Arch. Environ. Contam. Toxicol. 52, 163–170 (2007)DOI: 10.1007/s00244-005-7190-7 Effects of Pharmaceuticals on Aquatic Invertebrates. Part II: The AntidepressantDrug Fluoxetine Department of Aquatic Ecotoxicology, J.W. Goethe-University Frankfurt am Main, Siesmayerstrasse 70, D-60054 Frankfurt, Germany Received: 27 July 2005 /Accepted: 2 May 2006 Abstract. Fluoxetine, a selective serotonin reuptake inhibitor This is of concern because some residues have been detected antidepressant and high-prescription-volume drug, is excreted in drinking water (Ternes 2000). Although most of these unchanged or as a glucuronide from the human organism.
compounds occur in surface waters in the nanogram-per-liter Little is known about its fate in sewage treatment plants. Ef- range, hazards for aquatic biota cannot be excluded because of fects of fluoxetine on life-cycle parameters of the midge high biological activity. This has been demonstrated for Chironomus riparius, especially development (mean emer- endocrine active pharmaceuticals such as ethinylestradiol, gence time), emergence, sex ratio, and fecundity, were as- which already affects aquatic wildlife at concentrations be- sessed, as well as effects on reproduction of the oligochaete tween 1 and 10 ng/L (Jobling et al. 2004) and particularly fish Lumbriculus variegatus and of the freshwater mudsnail populations, even in the subnanogam-per-liter range (Young Potamopyrgus antipodarum. Due to the moderate lipophilic et al. 2002). Because the active ingredients of many drugs are properties of the compound with a log POW of 4.05, C. riparius quite stable, they persist in the environment and are hardly and L. variegatus were exposed to fluoxetine via spiked arti- changed during sewage treatment. Such is the case for ficial sediment at a nominal concentration range between 0.15 the antiepileptic agent carbamazepine, of which only 7% is and 5.86 mg/kg (dry weight). Additionally, a test was eliminated by sewage treatment, and the lipid-lowering agent performed exposing P. antipodarum via water in a nominal clofibric acid, persistent with a half-life-time (DT50) greater concentration range between 0.64 and 400 lg/L. As endpoints, than 365 days (Ternes 1998). Despite the widespread occur- emergence rate and timing, sex ratio, clutch numbers and rence of pharmaceuticals, chronic ecotoxicological effect data clutch size of the midges, the number of worms in the oligo- are sparse (Kolpin et al. 2002; Ternes 1998; Tixier et al. 2003).
chaete test, as well as the number of embryos in the snail test In the present study, part of a project assessing the envi- were monitored. For C. riparius, no clear substance-related ronmental impact of a range of pharmaceuticals, the effects of effects were observed; for L. variegatus, the results indicated a the antidepressant drug fluoxetine on the freshwater mudsnail slight increase in reproduction, which was statistically signif- Potamopyrgus antipodarum, the nonbiting midge Chironomus icant at nominal fluoxetine concentrations of 0.94 and 2.34 riparius, and the oligochaete Lumbriculus variegatus were mg/kg. In P. antipodarum, the antidepressant reduced repro- assessed. Ecotoxicological research on drugs such as fluoxe- duction significantly. No observed effect concentration tine is important because they are prescribed in large amounts.
(NOEC) and 10% effect concentration (EC10) were determined Schwabe and Paffrath (2004) reported that 23.1 million De- to be 0.47 and 0.81 lg/L, respectively, based on measured fined Daily Doses were prescribed in 2003 in Germany, fluoxetine concentrations in water. These low values indicate reflecting a total amount of 4.62 tons. In the United States, that P. antipodarum and possibly other aquatic mollusks are fluoxetine was widely prescribed after its introduction in 1988 sensitive to fluoxetine and that the drug might pose a risk to under the brand names of ProzacÒ and SarafemÒ. It was soon advertised in the lay press and, according to Olfson et al.
(1998), is often used without any medical necessity, as alifestyle drug. Medawar (1994) stated that annual sales ofProzac exceeded 1.2 billion US dollars in 1994. Prescriptionamounts continued to increase after less costly generic prod- During the last 10–15 years, an increasing number of phar- ucts became available (Schwabe and Paffrath 2004) and it is maceutical residues have been detected in the aquatic envi- often used for the treatment of maladies other than depression ronment (Sattelberger 1999; Ternes 1998; Tixier et al. 2003).
(Barondes 1994). Fluoxetine is excreted 20–30% unchanged;the rest is excreted as fluoxetine glucuronide and norfluoxe-tine, the active metabolite (Hartke and Mutschler 1993). Theparent compound can be reactivated in wastewater treatment plants by cleavage of the glucuronides (Mçhle et al. 1999).
Fluoxetine has previously been detected in the environment.
Metcalfe et al. (2003) found quantities up to 0.099 lg/L in the The midge, C. riparius, usually breeds within 24 h after emergence.
Little River (Canada) below a sewage treatment plant. Kolpin Females extrude gelatinous egg clutches containing approximately et al. (2002) reported fluoxetine levels up to 0.012 lg/L in US 400 eggs into the water and the larvae hatch after 2–4 days. After four streams. Weston et al. (2001) estimated fluoxetine concen- instar stages, they molt to a pharate pupa and emerge.
trations of 0.54 lg/L in sewage treatment plant effluents.
The oligochaete L. variegatus is a common subject for sediment toxicity tests (Egeler et al. 1997; Leppänen and Kukkonen 1998; Because of its serotonergic action, fluoxetine can influence Phipps et al. 1993; West and Ankley 1998) and thus recommended by the reproductive behavior of mollusks (Hecker 2004). Several the American Society for Testing and Materials (ASTM) as a standard studies have shown that spawning and oocyte maturation is organism to be used in bioaccumulation and sediment studies (ASTM directly controlled by serotonin in several taxa of this phylum (Fong et al. 1994; Fong 1998; Hirai et al. 1988, Krantic et al.
1991, Ram et al. 1993). Exogenous application of serotonin aswell as fluoxetine to Dreissena polymorpha induced spawning Fifty-Six-Day Water Test with P. antipodarum (Fong et al. 1993, 1996, 1998; Ram et al. 1993). The lowestobserved effect concentration (LOEC) of 0.155 mg fluoxetine/ Sexually mature snails of the prosobranch P. antipodarum (shell L for male mussels and 1.55 mg/L for female mussels has been height >3.7 mm) were exposed to fluoxetine via water at a nominal concentration of 0.64, 3.2, 16, 80, and 400 lg/L. For each concen- We assessed the effects of fluoxetine on the mudsnail tration and the control, three replicates were used. The experiment P. antipodarum to investigate whether representatives of was conducted in a semistatic system with complete renewal of the different mollusk classes react in a similar way. Recent re- test medium every 48 h. The snails were kept in 1-L Erlenmeyer ports have dealt with the effects in bivalve mollusks. Mud- flasks at 16 € 1°C and a light–dark rhythm of 16:8 h. All snails were snails have proved to be sensitive test organisms in several fed with ground TetraPhyllÒ daily ad libitum. At the beginning of the studies (Duft et al. 2003a, 2003b; Schulte-Oehlmann 1997; experiment (day 0), 80 snails per replicate were exposed to fluoxetine Schulte-Oehlmann et al. 2001). Additionally, Brooks et al.
in the test vessels. The number of embryos (differentiated by indi- (2003) detected effects of fluoxetine on the midge Chirono- viduals with and without a shell) of 20 individuals per replicate in thebrood pouch of each maternal snail was determined at days 14, 21, 28, mus tentans. For this reason we assessed effects via sediment and 56. To count the embryos, the maternal snails were anesthetized exposure on the sediment-dwelling organisms Chironomus in MgCl2 (2.5%), and the shell was broken (for details, cf. Duft et al.
riparius and Lumbriculus variegatus. Because sediments can serve as a repository for many toxic compounds (Fiedler andRçsler 1993; Loeffler 2003), this study was designed toinvestigate whether representatives of the benthic biological Twenty-Eight-Day Sediment Tests with C. riparius and community are affected by fluoxetine when exposed via spiked sediments. Because fluoxetine has a log POW of 4.05,its water solubility is not high. Therefore, accumulation in thesediment is likely.
The sediment tests were performed according to the OECD Guide-line 218 (OECD 2004) except that kaolin was not mixed into thesediment and ground leaves were used instead of peat moss ascarbon sources. Quartz sand was purchased from Quarzwerke Fre- chen (Germany). The grain size of test sediments was as follows:90–125 lm, 1%; 125–180 lm, 27%; 180–250 lm, 57%; 250–355 lm, 14%; 355–500 lm, 1%. For the Lumbriculus assay, 1.6% (dry weight [dw]) pulverized alder leaves (Alnus glutinosa) wereused as the carbon source. In the experiment with C. riparius, 0.5% Fluoxetine (CAS 54910-89-3) was purchased as fluoxetine hydro- (dw) pulverized leaves of stinging nettle (Urtica dioica) and alder chloride from Alltech Associates Inc. (State College, PA, USA).
(Alnus glutinosa) were added. Thus, it was not necessary to feed the Relevant physical and chemical properties are as follows: chemical animals during the experiments. The total content of organic carbon purity >99%, water solubility = 38.4 mg/l at 25°C, log KOW = 4.05, in the sediment, per beaker, was 1.36% for L. variegatus and 0.85% and vapor pressure = 8.9E-007 mm Hg (25°C).
for C. riparius. In both assays, the light regime was 16:8 h light:dark The compound exerts its effects by raising the serotonin level by (light intensity 500–1000 lux) and the temperature was 20 € 1°C.
means of inhibiting neuronal and muscle 5-hydroxytryptamine (5-HT) For the life-cycle test with C. riparius, the artificial sediment was receptors, thereby increasing the serotonergic synaptic action. It is spiked with fluoxetine in the following concentrations: 0.15, 0.38, mainly used for depression treatment and against premenstrual dis- 0.94, 2.34, and 5.86 mg/kg, expressed on a dry-weight basis. The orders (Wong et al. 1995). Because the drug also has tranquillizing concentrations are referred to as treatment 0.15, 0.38, 0.94, 2.34, and and mood-lightening effects, it is often used for the treatment of 5.86, respectively. The experiments were conducted in 600-ml glass nongenuine depression (Olfson et al. 1998).
beakers measuring 9 cm in diameter. The beakers contained 1 cm ofartificial sediment corresponding to a total of 100 g dw, coveredwith 400 ml reconstituted water (Oetken et al. 2005). As fluoxetineis easily soluble in water, no solvent was needed for spiking. A stock solution of 4.91 mg fluoxetine hydrochloride in 100 ml de-ionized water was prepared. From this solution, the necessary All tests were conducted as part of a diploma thesis (Hecker 2004). The amount of fluoxetine was removed and diluted in 30 ml reconsti- organisms used were the same as described by Oetken et al. (2005).
tuted water. The sediment was soaked with this solution and left P. antipodarum is a small freshwater snail with shell heights up to 6 overnight to dry. After complete drying, 400 ml reconstituted water mm. The snails feed on plants and detritus. Due to parthenogenecity, were added without disturbing the sediment. Due to the low vapor European populations consist almost exclusively of females.
pressure of fluoxetine, it is unlikely that a significant amount of the Effects of Fluoxetine on Aquatic Invertebrates Table 1. The 56-day reproduction test with P. antipodarum Measured concentrations of fluoxetine and norfluoxetine directly and 24, 48, and 72 h after a change of test medium [detection limit in water:1 lg/L; therefore, the lowest concentration (0.64 lg/L) was not detectable (n.d.)].
Data from Hecker (2004).
substance evaporated while drying. All tests were run with four ment samples were centrifuged; the samples were then mixed with replicates, including a control. In each beaker, a glass Pasteur pipette 100 ml methanol and extracted in an ultrasonic bath for 10 min. The was fixed 2–3 cm above the sediment layer for gentle aeration. After the end of the equilibration period, 20 first-instar larvae were placedrandomly in each test beaker. Emergence and sex ratio were re-corded daily and emerged adults were removed. All midges fromone treatment were collected in a glass aquarium in which a water beaker was placed. The number of clutches and the clutch size(number of eggs per clutch) were counted as additional end points Statistical analysis was performed using GraphPad Prism 4.0 for next to the percentage of emerged midges, the mean emergence time Windows (GraphPad Software, San Diego, CA). The no observed (EmT50) (i.e., the time at which 50% of the midges emerged), and effect concentration (NOEC)/LOEC values were determined by analysis of variance (one-way analysis of variance [ANOVA]) fol- The reproduction test with L. variegatus was conducted using 500- lowed by DunnettÕs post hoc test. In case of non-Gaussian distribution, ml glass beakers that measured 8 cm in diameter and were covered by a Kruskal–Wallis test with DunnÕs post hoc test was used. Effects a plastic screw cap (Oetken et al. 2005). Each beaker was filled with concentrations (EC(x)) concentrations were calculated using a 40 g dw artificial sediment and 200 ml reconstituted water. In this LogNorm or Weibull nonlinear regression model (Kusk 2003).
experiment, the same fluoxetine concentrations were used as in the Differences in EmT50 values were analyzed according to Sprague and experiment with C. riparius. Ten worms of the same developmental status were randomly inserted in each test beaker. For aeration, a glassPasteur pipette was fixed with the plastic cap 0.5 cm above the sed-iment layer. At the end of the test, the worms were removed from thesediment and the number of worms as well as their biomass (dry weight) were recorded as end points.
Table 1 summarizes the measured fluoxetine and norfluoxe-tine concentrations in the P. antipodarum assay directly after The chemical analysis was performed by Medizinisches Labor Bre- the changing and spiking of the test medium (0 h) and 24, 48, men GmbH. Water samples were taken directly after placing the snails and 72 h after a water change. Because the detection limit was in fresh test medium and 24, 48, and 72 h after changing the test 1 lg/L, water from the 0.64-lg/L exposure group was not medium. They were shipped to the analyzing laboratory in glass analyzed. The data show that concentrations did not vary bottles without being frozen. Samples were mixed with the internal exorbitantly during the cycle. Thus, snails were exposed to a standard Perphenazin, then diluted in a 1:8 ratio and injected into a relatively constant concentration of fluoxetine in the assay.
high-performance liquid chromatography (HPLC) system. The ana- The rate of recovery after an exposure of 72 h was between lytes were separated using a HPLC column (Chromolith Speed ROD 62.5% (3.2 lg/L) and 86.3% (400 lg/L). Due to a mean flu- C18 5 lm, 50 · 4.6 mm;, VWR/Merck). The mobile phase, a mixtureof acetonitrile and 5 mM acetic acid (36:64 v/v), was adjusted with oxetine recovery rate of 73.4% in water, the concentration of ammonia to pH 3.9. The flow rate was 1 ml/min. Subsequently, the the lowest treatment can be estimated at 0.47 lg/L. Table 2 analyte was analyzed with a tandem mass spectrometer (ABI 4000 shows that the recovery rates of fluoxetine are low when Mass Spectrometer; Applied Biosystems) turbo ion spray interface sediment was used in the tests (C. riparius assay). The con- using a positive multiple reaction monitoring (MRM) mode. At a centration in the water samples of the treatments varied from retention time of 2 min, separation of the fluoxetine molecule ion <1 to 130 lg/L. The fluoxetine concentration of the sediment occurred at 310.1 m/z and at 148.1 m/z for the fluoxetine fragment ion.
samples ranged from 53 to 1120 lg/kg. Thus, between 18.1% Given a retention time of 1.8 min, the values were 296.1 m/z and (2.34 mg/kg) and 35.3% (0.15 mg/kg) of the nominal con- 134.1 m/z, respectively. In the analysis, the fragment ions were de- centrations could be detected analytically.
tected and quantified. Validation data from the laboratory were as On day 28, a decrease of fluoxetine in both water and follows: In a linear array of 5–500 ll/min, the detection limit was1 lg/L for water samples and sediment extracts. The serial precision sediment samples associated with a slight increase of the main was 11.4% and the recovery rate was 111%. Water samples were metabolite norfluoxetine was observed. Measured initial flu- filtered before analysis and directly measured. Before analysis, sedi- oxetine concentrations between 8.7% and 16.8% were still Table 2. Life-cycle test with C. riparius Measured concentrations in sediment (mg/kg)Control Measured concentrations in water (lg/l)Control Detected concentrations of fluoxetine (FLX) and its metabolite norfluoxetine (NFL) in water and sediment at day 0 and day 28 (detection limit:1 lg/L in water and 1 lg/kg dw in sediment; n.d. = not detectable).
Data from Hecker (2004).
present in the sediments. The low recovery might be due to action of the neurotransmitter serotonin (5-HT) by raising strong adsorption or covalent binding between substance and serotonin concentrations in the synaptic cleft. A range of ef- sediment. If such a covalent binding did occur, the bound part fects on aquatic invertebrates, mainly mollusks and arthropods, of the analyte would not have been detected in the analysis by caused by 5-HT and antidepressants has been reported (Avila et al. 1996; Fong et al. 1998). Fong (1998) performed labo-ratory experiments with the zebra mussel Dreissena poly-morpha to determine the effects of some antidepressants. After Fifty-Six-Day Water Test with P. antipodarum fluoxetine application, spawning was observed in both sexes.
The LOEC was 155 lg/L for male mussels and 1.5 mg/L for Potamopyrgus antipodarum has been shown to be a suitable female mussels. Honkoop et al. (1999) confirmed these results test organism for toxicity testing (Duft et al. 2003a, 2003b; for a marine bivalve species, Macoma balthica, at a fluoxetine Oetken et al. 2005; Schulte-Oehlmann 1997). In this investi- concentration of 1 mg/L. In gastropods, spawning was not gation, the snails were used to evaluate the reproductive tox- reported after application of fluoxetine, but a SSRI-induced icity of fluoxetine in an aqueous exposure assay. From the cilia-driven rotational behavior of embryos in the freshwater beginning of the assay, almost all snails exposed to the highest gastropod Physa elliptica was observed at nominal fluoxetine level of fluoxetine were immobile on the bottom of the test concentrations of 309 lg/L and 3.09 mg/L (Uhler et al. 2000).
beaker. A small percentage of the snails recovered and began Avila et al. (1996) found an increased metamorphosis success grazing on food after a few days. Up to 70 of the 80 snails per in laboratory cultures of the nudibranch Hermissenda crassi- replicate remained immobile, and at day 56, 100% mortality cornis at serotonin concentrations of 1.76 and 17.6 mg/L. EC10 occurred in all replicates exposed to the highest fluoxetine and NOEC values determined here show that effects of fluo- level. The embryos in the dead snails, if present, were counted.
xetine can occur at much lower concentrations than have At the first evaluation on day 14, a significant reduction of the mean embryo number was detected at nominal concentrationsof 80 and 400 lg/L, following a concentration response curve(Figure 1A). This reduction was detected over the whole Twenty-Eight-Day Sediment Test with C. riparius exposure time. At day 56, the three highest fluoxetine treat-ment levels significantly reduced reproduction in P. anti- As shown in Table 3, fluoxetine had no effect on emergence podarum (Figure 1C). The number of embryos without a shell except at the highest exposure level (5.86 mg/kg dw). Brooks et was already significantly reduced at measured fluoxetine al. (2003) evaluated the potential aquatic toxicity of fluoxetine concentrations of 11.5 lg/L (Figure 1B, p < 0.001) and using the arthropods Ceriodaphnia dubia and C. tentans.
2.25 lg/L (Figure 1D, p < 0.001) at days 28 and 56, respec- Fecundity of the crustacean was decreased at a concentration of tively, resulting in a NOEC of 0.47 lg/L and an EC10 of 223 lg/L fluoxetine. In a 10-day sediment toxicity test with 0.81 lg/L, based on measured concentrations, at day 56.
C. tentans, a LC50 of 15.2 mg/kg dw was found (Brooks et al.
Therefore, the endpoint—embryos without a shell—was more 2003). A significant reduction in the growth of C. tentans oc- sensitive to fluoxetine than the total number of embryos.
curred already at a LOEC of 1.3 mg/kg. If the reduction in Selective serotonin reuptake inhibitors (SSRIs) increase the emergence of C. riparius is due to fluoxetine, the LOEC found Effects of Fluoxetine on Aquatic Invertebrates day 28 total number of
embryos (mean
day 28 number of embryos
without shell (mean
fluoxetine concentrations [µg/L]
fluoxetine concentrations [µg/L]
Fig. 1. The 56-day reproductiontest with P. antipodarum. Total number of embryos (A, C) andnumber of embryos without a shell days (mean € SD). Asterisksindicate significant differences compared to the control (Kruskal–Wallis test with DunnÕs post day 56 total number of
embryos (mean
day 56 number of embryos
without shell (mean
hoc test: *p < 0.05, **p < 0.01, ***p fluoxetine concentrations [µg/L]
fluoxetine concentrations [µg/L]
Table 3. Life-cycle test with C. riparius Mean emergence (€ SD), sex-specific mean emergence times (EmT50), clutch size (eggs per clutch), and numbers for all treatments (one-wayANOVA with DunnettÕs post hoc test, *p < 0.05; **p < 0.01).
Data from Hecker (2004).
in our experiment would be 1.12 mg/kg, based on measured Twenty-Eight-Day Sediment Test with L. variegatus values, and thus at a comparable concentration to that reportedby Brooks et al. (2003) for C. tentans. Regarding the EmT50 of Fluoxetine effects on reproduction in L. variegatus resemble both males and females, no differences between the control and an inverted U-shaped concentration–response curve (Table 4 the treatments were observed. Egg clutches exposed to the and Figure 2). Starting at the lowest fluoxetine concentration, highest fluoxetine concentration contained significantly more the total number of worms increases, compared to the control.
eggs than the control (Table 3). However, because this effect For the treatments 0.94 mg/kg dw and 2.34 mg/kg dw, sig- occurred at only one treatment level, the data do not allow nificantly more worms were found (18.8 and 16.5, respec- conclusions to be drawn about possible effects of fluoxetine on tively). At the highest exposure level, the mean number of reproduction in C. riparius. The increased number of eggs at worms was lower (15.3). The mean number of juvenile worms the highest exposure level could be due to an enhanced egg cell showed the same tendency as the total numbers, with signifi- proliferation rate. Williams and Herrup (1988) showed that cantly more worms than at 0.94 mg/kg dw. This could indicate fluoxetine could accelerate cell proliferation. Therefore, the a stimulating effect on reproduction of L. variegatus at low increased clutch size could be due to fluoxetine. Further concentrations of fluoxetine, possibly caused by an increased experiments at higher concentrations would be necessary to division rate in the worms. However, because the reproduction confirm a potential reduced emergence and increased clutch rate in the control is low, this potential effect needs verifica- size. However, higher sediment concentrations of fluoxetine than employed in our study are beyond environmental The observation could be explained either by a specific effect on reproduction or by an unspecific stimulation of Table 4. Number of worms in the 28-day sediment test with L. variegatus Data given as mean € SD. One-way ANOVA with DunnettÕs post hoc test: *p < 0.05; **p < 0.01.
Data from Hecker (2004).
L. variegatus. This might be due to a higher reproduction ratewith exclusively asexual reproduction under laboratory con-ditions (Brust et al. 2001). Accelerated proliferation could lead to more and faster division of the worms. Because the test didnot match the validity criterion of a minimum of 20% repro- duction in the controls, proposed by Egeler et al. (2005), theresults need confirmation in further experiments. In these as-says, use of the sediment mixture proposed by Egeler et al.
(2005) should be considered. When repeating the experiments, worms (mean
mixtures with and without kaolin should be compared to day 28 total number of
determine the influence of kaolin on the bioavailability offluoxetine.
fluoxetine concentrations [mg/kgdw]
Environmental Risk Assessment of Fluoxetine The European Agency for the Evaluation of Medicinal Prod-ucts (EMEA) has proposed a scheme for environmental riskassessment (ERA) for pharmaceuticals (EMEA 2005), based on a two-phased, tiered assessment concept. Phase I consists of a crude initial predicted environmental concentration assess-ment of the substance in surface water (PECsw). If the PECsw is below 0.01 lg/L, no testing or evaluations will be requiredunless the compound exhibits specific modes of action such asendocrine activity. If the PECsw is above 0.01 lg/L, a Phase II, worms (mean
Tier A environmental effect analysis should be performed.
day 28 number of juvenile
Metcalfe et al. (2003) investigated surface water of the LittleRiver (Canada), measuring mean fluoxetine concentrations of 0.099 lg/L near a sewage treatment plant. Kolpin et al. (2002) reported a median fluoxetine concentration of 0.012 lg/L in fluoxetine concentrations [mg/kg dw]
American streams, indicating that the threshold value forPhase II analyses according to EMEA (2005) is exceeded by Fig. 2. The 28-day reproduction test with L. variegatus. Total number of worms (A) and number of juvenile worms (B) after 28 days In the present study, the ratio between predicted environ- (mean € SD). Asterisks indicate significant differences compared to mental concentration and predicted no effect concentration the control (one-way-ANOVA with DunnettÕs post hoc test: *p < 0.05, (PEC/PNEC) is 1.48, indicating a risk to the population level.
**p < 0.01; C = control). Data from Hecker (2004) The calculation is founded on an EC10 of 0.81 lg/L (based on physiological parameters in the sense of a general stress re- measured concentrations) for reproduction in P. antipodarum sponse. In the latter case, fluoxetine would not directly affect with an assessment factor of 100 (EU 2003) and using the reproductive mechanisms, but would constitute a stressor for median fluoxetine concentrations of 0.012 lg/L from Kolpin which L. variegatus compensates with increased reproduction.
et al. (2002) as the PEC. The use of the assessment factor 100 This explanation is not likely due to the declining reproduction according to EU (2003) is warranted because all test organisms rate at the highest fluoxetine concentration. Because annelids in the present study represent one trophic level (consumer).
have serotonergic neurons (Hessling et al. 1999), an increased Based on this calculation, it is likely that the drug poses a risk serotonin level might have specific effects on the test organ- to the survival of gastropod populations in the field. Sebastine ism. Furthermore, because serotonin acts as a mitogenic factor, and Wakeman (2003) quoted a PEC/PNEC ratio of 14.2 for fluoxetine might lead to an enhanced proliferation rate in fluoxetine, one order of magnitude higher. This supports the Effects of Fluoxetine on Aquatic Invertebrates evaluation of fluoxetine as an environmentally relevant sub- Fong PP, Wall DM, Ram JL (1993) Characterization of serotonin stance. Significant effects on reproduction as a population- receptors in the regulation of spawning in the zebra mussel relevant end point occurred at a measured concentration of Dreissena polymorpha (Pallas). J Exp Zool 267:475–482 2.25 lg/L (nominal concentration = 3.2 lg/L). In the field, Fong PP, Duncan J, Ram JL (1994) Inhibition and sex specific induction of spawning by serotonergic ligands in the zebra other stress factors act on a population, and in this way, toxic mussel Dreissena polymorpha (Pallas). Experientia 50:506– compounds might affect wildlife populations at even lower concentrations than in the laboratory.
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Brett charles plyler

Brett Charles Plyler, M.D. Employment 2008-Present Northwestern Memorial Hospital. Instructor for second year residents’ psychotherapy class and individual resident supervision. Chicago IL. Chicago Research Center, Inc. Private Practice. Outpatient/Inpatient and psychotherapy/psychopharmacology. Chicago IL. Northwestern Memorial Hospital. Attending psychiatri

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