RESEARCH ARTICLE. Meat Consumption, Animal Products, and the Risk of Bladder Cancer: A Case-Control Study in Uruguayan Men

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1 Met Consumption, Animl Products, nd the Risk of Bldder Cncer: A Cse-Control Study in Uruguyn Men RESEARCH ARTICLE Met Consumption, Animl Products, nd the Risk of Bldder Cncer: A Cse-Control Study in Uruguyn Men Alvro Luis Ronco 1, Mri Mendilhrsu 2, Polo Boffett 3, Hugo Deneo- Pellegrini 2, Edurdo De Stefni 2 * Abstrct In the time period , ll incident cses of bldder cncer were included in cse-control study in order to study the role of met consumption nd product nimls in the etiology of urothelil cncer. The study included 225 cses nd 1,510 hospitlized controls with non-neoplstic conditions, not relted to smoking nd lcohol drinking. Reltive risks, pproximted by the odds rtios, were clculted in order to clrify the effect of met consumption in the etiology of urothelil cncer. Totl met consumption (OR 1.47, 95% CI ), totl processed met (OR 1.57, 95% CI ), frnkfurters (hot dogs) (OR 2.03, 95% CI ), hm (OR 1.79, 95% CI ) nd slted met (OR 2.73, 95% CI ) were positively ssocited with risk of bldder cncer. Animl products, like cheese, whole milk, nd totl eggs were lso ssocited with bldder cncer risk (OR for eggs 4.05, 95% CI ). In conclusion, totl met, processed met, nd eggs could ply n importnt role in the etiology of bldder cncer in Uruguy. Keywords: Bldder cncer - met consumption - red met - processed met - eggs - cholesterol - Uruguy Asin Pc J Cncer Prev, 15 (14), Introduction Urinry bldder crcinom (minly trnsitionl crcinom) is frequent mlignncy mong the mle Uruguyn popultion (ge-stndrdized incidence rte 23.4 per 100,000 men) (Brrios et l., 2010). According to the recent monogrph by the World Cncer Reserch Fund/Americn Institute for Cncer Reserch (World Cncer Reserch Fund, 2007) there is limited evidence suggesting tht milk nd clcium protect ginst bldder cncer nd tht rsenic in drinking wter is cuse of this mlignncy. Moreover, ccording to this monogrph (World Cncer Reserch Fund, 2007) met intke is not convincing cuse of bldder cncer. Studies conducted in Irn (Rohni-Rsf et l., 2013) nd in the Pcific Islnds (Moore et l., 2009) showed lower incidence rtes of bldder cncer. Conversely, multisite cse-control conducted in Uruguy (De Stefni et l., 2012) reported n incresed risk of bldder cncer ssocited with processed met intke. Also, the study by Tvni et l. (2000) showed n incresed risk of bldder cncer ssocited with red met consumption. Therefore, the reltionship between red nd processed met consumption nd bldder cncer deserves to be studied further. For this reson we decided to conduct cse-control study in Uruguy, in order to explore the reltionship between met consumption nd risk of bldder cncer in high risk country like Uruguy. Mterils nd Methods Selection of cses In the time period , ll newly dignosed nd microscopiclly vlidted cses of trnsitionl-cell crcinom of the urinry bldder occurring in men were considered eligible for this study. A totl of 230 mle cses were pproched for possible interview nd five ptients refused, leving 225 cses for inclusion in the study (response rte 97.8%). All the cses were drwn from the four mjor public helth hospitls in Montevideo, Uruguy. Selection of controls In the sme time period nd in the sme hospitls, ll men fflicted with non neoplstic conditions not relted to smoking nd lcohol drinking were considered eligible for the study. A totl of 1,555 potentil controls were pproched for possible interview, nd 45 ptients refused, leving finl totl of 1,510 controls, which were included in the study (response rte 97.1%). These controls presented the following diseses: eye disorders (382 ptients, 25.3%), bdominl herni (337, 22.3%), frctures (158, 10.5%), injuries (122, 8.1%), diseses of the skin 1 Deprtment of Epidemiology, School of Medicine IUCLAEH, Mldondo, 2 Epidemiology Group, Deprtment of Pthology, School of Medicine, Uruguy, 3 The Tisch Cncer Institute, Mount Sini School of Medicine, New York, USA *For correspondence: edestefni@gmil.com Asin Pcific Journl of Cncer Prevention, Vol 15,

2 Alvro Luis Ronco et l (112, 7.4%), cute ppendicitis (91, 6.0%), vricose veins (80, 5.3%), hydtid cyst (66, 4.4%), urinry stones (56, 3.7%), blood disorders (52, 3.4%), prostte hypertrophy (33, 2.2%), nd diseses of the bone (21, 1.4%). Interviews nd questionnire All the prticipnts (cses nd controls) were dministered structured questionnire by two trined socil workers shortly fter dmittnce to the hospitls. All the interviews were performed fce-to-fce nd proxy interviews were not llowed. The questionnire included the following sections: sociodemogrphics (lst nme, first nme, ge, residence, eduction, monthly income, identifiction number), self-reported height nd weight five yers before the dte of interview, fmily history of bldder cncer mong first-degree reltives, complete occuptionl history bsed on the lst four jobs nd their durtion, complete history of smoking (ge t strt, ge t quit, number of cigrettes smoked per dy, type of tobcco, type of cigrette, inhltion prctices), complete lcohol drinking history (ge t strt, ge t quit, number of glsses per dy or week, type of lcoholic beverge), complete history of non-lcoholic beverges (mte, coffee, coffee with milk, te, te with milk, soft drinks), nd food frequency questionnire (FFQ) on 64 food items. The FFQ recorded the consumption of foods in servings/yers nd the corresponding portion size per food. Therefore, we mnged the consumption of foods in grms per dy. The nutrients were clculted following Tble of chemicl consumption of the foods. This FFQ llowed the estimtion of totl energy intke nd ws considered representtive of the Uruguyn diet. Although it ws not vlidted, it ws tested for reproducibility with good results (Ronco et l., 2006). Foods nd nutrients included into the study The following items were included in the study: totl met (beef, lmb, poultry, fish, liver, processed met), red met (beef, lmb), poultry, fish, totl processed met (bcon, susge, mortdell, slmi, sucisson, hot dog, hm, slted met), liver, totl vegetbles nd fruits, boiled eggs, fried eggs, totl eggs, cheese, butter, whole milk, dietry cholesterol, sodium, nitrite, nitrte, nitroso compounds. All the food nd nutrients were energy djusted using the residuls method (Willett, 1998). Sttisticl nlysis Reltive risks of bldder cncer, pproximted by the odds rtios, were estimted by unconditionl multiple logistic regression (Rothmn et l., 2008). We fitted the following model: ge (continuous), residence (ordinl), eduction (ctegoricl), tobcco smoking in pck yers (ctegoricl), lcohol drinking (ctegoricl), mte consumption (ctegoricl), totl energy intke (continuous), totl vegetbles nd fruits (continuous). This bsic model further included severl terms of risk fctors for the study (met intke, diry foods, totl eggs, nd selected nutrients). All the estimtes were two-sided nd P vlue ws considered s significnt s lph of 95%. All the clcultions were estimted using the sttisticl softwre Stt, relese 13.1 (Stt Corp, 2013) Asin Pcific Journl of Cncer Prevention, Vol 15, 2014 Results Distribution of cses nd controls by sociodemogrphics nd selected risk fctors re shown in Tble 1. Age, residence, eduction, nd monthly income were rther similr mong both groups of prticipnts. Smoking nd mte consumption showed significntly higher percentges mong cses compred with controls. Odds rtios of bldder cncer for types of met re shown in Tble 2. Odds rtios for the higher tertile versus the first tertile were positively ssocited with bldder cncer risk for totl met (OR 1.47, 95% CI ), processed met (OR 1.55, 95% CI ), hot dog (OR 2.16, 95% CI ), hm (OR 1.83, 95% CI ), nd slted met (OR 2.37, 95% CI ). Red met, poultry, fish, liver, bcon, susge, sucisson, mortdell, nd slmi were not ssocited with risk of bldder cncer. The ORs of red met for cooking methods re shown in Tble 3. Brbecued red met ws positively ssocited with risk of bldder crcinom (OR 1.96, 95% CI ). Boiled red met ws lso positively ssocited with bldder cncer (OR 1.52, 95% CI ). Fried red met ws not ssocited with bldder cncer (OR 1.04, 95% ). The effect of niml products is shown in Tble 4. Cheese consumption ws protective (OR 0.60, 95% CI , P vlue for trend = 0.006) nd whole milk ws positively ssocited with bldder cncer (OR 1.45, 95% , P vlue for trend = 0.04). Eggs consumption (boiled eggs, fried eggs, nd totl eggs) displyed high Tble 1. Distribution of Cses nd Controls by Sociodemogrphics nd Selected Risk Fctors Vrible Ctegory Cses Controls Globl No % No % p vlue Age (yers) Residence Urbn Rurl Eduction (yrs) Monthly income (US dollrs) Missing vlues Smoking Never smokers (pck yers) Alcohol Never drinkers drinking (ml/ethnol) Mte Never drinkers consumption (liters/dy) < No ptients

3 Met Consumption, Animl Products, nd the Risk of Bldder Cncer: A Cse-Control Study in Uruguyn Men Tble 2. Odds Rtios of Bldder Cncer for Met Consumption b Type of met Tertiles p vlue trend Totl met b 60/503 74/504 91/ ( ) 1.47 ( ) Red met 71/503 64/504 90/ ( ) 1.18 ( ) 0.33 Poultry 74/503 68/504 83/ ( ) 1.16 ( ) 0.41 Fish 68/503 80/504 77/ ( ) 1.24 ( ) /503 76/504 90/503 Processed met ( ) 1.55 ( ) /503 94/504 62/503 Bcon, susge mortdell ( ) 0.91 ( ) /925 37/248 48/337 Slmi ( ) 0.99 ( ) / /237 44/188 Hot dog ( ) 2.16 ( ) < / /190 51/234 Hm ( ) 1.83 ( ) / /69 41/128 Slted met ( ) 2.37 ( ) /503 92/504 65/503 Liver ( ) 0.95 ( ) 0.61 Multivrite ORs djusted for ge, residence, eduction, body mss index, smoking, lcohol drinking, mte consumption, totl energy, nd totl vegetbles nd fruits intkes. b Number of cses nd controls by tertiles Tble 3. Odds Rtios of Bldder Cncer for Cooked Red Met b Met cooking Tertiles p vlue trend Fried met b 73/503 78/504 74/ ( ) 1.04 ( ) 0.91 Brbecued met 58/503 60/ / ( ) 1.96 ( ) Boiled met 65/503 62/504 98/ ( ) 1.52 ( ) 0.03 Multivrite ORs djusted for ge, residence, eduction, body mss index, smoking, lcohol drinking, mte consumption, totl energy, nd totl vegetbles nd fruits intkes; b Number of cses nd controls by tertiles Tble 4. Odds Rtios of Bldder Cncer for Animl Products b Food Tertiles p vlue trend Cheese b 92/503 78/504 55/ ( ) 0.60 ( ) Butter 80/503 58/504 87/ ( ) 1.06 ( ) 0.70 Whole milk 62/503 73/504 90/ ( ) 1.45 ( ) 0.04 Boiled eggs 45/503 59/ / ( ) 2.76 ( ) < Fried eggs 43/503 57/ / ( ) 2.79 ( ) < Totl eggs 33/503 61/ / ( ) 4.05 ( ) < Multivrite ORs djusted for ge, residence, eduction, body mss index, smoking, lcohol drinking, mte consumption, totl energy, nd totl vegetbles nd fruits intkes; b Number of cses nd controls by tertiles Tble 5. Odds Rtios of Bldder Cncer for Dietry Cholesterol, Sodium, Nitrite, Nitrte, nd NOC Compounds Nutrients Tertiles p vlue trend risk of bldder cncer (OR 4.05, 95% CI , P vlue for trend <0.0001). The effect of selected nutrients in bldder cncer etiology is shown in Tble 5 Dietry cholesterol ws strongly ssocited with risk of bldder cncer (OR 4.84, 95% , P vlue for liner trend <0.0001). Also higher risk ws observed mong sodium nd NDMA (OR for the higher tertile vs the lower tertile of NDMA 2.14, 95% CI , P vlue trend = ). Nitrite intke ws not ssocited with bldder cncer risk. The finl model for foods ws fitted using the stepwise forwrd method (Tble 6). The following vribles were included in this finl model: totl eggs (OR 1.90, 95% CI ), slted met (OR 1.41, 95% CI ), hot dog (frnkfurter) (OR 1.39, 95% CI ) nd cheese (OR 0.78, 95% CI ). Discussion Cholesterol ( ) 4.84 ( ) < Sodium ( ) 2.07 ( ) Nitrite ( ) 1.35 ( ) 0.11 Nitrte ( ) 1.86 ( ) NDMA b ( ) 2.14 ( ) Multivrite ORs djusted for ge, residence, eduction, body mss index, smoking, lcohol drinking, mte consumption, totl energy, nd totl vegetbles nd fruits intkes Tble 6. Finl Model Fitted by Stepwise Forwrd Method Foods OR (95% CI) z p vlue Totl eggs 1.90 ( ) 6.24 < Slted met 1.41 ( ) Hot dog 1.39 ( ) Cheese 0.78 ( ) Multivrite ORs djusted for ge, residence, eduction, body mss index, smoking, lcohol drinking, mte consumption, totl energy, nd totl vegetbles nd fruits intkes According to the results of the present study, positive ssocitions between met consumption nd bldder cncer risk were observed. Totl met, totl processed met, frnkfurter (hot dog), hm, nd slted met showed moderte to high risk increse of bldder cncer. Severl studies hve reported results concerning met intke nd bldder cncer risk (L Vecchi nd Negri, 1996; Wilkens et l., 1996; Tvni et l., 2000; Cstelo et l., 2004; Wki et l., 2004; Grci-Closs et l., 2007; Hu et l., 2008; De Stefni et l., 2012). Associtions from cse-control studies of bldder cncer nd met intke hve been somewht inconsistent. A mrginlly significnt 30% incresed risk ws reported for red met nd significnt 60% incresed risk ws reported for processed met in Cndin cse-control study (Hu et l., 2008). Tvni et l. (2000) observed significnt 60% incresed risk mong the highest consumers of red met in study conducted in Itly. In contrst, Wki et l. (2004) observed non-significnt decresed risks for beef, Asin Pcific Journl of Cncer Prevention, Vol 15,

4 Alvro Luis Ronco et l pork, hm nd susge, nd Cstelo et l. (2004) reported non-significnt inverse ssocitions for the highest intke levels of processed met nd preformed nitrosmine. In recently published cse-control study conducted in Spin, non-significnt odds rtio of 0.8 ws reported for red met intke nd non-significnt odds rtio of 1.2 ws reported for processed met intke (Grci-Closs et l., 2007). Finlly, Wilkens et l. (1996) showed n incresed risk of bldder cncer ssocited with bcon consumption. Two recent prospective studies reported conflictive results concerning processed met consumption nd bldder cncer risk (Michud et l., 2006; Jkszyn et l., 2011). Wheres the EPIC prospective study reported null results (Jkszyn et l., 2011), the study by Michud et l. showed n incresed risk of bldder cncer ssocited with bcon intke (Michud et l., 2006). A third prospective study on met intke nd risk of bldder cncer displyed gin null results on the effect of met consumption (Lrsson et l., 2009). Thus, both cse-control nd prospective studies showed conflicting results concerning met intke nd bldder cncer risk. A multisite cse-control study conducted by Aune et l. (2009) in Uruguy displyed significnt positive ssocition between red met nd beef with bldder cncer. In similr study bsed on different popultion, red met nd beef were gin ssocited with n incresed risk of bldder cncer (Aune et l., 2009b). Both multisite studies showed null ssocition between processed met nd bldder cncer risk. Finlly, nother multisite study focused on slted met nd cncer showed strong positive ssocition between slted met intke nd risk of bldder cncer (De Stefni et l., 2009). Slted met, lso known s chrque, is food which is considered prt of the group of processed mets nd is chrcterized by rich content in N-Nitroso compounds. It is thus noteworthy tht the present study showed strong positive ssocition of chrque (slted met) with bldder cncer, replicting the findings of the previous study. Eggs consumption nd dietry cholesterol displyed elevted ORs for bldder cncer. The effect of both vribles ws, in fct, strongly nd positively ssocited with bldder cncer nd totl eggs showed the highest risk of bldder cncer mong foods studied in the finl model. Previous studies (Blbi et l., 2001; Aune et l., 2009c; De Stefni et l., 2011; Hu et l., 2012; Fng et l., 2012) reported n increse in risk of bldder cncer for dietry cholesterol nd totl eggs consumption. Also, diry foods were relted with risk of bldder cncer. In our study, cheese intke ws protective, wheres whole milk displyed modertely positively ssocition with bldder cncer risk. Our findings replicted the findings of Brennn et l. (2000), showing n inverse ssocition of cheese with non-smokers in lung cncer. As other cse-control studies, the present study hs strengths nd limittions. The high response rtes, both for cses nd controls, is mjor strength of the study. Selection bis nd recll bis re the mjor limittions. Selection bis is unlikely since cses nd controls were drwn from the sme bse popultion. On the other hnd, recll bis is very difficult to mnge, since this bis could result in misclssifiction, differentil or non-differentil, 5808 Asin Pcific Journl of Cncer Prevention, Vol 15, 2014 which could led to erroneous estimtes. In conclusion, the present study showed tht totl met, processed met, hot dog, hm, slted met, boiled eggs, fried eggs, totl eggs, nd whole milk were positively ssocited with incresed risk of bldder cncer. These ssocitions suggest tht met intke nd eggs could be importnt risk fctors in urothelil crcinom of the urinry bldder. References Aune D, De Stefni E, Ronco AL, et l (2009). Met consumption nd cncer risk: cse-control study in Uruguy. Asin Pc J Cncer Prev, 10, Aune D, Ronco A, Boffett P, et l (2009b). Met consumption nd cncer risk: multisite cse-control study in Uruguy. Cncer Therpy, 7, Aune D, De Stefni E, Ronco AL, et l (2009c). 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