Metformin Chlorination Byproducts in Drinking Water Exhibit Marked Toxicities of a Potential Health Concern
Open accessAbstract
Metformin (MET), a worldwide used drug for type 2 diabetes, has been found with the largest amount by weight among all drugs in aquatic environment, including the drinking water systems where this emerging micropollutant is inevitably transformed during chlorination process. Whether MET chlorination byproducts Y (C4H6ClN5) and C (C4H6ClN3) exist in drinking water remains unknown. Although MET has health-promoting properties, whether or how its chlorination byproducts affect health is still uncharacterized. Here we reveal that MET and byproduct C are present in worldwide drinking water with the highest doses detected for MET and C as 1203.5 ng/L and 9.7 ng/L respectively. Under simulated chlorination conditions, we also demonstrate that both byproducts can be increasingly produced with increment of MET concentration, suggesting a hidden threat on the safety and sustainability of global water supply. Through systematic evaluations, we demonstrate that MET chlorination byproducts Y and C exhibit toxicities instead of genotoxicity to live worms and human HepG2 cells at millimolar doses. Moreover, both byproducts are harmful to mice and particularly Y at 250 ng/L destroys the mouse small intestine integrity. Unprecedentedly, we unveil boiling and activated carbon adsorption as effective alternative solutions that may be in urgent demand globally for removing these byproducts from drinking water.
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Common drugs including metformin, diclofenac, and tamoxifen entering freshwater sources are subject to direct chlorination causing drinking water contamination associated with largely unexplored implications for human health.
“For example, common drugs including metformin, diclofenac, and tamoxifen entering freshwater sources are subject to direct chlorination causing drinking water contamination associated with largely unexplored implications for human health (126–129).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [127]
PPCPs introduced into the water supply are subject to HOCl-mediated chlorination and subsequent formation of CBPs.
“Additionally, PPCPs introduced into the water supply are subject to HOCl-mediated chlorination and subsequent formation of CBPs.”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [127]
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Cites
1 retracted
MacLaren, R., Wisniewski, K., & MacLaren, C. (2018) · PLoS ONE · doi:10.1371/journal.pone.0197259 · Cited by 47 · see citing works
RetractedReduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa012512 · Cited by 19,011 · see citing works
The mechanisms of action of metformin
Rena, G., Hardie, D. G., & Pearson, E. R. (2017) · Diabetologia · doi:10.1007/s00125-017-4342-z · Cited by 2,287 · see citing works
Contamination of drinking-water by arsenic in Bangladesh: a public health emergency.
Smith, A. H., Lingas, E. O., & Rahman, M. (2000) · PubMed · Cited by 1,988 · see citing works
The intestinal crypt, a prototype stem cell compartment
Clevers, H. (2013) · Cell · doi:10.1016/j.cell.2013.07.004 · Cited by 1,223 · see citing works
Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism
Cabreiro, F., Au, C., Leung, K.-Y., Vergara-Irigaray, N., Cochemé, H. M., Noori, T., Weinkove, D., Schuster, E., Greene, N. D. E., & Gems, D. (2013) · Cell · doi:10.1016/j.cell.2013.02.035 · Cited by 967 · see citing works
Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889 · see citing works
Physiology of Intestinal Absorption and Secretion
Kiela, P. R., & Ghishan, F. K. (2016) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2016.02.007 · Cited by 752 · see citing works
Metformin and the gastrointestinal tract
McCreight, L. J., Bailey, C. J., & Pearson, E. R. (2016) · Diabetologia · doi:10.1007/s00125-015-3844-9 · Cited by 733 · see citing works
Gerets, H. H. J., Tilmant, K., Gerin, B., Chanteux, H., Depelchin, B. O., Dhalluin, S., & Atienzar, F. A. (2012) · Cell Biology and Toxicology · doi:10.1007/s10565-011-9208-4 · Cited by 698 · see citing works
Arsenic Epidemiology and Drinking Water Standards
Smith, A. H., Lopipero, P. A., Bates, M. N., & Steinmaus, C. M. (2002) · Science · doi:10.1126/science.1072896 · Cited by 620 · see citing works
Ju, F., Beck, K., Yin, X., Maccagnan, A., McArdell, C. S., Singer, H., Johnson, D. R., Zhang, T., & Bürgmann, H. (2018) · The ISME Journal · doi:10.1038/s41396-018-0277-8 · Cited by 457 · see citing works
Self-citationZang, M., Zuccollo, A., Hou, X., Nagata, D., Walsh, K. X., Herscovitz, H., Brecher, P. I., Ruderman, N. B., & Cohen, R. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408149200 · Cited by 450 · see citing works
Blair, B. D., Crago, J., Hedman, C., & Klaper, R. (2013) · Chemosphere · doi:10.1016/j.chemosphere.2013.07.057 · Cited by 446 · see citing works
Redefining the gut as the motor of critical illness
Mittal, R., & Coopersmith, C. M. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.08.004 · Cited by 342 · see citing works
Bailey, C. J., Wilcock, C., & Scarpello, J. H. B. (2008) · Diabetologia · doi:10.1007/s00125-008-1053-5 · Cited by 275 · see citing works
Metformin as Anti-Aging Therapy: Is It for Everyone?
Soukas, A. A., Hao, H., & Wu, L. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.07.015 · Cited by 260 · see citing works
Self-citationScheurer, M., Michel, A., Brauch, H., Ruck, W., & Sacher, F. (2012) · Water Research · doi:10.1016/j.watres.2012.06.019 · Cited by 235 · see citing works
Diana, M., Felipe-Sotelo, M., & Bond, T. (2019) · Water Research · doi:10.1016/j.watres.2019.07.014 · Cited by 232 · see citing works
An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. Elegans and Cancer
Wu, L., Zhou, B., Oshiro-Rapley, N., Li, M., Paulo, J. A., Webster, C. M., Mou, F., Kacergis, M. C., Talkowski, M. E., Carr, C. E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.055 · Cited by 227 · see citing works
Self-citationCuthbertson, A. A., Kimura, S. Y., Liberatore, H. K., Summers, R. S., Knappe, D. R. U., Stanford, B. D., Maness, J. C., Mulhern, R., Selbes, M., & Richardson, S. D. (2019) · Environmental Science & Technology · doi:10.1021/acs.est.9b00023 · Cited by 184 · see citing works
de Solla, S. R., Gilroy, È. A. M., Klinck, J. S., King, L. E., McInnis, R., Struger, J., Backus, S. M., & Gillis, P. L. (2015) · Chemosphere · doi:10.1016/j.chemosphere.2015.12.022 · Cited by 183 · see citing works
Penzias, A. S., Bendikson, K. A., Butts, S. F., Coutifaris, C., Falcone, T., Fossum, G., Gitlin, S., Gracia, C. R., Hansen, K. R., LaBarbera, A. R., et al. (2017) · Fertility and Sterility · doi:10.1016/j.fertnstert.2017.06.026 · Cited by 181 · see citing works
Monitoring of 1300 organic micro-pollutants in surface waters from Tianjin, North China
Kong, L., Kadokami, K., Wang, S., Duong, H. T., & Chau, H. T. C. (2014) · Chemosphere · doi:10.1016/j.chemosphere.2014.11.025 · Cited by 160 · see citing works
Lantagne, D., & Clasen, T. (2012) · Environmental Science & Technology · doi:10.1021/es301842u · Cited by 117 · see citing works
Schmidt, S.-A., Gukelberger, E., Hermann, M., et al. (2016) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2016.06.005 · Cited by 95 · see citing works
The pharmacogenetics of metformin
Florez, J. C. (2017) · Diabetologia · doi:10.1007/s00125-017-4335-y · Cited by 91 · see citing works
Endl, E., & Gerdes, J. (2000) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(200003)182:3 · Cited by 89 · see citing works
O'Brien, P. J. (2014) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.12227 · Cited by 79 · see citing works
Caldwell, D. J., D’Aco, V. J., Davidson, T., Kappler, K., Murray‐Smith, R., Owen, S. F., Robinson, P. F., Simon-Hettich, B., Straub, J. O., & Tell, J. G. (2018) · Chemosphere · doi:10.1016/j.chemosphere.2018.10.038 · Cited by 70 · see citing works
Poursat, B. A. J., van Spanning, R. V., Braster, M., Helmus, R., de Voogt, P., & Parsons, J. (2019) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2019.109414 · Cited by 61 · see citing works
Armbruster, D., Happel, O., Scheurer, M., Harms, K., Schmidt, T. C., & Brauch, H. (2015) · Water Research · doi:10.1016/j.watres.2015.04.020 · Cited by 60 · see citing works
Hua, G., Wang, C., Pan, Y., Zeng, Z., Lee, S. G., Martín, M. L., Haimovitz‐Friedman, A., FUKS, Z. Y., Paty, P. B., & Kolesnick, R. (2017) · Cancer Research · doi:10.1158/0008-5472.can-15-2870 · Cited by 59 · see citing works
Self-citationWastewater analysis reveals spatial pattern in consumption of anti-diabetes drug metformin in China.
Yan, J.-H., Xiao, Y., Tan, D.-Q., Shao, X., Wang, Z., & Wang, D.-G. (2019) · Chemosphere · doi:10.1016/j.chemosphere.2019.01.151 · Cited by 55 · see citing works
Elliott, S. M., Brigham, M. E., Kiesling, R. L., Schoenfuss, H. L., & Jorgenson, Z. G. (2018) · Integrated Environmental Assessment and Management · doi:10.1002/ieam.4041 · Cited by 44 · see citing works
GAC removal of organic nitrogen and other DBP precursors
Chili, C., Westerhoff, P. K., & Ghosh, A. (2012) · American Water Works Association · doi:10.5942/jawwa.2012.104.0090 · Cited by 40 · see citing works
Ussery, E. J., Nielsen, K. M., Pandelides, Z., Kirkwood, A. E., Guchardi, J., & Holdway, D. A. (2019) · Environmental Toxicology and Chemistry · doi:10.1002/etc.4403 · Cited by 36 · see citing works
Ludman, T., & Melemedjian, O. K. (2019) · Molecular Pain · doi:10.1177/1744806919850043 · Cited by 34 · see citing works
The ironic economics and equity of water budget rates
Beecher, J. A. (2012) · American Water Works Association · doi:10.5942/jawwa.2012.104.0021 · Cited by 15 · see citing works
Stütz, L., Leitner, P., Schulz, W. W., & Winzenbacher, R. (2019) · Journal of Planar Chromatography – Modern TLC · doi:10.1556/1006.2019.32.3.1 · Cited by 11 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Fertil Steril 108 (3), 2017, 426-441.
- Scholzen, T., Gerdes, J., 2000. The Ki-67 protein: from the known and the unknown. J Cell Physiol 182 (3), 311-322.
Cited by
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El-Sheekh, M. M., El-Kassas, H. Y., & Ali, S. S. (2025) · Microbial Cell Factories · doi:10.1186/s12934-024-02638-0 · Cited by 86 · see citing works
Snell, J. A., Jandova, J., & Wondrak, G. T. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.887220 · Cited by 37 · see citing works
He, Y., Jin, H., Gao, H., Zhang, G., & Ju, F. (2022) · Science of The Total Environment · doi:10.1016/j.scitotenv.2021.151665 · Cited by 26 · see citing works
- Authors
- Zhang, R., He, Y., Yao, L., Chen, J., Zhu, S., Rao, X., Tang, P., You, J., Hua, G., Zhang, L., Ju, F., & Wu, L.
- Affiliations
- Westlake University (CN)
- Shanghai Medical College of Fudan University (CN)
- Corresponding author
- Ju, Feng
- Wu, Lianfeng
- ORCID
- Venue
- Environment International
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 146
- Pages
- 106244
- ISSN
- 0160-4120 (ISSN-L)
- OpenAlex
- W3096265658
- Cited by
- 65
- References
- 40
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 13 · 2023: 7 · 2022: 16 · 2021: 6
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Environment International (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (31670858, 51908467)
- Westlake Institute for Advanced Study
- Young Scientists Fund
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Water Treatment and Disinfection
- Physical Sciences › Environmental Science › Pollution › Pharmaceutical and Antibiotic Environmental Impacts
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Environmental Toxicology and Ecotoxicology
- Keywords
- metformin, chlorination by-products, drinking water, micropollutants, toxicity, genotoxicity, type 2 diabetes drugs, HepG2 cells, Caenorhabditis elegans, activated carbon adsorption, boiling
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Disinfection, Metformin, Water Pollutants, Chemical, Water Purification, Mice, Halogenation, Drinking Water
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