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Cited by 94Water Treatment and DisinfectionMetabolomics and Mass Spectrometry StudiesHealth, Environment, Cognitive Aging

Effects of exposure to water disinfection by-products in a swimming pool: A metabolome-wide association study

Open access
van Veldhoven, Karin, Keski-Rahkonen, Pekka, Barupal, Dinesh K., Villanueva, Cristina M., Font-Ribera, Laia, Scalbert, Augustin, Bodinier, Barbara, Grimalt, Joan O. +7 more·2018·Environment International
DOI 10.1016/j.envint.2017.11.017PMC PMC5786667
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Abstract

BACKGROUND: Exposure to disinfection by-products (DBPs) in drinking water and chlorinated swimming pools are associated with adverse health outcomes, but biological mechanisms remain poorly understood. OBJECTIVES: Evaluate short-term changes in metabolic profiles in response to DBP exposure while swimming in a chlorinated pool. MATERIALS AND METHODS: The PISCINA-II study (EXPOsOMICS project) includes 60 volunteers swimming 40min in an indoor pool. Levels of most common DBPs were measured in water and in exhaled breath before and after swimming. Blood samples, collected before and 2h after swimming, were used for metabolic profiling by liquid-chromatography coupled to high-resolution mass-spectrometry. Metabolome-wide association between DBP exposures and each metabolic feature was evaluated using multivariate normal (MVN) models. Sensitivity analyses and compound annotation were conducted. RESULTS: Exposure levels of all DBPs in exhaled breath were higher after the experiment. A total of 6,471 metabolic features were detected and 293 features were associated with at least one DBP in exhaled breath following Bonferroni correction. A total of 333 metabolic features were associated to at least one DBP measured in water or urine. Uptake of DBPs and physical activity were strongly correlated and mutual adjustment reduced the number of statistically significant associations. From the 293 features, 20 could be identified corresponding to 13 metabolites including compounds in the tryptophan metabolism pathway. CONCLUSION: Our study identified numerous molecular changes following a swim in a chlorinated pool. While we could not explicitly evaluate which experiment-related factors induced these associations, molecular characterization highlighted metabolic features associated with exposure changes during swimming.

AI snapshot

Written from the paper’s full text.

TL;DR

In 60 adults who swam for 40 min in an indoor chlorinated pool, DBP exposure increased and hundreds of serum metabolic features changed. Associations were strongly entangled with physical activity, but annotation implicated tryptophan metabolism and other pathways.

Key findings

  • Exhaled breath THMs increased after swimming: chloroform rose from 0.44 ± 0.31 to 11.54 ± 4.74 μg/m³, and total THMs from 0.55 ± 0.37 to 14.68 ± 6.06 μg/m³; creatinine-adjusted urinary TCAA rose from 3.66 ± 3.41 to 10.05 ± 10.10 mmol TCAA/mol creatinine.
  • A total of 6,471 metabolic features were analyzed; 293 were associated with at least one DBP in exhaled breath after Bonferroni correction, and 333 were associated with at least one DBP measured in water or urine. Of the 293 exhaled-breath-associated features, 224 (76%) were upregulated with increased exposure.
  • Adjusting for energy expenditure drastically reduced significant associations: for exhaled breath, chloroform went from 249 to 4 features, BDCM from 269 to 1, DBCM from 222 to 0, bromoform from 151 to 0, and BrTHM/TTHM from 258 to 1. None of the Model 1 associations remained significant after adjusting for the pre-post swimming indicator.
  • From the 293 features, 20 were identified corresponding to 13 metabolites, including tryptophan-pathway compounds; kynurenine and tryptophan were down-regulated, xanthosine was up-regulated, and cortisol/cortisone were lower. Four unidentified chlorinated compounds were also found.

Methods

  • PISCINA-II study (EXPOsOMICS): 116 volunteers swam 40 min in a 25 m indoor chlorinated pool in Barcelona; 60 were selected for metabolomic profiling, with blood serum collected before and 2 h after swimming.
  • Exposures included DBPs in swimming pool water, exhaled breath THMs before and after swimming, and urinary TCAA before and 30 min after swimming; metabolomics used UHPLC-QTOF-MS.
  • Metabolome-wide association used multivariate normal models with repeated measures, adjusted for age, sex, and BMI, with Bonferroni correction; sensitivity analyses included random 90% subsampling and compound annotation.

Limitations

  • The paper states that DBP levels, physical activity, and the metabolome were highly correlated, so it could not clearly separate effects of DBPs from physical activity or other experiment-related factors; none of the main exposure associations remained significant after adjusting for the pre-post swimming indicator.
  • The paper reports incomplete annotation: 185 of 293 features did not match HMDB by mass, only 20 features were identified to 13 metabolites, and four chlorinated compounds remained unidentified.
  • Evident from the text: the sample was 60 healthy non-smoking adults aged 18–37 from a single indoor pool, with short-term before/after sampling, limiting generalizability and long-term inference; exposures with >25% missing measurements were excluded.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.envint.2017.11.017

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    From the 293 features, 20 could be identified corresponding to 13 metabolites including compounds in the tryptophan metabolism pathway.

    “From the 293 features, 20 could be identified corresponding to 13 metabolites including compounds in the tryptophan metabolism pathway.”
    Quote in the paperSubstantial claim
  • Findingown data

    Uptake of DBPs and physical activity were strongly correlated.

    “Uptake of DBPs and physical activity were strongly correlated”
    Quote in the paperSubstantial claim
  • Findingown data

    333 metabolic features were associated with at least one DBP measured in water or urine.

    “A total of 333 metabolic features were associated to at least one DBP measured in water or urine.”
    Quote in the paperSubstantial claim
  • Findingown data

    Mutual adjustment for physical activity reduced the number of statistically significant associations between DBP exposure and metabolic features.

    “mutual adjustment reduced the number of statistically significant associations.”
    • Also stated in: § Metabolic profiles · plain
      “Adjusting Model 1 for energy expenditure (kcal, Model 2) drastically reduced the number of statistically significant associations: 4 metabolic features were found associated with CHCl3, and one with BDCM, BrTHM and TTHM (Table 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    Exposure levels of all DBPs in exhaled breath were higher after the experiment.

    “Exposure levels of all DBPs in exhaled breath were higher after the experiment.”
    • Also stated in: § Study population and DBP exposures · plain
      “Exposure to all four trihalomethanes measured in exhaled breath, as well as the total trihalomethanes and the brominated trihalomethanes were all significantly higher after the swimming experiment compared to levels measured before the swim (Table 2).”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 41
  • May combine two claims. 28

  • The quote only partly states this claim.

    Findingown data

    293 metabolic features were associated with at least one DBP in exhaled breath following Bonferroni correction.

    “Our model identified a total of 293 metabolic features that were associated with at least one exposure level.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A total of 6,471 metabolic features were detected or included in the analyses.

    “A total of 6,471 metabolic features were detected”
    • Also stated in: § Metabolic profiles · plain
      “After imputation, a total of 6471 metabolic features were included in the analyses”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Searching the computed formulas in PubChem, TOXNET, and ChemSpider returned matches only for Compound 1 (1679 results, ChemSpider), and lack of MS/MS spectra for Compound 1 prevented in-silico fragmentation-based screening of database candidates for its structural elucidation.

    “Searching these formulas in the chemical structure databases PubChem, TOXNET, and ChemSpider returned matches only for the Compound 1 (1679 results, ChemSpider), but the lack of MS/MS spectra for Compound 1 prevented in-silico fragmentation based screening of the database candidates for its structural elucidation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Reanalysis of representative samples in negative ionization mode did not detect any of the four compounds, indicating a lack of anionic functionality such as carboxylic acid groups.

    “Reanalysis of representative samples using negative ionization mode did not result in the detection of any of the four compounds, indicating a lack of anionic functionality such as carboxylic acid groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The best-fitting computed formulas for Compounds 1-4 were C13H11ClN2O3S, C15H31ClO8, C18H37ClO10, and C18H36Cl2O9, respectively.

    “The best-fitting computed formulas were C13H11ClN2O3S, C15H31ClO8, C18H37ClO10, and C18H36Cl2O9 for the Compounds 1–4, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    MS/MS analysis of Compound 1 was unsuccessful, but other compounds yielded comparable product ion spectra with m/z 57.033 and 99.081 as the most intense common fragments.

    “MS/MS analysis of Compound 1 was unsuccessful, but other compounds yielded comparable product ion spectra with m/z 57.033 and 99.081 as the most intense common fragments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Correlation across internal and external exposure measurements showed strong block correlation within internal exposure levels, and moderate correlations within exposures measured in water and between both types of exposure measurements.

    “This plot suggests strong block correlation within internal exposure levels, and moderate correlations within exposures measurement in the water and between both types of exposure measurements.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Overall, of the 293 metabolic features, aside from the 12 exclusive associations and the 137 features associated with all exposures, 29 features were associated with two exposures, 15 with three exposures, 30 with four exposures, and 70 with five exposures.

    “Overall, of the 293 metabolic features (Table S1), aside from the 12 exclusive associations and of the 137 features associated with all exposures, we identified 29 features associated with two exposure, 15 with three exposures, 30 with four exposures, 70 with five exposures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In swimming pool water, the highest concentrations of trihalomethanes, haloacetic acids, haloacetonitriles, and chloramines were measured for chloroform (mean: 37.53 μg/L), dichloroacetic acid (mean: 29.47 μg/L) and trichloroacetic acid (mean: 59.9 μg/L), dichloroacetonitrile (mean: 7.16 μg/L), and monochloramines (mean: 0.31 mg/L), respectively.

    “In swimming pool water, the highest concentrations of trihalomethanes, haloacetic acids, haloacetonitriles, and chloramines were measured for chloroform (mean: 37.53 μg/L), dichloroacetic acid (mean: 29.47 μg/L) and trichloroacetic acid (mean: 59.9 μg/L), dichloroacetonitrile (mean: 7.16 μg/L), and monochloramines (mean: 0.31 mg/L), respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Several associations between exhaled breath DBP exposures and metabolic features were found by Model 1, but most did not reach statistical significance after adjustment for energy expenditure (Model 2).

    “As for the exposures measured in exhaled breath, several associations were found by Model 1, most of which did not reach statistical significance upon adjustment for energy expenditure (Model 2 in Table 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compounds 2-4 were detected as both [M + H]+ and [M + Na]+ ions, with the [M + Na]+ ions 11-19 times greater in intensity.

    “Compounds 2–4 were detected as both [M + H]+ and [M + Na]+ ions, with the latter 11–19 times greater in intensity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    There was a high correlation between physical activity, measured by kcal, and THM concentrations.

    “There was a high correlation between physical activity, measured by kcal, and THM concentrations, notably due to the fact that the internal dose increases significantly with intensity of physical activity (Marco et al., 2015).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Principal component analyses showed that 12 and 26 components are necessary to explain 80 and 90% of the total variance of the 293 metabolic features.

    “This high level of correlation was further supported by principal component analyses, which showed that 12 and 26 components are necessary to explain 80 and 90% of the total variance of the 293 metabolic features.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    We observed very high and consistent correlation levels across exposure concentrations measured in exhaled breath both before and after the experiment, though these were strengthened after the swim.

    “We observed very high and consistent correlation levels across exposure concentrations measured in exhaled breath both before and after the experiment (Fig. S1), though these were strengthened after the swim (Fig. S1-B).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    None of the chlorinated metabolites from the earlier TCE study matched by mass with the ones found in the present study.

    “None of these however matched by mass with the ones found in the present study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Propionylcarnitine, like various other carnitines, was found to decrease after swimming.

    “Similarly, propionylcarnitine (Reznick et al., 1992, Scioli et al., 2015) was found, like various other carnitines, to decrease after swimming.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Reznick et al., 1992 source

      Not checked in the free run.

    • cites Scioli et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    For three of the four chlorinated compounds, structural analysis could be performed and MS/MS experiments confirmed the presence of chlorine.

    “For three compounds, structural analysis could be performed and the MS/MS experiments confirmed the presence of Cl.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several epidemiological studies have investigated health effects of long-term exposure to residential DBPs and all identified an association with increased risk of bladder cancer.

    “Several epidemiological studies have investigated health effects of long-term exposure to residential DBPs and all identified an association with increased risk of bladder cancer.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Costet et al., 2011 source

      Not checked in the free run.

    • cites Villanueva et al., 2004 source

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    • cites Villanueva et al., 2015 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Metabolic features detected in <60% of samples were excluded and missing data in remaining features were imputed using quantile regression.

    “Metabolic features that were detected in < 60% of the samples were excluded from the analysis and missing data in the remaining features were imputed using a quantile regression approach for left-censored missing data”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Interpretationown data

    The PCA correlation results support a high level of consistency between results found using water measurements of exposures and those using exhaled breath measurements.

    “This further supports the high level of consistency of the results found using water measurement of exposures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    As a sensitivity analysis, Model 1 was further adjusted for the binary pre-post swimming indicator.

    “As a sensitivity analysis and in order to identify potential effect of exposure(s) that would not be captured by the pre-post swimming indicator, but by exposures only, we further adjusted Model 1 for this binary variable.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The simultaneous acquisition of information of hundreds or thousands of metabolites in biospecimens from human subjects exposed to environmental toxicity has been used to successfully identify new biomarkers of exposure or effect, and to generate new hypotheses on possible mechanisms linking exposures to diseases.

    “The simultaneous acquisition of information of hundreds or thousands of metabolites in biospecimens from human subjects exposed to environmental toxicity has been used to successfully identify new biomarkers of exposure or effect, and to generate new hypotheses on possible mechanisms linking exposures to diseases (Bonvallot et al., 2013, Yuan et al., 2016, Zhang et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bonvallot et al., 2013 source

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    • cites Yuan et al., 2016 source

      Not checked in the free run.

    • cites Zhang et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Experimental studies in cell lines and in blood biosamples have identified a link between genotoxicity/mutagenicity and oxidative stress, notably through the production of reactive oxygen species following exposure to various forms of DBPs.

    “Experimental studies in cell lines (Beddowes et al., 2003, Yuan et al., 2005) and in blood biosamples (Du et al., 2013, Pals et al., 2013, Pals et al., 2011, Wang et al., 2014) have identified a link between genotoxicity/mutagenicity and oxidative stress, notably through the production of reactive oxygen species following exposure to various forms of DBPs.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Beddowes et al., 2003 source

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    • cites Yuan et al., 2005 source

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    • cites Du et al., 2013

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study performed stability analyses assessing robustness to outlying observations by running models on 1000 random subsamples (90% of the study population).

    “For models on exhaled breath exposures, we also performed series of stability analyses assessing the robustness of our findings to outlying observations. Specifically, we ran the models on 1000 random subsamples (90% of the study population), and reported the number of times each of the associations we identified in the main analysis was declared significant across the 1000 sub-populations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Samples were randomized into the batch and analysed as a single uninterrupted batch.

    “After randomization into the batch, samples were analysed as a single uninterrupted batch with an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) system”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Identification of metabolic features was confirmed by reanalysis of representative samples and pure standards when available and comparison of retention times and MS/MS spectra.

    “Identification was confirmed by reanalysis of representative samples and pure standards when available and comparison of the retention times and the MS/MS spectra acquired at 10 V, 20 V, and 40 V collision energies.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Selection criteria were defined to ensure complete exposure measurements, biological samples, even proportion of men and women, and data on physical activity, lifestyle, and covariates.

    “Selection criteria were defined to ensure that: i) complete exposure measurements in the swimming pool were available, ii) biological samples were available; iii) there was an even proportion of men and women; iv) data on physical activity, lifestyle, and all possible adjustments covariates (see below) were available.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Associations were declared significant based on a Bonferroni corrected significance level ensuring a family-wise error rate <0.05.

    “In all models, associations were declared significant based on a Bonferroni corrected significance level (ensuring a family-wise error rate < 0.05).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A common set of potential confounders at baseline was included in all statistical models: age, sex and BMI.

    “A common set of potential confounders at baseline was included in all statistical models: age, sex and BMI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Measurements of DMNA and NDMA in swimming water were missing for 68 and 57% of the study population, respectively, and were excluded from subsequent analyses.

    “Measurements of Dimethylnitrosamine (DMNA) and Nitrosodimethylamine (NDMA) in the swimming water were missing for 68 and 57% of the study population, respectively, and were excluded form subsequent analyses.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Model 1 was additionally adjusted for physical activity as measured by energy expenditure (Model 2).

    “To disentangle the effect of physical activity from that of exposures themselves, we also ran Model 1 additionally adjusting for physical activity as measured by energy expenditure (Model 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Continuous mass axis calibration was performed by monitoring two reference ions throughout the runs.

    “Continuous mass axis calibration was performed by monitoring two reference ions throughout the runs (m/z 121.050873 and m/z 922.009798).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Exposures for which >25% of measurements were missing were excluded from subsequent analyses.

    “Exposures for which > 25% of the measurements were missing (i.e. across participants and for both sampling occasions, before and after the swim) were excluded from subsequent analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The lower number of associations for some exposures may be attributed to greater variability in these exposure measurements, which can relate to differential measurement precision or to additional confounding factors not related to the swimming experiment.

    “This may be attributed to a greater variability in these exposure measurements, which in turn can relate to differential measurement precision, or to additional confounding factors which do not relate to the swimming experiment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The analytical run was initiated with priming injections of a pooled quality control (QC) sample and study samples were intervened after every 10 injections with a QC sample and a solvent blank to monitor instrument performance.

    “The analytical run was initiated with priming injections of a pooled quality control (QC) sample to achieve stable instrument response, followed by study samples that were intervened after every 10 injections with a QC sample and a solvent blank to monitor instrument performance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In another recent study, a number of chlorinated lipids and their metabolites were discovered in the lungs and plasma of mouse and rat models after chlorine gas exposure.

    “In another recent study a number of chlorinated lipids and their metabolites were discovered in the lungs and plasma of mouse and rat models after chlorine gas exposure (Ford et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ford et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The observed increased levels of xanthosine associated with BDCM and total brominated THM and total THM are consistent with results from two previous studies.

    “In addition, we observed increased levels of xanthosine associated with BDCM and total brominated THM and total THM, which is consistent with results from two previous studies (Daskalaki et al., 2015, Lewis et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Daskalaki et al., 2015

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    • cites Lewis et al., 2010 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exposure to high concentrations of certain DBPs has been shown to lead to depression of the central nervous system in both animal and human studies.

    “exposure to (high) concentrations of certain DBPs has been shown to lead to depression of the CNS in both animal and human studies (U.S. Department of Health And Human Services, P.H.S, 2005, World Health Organization, 2004a).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites U.S. Department of Health And Human Services, P.H.S, 2005

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    • cites World Health Organization, 2004a

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Walker et al. observed lower levels of tryptophan with increasing trichloroethylene (TCE) exposure in an occupational untargeted plasma metabolomics study.

    “Walker et al. investigated occupational exposure to trichloroethylene (TCE) in relation to untargeted plasma metabolomics, and similarly observed lower levels of tryptophan with increasing levels of TCE (Walker et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Walker et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The inverse association of caffeine with DBP levels may indicate that the study is capturing the time elapsed between last coffee drinking and the end of the experiment.

    “This result may indicate that we may simply be capturing the time elapsed between last coffee drinking and the end of the experiment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Other identifiable chlorine adducts include 3-chlorotyrosine and 3,5-dichlorotyrosine, which are known to form after chlorine exposure and have been proposed as biomarkers of chlorine exposure.

    “Other identifiable chlorine adducts include 3-chlorotyrosine and 3,5-dichlorotyrosine that are known to form after chlorine exposure and have been proposed as biomarkers of chlorine exposure (Crow et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Crow et al., 2016 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A study of urinary metabolites found significant perturbations of the kynurenine pathway, with tryptophan levels consistently lower in bladder cancer cases than in non-bladder cancer controls.

    “Moreover, a study of urinary metabolites of bladder cancer cases compared with non-bladder cancer controls found significant perturbations of the kynurenine pathway, with tryptophan levels consistently lower in cases (Pasikanti et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pasikanti et al., 2013 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Because propionylcarnitine is related to meat and fish intake, its decrease may also be related to the time elapsed since last meal rather than to DBP exposure.

    “Since it is related to meat and fish intake (Cheung et al., 2017), its decrease may also be related to the time elapsed since last meal rather than to exposure to DBP.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cheung et al., 2017 source

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    Premisecitation

    Other studies have observed higher levels of uric acid with lower levels of oxidative stress but higher levels of inflammation.

    “Other studies have also observed higher levels of uric acid with lower levels of oxidative stress but higher levels of inflammation (Wu et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wu et al., 2015

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The elevated uric acid after swimming could be a response to exercise-induced oxidative stress or to DBP exposure-induced oxidative stress.

    “We observed elevated levels of uric acid after our swimming experiment which could be a response to exercise-induced oxidative stress or due to DBP exposure induced oxidative stress, as Walker et al. similarly identified higher levels of uric acid after occupational TCE exposure (Walker et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Walker et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Polotow et al. observed xanthine oxidase activation and altered levels of uric acid in plasma of trained participants after exercise, and hypothesized that uric acid plays an important role as an antioxidant in plasma.

    “Polotow et al. observed xanthine oxidase activation and altered levels of uric acid in plasma of trained participants after exercise (one-repetition maximum test with a bench press) and hypothesized that uric acid plays an important role as an antioxidant in plasma (Polotow et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Polotow et al., 2017 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    HOCl is reactive with a number of biomolecules in vivo and ex vivo, including fatty acids, lipids and aromatic amino acids, and different chlorinated metabolites are known to form after chlorine exposure.

    “HOCl is reactive with a number of biomolecules in vivo and ex vivo, including fatty acids, lipids and aromatic amino acids and different chlorinated metabolites are known to form after chlorine exposure (Fu et al., 2000, Hazen et al., 1996, Schroter and Schiller, 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Fu et al., 2000

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    • cites Hazen et al., 1996 source

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    • cites Schroter and Schiller, 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The relative retention times of the compounds support such identifications.

    “The relative retention times of the compounds support such identifications (Crow et al., 2016) (see Fig. S6 for details).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Crow et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The study assessed more than the usual four trihalomethanes in exhaled air and additionally included external exposures consisting of various DBPs measured in swimming pool water.

    “Firstly, contrary to most studies, it assessed more than the usual four trihalomethanes in exhaled air, and additionally included external exposures consisting of various DBPs measured in swimming pool water.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The two compounds could be reaction products of HOCl or Cl2 addition to a double bond or mono-/dichlorinated products through aromatic substitution.

    “The two compounds could thus be two reaction products after an addition of HOCl or Cl2 to a double bond of a compound R to yield HO-R-Cl and Cl2-R, or the mono- and dichlorinated products of two compounds HO-R and R through aromatic substitution.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: This paper is the first study to investigate the effect on the metabolome of short-term exposure to DBPs during a swimming pool experiment.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In an earlier metabolomic study on occupational exposure to trichloroethylene, a full shift exposure range of 0.4 to 230 ppm resulted in the detection of several unidentifiable chlorinated metabolites.

    “In an earlier metabolomic study on occupational exposure to trichloroethylene, it was found that a full shift exposure range of 0.4 to 230 ppm resulted in the detection of several unidentifiable chlorinated metabolites (Walker et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Walker et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Some metabolic changes appear to be related to physical exercise whereas other changes are more likely attributable to exposure to DBPs.

    “Some metabolic changes appear to be related to physical exercise whereas other changes are more likely attributable to exposure to DBPs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    One metabolomic study reported lower levels of cortisol after physical activity, but other studies reported higher hormone levels after exercise.

    “One metabolomic study investigating metabolic changes after physical activity reported lower levels of cortisol (Xiao et al., 2016) but other studies also reported higher hormone levels after exercise (Di Luigi et al., 2014, Sato et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Xiao et al., 2016 source

      Not checked in the free run.

    • cites Di Luigi et al., 2014 source

      Not checked in the free run.

    • cites Sato et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationnone given

    The untargeted approach applied provides unique opportunities for identification of new metabolic features, which once annotated may help identifying affected pathways.

    “Finally, the untargeted approach we applied provides unique opportunities for identification of new metabolic features, which once annotated may help identifying affected pathways.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The internal dose of THMs increases significantly with intensity of physical activity.

    “There was a high correlation between physical activity, measured by kcal, and THM concentrations, notably due to the fact that the internal dose increases significantly with intensity of physical activity (Marco et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Marco et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tryptophan metabolism plays a role in the generation of various neuroactive compounds within the central nervous system.

    “Tryptophan metabolism plays a role in the generation of various neuroactive compounds within the central nervous system (CNS) (Lovelace et al., 2017)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lovelace et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given

    Physical activity was accurately measured.

    “Second, physical activity was accurately measured.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some studies have observed altered tryptophan and kynurenine levels after physical exercise.

    “However, some studies have also observed altered tryptophan and kynurenine levels after physical exercise (Daskalaki et al., 2015, Mukherjee et al., 2014, Pechlivanis et al., 2010, Xiao et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Daskalaki et al., 2015

      Not checked in the free run.

    • cites Mukherjee et al., 2014 source

      Not checked in the free run.

    • cites Pechlivanis et al., 2010 source

      Not checked in the free run.

58 of 58

  • The authors state this as an assumption.

    The variance covariance across observations per participant is unstructured.

    “assuming an unstructured variance covariance across observations per participants (before and after the swim).”

  • The paper relies on this without support.

    This paper is the first study to investigate the effect on the metabolome of short-term exposure to DBPs during a swimming pool experiment.

    “This paper describes the first study to investigate the effect on the metabolome of short-term exposure to DBPs during a swimming pool experiment.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Environmental exposure-relevant chlorination agents include hypochlorous acid and its anion as well as diverse chloramines formed as a result of freshwater chlorination.

    “Specifically, environmental exposure-relevant chlorination agents include hypochlorous acid (and its corresponding anion) as well as diverse chloramines (e.g. monochloramine, dichloramine, nitrogen trichloride, chlorinated isocyanuric acid-derivatives) formed as a result of freshwater chlorination ( Figure 5A ) (119, 120).”

    From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [119]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A DBCM-only metabolite contradicts the stated overlap

    Minor

    The text says every feature associated with DBCM was also associated with another exposure, but Table 5 lists propionylcarnitine as associated only with DBCM.

  • Free-chlorine SD is incompatible with its reported range

    Minor

    The reported range is 0.62-2.01 mg/L. For 59 observations with a mean of 1.33 mg/L within that range, the sample SD cannot exceed approximately 0.70 mg/L, yet the table reports 1.24 mg/L.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Ainsworth, 2011, Compendium of physical activities: a second update of codes and MET values, Med. Sci. Sports Exerc., 43, 1575, 10.1249/MSS.0b013e31821ece12 · DOI · Paper page
  2. Khallef, 2015, Genotoxicity of drinking water disinfection by-products (bromoform and chloroform) by using both allium anaphase-telophase and comet tests, Cytotechnology, 67, 207, 10.1007/s10616-013-9675-y · DOI
  3. Sumner, 2007, Proposed minimum reporting standards for chemical analysis chemical analysis working group (CAWG) metabolomics standards initiative (MSI), Metabolomics, 3, 211, 10.1007/s11306-007-0082-2 · DOI · Paper page
  4. Villanueva, 2004, Disinfection byproducts and bladder cancer: a pooled analysis, Epidemiology, 15, 357, 10.1097/01.ede.0000121380.02594.fc · DOI · Paper page

Cited by

Sorted by citations

Authors
van Veldhoven, K., Keski-Rahkonen, P., Barupal, D. K., Villanueva, C. M., Font-Ribera, L., Scalbert, A., Bodinier, B., Grimalt, J. O., Zwiener, C., Vlaanderen, J., Portengen, L., Vermeulen, R., Vineis, P., Chadeau-Hyam, M., & Kogevinas, M.
Affiliations
  • Centre international de recherche sur le cancer (FR)
  • Universitat Pompeu Fabra (ES)
  • MRC Centre for Environment and Health (GB)
  • Institute of Environmental Assessment and Water Research (ES)
  • University of Tübingen (DE)
  • Utrecht University (NL)
  • Italian institute for Genomic Medicine (IT)
ORCID
Venue
Environment International
Publisher
Elsevier BV
Published
2018-02
Volume
111
Pages
60-70
ISSN
0160-4120 (ISSN-L)
DOI
10.1016/j.envint.2017.11.017
PMC
PMC5786667
OpenAlex
W2770150138
Cited by
94
References
50
Citations by year
2026: 8 · 2025: 4 · 2024: 8 · 2023: 5 · 2022: 12 · 2021: 13 · 2020: 17 · 2019: 11 · 2018: 13 · 2017: 1 · 2016: 1 · 2015: 1
FWCI
6.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Environment International (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • eScholarship (California Digital Library) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
European Commission (FP7)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Water Treatment and Disinfection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Health, Environment, Cognitive Aging
Keywords
water disinfection by-products, chlorinated swimming pools, exhaled breath, blood metabolome, tryptophan metabolism, physical activity, exposure assessment, exposomics
MeSH terms
Adolescent, Adult, Disinfection, Environmental Monitoring, Female, Humans, Male, Swimming, Swimming Pools, Water Pollutants, Chemical, Halogenation, Metabolome, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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