Skip to main content

Advertisement

Springer Nature Link
Log in

Early Life-Stage Toxicity of Eight Pharmaceuticals to the Fathead Minnow, Pimephales promelas

  • Published:
Archives of Environmental Contamination and Toxicology Aims and scope Submit manuscript

Abstract

Human pharmaceuticals are routinely being detected in the environment, and there is growing concern about whether these drugs could elicit effects on aquatic organisms. Regulatory paradigms have shifted accordingly, with a greater emphasis on chronic toxicity data compared with acute data. The Organisation for Economic Co-operation and Development 210 Early Life Stage Test has been proposed as a good measure of the potential for pharmaceuticals to elicit chronic toxicity. To begin building a data set regarding the early life-stage toxicity of pharmaceuticals to fish, fathead minnows (FHM) were exposed to amiodarone, carbamazepine, clozapine, dexamethasone, fenofibrate, ibuprofen, norethindrone, or verapamil. Survival and growth were used to assess chronic toxicity in FHM at 28 days posthatch. Exposure of FHM to carbamazepine, fenofibrate, and ibuprofen resulted in no significant adverse effects at the concentrations tested. FHM survival was not impacted by verapamil exposure; however, growth was significantly decreased at 600 μg/L. Dexamethasone-exposed FHM showed a significant decrease in survival at a concentration of 577 μg/L; however, growth was not impacted at the concentration tested. Norethindrone exposure resulted in a significant decrease in survival and dry weight at 14.8 and 0.74 μg/L, respectively. Exposure to amiodarone and clozapine resulted in a significant decrease in survival and a significant increase in growth at concentrations of 1020 and 30.8 μg/L, respectively. Although the effect levels derived in this study are greater then concentrations observed in the environment, these data suggest that synthetic progestins may require additional research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  • Akande MG, Orn S, Norrgren L (2010) Evaluation of the toxic effects of clozapine in zebrafish (Danio rerio) embryos with the fish embryo toxicity test. Int J Pharm Biomed Res 1:90–94

    Google Scholar 

  • American Public Health Association (2005) Standard methods for the evaluation of water and wastewater, 21st edn. United Book Press, Baltimore, MD

    Google Scholar 

  • Ankley GT, Black MC, Garric J, Hutchinson TH, Iguchi T (2005) A framework for assessing the hazard of human pharmaceuticals to aquatic life. In: Williams RT (ed) Human pharmaceuticals: assessing the impacts on aquatic ecosystems. SETAC Press, Pensacola, FL, pp 183–222

    Google Scholar 

  • Ankley GT, Brooks BW, Huggett DB, Sumpter JP (2007) Repeating history: Pharmaceuticals in the environment. Environ Sci Technol 41:8211–8217

    Article  CAS  Google Scholar 

  • Bai YM, Lin CC, Chen JY, Chen TT, Su TP, Chou P (2011) Association of weight gain and metabolic syndrome in patients taking clozapine: an 8-year cohort study. J Clin Psychiatry 72:751–756

    Article  CAS  Google Scholar 

  • Baldessarini RJ, Tarazi FI (2001) Drugs and the treatment of psychiatric disorders: psychosis and mania. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman & Gilman’s The pharmacological basis of therapeutics. McGraw-Hill, New York, NY, pp 485–520

    Google Scholar 

  • Besse JP, Garric J (2008) Human pharmaceuticals in surface waters: implementation of a prioritization methodology and application to the French situation. Toxicol Lett 176:102–123

    Article  Google Scholar 

  • Bogers R, De Vries-Buitenweg S, Van Gils M, Baltussen E, Hargreaves A, van de Waart B et al (2006) Development of chronic tests for endocrine active chemicals. Part 2: an extended fish early-life stage test with an androgenic chemical in the fathead minnow (Pimephales promelas). Aquat Toxicol 80:119–130

    Article  CAS  Google Scholar 

  • Brodie MJ (2010) Antiepileptic drug therapy the story so far. Seizure 19:650–655

    Article  Google Scholar 

  • Burgess AM, Vere DW (1989) Teratogenic effects of some calcium channel blocking agents in Xenopus embryos. Pharmacol Toxicol 64:78–82

    Article  CAS  Google Scholar 

  • Caldwell DJ, Mastrocco F, Hutchinson TH, Länge R, Heijerick D, Janssen C et al (2008) Derivation of a aquatic predicted no-effect concentration for the synthetic hormone, 17 alpha-ethinyl estradiol. Environ Sci Technol 42:7046–7054

    Article  CAS  Google Scholar 

  • Cappon GD, Cook JC, Hurtt ME (2003) Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure. Birth Defects Res B Dev Reprod Toxicol 68:47–56

    Article  CAS  Google Scholar 

  • Chang H, Hu J, Shao B (2007) Occurrence of natural and synthetic glucocorticosteroids in sewage treatment plants and receiving river waters. Environ Sci Technol 41:3462–3468

    Article  CAS  Google Scholar 

  • Cleuvers M (2003) Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Toxicol Lett 142:185–194

    Article  CAS  Google Scholar 

  • Crockett AB (2005) Use of prescription drugs: rising or declining. Nurs Clin North America 40:33–49

    Article  Google Scholar 

  • DellaGreca M, Fiorentino A, Isidori M, Lavorgna M, Previtera L, Rubino M et al (2004) Toxicity of prednisolone, dexamethasone and their photochemical derivatives on aquatic organism. Chemosphere 54:629–637

    Article  CAS  Google Scholar 

  • Escher BI, Baumgartner R, Koller M, Treyer K, Lienert J, McArdell CS (2011) Environmental toxicology and risk assessment of pharmaceuticals from hospital wastewater. Water Res 45:75–92

    Article  CAS  Google Scholar 

  • European Medicines Agency (2006) Guideline on the environmental risk assessment of medicinal products for human use. Available at: http://www.ema.europa.eu/pdfs/human/swp/444700en.pdf. Accessed January 2011

  • Ferrari B, Paxéus N, Giudice RL, Pollio A, Garric J (2003) Ecotoxicological impact of pharmaceuticals found in treated wastewaters: study of carbamazepine, clofibric acid, and diclofenac. Ecotoxicol Environ Saf 55:359–370

    Article  CAS  Google Scholar 

  • Flippin JL, Huggett D, Foran CM (2007) Changes in the timing of reproduction following chronic exposure to ibuprofen in Japanese medaka, Oryzia latipes. Aquat Toxicol 81:73–81

    Article  CAS  Google Scholar 

  • Gomez CF, Constantine L, Huggett DB (2010) The influence of gill and liver metabolism on the predicted bioconcentration of three pharmaceuticals in fish. Chemosphere 81:1189–1195

    Article  CAS  Google Scholar 

  • Goto T, Hiromi J (2003) Toxicity of 17alpha-ethynylestradiol and norethindrone, constituents of an oral contraceptive pill to the swimming and reproduction of cladoceran Daphnia magna, with special reference to their synergetic effect. Mar Pollut Bull 47:139–142

    Article  CAS  Google Scholar 

  • Gravel A, Vijayan MM (2007) Non-steroidal anti-inflammatory drugs disrupt the heat shock response in rainbow trout. Aquat Toxicol 81:197–206

    Article  CAS  Google Scholar 

  • Gross-Sorokin MY, Roast SD, Brightly GC (2006) Assessment of feminization of male fish in English rivers by the environment agency of England and Wales. Environ Health Perspect 114:147–151

    Article  Google Scholar 

  • Gunnarsson L, Jauhiainen A, Kristiansson E, Nerman O, Larsson DG (2008) Evolutionary conservation of human drug targets in organisms used for environmental risk assessments. Environ Sci Technol 42:5807–5813

    Article  CAS  Google Scholar 

  • Hala D, Overturf MD, Petersen LH, Huggett DB (2011) Quantification of 2-hydrazinopyridine derivatized steroid hormones in fathead minnow (Pimephales promelas) blood plasma using LC-ESI +/MS/MS. J Chromatogr B 879:591–598

    Article  CAS  Google Scholar 

  • Hallare AV, Köhler HR, Triebskorn R (2004) Developmental toxicity and stress protein responses in zebrafish embryos after exposure to diclofenac and its solvent, DMSO. Chemosphere 56:659–666

    Article  CAS  Google Scholar 

  • Han GH, Hur HG, Kim SD (2006) Ecological risk of pharmaceuticals from wastewater treatment plants in Korea: occurrence and toxicity to Daphnia magna. Environ Toxicol Chem 25:256–271

    Article  Google Scholar 

  • Henschel KP, Wenzel A, Diedrich M, Fliedner A (1997) Environmental hazard assessment of pharmaceuticals. Regul Toxicol Pharm 25:220–225

    Article  CAS  Google Scholar 

  • Hernando MD, Petrovic M, Fernández-Alba AR, Barceló D (2004) Analysis by liquid chromatography–electrospray ionization tandem mass spectrometry and acute toxicity evaluation for β-blockers and lipid-regulating agents in wastewater samples. J Chrom A 1046:133–140

    CAS  Google Scholar 

  • Hoeger B, Köllner B, Dietrich DR, Hitzfeld B (2005) Water-borne diclofenac affects kidney and gill integrity and selected immune parameters in brown trout. Aquat Toxicol 75:53–64

    Article  CAS  Google Scholar 

  • Huggett DB, Cook JC, Ericson JE, Williams RT (2003) Theoretical model for prioritizing potential impacts of human pharmaceuticals to fish. J Human Ecol Risk Assess 9:1789–1799

    Article  CAS  Google Scholar 

  • Hummel D, Löffler D, Fink G, Ternes TA (2006) Simultaneous determination of psychoactive drugs and their metabolites in aqueous matrices by liquid chromatography mass spectrometry. Environ Sci Technol 40:7321–7328

    Article  CAS  Google Scholar 

  • Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evans RE, Lazorchak JM et al (2007) Collapse of a fish population after exposure to a synthetic estrogen. Proc Natl Acad Sci U S A 104:8897–8901

    Article  CAS  Google Scholar 

  • Kollroser M, Schober C (2002) Direct-injection high performance liquid chromatography ion trap mass spectrometry for the quantitative determination of olanzapine, clozapine and N-desmethylclozapine in human plasma. Rapid Commun Mass Spectrom 16:1266–1272

    Article  CAS  Google Scholar 

  • Kolpin DW, Furlong ET, Meyer MT, Thurman EM, Zaugg SD, Barber LB et al (2002) Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999–2000: a national reconnaissance. Environ Sci Technol 15:1202–1211

    Article  Google Scholar 

  • Kuhn J, Götting C, Kleesiek K (2010) Simultaneous measurement of amiodarone and desethylamiodarone in human plasma and serum by stable isotope dilution liquid chromatography-tandem mass spectrometry assay. J Pharm Biomed Anal 51:210–216

    Article  CAS  Google Scholar 

  • Länge R, Hutchinson TH, Croudace CP, Siegmund F, Schweinfurth H, Hampe P et al (2001) Effects of the synthetic estrogen 17 alpha-ethinylestradiol on the life-cycle of the fathead minnow (Pimephales promelas). Environ Toxicol Chem 20:1216–1227

    Google Scholar 

  • Liu YW, Chen WK (2002) Thyroid hormones are important for embryonic to larval transitory phase in zebrafish. Differentiation 70:36–45

    Article  CAS  Google Scholar 

  • Lizotte RE, Wong DCL, Dorn PB, Rodgers JH (1999) Effects of a homologous series of linear alcohol ethoxylate surfactants on fathead minnow early life stages. Arch Environ Contam Toxicol 37:536–541

    Article  CAS  Google Scholar 

  • Loose-Mitchell DS, Stancel GM (2001) Estrogens and progestins. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman & Gilman’s The pharmacological basis of therapeutics. McGraw-Hill, New York, NY, pp 1597–1634

    Google Scholar 

  • Mahley RW, Bersot TP (2001) Drug therapy for hypercholesterolemia and dyslipidemia. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman & Gilman’s The pharmacological basis of therapeutics. McGraw-Hill, New York, NY, pp 971–1002

    Google Scholar 

  • McNamara JO (2001) Drugs effective in the therapy of the epilepsies. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman & Gilman’s The pharmacological basis of therapeutics. McGraw-Hill, New York, NY, pp 521–547

    Google Scholar 

  • Mehlman MA, Pfitzer EA, Scala RA (1989) A report on methods to reduce, refine and replace animal testing in industrial toxicology laboratories. Cell Biol Toxicol 5:349–358

    Article  CAS  Google Scholar 

  • Nallani GC, Paulos PM, Venables BJ, Edziyie RE, Constantine LA, Huggett DB (2011) Tissue-specific uptake and bioconcentration of the oral contraceptive norethindrone in two freshwater fishes. Arch Environ Contam Toxicol

  • Organization for Economic Co-Operation and Development (1992) 210 Fish early life stage toxicity test protocol. Available at: http://www.oecd.org/dataoecd/17/62/1948269.pdf. Accessed November 2010

  • Oxendine SL, Cowden J, Hinton DE, Padilla S (2006) Vulnerable windows for developmental ethanol toxicity in the Japanese medaka fish (Oryzia latipes). Aquat Toxicol 80:396–404

    Article  CAS  Google Scholar 

  • Petrovic M, Monteserrat S, Lopez de Alda MJ, Barcelo D (2002) Endocrine disruptors in sewage treatment plants, receiving river waters, and sediments: integration of chemical analysis and biological effects on feral carp. Environ Toxicol Chem 21:2146–2156

    Article  CAS  Google Scholar 

  • Petrovic M, Gonzalez S, Barcelo D (2003) Analysis and removal of emerging contaminants in wastewater and drinking water. Trends Anal Chem 22:686–696

    Article  Google Scholar 

  • Raldúa D, Babin PJ (2009) Simple, rapid zebrafish larval bioassay for assessing the potential of chemical pollutants and drugs to disrupt thyroid gland function. Environ Sci Technol 43:6844–6850

    Article  Google Scholar 

  • Ramirez AJ, Mottaleb MA, Brooks BW, Chambliss CK (2007) Analysis of pharmaceuticals in fish using liquid chromatography-tandem mass spectrometry. Anal Chem 79:3155–3163

    Article  CAS  Google Scholar 

  • Rang HP, Dale MM, Ritter JM, Flower RJ (2007) Rang and Dale’s pharmacology, 6th edn. Elsevier, China

    Google Scholar 

  • Richards SM, Cole SE (2006) A toxicity and hazard assessment of fourteen pharmaceuticals on Xenopus laevis larvae. Ecotoxicology 15:647–656

    Article  CAS  Google Scholar 

  • Rosal R, Rodea-Palomares I, Boltes K, Fernádez-Piñas F, Leganés F, Gonzalo S et al (2010) Ecotoxicity assessment of lipid regulators in water and biologically treated wastewater using three aquatic organisms. Environ Sci Pollut Res 17:135–144

    Article  CAS  Google Scholar 

  • Sacher F, Lange FT, Brauch HJ, Blankenhorn I (2001) Pharmaceuticals in groundwater: analytical methods and results of a monitoring program in Baden-Württemberg, Germany. J Chromatogr A 938:199–210

    Article  CAS  Google Scholar 

  • Santos JL, Aparicio I, Callejón M, Alonso E (2009) Occurrence of pharmaceutically active compounds during 1-year period in wastewaters from four wastewater treatment plants in Seville (Spain). J Hazard Mater 164:1509–1516

    Article  CAS  Google Scholar 

  • Schimmer BP, Parker KL (2001) Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman & Gilman’s The pharmacological basis of therapeutics. McGraw-Hill, New York, NY, pp 1649–1677

    Google Scholar 

  • Stolker AA, Niesing W, Hogendoorn EA, Versteegh JFM, Fuchs R, Brinkman UAT (2004) Liquid chromatography with triple-quadrupole or quadrupole-time of flight mass spectrometry for screening and confirmation of residues of pharmaceuticals in water. Anal Bioanal Chem 378:955–963

    Article  CAS  Google Scholar 

  • Stumpf M, Ternes TA, Wilken RD, Rodrigues SV, Baumann W (1999) Polar drug residues in sewage and natural waters in the state of Rio de Janeiro, Brazil. Sci Total Environ 225:135–141

    Article  Google Scholar 

  • Sun L, Zhang S, Zhong F (2004) In vitro identification of metabolites of verapamil in rat liver microsomes. Acta Pharmacol Sin 25:121–128

    CAS  Google Scholar 

  • Ternes TA (1998) Occurrence of drugs in German sewage treatment plants and rivers. Water Res 32:3245–3260

    Article  CAS  Google Scholar 

  • van Aerle R, Pounds N, Hutchinson TH, Maddix S, Tyler CR (2002) Window of sensitivity for the estrogenic effects of ethinylestradiol in early life-stages of fathead minnow, Pimephales promelas. Ecotoxicology 11:423–434

    Article  Google Scholar 

  • van den Brandhof EJ, Montforts M (2010) Fish embryo toxicity of carbamazepine, diclofenac and metoprolol. Ecotoxicol Environ Saf 73:1862–1866

    Article  Google Scholar 

  • Vassallo P, Trohman RG (2007) Prescribing amiodarone: an evidence based review of clinical indications. J Am Med Assoc 298:1312–1322

    Article  CAS  Google Scholar 

  • Vazquez-Roig P, Segarra R, Blasco C, Andreu V, Picó Y (2010) Determination of pharmaceuticals in soils and sediments by pressurized liquid extraction and liquid chromatography tandem mass spectrometry. J Chromatogr A 1217:2471–2483

    Article  CAS  Google Scholar 

  • Viglino L, Aboulfadl K, Prevost M, Sauve S (2008) Analysis of natural and synthetic estrogenic endocrine disruptors in environmental waters using online preconcentration coupled with LC-APPI-MS/MS. Talanta 76:1088–1096

    Article  CAS  Google Scholar 

  • Wibbels T, Crews D (1995) Steroid-induced sex determination at incubation temperatures producing mixed sex ratios in a turtle with TSD. Gen Comp Endocrinol 100:53–60

    Article  CAS  Google Scholar 

  • Williams TD, Caunter JE, Lillicrap AD, Hutchinson TH, Gillings EG, Duffell S (2007) Evaluation of the reproductive effects of tamoxifen citrate in partial and full life-cycle studies using fathead minnow (Pimephales promelas). Environ Toxicol Chem 26:695–707

    Article  CAS  Google Scholar 

  • Winter MJ, Lillicrap AD, Caunter JE, Schaffner D, Alder AC, Ramil M et al (2008) Defining the chronic impacts of atenolol on embryo-larval development and reproduction in the fathead minnow (Pimephales promelas). Aquat Toxicol 86:361–369

    Article  CAS  Google Scholar 

  • Zeilinger J, Steger-Hartmann T, Maser E, Goller S, Vonk R, Länge R (2009) Effects of synthetic gestagens on fish reproduction. Environ Toxicol Chem 12:2663–2670

    Article  Google Scholar 

  • Zhang M, Moore GA, Jensen BP, Begg EJ, Bird PA (2011) Determination of dexamethasone and dexamethasone sodium phosphate in human plasma and cochlear perilymph by liquid chromatography/tandem mass spectrometry. J Chromatogr B 879:17–24

    Article  CAS  Google Scholar 

  • Zurita JL, Repetto G, Jos A, Salguero M, López-Artíguez M, Camean AM (2007) Toxicological effects of the lipid regulator gemfibrozil in four aquatic systems. Aquat Toxicol 81:106–115

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Tom Waller at the University of North Texas for review and critique of an earlier version of this manuscript. Funding for this project was supplied by Pfizer Global Research and Development.

Author information

Authors and Affiliations

  1. Department of Biology, University of North Texas, Denton, TX, 76203, USA

    M. D. Overturf, C. L. Overturf, D. Baxter, D. N. Hala, B. Venables & D. B. Huggett

  2. Pfizer Global Research and Development, Groton, CT, 06773, USA

    L. Constantine

Authors
  1. M. D. Overturf
    View author publications

    Search author on:PubMed Google Scholar

  2. C. L. Overturf
    View author publications

    Search author on:PubMed Google Scholar

  3. D. Baxter
    View author publications

    Search author on:PubMed Google Scholar

  4. D. N. Hala
    View author publications

    Search author on:PubMed Google Scholar

  5. L. Constantine
    View author publications

    Search author on:PubMed Google Scholar

  6. B. Venables
    View author publications

    Search author on:PubMed Google Scholar

  7. D. B. Huggett
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to D. B. Huggett.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Overturf, M.D., Overturf, C.L., Baxter, D. et al. Early Life-Stage Toxicity of Eight Pharmaceuticals to the Fathead Minnow, Pimephales promelas . Arch Environ Contam Toxicol 62, 455–464 (2012). https://doi.org/10.1007/s00244-011-9723-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00244-011-9723-6

Keywords