Halogenation of Pharmaceuticals Is an Impediment to Ready Biodegradability
Abstract
:1. Introduction
2. Materials and Methods
2.1. Basic Data
2.2. Statistics
3. Results
3.1. Dataset
3.2. Comparing Halogenated and Hydrophilic Pharmaceuticals
3.3. Comparing Wastewater Treatment Plant Removal Pathways
3.4. Comparing Halogenated and In Silico Dehalogenated Pharmaceuticals
4. Discussion
4.1. Ready Biodegradability
4.2. Experimental Ready Biodegradability Dataset
4.3. Representativity of the Ready Biodegradability plus Halogenated Dataset
4.4. Halogenation vs. Biodegradability, What Options Are There?
4.5. Reality Check
5. Conclusions
6. Limitations
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Richardson, M.I.; Bowron, J.M. The fate of pharmaceuticals in the environment. J. Pharm. Pharmacol. 1985, 37, 1–12. [Google Scholar] [CrossRef]
- Kümmerer, K. Sustainable from the very beginning: Rational design of molecules by life cycle engineering as an important approach for green pharmacy and green chemistry. Green Chem. 2007, 9, 899907. [Google Scholar] [CrossRef]
- Kümmerer, K.; Schramm, E. Arzneimittelentwicklung: Die Reduzierung von Umweltbelastungen durch gezieltes Moleküldesign. Umweltwiss. Schadst. Forsch. 2008, 20, 249–263. [Google Scholar] [CrossRef]
- Moermond, C.T.A.; Puhlmann, N.; Ross Brown, A.; Owen, S.F.; Ryan, J.; Snape, J.; Venhuis, B.J.; Kümmerer, K. GREENER pharmaceuticals for more sustainable healthcare. Environ. Sci. Technol. Lett. 2022, 9, 699–705. [Google Scholar] [CrossRef]
- Halogen, Chemical Element Group. Britannica Online; Encyclopædia Britannica, Inc.: Chicago, IL, USA; Available online: https://www.britannica.com/science/halogen (accessed on 21 April 2023).
- Thomas, P.M.; Foster, G.D. Determination of nonsteroidal anti-inflammatory drugs, caffeine and triclosan in wastewater by gas chromatography-mass spectrometry. J. Environ. Sci. Health 2004, A39, 1969–1978. [Google Scholar] [CrossRef]
- Adams, D.E.C.; Halden, R.U. Fluorinated Chemicals and the Impact of Anthropogenic Use. In Contaminants of Emerging Concern in the Environment: Ecological and Human Health Considerations; Halden, R., Ed.; ACS Symposium Series; American Chemical Society: Washington, DC, USA, 2010; pp. 539–560. [Google Scholar]
- Xu, Z.; Yang, Z.; Liu, Y.; Lu, Y.; Chen, K.; Zhu, W. Halogen bond: Its role beyond drug-target binding affinity for drug discovery and development. J. Chem. Inf. Model. 2014, 54, 69–78. [Google Scholar] [CrossRef]
- Gerebtzoff, G.; Li-Blatter, X.; Fischer, H.; Frentzel, A.; Seelig, A. Halogenation of drugs enhances membrane binding and permeation. ChemBioChem 2004, 5, 676–684. [Google Scholar] [CrossRef] [PubMed]
- Smith, B.R.; Eastman, C.M.; Njarðarson, J.T. Chlorinated Pharmaceuticals. Poster Created by the Njardarson Group, The University of Arizona, Tucson AZ, USA, 2014. Available online: https://njardarson.lab.arizona.edu/sites/njardarson.lab.arizona.edu/files/Chlorinated%20Pharmaceuticals-1.pdf (accessed on 21 April 2023).
- Ilardi, E.A.; Vitaku, E.; Njarðarson, J.T. Data-mining for sulfur and fluorine: An evaluation of pharmaceuticals to reveal opportunities for drug design and discovery; Miniperspective. J. Med. Chem. 2014, 57, 2832–2842. [Google Scholar] [CrossRef] [PubMed]
- Inoue, M.; Sumii, Y.; Shibata, N. Contribution of organofluorine compounds to pharmaceuticals. ACS Omega 2020, 5, 10633–10640. [Google Scholar] [CrossRef] [PubMed]
- Monserrate, E.; Häggblom, M.M. Dehalogenation and biodegradation of brominated phenols and benzoic acids under iron-reducing, sulfidogenic, and methanogenic conditions. Appl. Environ. Microbiol. 1997, 63, 3911–39151. [Google Scholar] [CrossRef] [Green Version]
- Milligan, P.W.; Häggblom, M.M. Anaerobic degradation and dehalogenation of chlorosalicylates and salicylate under four reducing conditions. Biodegradation 2001, 12, 59–167. [Google Scholar] [CrossRef]
- Löffler, D.; Römbke, J.; Meller, M.; Ternes, T.A. Environmental Fate of Pharmaceuticals in Water/Sediment Systems. Environ. Sci. Technol. 2005, 39, 5209–5218. [Google Scholar] [CrossRef]
- Bhatt, P.; Suresh Kumar, M.; Mudliar, S.; Chakrabarti, T. Biodegradation of Chlorinated Compounds—A Review. Crit. Rev. Environ. Sci. Technol. 2007, 37, 165–198. [Google Scholar] [CrossRef]
- Miller, T.R.; Heidler, J.; Chillrud, S.N.; DeLaquil, A.; Ritchie, J.C.; Mihalic, J.N.; Bopp, R.; Halden, R.U. Fate of triclosan and evidence for reductive dechlorination of triclocarban in estuarine sediments. Environ. Sci. Technol. 2008, 42, 4570–4576. [Google Scholar] [CrossRef] [Green Version]
- Zhao, Z.; Rogers, M.J.; He, J. Abundance of organohalide respiring bacteria and their role in dehalogenating antimicrobials in wastewater treatment plants. Water Res. 2020, 181, 115893. [Google Scholar] [CrossRef]
- Hai, F.I.; Tadkaew, N.; McDonald, J.A.; Khan, S.J.; Nghiem, L.D. Is halogen content the most important factor in the removal of halogenated trace organics by MBR treatment? Bioresour. Technol. 2011, 102, 6299–6303. [Google Scholar] [CrossRef] [Green Version]
- Boethling, R.S.; Sommer, E.; DiFiore, D. Designing Small Molecules for Biodegradability. Chem. Rev. 2007, 107, 2207–2227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- OECD Guidelines for the Testing of Chemicals; Organisation for Economic Co-Operation and Development: Paris, France. 2023. Available online: www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals_72d77764-en (accessed on 22 April 2023).
- Estimation Program Interface Suite (EPISuite), v.4.11; United States Environmental Protection Agency, Office of Pollution Prevention and Toxic Risk Assessment Division: Washington, DC, USA, 2017. Available online: www.epa.gov/tsca-screening-tools/download-epi-suitetm-estimation-program-interface-v411 (accessed on 22 April 2023).
- Straub, J.O.; Le Roux, J.; Tedoldi, D. Are newer pharmaceuticals more recalcitrant to removal in wastewater treatment? Sustain. Chem. Pharm. 2022, 30, 100834. [Google Scholar] [CrossRef]
- LibreOffice for Linux Ubuntu, Version: 6.4.7.2, Build ID: 1:6.4.7-0ubuntu0.20.04.2. 2020. Available online: www.libreoffice.org/download/download/ (accessed on 22 April 2023).
- Python3. 2020. Available online: www.python.org/downloads/ (accessed on 22 April 2023).
- Linux Mint. Available online: Linuxmint.com (accessed on 22 April 2023).
- R Core Team. R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing: Vienna, Austria, 2023; Available online: www.r-project.org (accessed on 19 May 2023).
- Greenland, S.; Senn, S.J.; Rothman, K.J.; Carlin, J.B.; Poole, C.; Goodman, S.N.; Altman, D.G. Statistical tests, P values, confidence intervals, and power: A guide to misinterpretations. Eur. J. Epidemiol. 2016, 31, 337–350. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Amrhein, V.; Greenland, S.; McShane, B. Retire statistical significance. Comment. Nature 2019, 567, 305–307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chloroethane. REACH Substance Factsheet, European Chemicals Agency, Helsinki, Finland. Available online: echa.europa.eu/information-on-chemicals/registered-substances/-/disreg/substance/100.000.755 (accessed on 30 June 2023).
- Kennes-Veiga, D.M.; Gózalez-Gil, L.; Carballa, M.; Lena, J.M. Enzymatic cometabolic biotransformation of organic micropollutants in wastewater treatment plants: A review. Bioresour. Technol. 2022, 344, 126291. [Google Scholar] [CrossRef]
- Anastas, P.T.; Heine, L.G.; Williamson, T.C. Green Chemical Syntheses and Processes: Introduction 2000. In Green Chemical Syntheses and Processes; Anastas, P.T., Heine, L.G., Williamson, T.C., Eds.; ACS Symposium Series; American Chemical Society: Washington, DC, USA, 2000; pp. 1–6. [Google Scholar]
- Caldeira, C.; Farcal, R.; Moretti, C.; Mancini, L.; Rasmussen, K.; Rauscher, H.; Riego Sintes, J.; Sala, S. Safe and Sustainable by Design Chemicals and Materials—Review of Safety and Sustainability Dimensions, Aspects, Methods, Indicators, and Tools; EUR 30991 EN, JRC127109; Publications Office of the European Union: Luxembourg, 2022; ISBN 978-92-76-47560-6. [Google Scholar] [CrossRef]
- European Chemicals Agency. PBT/vPvB Assessment. In Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.11; European Chemicals Agency: Helsinki, Finland, 2017; Available online: echa.europa.eu/documents/10162/17235/information_requirements_part_c_en.pdf (accessed on 24 April 2023).
- Feng, S.; Ngo, H.H.; Guo, W.; Chang, S.W.; Nguyen, D.D.; Cheng, D.; Varjani, S.; Lei, Z.; Liu, Y. Roles and applications of enzymes for resistant pollutants removal in wastewater treatment. Bioresour. Technol. 2021, 95, 125278. [Google Scholar] [CrossRef] [PubMed]
- Mishra, B.; Varjani, S.; Agrawal, D.C.; Mandal, S.K.; Ngo, H.H.; Taherzadeh, M.J.; Chang, J.-S.; You, S.; Guo, W. Engineering biocatalytic material for the remediation of pollutants: A comprehensive review. Environ. Technol. Innov. 2020, 20, 101063. [Google Scholar] [CrossRef]
- Kim, B.R.; Suidan, M.T.; Wallington, T.J.; Du, X. Biodegradability of trifluoroacetic acid. Environ. Eng. Sci. 2000, 17, 337–342. [Google Scholar] [CrossRef]
- Straub, J.O. Combined environmental risk assessment for 5-fluorouracil and capecitabine in Europe. Integr. Environ. Assess. Manag. 2009, 6, 540–566. [Google Scholar] [CrossRef]
- Buerge, I.; Buser, H.-R.; Poiger, T.; Müller, M.D. Occurrence and fate of the cytostatic drugs cyclophosphamide and ifosfamide in wastewater and surface waters. Environ. Sci. Technol. 2006, 40, 7242–7250. [Google Scholar] [CrossRef]
- EMA. Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. CPMP/SWP/4447/00 Corr 2. European Medicines Agency. Safety Working Party, London, UK. 13 January 2015. Available online: www.ema.europa.eu/en/documents/scientific-guideline/guideline-environmental-risk-assessment-medicinal-products-human-use-first-version_en.pdf (accessed on 23 April 2023).
- Paffoni, C.; Welte, B.; Gousailles, M.; Montiel, A. Nouvelles molécules mises en cause par les directives européennes: De la station d’épuration à l’usine de traitement d’eau potable. Eur. J. Water Qual. 2006, 37, 21–38. [Google Scholar]
- Kosjek, T.; Perko, S.; Zupanc, M.; Zanoški Hren, M.; Landeka Dragicevic, T.; Zigon, D.; Kompare, B.; Heath, E. Environmental occurrence, fate and transformation of benzodiazepines in water treatment. Water Res. 2012, 46, 355–368. [Google Scholar] [CrossRef]
- Ghosh, G.C.; Okuda, T.; Yamashita, N.; Tanaka, H. Occurrence and elimination of antibiotics at four sewage treatment plants in Japan and their effects on bacterial ammonia oxidation. Water Sci. Technol. 2009, 59, 779–786. [Google Scholar] [CrossRef]
- Gros, M.; Petrovič, M.; Ginebreda, A.; Barceló, D. Removal pf pharmaceuticals during wastewater treatment and environmental risk assessment using hazard indexes. Environ. Int. 2010, 36, 15–26. [Google Scholar] [CrossRef]
- Dunlavey, E.; Ticker, D.; Ervin, J. Environmental fate and transport of microconstituents. Water Environ. Technol. 2010, 43–46. [Google Scholar]
- Verschueren, K. Handbook of Environmental Data on Organic Chemicals; Van Nostrand Reinhold: New York, NY, USA, 1983. [Google Scholar]
- Van der Ven, K.; van Dongen, W.; Maes, B.U.W.; Esmans, E.L.; Blust, R.; De Coen, W.M. Determination of diazepam in aquatic samples by capillary liquid chromatography–electrospray tandem mass spectrometry. Chemosphere 2004, 57, 967–973. [Google Scholar] [CrossRef] [PubMed]
- Castiglioni, S.; Bagnati, R.; Fanelli, R.; Pomati, F.; Calamari, D.; Zuccato, E. Removal of pharmaceuticals in sewage treatment plants in Italy. Environ. Sci. Technol. 2006, 40, 357–363. [Google Scholar] [CrossRef] [PubMed]
- Straub, J.O. Deterministic and probabilistic environmental risk assessment for diazepam. In Pharmaceuticals in the Environment; Sources, Fate, Effects and Risks, 3rd ed.; Kümmerer, K., Ed.; Springer: Berlin/Heidelberg, Germany, 2008; pp. 343–383. [Google Scholar]
- Schneider, C. Synthetische Organische Spurenstoffe in der Aquatischen Umwelt und ihr Verhalten im Klärprozess. Ph.D. Dissertation, University of Stuttgart, Stuttgart, Germany, 2005. Available online: elib.uni-stuttgart.de/bitstream/11682/244/1/2003CS_D.pdf (accessed on 20 April 2023).
- Yu, J.T.; Bouwer, E.J.; Coelhan, M. Occurrence and biodegradability setudies of selected pharmaceuticals and personal care products in sewage effluent. Agric. Water Manag. 2006, 86, 72–80. [Google Scholar] [CrossRef]
- Zhang, Y.; Geissen, S.-U.; Gal, C. Carbamazepine and diclofenac: Removal in wastewater treatment plants and occurrence in water bodies. Chemosphere 2008, 73, 1151–1161. [Google Scholar] [CrossRef] [PubMed]
- Radjenovic, J.; Petrovič, M.; Barceló, D. Analysis of pharmaceuticals in wastewater and removal using a mebrane bioreactor. Anal. Bioanal. Chem. 2007, 387, 1365–1377. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Radjenovic, J.; Petrovič, M.; Barceló, D. Fate and distribution of pharmaceuticals in wastewater and sewage sludge of the conventional activated sludge (CAS) and advances membrane bioreactor (MBR) treatment. Water Res. 2009, 43, 831–841. [Google Scholar] [CrossRef]
- Zhou, L.J.; Zhang, Z.L.; Banks, E.; Grover, D.; Jiang, J.Q. Pharmaceutical residues in wastewater treatment works effluents and their impact on receiving river water. J. Hazard. Mater. 2009, 166, 655–661. [Google Scholar] [CrossRef]
- Dussault, È.B.; Balakrishnan, V.K.; Sverko, E.; Solomon, K.R.; Sibley, P.K. Toxicity of human pharmaceuticals and personal care products to benthic invertebrates. Environ. Toxicol. Chem. 2008, 27, 425–432. [Google Scholar] [CrossRef]
- Singer, H.; Müller, S.; Tixier, C.; Pillonel, L. Triclosan: occurrence and fate of a widely used biocide in the aquatic environment: field measurements in wastewater treatment plants, surface waters, and lake sediments. Environ. Sci. Technol. 2002, 36, 4998–5004. [Google Scholar] [CrossRef]
- Sabaliunas, D.; Webb, S.F.; Hauk, A.; Jacob, M.; Eckhoff, W.S. Environmental fate of triclosan in the River Aire basin, UK. Water Res. 2003, 37, 3145–3154. [Google Scholar] [CrossRef]
- Calamari, D.; Zuccato, E.; Castiglioni, S.; Bagnati, R.; Fanelli, R. Strategic survey of therapeutic drugs in the Rivers Po and Lambro in Northern Italy. Environ. Sci. Technol. 2003, 37, 1241–1248. [Google Scholar] [CrossRef]
- Blok, H. A Quest for the Right Order. Biodegradation rates in the Scope of Environmental Risk Assessment of Chemicals. Ph.D. Thesis, Utrecht University, Utrecht, The Netherlands, 2001. [Google Scholar]
- Strenn, B.; Clara, M.; Gans, O.; Kreuzinger, N. Carbamazepine, diclofenac, ibuprofen and bezafibrate—Investigations on the behaviour of selected pharmaceuticals during wastewater treatment. Water Sci. Technol. 2004, 55, 269–276. [Google Scholar] [CrossRef]
- Sumpter, J.P.; Runnalls, T.J.; Johnson, A.C.; Barceló, D. A ‘Limitations’ section should be mandatory in all scientific papers. Discussion. Sci. Total Environ. 2023, 857, 159395. [Google Scholar] [CrossRef] [PubMed]
- Naddaf, M. The world faces a water crisis—Four powerful charts show how. Nature 2023, 615, 774–775. [Google Scholar] [CrossRef]
- Oh, S.Y.; Seo, Y.D. Sorption of halogenated phenols and pharmaceuticals to biochar: Affecting factors and mechanisms. Environ. Sci. Pollut. Res. 2016, 23, 951–961. [Google Scholar] [CrossRef]
Molecular Fragment | Empirical Biodegradability | Fisher’s Exact Test | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Groups | Fragments per molecule, n | AOPSs, n | RB, n | RB, % | NRB, n | NRB, % | p-Value | Odds Ratio (95% CI) | ||
Substituents | ||||||||||
All AOPSs | NA | 230 | 33 | 14.3 | 197 | 85.7 | NA | NA | ||
Non-halogenated AOPSs | NA | 160 | 33 | 20.6 | 127 | 79.4 | NA | NA | ||
Halogenated AOPSs | ||||||||||
Fluorine | 1–7 | 39 | 0 | 0 | 39 | 100 | 0.0020 | 0 (0–0.51) | ||
Chlorine | 1–6 | 38 | 0 | 0 | 38 | 100 | 0.0021 | 0 (0–0.53) | ||
Bromine | 1–2 | 3 | 0 | 0 | 3 | 100 | 1 | 0 (0–14.7) | ||
Iodine | 1–4 | 2 | 0 | 0 | 2 | 100 | 1 | 0 (0–32.1) | ||
Sum of all halogens | 1–7 | 70 | 0 | 0 | 70 | 100 | 0.0000025 | 0 (0–0.22) | ||
Hydrophilic substituents | ||||||||||
Hydroxy group | 1–13 | 102 | 24 | 23.5 | 78 | 76.5 | 0.00053 | 4.1 (1.7–10.4) | ||
Carboxylic acid | 1–8 | 37 | 12 | 32.4 | 25 | 67.6 | 0.0017 | 3.9 (1.5–9.6) | ||
Terminal amine | 1–2 | 42 | 8 | 19.0 | 34 | 81.0 | 0.34 | 1.5 (0.55–3.9) | ||
Sum of above hydro philic substituents | 1–15 | 142 | 33 | 23.2 | 109 | 76.8 | <10−6 | ∞ (6.5–∞) |
Removal Pathway | AOPSs | M-W-W Test p-Value | |||
---|---|---|---|---|---|
Readily Biodegradable | Not Readily Biodegradable | ||||
Median | 1st–9th Deciles | Median | 1st–9th Deciles | ||
AOPSs, n | 33 | 197 | |||
Sorption to sludge, % | 0.4 | 0.4–6.6 | 2.9 | 0.6–61.0 | <10−6 |
Biodegradation, % | 90.2 | 88.9–90.3 | 14.0 | 0.1–84.7 | <10−6 |
Total removal, % | 90.7 | 90.6–95.5 | 27.8 | 7.7–92.1 | <10−6 |
Results | AOPSs | WSR Test p-Value | |||
---|---|---|---|---|---|
Original Halogenated | In Silico Dehalogenated | ||||
Median Value | 1st–9th Deciles | Median Value | 1st–9th Deciles | ||
AOPSs, n | 70 | 70 | |||
Readily biodegradable, n | 0 (exp.), 4 (pred.) a | 6 (pred.) b | |||
Sorption to sludge, % | 5.0 | 1.6–87.6 | 4.8 | 1.0–60.6 | 1.5 × 10−4 |
Biodegradation, % | 0.8 | 0.1–28.9 | 22.0 | 0.6–80.3 | <10−6 |
Total removal, % | 26.1 | 3.0–92.2 | 45.9 | 9.1–95.3 | 0.015 |
AOPS Name | Halogens, n | Removal Pathways | References | ||||||
---|---|---|---|---|---|---|---|---|---|
Br | Cl | F | Aerobic | Co-Metabolic | Anaerobic | Sorption | Total, % | ||
Bezafibrate | 1 | + | ? | ? | + | –10 to 99% | [41,42] | ||
Bromazepam | 1 | ? | ? | ? | ? | up to 72% a | [41,42,43,44,45] | ||
Chlorhexidine | 2 | ? | ? | – | ? | 60 to 100% | [46] | ||
Ciprofloxacin | 1 | ? | ? | + | + | 62 to 87% | [47,48] | ||
Diazepam | 1 | + | ? | + | ? | 0 to 99% | [49] | ||
Diclofenac | 2 | ? | ? | ? | + | 0 to 99% | [41,44,50,51,52] | ||
5-Fluorouracil | 1 | + | ? | ? | – | 100% | [38] | ||
Fluoxetine | 3 | ? | ? | ? | + | negative | [45] | ||
Glyburide | 1 | ? | ? | ? | + | 45 to 96% | [44,50,53,54,55] | ||
Hydrochlorothiazide | 1 | ? | ? | ? | + | 0 to 76% | [53,56] | ||
Indomethacin | 1 | ? | ? | ? | ? | 0 to 99% | [41,49,55] | ||
Nord(i)azepam | 1 | + | ? | ? | + | NQ | [42] | ||
Norfloxacin | 1 | ? | ? | ? | + | 30 to 98% | [43,44] | ||
Ofloxacin | 1 | ? | ? | ? | + | 20 to 99% | [41,44] | ||
Oxazepam | 1 | + | ? | ? | ? | 20 to 24% | [52,53] | ||
Triclosan | 3 | ? | ? | ? | + | up to 95% | [56,57,58] |
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Straub, J.O.; Le Roux, J.; Tedoldi, D. Halogenation of Pharmaceuticals Is an Impediment to Ready Biodegradability. Water 2023, 15, 2430. https://doi.org/10.3390/w15132430
Straub JO, Le Roux J, Tedoldi D. Halogenation of Pharmaceuticals Is an Impediment to Ready Biodegradability. Water. 2023; 15(13):2430. https://doi.org/10.3390/w15132430
Chicago/Turabian StyleStraub, Jürg Oliver, Julien Le Roux, and Damien Tedoldi. 2023. "Halogenation of Pharmaceuticals Is an Impediment to Ready Biodegradability" Water 15, no. 13: 2430. https://doi.org/10.3390/w15132430