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Several epidemiological studies have investigated the association between the dietary flavonoid intake and gastric cancer (GC) risk; however, the results remain inconclusive. Investigating the relationship between the different classes of flavonoids and the histological types and origin of GC can be of interest to the research community. We used data from a population-based multi-case control study (MCC-Spain) obtained from 12 different regions of Spain. 2700 controls and 329 GC cases were included in this study. Odds ratios (ORs) were calculated using the mixed effects logistic regression considering quartiles of flavonoid intakes and log2. Flavonoid intake was associated with a lower GC risk (ORlog2 = 0.76; 95% CI = 0.65-0.89; ORq4vsq1 = 0.60; 95%CI = 0.40-0.89; ptrend = 0.007). Inverse and statistically significant associations were observed with anthocyanidins, chalcones, dihydroflavonols and flavan-3-ols. The isoflavanoid intake was positively associated with higher cancer risk, but without reaching a statistical significance. In general, no differences were observed in the GC risk according to the location and histological type. The flavonoid intake seems to be a protective factor against GC within the MCC-study. This effect may vary depending on the flavonoid class but not by the histological type and location of the tumor. Broader studies with larger sample size and greater geographical variability are necessary. ; The study was partially funded by the "Accion Transversal del Cancer", approved on the Spanish Ministry Council on 11 October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI17CIII/00034), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)), by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, salud201200057018tra), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation – grant GCTRA18022MORE, by the Catalan Government- Agency for Management of University and Research Grants (AGAUR) grants 2017SGR723 and 2014SGR850, by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya.

BACKGROUND: Exposure to trihalomethanes (THMs) in drinking water has consistently been associated with an increased risk of bladder cancer, but evidence on other cancers including the breast is very limited. OBJECTIVES: We assessed long-term exposure to THMs to evaluate the association with female breast cancer (BC) risk. METHODS: A multi case-control study was conducted in Spain from 2008 to 2013. We included 1003 incident BC cases (women 20-85years old) recruited from 14 hospitals and 1458 population controls. Subjects were interviewed to ascertain residential histories and major recognized risk factors for BC. Mean residential levels of chloroform, brominated THMs (Br-THMs) and the sum of both as total THM (TTHMs) during the adult-lifetime were calculated. RESULTS: Mean adult-lifetime residential levels ranged from 0.8 to 145.7μg/L for TTHM (median=30.8), from 0.2 to 62.4μg/L for chloroform (median=19.7) and from 0.3 to 126.0μg/L for Br-THMs (median=9.7). Adult-lifetime residential chloroform was associated with BC (adjusted OR=1.47; 95%CI=1.05, 2.06 for the highest (>24μg/L) vs. lowest (31μg/L vs. 48μg/L vs. <22μg/L). CONCLUSIONS: At common levels in Europe, long-term residential total THMs were not related to female breast cancer. A moderate association with chloroform was suggested at the highest exposure category. This large epidemiological study with extensive exposure assessment overcomes several limitations of previous studies but further studies are needed to confirm these results. ; This work was supported by the Acción Transversal del Cáncer del Consejo de Ministros del 11/10/2007, from the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI11/00226, PI11/02213, PI14/00613) FIS grants and Hiwate EU project (036224), Catalan Government DURSI grant 2014SGR647. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. ; Sí

Several epidemiological studies have investigated the association between the dietary flavonoid intake and gastric cancer (GC) risk; however, the results remain inconclusive. Investigating the relationship between the different classes of flavonoids and the histological types and origin of GC can be of interest to the research community. We used data from a population-based multi-case control study (MCC-Spain) obtained from 12 different regions of Spain. 2700 controls and 329 GC cases were included in this study. Odds ratios (ORs) were calculated using the mixed effects logistic regression considering quartiles of flavonoid intakes and log2. Flavonoid intake was associated with a lower GC risk (ORlog2 = 0.76; 95% CI = 0.65–0.89; ORq4vsq1 = 0.60; 95%CI = 0.40–0.89; ptrend = 0.007). Inverse and statistically significant associations were observed with anthocyanidins, chalcones, dihydroflavonols and flavan-3-ols. The isoflavanoid intake was positively associated with higher cancer risk, but without reaching a statistical significance. In general, no differences were observed in the GC risk according to the location and histological type. The flavonoid intake seems to be a protective factor against GC within the MCC-study. This effect may vary depending on the flavonoid class but not by the histological type and location of the tumor. Broader studies with larger sample size and greater geographical variability are necessary. ; The study was partially funded by the "Accion Transversal del Cancer", approved on the Spanish Ministry Council on 11 October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773-Cantabria, PS09/01286-León, PS09/01903-Valencia, PS09/02078-Huelva, PS09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI17CIII/00034), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL (The ICGC CLL-Genome Project is funded by Spanish Ministerio de Economía y Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)), by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, salud201200057018tra), by the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country, by the Consejería de Sanidad de la Región de Murcia, by the European Commission grants FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation – grant GCTRA18022MORE, by the Catalan Government- Agency for Management of University and Research Grants (AGAUR) grants 2017SGR723 and 2014SGR850, by the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya

BACKGROUND: Evidence on the association between colorectal cancer and exposure to disinfection by-products in drinking water is inconsistent. OBJECTIVES: We assessed long-term exposure to trihalomethanes (THMs), the most prevalent group of chlorination by-products, to evaluate the association with colorectal cancer. METHODS: A multicenter case-control study was conducted in Spain and Italy in 2008-2013. Hospital-based incident cases and population-based (Spain) and hospital-based (Italy) controls were interviewed to ascertain residential histories, type of water consumed in each residence, frequency and duration of showering/bathing, and major recognized risk factors for colorectal cancer. We estimated adjusted odds ratios (OR) for colorectal cancer in association with quartiles of estimated average lifetime THM concentrations in each participant's residential tap water (micrograms/liter; from age 18 to 2 years before the interview) and estimated average lifetime THM ingestion from drinking residential tap water (micrograms/day). RESULTS: We analyzed 2,047 cases and 3,718 controls. Median values (ranges) for average lifetime residential tap water concentrations of total THMs, chloroform, and brominated THMs were 30 (0-174), 17 (0-63), and 9 (0-145) μg/L, respectively. Total THM concentration in residential tap water was not associated with colorectal cancer (OR = 0.92, 95% CI: 0.66, 1.28 for highest vs. lowest quartile), but chloroform concentrations were inversely associated (OR = 0.31, 95% CI: 0.24, 0.41 for highest vs. lowest quartile). Brominated THM concentrations showed a positive association among men in the highest versus the lowest quartile (OR = 1.43, 95% CI: 0.83, 2.46). Patterns of association were similar for estimated average THM ingestion through residential water consumption. CONCLUSIONS: We did not find clear evidence of an association between detailed estimates of lifetime total THM exposure and colorectal cancer in our large case-control study population. Negative associations with chloroform concentrations and ingestion suggest differences among specific THMs, but these findings should be confirmed in other study populations. Citation: Villanueva CM, Gracia-Lavedan E, Bosetti C, Righi E, Molina AJ, Martín V, Boldo E, Aragonés N, Perez-Gomez B, Pollan M, Gomez Acebo I, Altzibar JM, Jiménez Zabala A, Ardanaz E, Peiró R, Tardón A, Chirlaque MD, Tavani A, Polesel J, Serraino D, Pisa F, Castaño-Vinyals G, Espinosa A, Espejo-Herrera N, Palau M, Moreno V, La Vecchia C, Aggazzotti G, Nieuwenhuijsen MJ, Kogevinas M. 2017. Colorectal cancer and long-term exposure to trihalomethanes in drinking water: a multicenter case---control study in Spain and Italy. Environ Health Perspect 125:56-65; http://dx.doi.org/10.1289/EHP155. ; We appreciate the contribution of the institutions and local governments that provided data on municipal water in Spain, particularly to J. Lázaro Arias Paredes (Mancomunidad de Canales del Taibilla, Murcia, Spain). We also thank F. Gallino (IRCCS, Istituto Nazionale dei Tumori, Milan, Italy), A. Tonini and C. Dellanoce (Ospedale Niguarda Cà Granda, Milan, Italy) for their collaboration in conducting the study. We appreciate the contribution of G. Sesana and D. Ravetta of the regional Environmental Health Agency "Arpa Lombardia" and the contribution of E. Zamparo and F. del Bianco of the Health Authority n.5 "Friuli Occidentale" for providing data on DBPs (disinfection by-products) in Italian drinking water. We thank L. Font-Ribera and L.A. Salas for comments on the draft manuscript and X. Basagaña for the contribution to the statistical approach. ; Sí