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The effects of antidepressants appear to be rapid and at environmentally relevant concentrations: Rapid effects of antidepressants

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Abstract

The effects of antidepressants on wildlife are currently raising some concern due to an increased number of publications indicating biological effects at environmentally relevant concentrations (<100ng/L). These results have been met with some scepticism due to the higher concentrations required to detect effects in some species and the perceived slowness to therapeutic effects recorded in humans and other vertebrates. Since their mode of action is thought to be by modulation of the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates that possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. We highlight studies on the effects of antidepressants, on particularly crustacean and molluscan groups showing they are susceptible to a wide variety of neuroendocrine disruption at environmentally relevant concentrations (pg-ng/L). Interestingly some effects observed in these species can be observed within minutes to hours of exposure. For example, exposure of amphipod crustaceans to several selective serotonin reuptake inhibitors (SSRIs) can invoke changes in swimming behaviour within hours. In molluscs, exposure to SSRIs can induce spawning in male and female mussels and foot detachment in snails within minutes of exposure. In the light of new studies indicating effects on the human brain with just of dose of SSRIs using magnetic resonance imaging (MRI) scans, we discuss possible reasons for the discrepancy in former results in relation to the "read-across" hypothesis, variation in biomarkers used, modes of uptake, phylogenetic distance, and the affinity to different targets and differential sensitivity to receptors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Critical Review
THE EFFECTS OF ANTIDEPRESSANTS APPEAR TO BE RAPID AND AT
ENVIRONMENTALLY RELEVANT CONCENTRATIONS
ALEX T. FORD and PETER P. FONG
Environ Toxicol Chem., Accepted Article DOI: 10.1002/etc.3087
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Critical Review Environmental Toxicology and Chemistry
DOI 10.1002/etc.3087
THE EFFECTS OF ANTIDEPRESSANTS APPEAR TO BE RAPID AND AT
ENVIRONMENTALLY RELEVANT CONCENTRATIONS
Running title: Rapid effects of antidepressants
ALEX T. FORD* and PETER P. FONG
Institute of Marine Sciences, School of Biological Sciences, University of Portsmouth, Ferry Road,
Portsmouth, United Kingdom
Department of Biology, Gettysburg College, 300 N. Washington St., Gettysburg, Pennsylvania, USA
* Address correspondence to alex.ford@port.ac.uk
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Submitted 27 February 2015; Returned for Revision 15 April 2015; Accepted 26 May 2015
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Abstract: The effects of antidepressants on wildlife are currently raising some concern due to an
increased number of publications indicating biological effects at environmentally relevant
concentrations (<100ng/L). These results have been met with some scepticism due to the higher
concentrations required to detect effects in some species and the perceived slowness to therapeutic
effects recorded in humans and other vertebrates. Since their mode of action is thought to be by
modulation of the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates that
possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially
affected by them. We highlight studies on the effects of antidepressants, on particularly crustacean and
molluscan groups showing they are susceptible to a wide variety of neuroendocrine disruption at
environmentally relevant concentrations (pg-ng/L). Interestingly some effects observed in these species
can be observed within minutes to hours of exposure. For example, exposure of amphipod crustaceans
to several selective serotonin reuptake inhibitors (SSRIs) can invoke changes in swimming behaviour
within hours. In molluscs, exposure to SSRIs can induce spawning in male and female mussels and foot
detachment in snails within minutes of exposure. In the light of new studies indicating effects on the
human brain with just of dose of SSRIs using magnetic resonance imaging (MRI) scans, we discuss
-
variation in biomarkers used, modes of uptake, phylogenetic distance, and the affinity to different
targets and differential sensitivity to receptors. This article is protected by copyright. All rights reserved
Keywords: SSRIs, pharmaceuticals; pollution; neuroendocrine
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BACKGROUND
A number of recent studies have raised concerns that antidepressants in aquatic ecosystems
maybe an environmental concern [1-6]. Prescriptions of antidepressants have been rapidly increasing in
some countries [7] with studies indicating that antidepressants are taken by 1 in 10 of the population
[8]. These drugs are used to treat a wide range from conditions from depression, anxiety and bipolar
disorders [9]. There are currently a wide range of antidepressants in medical use which include some of
the older prescribed tricyclic compounds (TCAs; e.g. Amitriptyline), the serotonin reuptake inhibitors
(SSRIs; e.g. Fluoxetine), the serotonin and norepinephrine reuptake inhibitors (SNRIs; e.g.
Venlaflaxine) plus serotonin antagonist and reuptake inhibitors (SARIs; e.g. Trazodone).
Concentrations of antidepressants in water bodies vary considerably but have been detected in
freshwater [3, 10-14], groundwater [15] and seawater [16]. In arid and semi-arid parts of the world,
ephemeral streams can be dominated by municipal and/or industrial effluent discharges, particularly in
urbanized watersheds [17]. Therefore some aquatic organisms are likely to be receiving relatively high
and constant exposure to serotonergic and neurologically active drugs. Furthermore, recent studies have
shown the capacity of aquatic organisms to bioaccumulate these compounds [18-21]. Despite the
widespread presence of antidepressants in the aquatic environment, bioactive properties (both
neruological and hormonal), capacity to bioaccumulate in tissues and relatively similar prescription
rates of the concentraceptive pill; it was recently highlighted that the body of research on synthetic
estrogen exposure hugely outweighs the amount currently known for neurological drugs [22].
EFFECTS IN WILDLIFE AT ENVIRONMENTALLY RELEVANT CONCENTRATIONS
The concentrations of antidepressants in the aquatic environment range from the ng to µg/L,
with most studies reporting concentrations sub-100ng/L. The scientific literature has increased in the
number publications highlighting effects of antidepressants observed at very low environmentally
relevant concentrations [6]. These include induction of spawning in bivalves [23,24], altered
cAMP/PKA pathways and serotonin (5-HT) expression in mussels [25]; altered mobility in snails [26],
altered memory, cognitive function and altered ability to camouflage in cuttlefish [27, 28]; induced
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phototaxis and altered activity in amphipods [4, 29-31]; gene expression of putative serotonergic
pathways in amphipods [31]; altered reproduction [21], activity [32] and embryonic/development
endpoints in fish [33]. Therefore one might conclude that the effects of these compounds are diverse
and potentially impact a wide range of invertebrate and vertebrate Phyla.
Fong and Ford [6] recently highlighted that many of these studies report non-monotonic
concentration response curves [6, 31-33]. The low dose effects reported by some studies have been
questioned as to whether they are in fact artefacts, and whether they are repeatable [34]. Several studies
have also been criticised due to limitations in study design including; use of novel biomarkers, large
interspecies variability; nominal concentrations and low numbers of concentrations used [34,35].
Therefore, calls [22] have been made for laboratories to repeat their studies and those of others to
appropriately assess the risk posed by these compounds. Vandenburg et al [36] recently conducted a
large review of cell culture, animal and epidemiology studies and concluded that non-monotonic
responses and low-dose effects are remarkably common in studies of natural hormones and EDCs.
They further went on to suggest that fundamental changes in chemical testing and safety determination
are needed to protect human health. Accepting some of the limitations of recent studies it seems
reasonable to assume that hormetic effects might also be found in serotonergic drugs.
ARE RAPID EFFECTS THAT UNUSUAL?
One of the most intriguing results of some of the reported studies is that effects can sometimes
be observed in very short periods of time [31]. Zebra mussels can be significantly induced to spawn
within minutes of both fluoxetine and fluvoxamine exposure at concentrations as low as 300 and 430
ng/L respectively. For example, Fong [23] found that 70 % of male zebra mussels could be induced to
spawn in one hour or less in 1 nM (430 ng/L) fluvoxamine. Altered oocyte and spermatozoan densities
were observed in zebra mussels exposure to fluoxetine at 20 & 200ng/L following several days
exposure [24]. A number of studies have looked at the effects of fluoxetine on activity measurements in
amphipods, and similarly found effects within very short timeframes [6, 29-31]. For example, within
less than 2 hours of exposure the freshwater amphipod, Gammarus pulex display altered activity
measured following exposure to fluoxetine at low concentrations [29,30]. The experimental protocol
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used a 30-minute acclimation period followed by a 1.5hrs recording using electrical conductance
 the greatest effects on activity were observed
at 10-100ng/L fluoxetine. In another study using the marine/estuarine amphipod Echinogammarus
marinus
fluoxetine exposure with the greatest effects observed at 10-100ng/L [4]. These behavioural effects
were also observed following two and three weeks exposure. The behavioural effects recorded in the
amphipods corresponded to those when exposed to serotonin (5-HT) or infected with serotonin
modulating parasites. Using an alternative method of behavioural analysis, the activity of E. marinus
was recorded using Daniovision (Noldus) with Ethovion XT software (v8.1) following exposure to the
SSRIs sertraline and fluoxetine [31]. Significant effects of the amphipods activity (velocity mm/s) were
recorded after 1 day for fluoxetine and both 1 hour and 1 day for sertraline. Similarly the greatest
effects were observed at 100ng/L with exposed organisms displaying elevated velocities under both
dark and light conditions. Following 8 days exposure there was a significant down regulation of genes

note that neither compounds (fluoxetine or sertraline) elicited effects on velocity after 8 days.
Therefore, albeit with nominal concentrations and the relatively few studies done to date, there is some
repeatability in the low dose effects observed.
Whilst we believe many of the observed effects can be attributed to different modes of action
(MOAs) and not exclusively by via 5-HT re-uptake inhibition, it is important to mention the role of pH
on the toxicokinetics and uptake of antidepressants. A number of recent studies have highlighted the
changes in the pH can strongly influence the ionization of antidepressants resulting in different uptake
rates and consequently toxicity [37-42]. Noteworthy is the increased toxicity observed at higher pH.
Whilst pH of the medium is undoubtedly important since the hydrophobicity of the compound
would affect its ability to cross membranes and enter cells, the route of uptake and the mechanism of
action would determine the target tissues and cell membranes to cross. The route of uptake of
antidepressants in aquatic vertebrates like fishes is likely through the gills or oral cavity. Once in the
blood and if capable, they would cross the blood-brain barrier, enter the brain and exert its action by
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blocking reuptake of 5-HT there. Aquatic anurans on the other hand would be capable gill or of
cutaneous uptake before entering the blood. Brooks [43] reported that using probabilistic hazard
assessment and fish plasma modeling approaches, SSRIs and tricyclic antidepressants are predicted to
result in therapeutic hazard to fish (internal fish plasma level equalling mammalian therapeutic dose)
when exposed to water(inhalational) at or below 1µg/L. However, Brooks [43] also stated due to data
limitations we don't know the internal doses of therapeutic or side effects of drugs in fish or
invertebrates.
By contrast to vertebrates the route of antidepressant uptake in invertebrates is likely to vary
with taxonomic group. In bivalve molluscs, the route of uptake could be direct internalization via the
gills. However since bivalves filter water, the entire mantle cavity containing gonads, foot, digestive
gland, and adductor muscles, as well as gills would be exposed to the water where contact with external
receptors would be possible. Matsutani and Nomura [44] have shown that isolated fragments of scallop
ovaries will release eggs when treated with 5-HT, suggesting that 5-HT receptors are located directly
on the gonad. Isolated mussel siphons and mantle tissues can also be induced to contract and relax with
externally applied 5-HT and these responses can be mimicked by vertebrate 5-HT2 receptor ligands
again suggesting the presence of 5-HT receptors directly on the siphon and mantle [45]. Similar to
bivalves, aquatic snails with gills (prosobranchs) or a modified lung (pulmonates) could take up
antidepressants via these respiratory surfaces, but the foot and all tissues within the mantle cavities are
also available surfaces for uptake.
In crustaceans with a heavy exoskeleton that covers most of their body like crabs, crayfish, and
shrimps, antidepressants could become internalized via the branchial cavity and then enter the
hemocoelomic cavity, but in others that lack gills, antidepressants would have to get across the general
body surface. Once in the hemocoelomic cavity they can become directly in contact with thoracic and
abdominal ganglia of the ventral nerve cord both receptive to and capable of producing 5-HT [46-48].
In planktonic crustaceans with a thin exoskeleton and a large surface area to volume ratio such as
Daphnia, uptake could occur via the feeding current into the filtering chamber, but a major site of
respiratory gas exchange occurs at the inner wall of the carapace [49]. Marine worms can have
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elaborate uptake structures such as parapodia, tentacles, gills, and palps, [50] and uptake could be
through those structures, across the general body surface, or via ingestion.
Recently, Karlsson et al [41] examined the route of uptake of the pharmaceuticals triclosan,
diclofen, and fluoxetine into the aquatic oligochaete, Lumbriculus variegatus. In this worm, the route
of uptake could either be integumental or through the oral cavity, and they cleverly used an oligochaete
that regenerates head and tail segments, thus head removal would inhibit ingestion but not integumental
uptake. They found that that there was no significant difference in uptake of 14C-labelled fluoxetine
between feeding and non-feeding (headless) worms, although they did find that the antibiotic triclosan
was taken up more by feeding worms. Their results indicate that even for an aquatic organism like an
oligochaete, there could be multiple routes of uptake and therefore the effect of pH on speed of an
antidepressant-induced response depends on the target cells and tissues. The behavioral responses that
workers are measuring (e.g. spawning in bivalves, locomotion in snails, phototaxis in amphipods,
learning and cognition in cephalopods, fecundity in Daphnia) would all be affected by the route of
uptake and mode of action.
Thus, how quickly a response to antidepressants occurs is likely to be dependent upon not only
pH, but whether or not the drug binds to external receptors or is somehow internalized first, travels
through blood vessels, makes its way into a coelomic or hemocoelomic cavity, and then binds to
potentially a multitude of molecular targets.
ANTIDEPRESSANTS AND READ-ACROSS HYPOTHESIS
The read-across hypothesis [51] suggests that a drug will have an effect in non-target organisms
only if the molecular targets have been conserved, resulting in a specific pharmacological effects only
if plasma concentrations are similar to human therapeutic concentrations [52]. One of the specific

appear to match the read-across hypothesis for therapeutic dose concentrations for humans [35].
Fluoxetine is generally prescribed over many weeks to allow for brain concentrations to rise enough to
a concentration whereby beneficial results are observed in the patients (usually within one month [35]).
Therefore, it has been highlighted [34] that the antidepressant concentrations in the water of some of
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these studies are unlikely to produce a concentration of fluoxetine in the nerve synapses matching the
therapeutic dose for humans (50-500µg/L plasma concentration). A recent study nicely demonstrated
that fathead minnows only responded in a tank diving test to measure anxiolytic behaviours when
plasma concentrations of fluoxetine were within a similar or higher concentration range to those of
human therapeutic doses [53]. Therefore, the authors concluded that their study represents the first
direct evidence of measured internal dose response effect of a pharmaceutical in fish, thereby validating
the read-across hypothesis for this compound. This was indeed an eloquent study that clearly
demonstrated that the endpoints observed within the fish (fish anxiety tests) matched those close to
human therapeuticplasma concentrations. How surprised might we have been if they were very much
different? Human therapeutic doses, particularly for antidepressants are often derived from
questionnaires given to patients post treatment, which have themselves been subject to criticism [54].
ading across when interpreting the read-across
hypothesis especially when interpreting disparate endpoints. This is especially true when drugs may
have multiple targets; different affinities for targets in different organisms; or similar biological targets
controlling different biological responses [23].
The evolution of the vertebrates represents a minute timeframe in history compared with the
biological divergence of the invertebrates and their targets for 5-HT and serotonin-like drugs. There are
a number of possible targets for antidepressants like fluoxetine in both vertebrates and invertebrates
other than 5-HT reuptake transporters. Ni and Miledi [55] showed that fluoxetine binds to and blocks
5-HT2C receptors in frog (Xenopus) oocytes. They concluded that fluoxetine is a competitive and
reversible receptor antagonist of 5-HT2C receptors. Garcia-Colunga et al. [56] showed that fluoxetine
blocks both muscle and neuronal nicotinic acetylcholine receptors. 
and SSNRIs has been questioned by clinical psychopharmacologists for many years. These drugs show
binding affinity not only to 5-HT2C receptors but to dopamine reuptake transporters, muscarinic
cholinergic receptors, sigma receptors, and to enzymes such as nitric oxide synthase and a variety of
cytochrome P450s [57]. Recently, studies on 5-HT receptors and 5-HT transporters in the nematode
Caenorhabitis elegans has suggested that antidepressants like fluoxetine are not acting as SSRIs.
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Ranganathan et al. [58] found that fluoxetine induces responses in C. elegans that lack a 5-HT
transporter (mod-5). They suggest that fluoxetine could be acting independently of 5-HT and any 5-HT
transporter. This study confirmed the earlier work by Choy and Thomas [59] who found that fluoxetine
induces neuromuscular activity in the anterior region of C. elegans in 5-HT-deficient mutants and
suggests that drugs like fluoxetine have targets other than 5-HT reuptake transporters. Dempsey et al
[60] showed that fluoxetine stimulates egg laying in C. elegans independent of 5-HT and independent
of the 5-HT transporter. Kullyev et al. [61] demonstrated that fluoxetine binds directly to G-protein
coupled 5-HT receptors in C. elegans. It should be noted that 5-HT transporters have been identified in
all major invertebrate phyla [62]. G-protein coupled 5-HT receptors may have evolved over 750
million years ago, whereas mammalian 5-HT receptor subtypes may have differentiated 90 million
years ago [63]. Thus, the number and type of potential targets of these drugs and the cellular responses
to them is likely to be as diverse as the groups of organisms in which they evolved. Therefore we must
be careful when matching endpoints over large phylogenetic distances even when the biological
systems such as the nervous system are relatively conserved; a point made in several studies
[17,34,35,51,52]. This is especially true when some endpoints are unfeasible to read across such
serotonin/dopamine modulated camouflage or photosensitivity. A recent human based study has
highlighted that a biological response to antidepressants (escitalopram) could be detected following a
single dose (20mg) within several hours using Resting-state functional magnetic resonance imaging (rs-
fMRI) [64]. The authors observed the single dose of a serotonin reuptake inhibitor dramatically alters
functional connectivity throughout the whole brain in healthy subjects. Specifically their analysis
suggested a widespread decrease in connectivity in most cortical and subcortical areas of the brain.
Therefore, some effects of antidepressants in humans are detectable quite rapidly following
antidepressants when measuring more sensitive endpoints. In this instance the plasma concentrations of
escitalopram were 25 ± 13 ng/ml which is not uncommon for this particular SSRI but steady state
concentrations are usually observed following 7-10 days and clinical signs of effects following 1-2
weeks [65,66]. Therefore, biological detectable endpoints might be quite different from human
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therapeutic dose concentrations but still have unknown biological disruption which is an important
distinction in environmental protection.
SUMMARY
Antidepressants are ubiquitous in the aquatic environments impacted by sewage effluent. Whilst
the number of studies assessing their potential for environmental impact is increasing, they still remain
few in number to enable us to fully understand the ecological risk posed by these compounds. Those
studies that have been published show quite variable effect concentrations and some have limitations in
their experimental designs. There does however appear to be mounting evidence that very low
concentrations can impact the biological function of multiple aquatic organisms. A number of studies
have recorded the rapid action of antidepressants on some aquatic species, coupled with this, non-
monotonic concentration response curves have been observed which suggests careful consideration
must be made in experimental design and recording. Given that some aquatic organisms are likely to be
exposed either continuously or sporadically throughout their life histories, especially during critical life
stages, it will be important to ascertain the long term impacts of serotonergic drugs on neural
development. Whilst we have provided strong evidence that we must be cautious when applying to
read-across hypothesis to distant invertebrates, evidence from mammalian models does point to the fact
that long-term exposure to antidepressants may cause damage to neural receptors and architecture. The
physiological and behavioural implications of these changes will be a future challenge for
environmental toxicologists.
AcknowledgmentATF would like to acknowledge the following awarding bodies for supporting this
research: The EU INTERREG programme entitled Peptide Research Network of Excellence (PeReNE)
and the UK Natural Environmental Research Council (NERC; NE/G004587/1). We are very grateful
for the very thoughtful and constructive comments provided by two anonymous reviewers.
Data availability No Data available, the present study is a review paper.
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... In recent decades, pharmaceuticals in the environment have been regarded as emerging chemicals of concern (ECCs). 1 In particular, antibiotics and psychiatric pharmaceuticals are receiving special attention, as antibiotics are capable of causing antimicrobial resistance (AMR) and psychiatric pharmaceuticals show rapid toxic effects on non-target organisms largely at the ng/mL levels. 2,3 Estuaries have been regarded as pollutant filters, 4 and with the pollution in these ecosystems being recently highlighted, a global estuaries monitoring program was launched in the United Nations Decade of Ocean Science for Sustainable Development (2021−2030). 5 In estuaries, tidal currents can significantly influence water quality parameters. ...
... 35 Levels of the aforementioned sulfonamides and erythromycin-H 2 O (a degradation product of erythromycin with higher hydrophilicity) were found to be positively correlated with TN. Several studies have revealed that tidal disturbance promotes the release of sulfonamides, NH 4 + −N, and NO 3 − −N from sediments, which could be attributed to either of the following: [1] higher suspended sediment after tidal disturbance as in the case of flow rate 35 or [2] sharply decreased salinity at ebb tides, which enhances the re-dissolution derived from the salting-out effect for pharmaceuticals and ion pairing with seawater anions for NH 4 + −N during flood tides. 36,37 Notably, such correlations with TN and flow rate were mainly found for sulfonamides, which showed relatively low sorption capacities compared with other groups of antibiotics (i.e., tetracyclines, fluoroquinolones, and macrolides). ...
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Pharmaceutical residues in the environment are of great concern as ubiquitous emerging contaminants. This study investigated the presence of 40 pharmaceuticals in water and sediment of the Pearl River Estuary (PRE) in the wet season of 2020. Among psychiatric drugs, only diazepam was found in water samples while six of them were detected in the sediment. The Σantibiotics levels ranged from 6.18 to 35.9 ng/L and 2.63 to 140 ng/g dry weight in water and sediment samples, respectively. Fluoroquinolones and tetracyclines were found well settling in the outlet sediment, while sulfonamides could be released from disturbed sediment under stronger tidal wash-out conditions. After entering the marine waters, pharmaceuticals tended to deposit at the PRE mouth by the influence of the plume bulge and onshore invasion of deep shelf waters. Low ecological risks to the aquatic organisms and of causing antimicrobial resistance were identified. Likewise, hydrological modeling results revealed insignificant risks: erythromycin-H2O and sulfamethoxazole discharged through the outlets constituted 30.8% and 6.74% of their environmental capacity, respectively. Source apportionment revealed that pharmaceutical discharges through the Humen and Yamen outlets were predominantly of animal origin. Overall, our findings provide strategic insights on environmental regulations to further minimize the environmental stress of pharmaceuticals in the PRE.
... Compared to the other groups, they have milder side effects. Another type are antidepressants that act as reversible inhibitors of monoamine oxidases (e.g., moclobemide) [14,15,20,21]. ...
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Over the past twenty years, the prescription of antidepressant drugs has increased all over the world. After their application, antidepressants, like other pharmaceuticals, are excreted and enter the aquatic environment. They are dispersed among surface waters mainly through waste water sources, typically at very low concentrations— from a tenth up to hundreds of ng/L. Frequently detected antidepressants include fluoxetine and citalopram—both selective serotonin reuptake inhibitors. The aim of our study was to assess the embryotoxicity of fluoxetine hydrochloride and citalopram hydrochloride on the early life stages of zebrafish (Danio rerio) and the African clawed frog (Xenopus laevis). The embryos were exposed to various concentrations of the individual antidepressants and of their mixtures for 96 h. The tested levels included both environmentally relevant and higher concentrations for the evaluation of dose-dependent effects. Our study demonstrated that even environmentally relevant concentrations of these psychiatric drugs influenced zebrafish embryos, which was proven by a significant increase (p < 0.01) in the embryos’ heart rates after fluoxetine hydrochloride exposure and in their hatching rate after exposure to a combination of both antidepressants, and thus revealed a potential risk to aquatic life. Despite these results, we can conclude that the African clawed frog is more sensitive, since exposure to the highest concentrations of fluoxetine hydrochloride (10,000 μg/L) and citalopram hydrochloride (100,000 μg/L) resulted in total mortality of the frog embryos.
... Pharmaceutical wastewater contains a large amount of recalcitrant or bio-refractory molecules which are very difficult to degrade through conventional treatments. Hence, the majority of times it gets converted into another complex by-products as fluoxetine and endocrine disruptors which has resulted in a multitude of undesirable problems like harm to the reproduction and metabolism of the aquatic organism and feminization of fish population (Ford & Fong 2016;Huang et al. 2016;Grandclément et al. 2019). Thus it is necessary to treat pharmaceutical wastewater efficiently before discharging it into any water bodies to avoid hazards to the environment and ecosystem further, which also pollutes water bodies (Gadipelly et al. 2014;Changotra et al. 2017Changotra et al. , 2019Singh & Prashant 2017;Martínez et al. 2018). ...
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In recent years industrialization has caused magnificent leaps in the high profitable growth of pharmaceutical industries, and simultaneously given rise to environmental pollution. Pharmaceutical processes like extraction, purification, formulation, etc., generate a large volume of wastewater that contains high chemical oxygen demand (COD), biological oxygen demand, auxiliary chemicals, and different pharmaceutical substances or their metabolites in their active or inactive form. Its metabolites impart non-biodegradable toxic pollutants as a byproduct and intense color, which increases ecotoxicity into the water, thus this requires proper treatment before being discharged. This study focuses on the feasibility analysis of the utilization of ultrasound cavitation (20 kHz frequency) together with a persulfate oxidation approach for the treatment of complex pharmaceutical effluent. Process parameters like pH, amplitude intensity, oxidant dosage were optimized for COD removal applying response surface methodology-based Box–Behnken design. The optimum value observed for pH, amplitude intensity and oxidant dosage are 5, 20% and 100 mg/L respectively with 39.5% removal of COD in 60 min of fixed processing time. This study confirms that a combination of ultrasound cavitation and persulfate is a viable option for the treatment of pharmaceutical wastewater and can be used as an intensification technology in existing effluent treatment plants to achieve the highest amount of COD removal. HIGHLIGHTS Synergistic effect of ultrasonication and persulfate oxidation studied on pharma wastewater.; Box–Behnken method applied for process parameter optimization.; Significant reduction in the COD from the pharma wastewater within one hour of the reaction.; Potential choice for the implementation of the process as a pre-treatment option for wastewater treatment.;
... Although the chemical contaminants typically found in WWTP effluent represent many use classes, pharmaceuticals warrant heightened scrutiny due to their designed bioactivity and the diversity of their protein targets, most of which are relevant to fish (Gunnarsson et al., 2019). In lab-based exposures with fish, deleterious impacts of exposure to pharmaceuticals have been documented at sublethal concentrations (ng/L-μg/L) (Ford and Fong, 2016) that would otherwise be considered safe by conventional toxicological endpoints (Chen, 2020;Corcoran et al., 2010;Strähle and Grabher, 2010). Impacts include reproductive impairments, altered stress responses, behavioural changes, and decreased disease resilience (Corcoran et al., 2010;Fent et al., 2006;Yan et al., 2018;Yang et al., 2018;Zindler et al., 2020). ...
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Wastewater treatment plant (WWTP) effluent-dominated streams provide critical habitat for aquatic and terrestrial organisms but also continually expose them to complex mixtures of pharmaceuticals that can potentially impair growth, behavior, and reproduction. Currently, few biomarkers are available that relate to pharmaceutical-specific mechanisms of action. In the experiment reported in this paper, zebrafish (Danio rerio) embryos at two developmental stages were exposed to water samples from three sampling sites (0.1 km upstream of the outfall, at the effluent outfall, and 0.1 km below the outfall) during base-flow conditions from two months (January and May) of a temperate-region effluent-dominated stream containing a complex mixture of pharmaceuticals and other contaminants of emerging concern. RNA-sequencing identified potential biological impacts and biomarkers of WWTP effluent exposure that extend past traditional markers of endocrine disruption. Transcriptomics revealed changes to a wide range of biological functions and pathways including cardiac, neurological, visual, metabolic, and signaling pathways. These transcriptomic changes varied by developmental stage and displayed sensitivity to variable chemical composition and concentration of effluent, thus indicating a need for stage-specific biomarkers. Some transcripts are known to be associated with genes related to pharmaceuticals that were present in the collected samples. Although traditional biomarkers of endocrine disruption were not enriched in either month, a high estrogenicity signal was detected upstream in May and implicates the presence of unidentified chemical inputs not captured by the targeted chemical analysis. This work reveals associations between bioeffects of exposure, stage of development, and the composition of chemical mixtures in effluent-dominated surface water. The work underscores the importance of measuring effects beyond the endocrine system when assessing the impact of bioactive chemicals in WWTP effluent and identifies a need for non-targeted chemical analysis when bioeffects are not explained by the targeted analysis.
... Ofloxacin, 17α-ethinylestradiol, erythromycin and sulfamethoxazole were found to be high risk quotients and concerned compounds found in hospital wastewater (Al Aukidy et al., 2014). Aquatic systems containing high concentrations of antimicrobial compounds lead to behavioral stress in various aquatic species and wildlife (Ford and Fong, 2016). In addition, extensive use of antimicrobial compounds in aquaculture causes hormonal disorders in fish (Tyler et al., 1998). ...
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In many developing countries, untreated hospital effluents are discharged and treated simultaneously with municipal wastewater. However, if the hospital effluents are not treated separately, they pose concerning health risks due to the possible transport of the antimicrobial genes and microbes in the environment. Such effluent is considered as a point source for a number of potentially infectious microorganisms, waste antimicrobial compounds and other contaminants that could promote antimicrobial resistance development. The removal of these contaminants prior to discharge reduces the exposure of antimicrobials to the environment and this should lower the risk of superbug development. At an effluent discharge site, suitable pre-treatment of wastewater containing antimicrobials could maximise the ecological impact with potentially reduced risk to human health. In addressing these points, this paper reviews the applications of decentralized treatment systems toward reducing the concentration of antimicrobials in wastewater. The most commonly used techniques in decentralized wastewater treatment systems for onsite removal of antimicrobials were discussed and evidence suggests that hybrid techniques should be more useful for the efficient removal of antimicrobials. It is concluded that alongside the cooperation of administration departments, health industries, water treatment authorities and general public, decentralized treatment technology can efficiently enhance the removal of antimicrobial compounds, thereby decreasing the concentration of contaminants released to the environment that could pose risks to human and ecological health due to development of antimicrobial resistance in microbes.
... During wastewater treatment, the primary removal process of sertraline is sorption onto activated sludge, followed by biodegradation, albeit to a much lower extent (Gornik et al., 2020). Although the concentrations of SSRIs, including sertraline, in the aquatic environment, are relatively low, particular concern has been raised about their uptake and bioaccumulation in the biota (Silva et al., 2015;Mole and Brooks, 2019) and their possible adverse effects on non-target organisms (Sehonova et al., 2018), even at environmentally relevant concentrations (Ford and Fong, 2016). Therefore, it is rather imperative to find efficient treatment methods for their elimination from WWTPs effluents. ...
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Antidepressants are released into the aquatic environment because of their incomplete removal from wastewater treatment plants. In the present work, we investigated the photochemical degradation of a commonly prescribed antidepressant, namely sertraline, in aqueous matrices. The molar absorption coefficient of sertraline at 254 nm and at various pH values in the range from 4.0 to 9.0 was 444±65 L•mol–1•cm–1, while the quantum yield of its direct photolysis under UVC radiation (λ = 254 nm) was (1.7±0.1) × 10⁻² mol∙einstein⁻¹ (i.e., both values were relatively low). Next, we investigated the photochemical degradation of sertraline under UVC radiation in the presence of hydrogen peroxide, H2O2 (i.e., UVC/H2O2) or persulfate ions, S2O8²⁻ (i.e., UVC/PS). Several parameters were studied, such as the initial concentrations of the oxidants, solution pH, and the composition of the aqueous matrix (experiments were carried out in aqueous phosphate buffers, in synthetic wastewater, as well as in synthetic fresh and hydrolyzed human urine). It was found that, in all aqueous matrices, the photochemical degradation of sertraline followed pseudo first-order kinetics. The values of the observed pseudo first-order rate constants in the UVC/H2O2 and UVC/PS processes were from one to three orders of magnitude higher than the corresponding value in the UVC process. The UVC/PS process was more efficient than the UVC/H2O2 process, either in aqueous phosphate buffer solutions or in synthetic wastewaters, despite the comparable reactivity of sertraline towards hydroxyl and sulfate radicals. However, both processes resulted in partial mineralization of the compound after prolonged irradiation. In the UVC/H2O2 process, there was an optimum H2O2 concentration which depended on the aqueous matrix, while in the UVC/PS process, there was an almost linear increase in treatment efficiency as a function of PS concentration, at least in the range of concentrations studied in the present work. Solution pH in the range from 6.0 to 9.0 had a relatively negligible effect on treatment performance for both processes. In synthetic urine matrices, despite the reduction in reaction rate (the observed pseudo first-order rate constants were reduced by approximately one to two orders of magnitude), the photochemical degradation of sertraline proceeded to a relatively satisfactory degree. Finally, the calculations of the electrical energy per order and the associated cost showed that the UVC/H2O2 and UVC/PS processes are cost-efficient and suitable for full-scale applications.
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Antidepressant prescriptions are on a rise worldwide and this increases the concerns for the impacts of these pharmaceuticals on nontarget organisms. Antidepressants are neuroactive compounds that can affect organism’s behavior. Behavior is a sensitive endpoint that may also propagate effects at a population level. Another interesting aspect of antidepressants is that they have shown to induce non-monotonic dose-response (NMDR) curves. While such NMDR relationships may have clear implications for the environmental risk, the resolution of current studies is often too coarse to be able to detect relevant NMDR. Therefore, the current study was performed into the behavioral effects (activity, feeding and chemotaxis) in Caenorhabditis elegans as the model organism of the selective serotonin reuptake inhibitors fluoxetine and sertraline and the acetylcholinesterase inhibiting pesticide chlorpyrifos, using a wide range of concentrations (ng/l to mg/l). In order to statistically examine the non-monotonicity, nonlinear regression models were applied to the results. The results showed a triphasic dose-response relationship for activity and chemotaxis after exposure to fluoxetine, but not to sertraline or chlorpyrifos. Effects of fluoxetine already occurred at low concentrations in the range of ng/l while sertraline only showed effects at concentrations in the μg/l range, similar to chlorpyrifos. The different responses between fluoxetine and sertraline, both SSRIs, indicate that response patterns may not always be extrapolated from chemicals with the same primary mode of action. The effects of fluoxetine at low concentrations, in a non-monotonic manner, confirm the relevance of examining such responses at low concentrations.
Thesis
Juveniles of the common cuttlefish, Sepia officinalis, and the green shore crab, Carcinus maenas, develop themselves in the intertidal zone and coastal waters impacted by continental pollution such as pharmaceutical residues. This research focused on the effects two antidepressants, the fluoxetine and the venlafaxine, on the camouflage and behaviour of cuttlefish and shore crabs. Both molecules are worrying because they are designed to act on serotonergic system and are commonly detected in aquatic environments. Thus, to approach realistic scenario of exposure fluoxetine was either combined or not with venlafaxine. The results show significant effects of antidepressants at environmentally realistic concentrations, especially the combination of fluoxetine and venlafaxine, on sensitive endpoints such as burying behaviour, colour change and background matching, locomotor activity in crabs and predatory behaviour in cuttlefish. Furthermore, the exposure to antidepressants at early development stage seems to alter maturation and/or learning processes in cuttlefish. Overall, these studies demonstrated the need to investigate further with low range concentrations on key behaviours of non-target species.
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Fluoxetine is one of the most studied and detected selective serotonin reuptake inhibitors in the aquatic environment, found at concentrations ranging from ng/L to μg/L. Its presence in this environment can induce effects on aquatic organisms that may compromise their fitness. Several experimental studies have demonstrated that fluoxetine can induce neurotoxicity, genetic and biochemical changes, and cause behavioral dysfunction in a wide range of fish species. However, contradictory results can be found. There is thus the need for a comprehensive review of the current state of knowledge on the effects of fluoxetine on fish at different levels of biological organization, highlighting inclusive patterns and discussing the potential causes for the contradictory results, that can be found in the available literature. This review also aims to explore and identify the main gaps in knowledge and areas for future research. We conclude that environmentally relevant concentrations of fluoxetine (e.g., from 0.00345 μg/L) produced adverse effects and often this concentration range is not addressed in conventional environmental risk assessment strategies. Its environmental persistence and ionizable properties reinforce the need for standardized testing with representative aquatic models, targeting endpoints sensitive to the specific mode of action of fluoxetine, in order to assess and rank its actual environmental risk to aquatic ecosystems.
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Venlafaxine (VEN) is a chiral antidepressant detected in aquatic compartments. It was recently included in the 3rd Watch List from the European Union. This work aimed to investigate VEN toxicity effects, targeting possible enantioselective effects, using two aquatic organisms, daphnia (Daphnia magna) and zebrafish (Danio rerio). Specimens were exposed to both racemate, (R,S)‐VEN, and to pure enantiomers. Acute assays with daphnia showed that up to 50 000 μg/L of the (R,S)‐VEN induced no toxicity. Organisms were also exposed to sublethal concentrations (25‐400 μg/L) of (R,S)‐, (R)‐ and (S)‐VEN, for 21 days. No significant effects on mortality, age at first reproduction, and size of the first clutch were observed. However, a decrease in fecundity was observed for both enantiomers at the highest concentration. Regarding zebrafish, the effects of VEN on mortality, embryo development, behaviour, biochemistry, and melanin pigmentation were investigated after 96 h of exposure to the range of 0.3‐3000 μg/L. (R)‐VEN significantly increased the percentage of malformations in comparison to (S)‐VEN. Behaviour was also enantiomer dependent, with a decrease in the total distance moved and an increase in avoidance behaviour observed in organisms exposed to (R)‐VEN. Despite the biochemical variations, no changes in redox homeostasis were observed. (R)‐VEN also led to an increase in zebrafish pigmentation. The different susceptibility to VEN, and enantioselective effects were observed in zebrafish. Our results suggest that at environmental levels, (R,S)‐VEN and pure enantiomers are not expected to induce harmful effects in both organisms, however (R)‐VEN increased malformations in zebrafish larvae, even at reported environmental levels. These results highlight the importance to include enantioselective studies for an accurate risk assessment of chiral pollutants. This article is protected by copyright. All rights reserved.
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