an epidemiological study documenting an increased risk in showers&#44; baths and swimming pools&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Hexavalent chromium</span><p id="par0070" class="elsevierStylePara elsevierViewall">It has also been suggested that the contamination of drinking water with hexavalent chromium derived from industrial activity and listed as a human carcinogen&#44; is associated with an increased incidence&#44; recurrence and mortality of BC&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Fluid intake</span><p id="par0075" class="elsevierStylePara elsevierViewall">Studies comparing total fluid intake with the risk of BC have given mixed results&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> High consumptions of liquids have been associated with lower risk&#44; higher risk and null effects&#46; The disparity of results is subject to methodological flaws and logistical difficulties of these studies&#46; We will highlight one of the best studies on a cohort of health professionals&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> which shows a protective effect of high intake&#44; with a risk reduction of 7&#37; for each 240<span class="elsevierStyleHsp" style=""></span>cc of total liquid increase&#46; This study also documents that the use of e &#8805;<span class="elsevierStyleHsp" style=""></span>2&#46;531 cc&#47;day reduces the risk between 24&#8211;40&#37; compared to those that ingest &#8804;<span class="elsevierStyleHsp" style=""></span>1&#46;290 cc&#47;day&#46; The assumptions underlying these results are that high intake dilutes urinary carcinogens and increased urinary frequency decreases contact time with the bladder mucosa&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Intake of coffee&#44; alcohol&#44; tea and mate</span><p id="par0080" class="elsevierStylePara elsevierViewall">A direct association between coffee intake and increased risk of BC was published in 1971&#44; with RR of 1&#46;3 for men and 2&#46;5 for women&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Numerous subsequent studies differ in results with respect to gender&#44; but document RR &#8764;<span class="elsevierStyleHsp" style=""></span>2&#46;0&#46; Listed by IARC in 1991 as 2<span class="elsevierStyleHsp" style=""></span>B &#40;possibly carcinogenic to the bladder&#41;&#46; A meta-analysis published in 2001 documents OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> &#40;95&#37; CI&#58;1&#46;09&#8211;1&#44; 46&#41; for men and OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;08 &#40;95&#37; CI&#58; 0&#46;79&#8211;1&#46;46&#41; for women&#44; and OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;18 &#40;IC 95&#37;&#58; 1&#46;01&#8211;1&#46;38&#41; 1&#46;18 &#40;95&#37; CI&#58; 1&#46;01&#8211;1&#46;38&#41; for the 2 genres combined&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Regarding alcohol intake results are still mixed&#46; A recent meta-analysis documents an increased risk but without statistical significance&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The possible association with specific alcoholic beverages has been also studied&#44; but the data are inconsistent&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Regarding tea consumption&#44; epidemiological studies control&#8211;cases&#44; cohort and meta-analysis found no protective effects of tea polyphenols on bladder carcinogenesis&#46; A recent meta-analysis<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> found that only the variety of green tea is associated with statistically significant lower risk with OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;814 &#40;95&#37; CI&#58; 0&#46;678&#8211;0&#46;976&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">High and maintained intake of mate&#44; infusion of the herb <span class="elsevierStyleItalic">Ilex paraguariensis</span>&#44; popular in South American countries&#44; increases the risk of BC&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Artificial sweeteners</span><p id="par0100" class="elsevierStylePara elsevierViewall">Saccharin was suggested as RF by the results obtained in intrauterine exposure to high doses in rats&#44; but not postnatally&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Numerous investigations performed on humans have ruled out the association&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Fruits and vegetables</span><p id="par0105" class="elsevierStylePara elsevierViewall">Among the dietary RF that have been evaluated with respect to the risk of BC&#44; a wide scientific evidence shows that high consumption of fruits and vegetables has protective effects&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Numerous epidemiological studies show that consumption of natural fruits&#44; juices and vegetables &#40;carrots&#44; cruciferous and dark-green leafy&#41; decreases the risk of BC&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> A meta-analysis found that diets low in fruits increase the RR 1&#46;4 &#40;95&#37; CI&#58;1&#46;1&#8211;1&#44; 8&#41; and in vegetables RR 1&#46;2 &#40;95&#37; CI&#58; 1&#46;0&#8211;1&#46;3&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The role of specific micronutrients is less clear&#46; In animal dietary supplements of natural or synthetic retinoids inhibit bladder carcinogenesis&#46; In humans&#44; some studies suggest that supplements of vitamin A&#44; vitamin C&#44; folate and carotenoids as well as vitamin E and selenium are protective&#44; but most results are inconsistent&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Other dietary factors</span><p id="par0110" class="elsevierStylePara elsevierViewall">Risk increases have been associated with high intakes of meat&#44; especially red meat&#44; animal fats and cholesterol&#44; fish&#44; animal foods cooked at high temperatures&#44; smoked and salted&#46; Temperatures &#62;<span class="elsevierStyleHsp" style=""></span>200&#176; generate the formation of heterocyclic amines&#44; classified as probable human carcinogens&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5&#44;22</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Biological plausibility of dietary RF &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; in the bladder carcinogenesis is based on&#58; &#40;a&#41; the protective effect of fruits and vegetables is consistent and similar to that observed in other neoplasias&#59; &#40;b&#41; the high consumption of red meat cooked at high temperatures is also associated with increased risks in other cancers&#44; and elevates the levels of heterocyclic amines in urine&#59; &#40;c&#41; flavonoids provided by many fruits and vegetables inhibit the mutagenicity of heterocyclic amines in cell cultures&#59; and &#40;d&#41; experimentally&#44; urinary acidity influences the metabolism of bladder carcinogens&#44; increasing the formation of genetic alterations in bladder mucosa&#46; Foods of animal origin generate acidic urine&#44; while consumption of vegetables generates alkaline urine&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Medicines&#47;drugs</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Analgesics</span><p id="par0120" class="elsevierStylePara elsevierViewall">High consumption of phenacetin increased between 2&#8211;6 times the risk of BC&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> This drug was banned for developing chronic interstitial nephropathy and it was replaced by acetaminophen paracetamol&#44; aromatic amino metabolite of phenacetin&#44; with no effects on the risk of BC in the short and medium term&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">NSAIDs&#44; including acetylsalicylic acid&#44; are associated with a lower risk of BC&#46; The biological plausibility is supported by experimental evidence that NSAIDs are potent inhibitors of BC developed by chemical carcinogens&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Phenobarbital</span><p id="par0130" class="elsevierStylePara elsevierViewall">Its long-term use as anticonvulsant drug decreases up to 40&#37; risk of BC&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;25</span></a> Apparently&#44; both phenobarbital and phenytoin induce deactivation of bladder carcinogens&#44; especially those contained in tobacco smoke&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Antineoplastic</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Alkylating agents</span><p id="par0135" class="elsevierStylePara elsevierViewall">Alkylating agents are a family of drugs used in the therapy of neoplastic and rheumatic diseases&#46; Its side effects include second neoplasms&#44; and therefore they are classified as human carcinogens&#46; Only 2 of them&#44; cyclophosphamide &#40;CFM&#41; and ifosfamide &#40;IFM&#41;&#44; are associated with the development of hemorrhagic cystitis and BC&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5&#44;25</span></a> CFM and MFIs need to be metabolized in order to develop antineoplastic and carcinogenic actions&#46; The major metabolite involved in bladder toxicity is acrolein&#46; If uroprotector Mesna &#40;2-mercaptoethane sulfonate&#41; is not used concomitantly&#44; the direct association between cumulative doses and risk of BC shows RR of 2&#46;4&#44; 6&#46;0 and 14&#46;5 in survivors with total doses of &#8804;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>g&#44; 20&#8211;49<span class="elsevierStyleHsp" style=""></span>g and &#8805;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>g&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However&#44; it is not entirely clear what role corresponds to acrolein and other metabolites in bladder carcinogenesis&#46; Although concomitant use of Mesna is universal&#44; all treated with CFM and IFM survivor should be monitored for BC&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Chlornaphazine</span><p id="par0140" class="elsevierStylePara elsevierViewall">This former antineoplastic drug was associated with increased risk of BC&#44; but its therapeutic use was very limited&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Other drugs</span><p id="par0145" class="elsevierStylePara elsevierViewall">Pioglitazone&#44; drug used in the treatment of diabetes mellitus type 2&#44; increases the risk of BC&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Isoniazid and some laxatives have been associated with an increased risk of BC&#44; but with inconsistent results&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;27</span></a></p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Ionizing radiation</span><p id="par0155" class="elsevierStylePara elsevierViewall">Consistent evidence of an association between ionizing radiation &#40;IR&#41; and the BC exists&#46; Numerous epidemiological studies have documented that people exposed to RI for medical reasons or because of nuclear accidents&#44; nuclear plant workers and survivors of atomic explosions are associated with increased risk of BC with respect to that expected in the normal population&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">It has been demonstrated an excess RR of 1&#46;02 per Sievert of exposure in the population cohorts exposed to atomic blasts of Hiroshima and Nagasaki&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The underlying biological mechanisms are of two types&#58; &#40;a&#41; the direct action on the DNA double helix and &#40;b&#41; indirect actions generated by oxygen free radicals&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Hair dyes</span><p id="par0165" class="elsevierStylePara elsevierViewall">Certain hair dyes contain 4-aminobiphenyl&#44; substance that is considered as occupational carcinogen of BC&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> People who use hair dyes usually excrete larger amounts of urine&#46; Epidemiological studies at the end of the last century did not document any association&#46; In 2001&#44; a case&#8211;control study found that women population with regular use of hair dyes had a 70&#37; higher risk of BC with respect to non-users&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> The risk was directly related to the time of use and the frequency of application&#46; However&#44; this association has not been subsequently replicated by other researchers&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Urologic diseases</span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Urinary tract infections</span><p id="par0170" class="elsevierStylePara elsevierViewall">Positive associations between bladder infections and increased risk of BC have been described in most case&#8211;control studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;25</span></a> A research carried out in U&#46;S&#46;A&#46; has documented the direct relationship between cystitis and BC in both sexes&#44; and that patients with &#8805;<span class="elsevierStyleHsp" style=""></span>3 infectious episodes present a 2-fold increased risk of BC with respect to unaffected individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;25</span></a> Furthermore&#44; the squamous cell histological subtype is predominant among the BCs of people with a history of chronic cystitis &#40;paraplegics&#44; SCI patients carrying catheters&#41;&#46; The mechanisms underlying the association cystitis-BC are&#58; &#40;a&#41; chronic inflammatory phenomena &#40;oxygen free radicals&#41;&#44; &#40;b&#41; alteration of the mucosal barrier to urinary carcinogens and &#40;c&#41; the formation of N-nitroso compounds by bacterial growth&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Infestation by the parasite <span class="elsevierStyleItalic">Schistosoma haematobium</span> is typically associated with the squamous cell variety&#46; In countries where the parasite is endemic such as Egypt&#44; more than 70&#37; of BCs are squamous cell carcinoma&#44; while in Western countries this type of cancer accounts for only 2&#37;&#46; Besides the underlying mechanisms discussed in the bacterial cystitis&#44; egg deposits cause urinary bladder stasis&#44; and parasitic antigens are immunosuppressive&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;25&#44;32</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Also papillomavirus &#40;HPV&#41; and polyomavirus &#40;BKV and JVC&#41; are associated with increased risk of BC&#44; but the scientific evidence for this is less&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;25&#44;33</span></a> High carcinogenic risk papillomavirus transfer to mucosal cells E6 and E7 genes&#44; which encode oncoproteins that disrupt the cell cycle&#44; the maintenance of telomerase and regulation of apoptosis&#46; HPV-infected immunosuppressed patients provide more convincing data&#46; Some meta-analysis find increases 2&#46;3&#8211;2&#46;8 times higher to submit BC in this group of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> A recent meta-analysis documented a significantly increased risk of bladder cancer associated with HPV positivity overall &#40;OR 2&#46;84 &#91;95&#37; CI 1&#46;39&#8211;5&#46;80&#93;&#41;&#59; other factors influencing this increase were&#58; the type of HPV&#44; the region of study&#44; DNA sample of the HPV and the detection method&#46; The 5 most common types of HPV identified&#44; in decreasing order of prevalence&#44; were HPV-16&#44; HPV-18&#44; HPV-33&#44; HPV-31 and HPV-5234&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Lithiasis</span><p id="par0185" class="elsevierStylePara elsevierViewall">The urinary tract lithiasis&#44; regardless of their association with local infections&#44; increases the risk of BC&#46; The most extensive study carried out up to date was conducted in a cohort of 61&#44;144 patients hospitalized with kidney or ureteral stones and 25-years follow-up&#46; A statistically significant increase in patients both with and without secondary infection was found&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Case&#8211;control studies have been less convincing&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Neoplasias</span><p id="par0190" class="elsevierStylePara elsevierViewall">Some studies in survivors of the renal pelvis carcinoma have greater RR of subsequently developing BC&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> The risk is inversely proportional to the time since diagnosis of kidney cancer&#44; suggesting that the same RFs&#44; such as smoking&#44; are involved in the two locations&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Higher risks have been also described after diagnoses of renal parenchyma&#44; prostate&#44; testes and even in non-melanocytic skin cancers&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;37&#44;38</span></a> If we do not consider tobacco as common RF with renal parenchymal tumors and prostate cancer&#44; the plausible hypotheses of the association are based on the effects of treatment&#44; greater evolutionary control and other unknown effects&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Bladder stasis and urinary pH</span><p id="par0200" class="elsevierStylePara elsevierViewall">Urine is the major route of elimination of soluble carcinogens&#44; so the retention time increases contact with the bladder mucosa and may be associated with an increased risk of BC&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Experimental and ecological studies attest that relationship&#46; In humans only a case&#8211;control study with positive results has been published&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Studies in vitro and in experimentation animals show that acid urine rapidly hydrolyze glucuronide conjugates of 4-aminobiphenyl and their nitro-hydroxylated derivative&#44; and metabolize into active forms which produce injuries and forming adducts in the DNA of the bladder mucosa&#46; In a recent study<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> conducted in Spain with 1219 patients and 1271 hospital controls urinary pH&#44; smoking and the risk of BC were analyzed&#46; The study documented that pH &#8804; 6&#46;0 was associated with increased risk of BC with OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;5 &#40;IC 95&#37;&#58; 1&#46;2&#8211;1&#46;9&#41;&#46; CI&#58; 1&#46;2&#8211;1&#46;9&#41;&#46; When comparing the BC risk with smoking intensity&#44; the risk was higher in active smokers with acid urine &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#46;8&#44; 11&#46;5 and 23&#46;8&#41; while the risk in smokers with basic urine &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;3&#44; 7&#46;7 and 5&#46;8&#41;&#41;&#59; the data relate to consumers of 1&#8211;19&#46;20&#8211;29 and &#8805; 30 cigarettes&#47;day&#44; respectively&#46; These data suggest that urine pH is an important RF of BC&#46;</p></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Finals remarks</span><p id="par0210" class="elsevierStylePara elsevierViewall">Exposure to smoke of tobacco combustion is associated in both sexes with 50&#37; of the BC and becomes the main RF of this neoplasm&#46; For this reason we present the following comments&#46; First&#44; we must think about the importance of urologists in the primary prevention of BC&#44; for recommending smoking cessation to smokers presenting any kind of disease&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Second&#44; we have to assess their importance in tertiary prevention of BC&#44; ordening to survivors of BC&#44; who are active or passive smokers&#44; to stop smoking&#44; in order to decrease the likelihood of local recurrence&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> Third&#44; it is important to emphasize the natural resilience of the bladder mucosa cell to the carcinogenic actions of numerous chemical substances that are contained in the combustion of tobacco&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Fourth&#44; it is necessary to highlight the synergistic action of carcinogens that reach the bladder uroepithelium via the blood and urinary tract&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Among the remaining RF analyzed&#44; urologists should advise all BC survivor relevant dietary modifications in order to increase plant-food intakes and to decrease animal-food ones&#44; as well as to increase total fluid intake&#44; mainly non-chlorinated water&#44; and to avoid using hair dyes&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Lastly&#44; all the survivors of malignancies&#44; both urological and any other location&#44; who have been treated with CFM&#44; MFIs and ionizing radiation&#44; should be candidates for secondary prevention of BC&#46;</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Funding</span><p id="par0225" class="elsevierStylePara elsevierViewall">This review was made possible by the funding and support from&#58; <span class="elsevierStyleGrantSponsor" id="gs0005">a Scientific Foundation of the AECC &#40;Spanish Association Against Cancer&#41; &#40;Macape Research Project&#41;</span> and <span class="elsevierStyleGrantSponsor" id="gs0010">Mount Sinai International Exchange Program for Minority Students</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0010">MD001452</span>&#44; National Center on Mino-rity Health and Health Disparities&#44; National Institutes of Health&#41;&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Conflict of interests</span><p id="par0230" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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            1 => "Context"
            2 => "Acquisition of evidence"
            3 => "Synthesis of evidence"
            4 => "Conclusions"
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          "titulo" => array:5 [
            0 => "Resumen"
            1 => "Contexto"
            2 => "Adquisici&#243;n de evidencia"
            3 => "S&#237;ntesis de evidencia"
            4 => "Conclusiones"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Smoking"
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        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Dietary factors &#40;Table 3&#41;"
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              "titulo" => "Water pollutants"
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                  "titulo" => "Arsenic"
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              "titulo" => "By-products of water chlorination"
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              "titulo" => "Fluid intake"
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              "titulo" => "Intake of coffee&#44; alcohol&#44; tea and mate"
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              "titulo" => "Artificial sweeteners"
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            6 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Fruits and vegetables"
            ]
            7 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Other dietary factors"
            ]
          ]
        ]
        7 => array:3 [
          "identificador" => "sec0065"
          "titulo" => "Medicines&#47;drugs"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Analgesics"
            ]
            1 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Phenobarbital"
            ]
            2 => array:3 [
              "identificador" => "sec0080"
              "titulo" => "Antineoplastic"
              "secciones" => array:1 [
                0 => array:2 [
                  "identificador" => "sec0085"
                  "titulo" => "Alkylating agents"
                ]
              ]
            ]
            3 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Chlornaphazine"
            ]
            4 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Other drugs"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "sec0100"
          "titulo" => "Ionizing radiation"
        ]
        9 => array:2 [
          "identificador" => "sec0105"
          "titulo" => "Hair dyes"
        ]
        10 => array:3 [
          "identificador" => "sec0110"
          "titulo" => "Urologic diseases"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0115"
              "titulo" => "Urinary tract infections"
            ]
            1 => array:2 [
              "identificador" => "sec0120"
              "titulo" => "Lithiasis"
            ]
            2 => array:2 [
              "identificador" => "sec0125"
              "titulo" => "Neoplasias"
            ]
            3 => array:2 [
              "identificador" => "sec0130"
              "titulo" => "Bladder stasis and urinary pH"
            ]
          ]
        ]
        11 => array:2 [
          "identificador" => "sec0135"
          "titulo" => "Finals remarks"
        ]
        12 => array:2 [
          "identificador" => "sec0140"
          "titulo" => "Funding"
        ]
        13 => array:2 [
          "identificador" => "sec0145"
          "titulo" => "Conflict of interests"
        ]
        14 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-02-12"
    "fechaAceptado" => "2013-02-14"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec272691"
          "palabras" => array:7 [
            0 => "Bladder cancer"
            1 => "Epidemiology"
            2 => "Risk factors"
            3 => "Smoking"
            4 => "Arsenic"
            5 => "Chlorination by-products"
            6 => "Schistosoma haematobium"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec272692"
          "palabras" => array:7 [
            0 => "C&#225;ncer vesical"
            1 => "Epidemiolog&#237;a"
            2 => "Factores de riesgo"
            3 => "Tabaquismo"
            4 => "Ars&#233;nico"
            5 => "Subproductos cloraci&#243;n"
            6 => "Schistosoma haematobium"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Context</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bladder carcinoma &#40;BC&#41;&#44; due its high morbidity and relapsing course&#44; generates significant economic and health care costs&#46; Accordingly&#44; we reviewed the environmental nonoccupational risk factors &#40;RF&#41;&#44; more or less evidence-based&#44; in the etiology and pathogenesis of BC&#44; because the involvement of urologists is essential for prevention&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Acquisition of evidence</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Review of the peer-reviewed literature &#40;1987&#8211;2012&#41; on nonoccupational environmental RF associated with BC retrieved from Medline&#44; Embase and Science Citation Index&#46; The search profiles have been &#8220;Risk factors&#47;Epidemiology&#47;Tobacco-smoking&#47;Diet-nutrition-water-liquids&#47;Radiation&#47;Infectious&#47;Farmacological drugs&#8221; and &#8220;Bladder cancer&#8221;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Synthesis of evidence</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Smoking was associated with 50&#37; of BC in both sexes&#46; Smokers have a 2&#8211;5 times higher risk than nonsmokers&#44; directly proportional to the amount and duration of addiction&#46; Drinking water contaminated with arsenic and chromium chlorination byproducts increases the risk of BC&#46; High consumption of red meat and saturated fat may increase the risk&#44; while high intake of fruits and vegetables decreases it&#46; Patients treated with cyclophosphamide&#44; ifosfamide and ionizing radiation have an increased risk of BC&#46; Frequent and prolonged use of hair dyes and Schistosoma haematobium infestation increases the risk of BC&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The reduction or the cessation of smoking decrease BC&#46; The contaminant-free water consumption with the increase of vegetal foods favors BC prevention&#46; Cancer survivors treated with cyclophosphamide&#44; ifosfamide and radiation therapy should be monitored for early diagnosis of BC&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Contexto</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El carcinoma vesical &#40;CV&#41;&#44; por su elevada morbilidad y evoluci&#243;n recidivante&#44; genera importantes costes asistenciales y econ&#243;micos&#46; Por ello revisaremos los factores de riesgo &#40;FR&#41; ambientales no ocupacionales implicados&#44; con mayor o menor evidencia cient&#237;fica&#44; en la etiopatogenia del CV&#44; pues la implicaci&#243;n de los urol&#243;gos es fundamental para su prevenci&#243;n&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Adquisici&#243;n de evidencia</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Revisi&#243;n bibliogr&#225;fica de los &#250;ltimos 25 a&#241;os de los mencionados FR asociados al CV&#44; obtenida de MedLine&#44; Science Citation Index y Embase&#46; Los perfiles de b&#250;squeda han sido <span class="elsevierStyleItalic">Risk Factors&#47;Epidemiology&#47;Tobacco-smoking&#47;Diet-nutrition-water-liquids&#47;Infectious&#47;Radiation&#47;Farmacological drugs</span> y <span class="elsevierStyleItalic">Bladder cancer</span>&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">S&#237;ntesis de evidencia</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El tabaquismo se asocia al 50&#37; de los CV en ambos sexos&#46; Los fumadores presentan riesgos 2&#8211;5 veces superiores&#44; dependiendo de la intensidad y duraci&#243;n de la adicci&#243;n&#46; El agua potable contaminada con ars&#233;nico&#44; subproductos de cloraci&#243;n y cromo&#44; incrementa el riesgo de CV&#46; Consumos altos de carne roja y grasa saturada posiblemente aumenten el riesgo&#44; mientras la ingesta elevada de frutas y verduras lo disminuye&#46; La administraci&#243;n de ciclofosfamida&#44; ifosfamida y radioterapia incrementa el riesgo de CV&#46; El uso frecuente y prolongado de tintes capilares y la infestaci&#243;n por Schistosoma haematobium se asocian a mayores riesgos&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La reducci&#243;n o eliminaci&#243;n del tabaquismo disminuir&#225; la prevalencia del CV&#46; El consumo de agua sin contaminantes&#44; con el incremento de alimentos vegetales favorece la prevenci&#243;n del CV&#46; Los supervivientes de c&#225;nceres tratados con ciclofosfamida&#44; ifosfamida y radioterapia deben ser monitorizados para el diagn&#243;stico precoz del CV&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Ferr&#237;s J&#44; Berbel O&#44; Alonso-L&#243;pez J&#44; Garcia J&#44; Ortega J&#46;A&#46; Factores de riesgo ambientales no ocupacionales asociados al c&#225;ncer vesical&#46; Actas Urol Esp&#46; 2013&#59;37&#58;579&#8211;586&#46;</p>"
      ]
    ]
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        "tabla" => array:1 [
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                  <table border="0" frame="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Smoking</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Dietary factors</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Water pollutants</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Arsenic&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>By-products of water chlorination&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Hexavalent chromium&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Liquid intake</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Intake of coffee&#44; alcohol&#44; tea and mate</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Fruits and vegetables</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Other dietary factors</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleBold">Medicines&#47;drugs</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Analgesics</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Phenobarbital</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Antineoplastic</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Alkylating agents&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Chlornaphazine&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Lithiasis</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Bladder stasis and urinary pH</span>&nbsp;\t\t\t\t\t\t\n
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Major non-occupational environmental RF associated with BC&#46;</p>"
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      1 => array:7 [
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        "etiqueta" => "Table 2"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Chemical group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">No&#46; of carcinogens&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Representative carcinogens&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Polycyclic aromatic hydrocarbons and heterocyclic analogs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Benzo&#40;a&#41;pyrene &#40;BaP&#41; Dibenzo&#40;a&#44;h&#41; anthracene&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N-nitrosamines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4-&#40;Methylnitrosamino&#41;-1-&#40;3-pyridyl&#41;-1-butanone &#40;NNK&#41; N&#8242;-nitrosonornicotine &#40;NNN&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aromatics amines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4-Aminobiphenyl 2-naphthylamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aldehydes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Formaldehyde acetaldehyde&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phenols&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Catechol caffeic acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Volatile hydrocarbons&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benzene1&#44;3-ButadieneIsoprene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other organics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ethylene oxideAcrylonitrile&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inorganic compounds&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CadmiumPolonio-210&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Nutrients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Association&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Vit&#46; A&#44; carotenoids&#44; retinoids</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dubious &#40;possibly &#8595; risk&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Selenium</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dubious &#40;possibly &#8595; risk&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Vit&#46; E</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dubious &#40;possibly &#8595; risk&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Vit&#46; C</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dubious &#40;possibly &#8595; risk&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Multivitamin</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dubious &#40;possibly &#8595; risk&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Meat products</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Fats</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Fruits</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decrease risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Vegetables</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decrease risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Soy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dubious &#40;possibly &#8595; risk&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Water</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Overall liquid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dubious &#40;possibly &#8595; risk&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Arsenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>By-products of water chlorination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hexavalent chromium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Alcohol</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Coffee&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increases risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Artificial sweeteners&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Dietary risk factors associated with bladder carcinoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5&#44;15&#8211;23</span></a></p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:40 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cancer Statistics&#44; 2012"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Siegel"
                            1 => "D&#46; Naishadham"
                            2 => "A&#46; Jemal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Cancer J Clin"
                        "fecha" => "2012"
                        "volumen" => "62"
                        "paginaInicial" => "10"
                        "paginaFinal" => "29"
                      ]
                    ]
                  ]
                ]
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            1 => array:3 [
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                  "contribucion" => array:1 [
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Article information

ISSN: 21735786
Original language: English

DOI:10.1016/j.acuroe.2013.02.008

The statistics are updated each day

Year/Month	Html	Pdf	Total

2023 March	1	0	1
2018 February	4	0	4
2018 January	6	1	7
2017 December	14	1	15
2017 November	8	1	9
2017 October	20	1	21
2017 September	10	1	11
2017 August	18	2	20
2017 July	14	7	21
2017 June	22	5	27
2017 May	10	2	12
2017 April	20	2	22
2017 March	4	2	6
2017 February	8	3	11
2017 January	5	0	5
2016 December	18	8	26
2016 November	19	6	25
2016 October	30	8	38
2016 September	21	1	22
2016 August	29	1	30
2016 July	14	1	15
2016 June	8	3	11
2016 May	16	10	26
2016 April	14	12	26
2016 March	23	18	41
2016 February	22	16	38
2016 January	18	15	33
2015 December	13	13	26
2015 November	10	12	22
2015 October	23	17	40
2015 September	0	1	1
2015 August	0	1	1
2015 April	0	1	1
2014 October	0	1	1
2014 January	11	6	17
2013 December	15	10	25
2013 November	17	13	30

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