Colorectal Cancer and Long-Term Exposure to Trihalomethanes in Drinking Water: A Multicenter Case–Control Study in Spain and Italy

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

. Previous studies evaluating colorectal cancer from individual-based studies (casecontrol or cohort designs) including incident cases with exposure assessment based on personal information from residential histories Table S2. Single nucleotide polymorphisms (SNPs) of CYP2E1 and GSTZ1 examined in the Spanish population of the study, and interaction p-value for total trihalomethanes (THM), chloroform (CHCl 3 ), and brominated THMs (BrTHM) dichotomized at the percentile 75, that are respectively 60, 20 and 40 µg/l. Figure S1. Distribution of exposure density of average lifetime THM concentrations in residential tap water (µg/l) among 1837 cases and 3488 controls with exposure estimates ≥70% of the exposure window. Note that scale of x-and y-axes differ by area. Figure S2. Exposure-response relationship between residential trihalomethane (THM) levels (X axis, in µg/l) and colorectal cancer risk (Y axis, expressed in odds ratios) among 1837 cases and 3454 controls. Odds ratios (95 CI) are adjusted for sex, age, area, education, smoking, physical activity, non-steroidal anti inflammatory drugs and family history of colorectal cancer. Excludes unsatisfactory questionnaires and subjects with THM estimated less than 70% from the exposure window. Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals. Figure S3. Spline of colorectal cancer risk (odds ratio, Y axis) associated with chloroform levels (µg/l, X axis) among men, from generalized additive models adjusted for age, sex, education, smoking, non-steroidal anti inflammatory drugs, smoking, physical activity and family history of colorectal cancer. P-value of gain from the linearity is statistically significant in Barcelona (p-value <0.001), Leon (p-value 0.03), Madrid (p-value 0.04), and Navarra (pvalue 0.01). Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals. Note that scale of x -axes differ by area. Figure S4. Spline of colorectal cancer risk (odds ratio, Y axis) associated with total brominated THM levels (µg/l, X axis) among men, from generalized additive models adjusted for age, sex, education, smoking, non-steroidal anti inflammatory drugs, smoking, physical activity and family history of colorectal cancer. P-value of gain from the linearity is statistically significant in Barcelona (p-value <0.001), Cantabria (p-value <0.01), and Navarra (p-value <0.01). Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals. Note that scale of x-axes differ by area. Figure S5. Exposure-response relationship between ingested THM levels (X axis) and colorectal cancer (Y axis, expressed in odds ratios (OR) with 95% confidence intervals (95% CI)) among 2047 cases and 3684 controls. Adjusted for sex, age, area, education, smoking, physical activity, non-steroidal anti inflammatory drugs, and family history of cancer.
Excludes unsatisfactory interviews and subjects with less than 70% THM estimated from the exposure window. P-value gain compared to linearity is <0.01 for all models, expect for chloroform in women (p-value=0.32). Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals.Note that scale of x-axes differ by area. Figure S6. Exposure-response relationship between shower-bath THM levels (X axis) and colorectal cancer risk (Y axis, expressed in odds ratios (OR) with 95% confidence intervals (95% CI)) among 1702 cases and 3269 controls. Adjusted for (sex), age, geographical area, education, non steroidal anti inflammatory drugs consumption, smoking, physical activity and family history of colorectal cancer Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals. Note that scale of x-axes differ by area.    . Exposure-response relationship between residential trihalomethane (THM) levels (X axis, in g/l) and colorectal cancer risk (Y axis, expressed in odds ratios) among 1837 cases and 3454 controls. Odds ratios (95 CI) are adjusted for sex, age, area, education, smoking, physical activity, non-steroidal anti inflammatory drugs and family history of colorectal cancer. Excludes unsatisfactory questionnaires and subjects with THM estimated less than 70% from the exposure window. Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals. Note that scale of x -axes differs by chemical.

OR (95% CI)
Chloroform ( Figure S3. Spline of colorectal cancer risk (odds ratio, Y axis) associated with chloroform levels (g/l, X axis) among men, from generalized additive models adjusted for age, sex, education, smoking, non-steroidal anti inflammatory drugs, smoking, physical activity and family history of colorectal cancer. P-value of gain from the linearity is statistically significant in Barcelona (p-value <0.001), Leon (p-value 0.03), Madrid (p-value 0.04), and Navarra (p-value 0.01). Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals. Note that scale of x -axes differs by area.
Asturias ( Figure S4. Spline of colorectal cancer risk (odds ratio, Y axis) associated with total brominated THM levels (g/l, X axis) among men, from generalized additive models adjusted for age, sex, education, smoking, non-steroidal anti inflammatory drugs, smoking, physical activity and family history of colorectal cancer. P-value of gain from the linearity is statistically significant in Barcelona (p-value <0.001), Cantabria (p-value <0.01), and Navarra (p-value <0.01). Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals. Note that scale of x-axes differs by area.
Asturias ( Figure S5. Exposure-response relationship between ingested THM levels (X axis) and colorectal cancer (Y axis, expressed in odds ratios (OR) with 95% confidence intervals (95% CI)) among 2047 cases and 3684 controls. Adjusted for sex, age, area, education, smoking, physical activity, non-steroidal anti inflammatory drugs, and family history of cancer. Excludes unsatisfactory interviews and subjects with less than 70% THM estimated from the exposure window. P-value gain compared to linearity is <0.01 for all models, expect for chloroform in women (p-value=0.32 Figure S6. Exposure-response relationship between shower-bath THM levels (X axis) and colorectal cancer risk (Y axis, expressed in odds ratios (OR) with 95% confidence intervals (95% CI)) among 1702 cases and 3269 controls. Adjusted for (sex), age, geographical area, education, non steroidal anti inflammatory drugs consumption, smoking, physical activity and family history of colorectal cancer Tick marks above the x-axes represent observations, and the dashed lines represent the 95% confidence intervals. Note that scale of x-axes differs by area.