2003 Progress Report: The Environmental Occurrence, Fate, and Ecotoxicity of Selective Serotonin Reuptake Inhibitors (SSRIs) in Aquatic Environments

EPA Grant Number: R829006
Title: The Environmental Occurrence, Fate, and Ecotoxicity of Selective Serotonin Reuptake Inhibitors (SSRIs) in Aquatic Environments
Investigators: Black, Marsha C. , Armbrust, Kevin L. , Henry, Theodore B. , Kwon, Jeong-Wook
Current Investigators: Black, Marsha C. , Armbrust, Kevin L.
Institution: University of Georgia
EPA Project Officer: Page, Angela
Project Period: September 1, 2001 through August 31, 2004 (Extended to April 30, 2007)
Project Period Covered by this Report: September 1, 2002 through August 31, 2003
Project Amount: $522,892
RFA: Drinking Water (2000) RFA Text |  Recipients Lists
Research Category: Drinking Water , Water Quality , Water


Pharmaceutical chemicals can enter aquatic environments after their prescribed use and lead to negative effects on aquatic organisms. For most pharmaceutical chemicals, the environmental fate and ecotoxicological characteristics are unknown. Drugs that are hormonally active are of particular concern because disruption of physiological processes in aquatic organisms can occur at low environmental concentrations. Hormonally active, selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed drugs. Low concentrations have been shown to affect aquatic organisms, and evidence indicates they can be present in effluents from wastewater treatment plants. This project will characterize the occurrence, environmental fate, and ecotoxicity of five SSRI drugs (fluoxetine, fluvoxamine, paroxetine, citalopram, and sertraline) and their relevant metabolites. Investigations on the environmental chemistry of these five medications will seek to identify the specific compounds that pose the greatest risk as contaminants in aquatic ecosystems and to assess their persistence in aquatic environments. Routine sampling of a wastewater treatment plant (Peachtree City, GA) combined with market information on the numbers of prescriptions for specific SSRIs will be used to gauge the potential environmental exposure of the different compounds. Acute and chronic toxicity testing with Ceriodaphnia dubia (C. dubia) followed by the determination of long-term reproductive effects on mosquitofish, Gambusia affinis (G. affinis), will help characterize the effects of these chemicals on the key components of aquatic ecosystems.

The specific objectives of this investigation are to determine: (1) the environmental fate of Prozac (fluoxetine), Luvox (fluvoxamine), Paxil (paroxetine), Zoloft (sertraline), and Celexa (citalopram) in laboratory studies similar to those used for pesticide registration; (2) their occurrence in raw wastewater, treated effluent, and downstream receiving waters; (3) the acute and chronic toxicity of the five SSRIs and their major environmental metabolites to C. dubia; and (4) the reproductive effects of chronic SSRI exposure on the mosquitofish.

Progress Summary:

Analyses of SSRI chemicals extracted from tablets as their salts showed high water solubilities and relatively low octanol-water partition coefficients (Kow). Solubilities ranged from 3,022-15,460 mg/L, and Kow ranged from 1.12-1.39. Adsorption coefficients were determined using two sediments—creek sediment: silt, 0.16 percent organic matter, and pond sediment: silt loam, 0.65 percent organic matter. Values of Kf, Kd, and Koc ranged from 50.7 to 419.1, from 87.6 to 1,304.0, and from 225.4 to 4,907.4, respectively, indicating very high sorption coefficients for all SSRIs. Hydroxyl radical rate constants, measured by competition kinetic methods, were conducted for SSRIs and ranged from 1.41×1012 to 1.99×1013 M-1 h-1. Paroxetine was the most reactive molecule measured by this method, followed by fluvoxamine, citalopram, fluoxetine, and sertraline.

No significant hydrolytic degradation was detected for any drug in any aqueous solution. Photolysis, however, is a potential route of degradation for several SSRIs. Fluoxetine was relatively resistant to photolysis at all pH ranges, and degradation generally was less than 10 percent over a 10-day period, with no detectable degradation products, attributable to the very low degradation rate. Paroxetine was photodegraded completely within 4 days after exposure to simulated sunlight. The photolysis of paroxetine was accelerated by increasing pH, and two degradation products were detected. Photolysis of sertraline in pH 5 and 7 buffer solutions was very slow, yet at pH 9 this drug was completely degraded by simulated sunlight within 10 days. Much slower degradation was observed in solutions of NaCl, indicating photonucleophilic substitution reactions could be responsible for the degradation.

Degradation in distilled-deionized water was similar to that in pH 9 buffer. Slower degradation of sertraline was observed in humic, acid-containing water or natural waters compared with pure water, suggesting that the fate of sertraline in aqueous environments may be different in the laboratory than in real aqueous environments. Photolysis of citalopram also was slow at pH 5 and 7; however, at pH 9, citalopram moderately degraded via a pseudo-first order kinetic model. Degradation was faster in synthetic humic water than in pH 9 buffer or two lake waters. Two photoproducts were detected over the irradiation period, and their structures were identified. Fluvoxamine was moderately degraded by simulated sunlight, and degradation kinetics were biphasic. In buffer solutions, the degradation shows a rapid drop for the first 7 days, followed by a slowly decreasing pattern for the remainder. The first stages have high degradation rate constants, whereas the second stages have low degradation rate constants. Photosensitized degradation of fluvoxamine was faster in synthetic, humic water, and in lake water than in pH 9 buffered solutions.

In the water/sediment degradation of sertraline, recoveries of approximately 100 percent and 90 percent were obtained from creek and pond sediments after 150 and 300 minute extraction by soxhlet with a methanol/water mixture. Free sertraline in the aqueous phase was degraded by photolysis when compared to dark controls. Once adsorbed to sediments, however, sertraline appeared stable. After 30 days of treatment, more than 80 percent of compound was found in the sediments, indicating that the sediments are an important sink for sertraline. Further physicochemical characterization of the remaining SSRIs will continue into Year 3 of the project.

The acute and chronic toxicities of each of the five SSRIs have been determined in experiments with C. dubia. For each SSRI, C. dubia mortality increased with increasing concentration. The 48-h LC50 values ranged from 0.14 mg/L for sertraline to 3.18 mg/L for citalopram. The LC50 values for other SSRIs were: fluoxetine, 0.47 mg/L; paroxetine, 0.59 mg/L; and fluvoxamine, 1.26 mg/L. In chronic tests, the SSRI with the lowest concentration to affect the mean number of neonates produced (LOEC) was sertraline (0.045 mg/L) while the highest LOEC was measured upon exposure to citalopram (4 mg/L). The time to first brood was not significantly affected after exposure to any of the SSRIs tested; however, the number of broods was reduced after exposure to fluvoxamine, fluoxetine, and paroxetine (but not by the other SSRIs at the concentrations tested).

Experiments were conducted to determine the acute and chronic toxicity of fluoxetine to western mosquitofish G. affinis. Fluoxetine was selected because it was found to be relatively resistant to hydrolysis and photolysis, was more toxic to C. dubia than other SSRIs (except for sertraline), and was commercially available. In 7-day acute toxicity tests with neonate (age 24-36 hours) G. affinis, the LC50 for fluoxetine HCl was 614 µg/L. A 91-day chronic test was conducted with neonate (age 24-48 hours) G. affinis based on toxicity data obtained from the acute test, and fish were exposed to 6, 0.6, and 0.06 µg/L fluoxetine HCl. Chronic exposure to fluoxetine did not significantly affect survival, sex ratio, or morphology of the male gonopodium. A second chronic test was conducted in lager tanks (100 L) beginning with older (age 5-6 weeks) juvenile fish and continued until fish were age 140-145 days. At the high exposure concentration (60 µg/L fluoxetine HCl), development of external sexual morphology was delayed relative to unexposed (control) fish. Further analyses including histological examination are planned to clarify developmental differences among exposed and unexposed fish.

Future Activities:

Experiments to determine the physicochemical properties of the five SSRIs will be completed during Year 3 of the project, including: (1) determinations of adsorption coefficients with three additional soils/sediments and water/sediment degradation; and (2) ready biodegradability measurements for all remaining compounds. Physicochemical properties will be incorporated in environmental fate characterizations for all compounds.

All acute and chronic toxicity tests with C. dubia, and range-finder and semi-chronic exposures with mosquitofish, were completed during Year 2 of the project. Mesocosm exposures with mosquitofish will be completed in Year 3 of the project. Identification of SSRI compounds in wastewater effluents, coupled with acute and chronic toxicity determinations, will be conducted along with concomitant surveys of SSRI drugs prescribed in Peachtree City, GA. These data will be analyzed in an attempt to correlate the amounts of SSRI drugs prescribed with their appearance in wastewaters.

Journal Articles on this Report : 2 Displayed | Download in RIS Format

Other project views: All 44 publications 11 publications in selected types All 9 journal articles
Type Citation Project Document Sources
Journal Article Henry TB, Kwon J-W, Armbrust KL, Black MC. Acute and chronic toxicity of five selective serotonin reuptake inhibitors to Ceriodaphnia dubia. Environmental Toxicology and Chemistry 2004;23(9):2229-2233. R829006 (2003)
R829006 (2004)
R829006 (Final)
  • Abstract from PubMed
  • Journal Article Kwon J-W, Armbrust KL. Hydrolysis and photolysis of paroxetine, a selective serotonin reuptake inhibitor, in aqueous solutions. Environmental Toxicology and Chemistry 2004;23(6):1394-1399. R829006 (2003)
    R829006 (2004)
    R829006 (Final)
  • Abstract from PubMed
  • Supplemental Keywords:

    pharmaceuticals, aquatic persistence, reproductive toxicity, selective serotonin reuptake inhibitors, SSRIs, ecotoxicity., RFA, Scientific Discipline, Waste, Water, Ecosystem Protection/Environmental Exposure & Risk, Ecology, Aquatic Ecosystems & Estuarine Research, Environmental Chemistry, Chemistry, Aquatic Ecosystem, Fate & Transport, Environmental Microbiology, Biochemistry, Ecology and Ecosystems, Drinking Water, ceriodaphnia dubia, fate and transport, pharmaceuticals, aquatic organisms, other - risk assessment, selective serotonin reuptake inhibitors (SSRIs), impact of pharmaceuticals, aquatic persistence, aquatic ecosystems, gambusia holbrooki

    Relevant Websites:

    http://www.mscl.msstate.edu Exit
    http://www.uga.edu/ehs/ Exit

    Progress and Final Reports:

    Original Abstract
  • 2002 Progress Report
  • 2004 Progress Report
  • 2005 Progress Report
  • 2006 Progress Report
  • Final Report