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Critical Reviews in Toxicology, 2010; 40(4): 287–304 Critical Reviews in Toxicology Pharmaceuticals in the aquatic environment: A critical review of the evidence for health effects in fish Jenna Corcoran1, Matthew J� Winter2, and Charles R� Tyler1 1Environmental and Molecular Fish Biology, School of Biosciences, The Hatherly Laboratories, University of Exeter, Exeter, Devon, UK, and 2AstraZeneca Safety, Health and Environment, Brixham Environmental Laboratory, Freshwater Quarry, Brixham, UK The authors review the current data on the presence and reported biological effects in fish of some of the most commonly detected pharmaceuticals in the aquatic environment; namely nonsteroidal anti-inflammatory drugs (NSAIDs), fibrates, β-blockers, selective serotonin reuptake inhibitors (SSRIs), azoles, and antibiotics� Reported biological effects in fish in the laboratory have often been shown to be in accordance with known effects of pharmaceuticals in mammals� Water concentrations at which such effects have been reported, however, are generally, between μg L−1 and mg L−1, typically at least 1 order of magnitude higher than concentrations normally found in surface waters (ng L−1)� There are exceptions to this, however, as for the case of synthetic oestrogens, which can induce biological effects in the low ng L−1 range� Although generally effect levels for pharmaceuticals are higher than those found in the environment, the risks to wild fish populations have not been thoroughly characterised, and there has been a lack of consideration given to the likely chronic nature of the exposures, or the potential for mixture effects� As global consumption of pharmaceuticals rises, an inevitable consequence is an increased level of contamination of surface and ground waters with these biologically active drugs, and thus in turn a greater potential for adverse effects in aquatic wildlife� Keywords: Aquatic environment; cytochrome P450; ecotoxicology; fish; pharmaceuticals
24 September 2009 29 September 2009 Address for Correspondence: Address for Correspondence: Charles R. Tyler, Hatherly Laboratory, Prince of Wales Road, Exeter, Devon, EX4 4PS, UK. Phone: +44 2010 Informa UK Ltd (0)1392 264450; Fax: +44 (0)1392 263700; E-mail: (Received 25 June 2009; revised 24 September 2009; accepted 29 September 2009) ISSN 1040-8444 print/ISSN 1547-6898 online 2010 Informa UK Ltd 288 J. Corcoran et al. system in wildlife species has a somewhat different physi-ological role, or is much more sensitive to the effects of a drug Pharmaceuticals are a large and diverse group of medicinal compared with that in humans or livestock animals� An, albeit compounds used for the diagnosis, cure, mitigation, treat- rare, example of this is for the nonsteroidal anti-inflammatory ment, or prevention of diseases in humans and animals� drug (NSAID) diclofenac, which has been shown to have a Pharmaceuticals are often classified according to therapeutic particularly severe effect on kidney function in some species purpose (i�e�, antibiotic, analgesic, antidepressant, etc�), and of Asian vultures, and this has resulted in their widespread the worldwide consumption of some of these ‘classes' is sub- decline and even localised population extinctions stantial )� In 2008, worldwide sales of phar- � Another example is for β-blocker drugs, which maceuticals totalled US$602 billion, this figure rising annually target the adrenergic system, which is thought to be involved by approximately 5–7% (IMS Health 2009), paralleling the in melanophore regulation in fish , a side significant advances in medical technology and increased effect not considered in humans� spending on health car)� In this paper, we critically assess the potential for impacts An inevitable consequence of this increased consumption of pharmaceuticals discharged into the aquatic environment, of pharmaceuticals is higher levels of their discharge into the focusing on possible biological effects in, and consequences environment� Many pharmaceuticals end up in the aquatic for, fish� Because of their ecological niche and similarities in environment, and over the past two decades there has been many of their physiological processes compared with mam- a growing number of reports detecting trace levels of vari- mals, fish are arguably the most likely vertebrate organism to ous prescription and over-the-counter pharmaceuticals in be affected by pharmaceuticals in the aquatic environment� In waste water treatment work (WWTW) effluents, surface and the first section of the paper, we consider which of the major ground waters, and, in some countries, even in drinking water classes of pharmaceuticals are entering surface waters, and supplies� (See assess what factors determine their persistence and bioavail- ability to fish� We then focus on the evidence from laboratory reviews)� The main routes of entry into the environment are studies for potential effects of the most commonly detected from treated patients, where the pharmaceutical may enter as classes: formulated steroidal oestrogens; NSAIDs; antide- the parent compound or as metabolites (Williams, 2005); via pressants (e�g�, selective serotonin reuptake inhibitors or direct release into the waste water system from manufactur- SSRIs); azoles; fibrates; beta blockers (β-adrenergic receptor ing, hospitals, or domestic discharges ( antagonists); and antibiotics in fish� The paper then critically ); and via leaching from terrestrial depositions (e�g�, solid analyses the potential for environmental impacts of pharma- waste landfills) (Barnes et al�, 2008)� ceuticals in the environment on fish health, by drawing on Generally, the concentrations of pharmaceuticals detected comparisons between effects observed in the laboratory and in the aquatic environment are relatively low, usually in the concentrations measured in the field, and attempts to assess ng L−1 to μg L−1 range, but in some countries (e�g�, India and the scale of the (potential) problem� China), relatively high concentrations of antibiotics, and other drugs, including β-blockers, antacids, and antidepres- Pharmaceuticals in the aquatic environment
sants, are entering the aquatic environment through effluent from plants serving drug production units The international market shows substantial regional differ- � The regulations gov- ences in the use of pharmaceuticals, influenced by economic erning the environmental impact of pharmaceuticals in such status, health requirements, capacity for local manufacture, countries are limited compared with those in place in Europe, and legal restrictions� As such, developed countries dominate Japan, and North America, where there are specific legislative global pharmaceutical sales, with North America account- requirements to ensure any pharmaceuticals reaching market ing for 45% (US$248 billion in 2004), Europe 13%, Japan are assessed for their likely environmental fate and biological 10%, and Australia 1% of recorded sales (IMS Health MIDAS effects (e�g�, EMEA, 2006), the results of which can, if neces- 2007)� In accordance with this pattern, the detection of phar- sary, dictate controls over use and disposal� maceuticals in the aquatic environment has predominantly Critically, pharmaceuticals are designed to alter physi- been reported in the developed world (USA, EU, Japan, and ological function and this is unlike most other chemicals Australia)� The exception to this is for some recent reports entering the environment, where biological effects generally from India and China, where exceptionally high levels of occur as an unintended consequence of their principal func- certain pharmaceuticals have been found in discharges tion� Furthermore, some of the mechanisms through which from newly established pharmaceutical production plants certain pharmaceuticals act are relatively conserved across animal phyla, thus some pharmaceuticals designed to induce Generally, there is a positive correlation between the most an effect in humans or livestock have a high probability of frequently used classes of pharmaceutical and their detection being biologically active in wildlife species� Supporting this in the aquatic environment� Many of the top pharmaceuti- assumption, recently Gunnarssan et al� (2009) concluded that cals sold in the USA and UK are in drug classes used to treat zebrafish possess orthologs to 86% of 1318 tested human gene diseases associated with westernised society: for example drug targets� It can also be the case that the biological target maintaining cholesterol balance, combating mental illness, Effects of pharmaceuticals in fish 289 treating stress, ulcers, asthma, etc�, and they include specific (an antidepressant) ()� As such, for these com- beta blockers, lipid regulators, antidiabetic, antianginal pounds a significant proportion of the administered drug will drugs, as well as analgesics and antibiotics ()� pass directly through the patient without having crossed the Paralleling this usage, these therapeutic classes are the most gut wall of the patient� commonly detected pharmaceuticals both in WWTW efflu- For some compounds absorbed by the body, they may ents and river water (where such analyses have taken place: undergo phase I and phase II metabolism, with the resultant ; Sacher et al�, 1998; ; Golet metabolites excreted via the urine and/or faeces ( et al�, 2001; Hartig et al�, 1999; Hirsch et al�, � The degree of metabolism that occurs can vary greatly between compounds; some are completely metabo- Roberts and Thomas, lised, whereas other compounds are not metabolised at all and are excreted completely as the parent compound� ; Bartelt-Hunt et al�, Metabolism modifies the chemical structure and thus properties of the active molecules, in some instances ren- For veterinary pharmaceuticals, the most commonly used dering them inactive� This is not always the case, however, class are the antibiotics, followed by azoles� Accordingly, and some produce metabolites that are biologically active� there are also many papers reporting the detection of these For example, clofibrate, a lipid-regulating drug, is a prodrug drugs in the aquatic environment, and other environmental whose pharmacological activity is dependent on metabolism compartments, including farm waste and in some cases at in the body to the active form, clofibric acid very high concentrations Peschka et al�, Excreted pharmaceuticals and their metabolites entering WWTWs may undergo biodegradation, remain suspended or dissolved in the water, or bind to biosolids or sewage sludge Examples of this include the antibiotics tetracycline and sul- )� Rates of degradation of pharmaceu- famethazine, which have been measured in farm manure at ticals in WWTWs vary depending on the pharmaceutical concentrations of 66 and 40 mg L−1, respectively (Winkler and and where they partition in the environment� For example, Grafe, 2001)� Importantly, this manure is commonly applied ibuprofen has a high elimination rate, generally >90%, and to agricultural fields as a fertiliser, and it is now accepted that so is rapidly degraded (; Metcalfe et al�, this constitutes a major route via which veterinary pharma- 2003a; ), whereas, in contrast, car- ceuticals may enter surface and groundwater bamazepine has an elimination rate of only 4–8% (Ternes, ; Martinez-Carbello et al�, 2007)� 1998b; ; )� The slow Reported concentrations of pharmaceuticals detected in elimination rate for carbamazine may explain why this drug is WWTW effluent are in the high ng L−1 to low μg L−1 range, frequently measured in both WWTW effluent and river water, whereas in surface waters pharmaceuticals rarely exceed even though it is not a pharmaceutical of high consumption concentrations of 100 ng L−1 (� Certain (IMS Health 2007). Considering the environmental compart- pharmaceuticals have also been detected in the low ng L−1 ment into which the pharmaceutical partitions, elimination concentration range in groundwater rates of various antibiotics tend to be considerably slower in in the oceans ), anaerobic conditions (as might occur within deep sediments) and even in drinking wat� compared with aerobic conditions (� Adsorption of pharmaceuticals to the sludge is dependent Factors influencing the concentration of
on hydrophobic and electrostatic properties of the chemical pharmaceuticals in the aquatic environment
� For example, acidic pharmaceuticals (e�g�, NSAIDs, clofibric acid, gemfibrozil) occur as ions at neutral The concentration of pharmaceuticals detected in the aquatic pH and so there is little adsorption to sludge and sediments environment is not only determined by usage levels, but also ; )� In turn, these by the degree of metabolism that occurs in the patients body pharmaceuticals are more likely to remain in the water col- (Winker et al�, 2008), degradation rates in the waste water umn and thus may more readily pass through WWTWs into system and receiving waters ), effluent discharges and their receiving surface waters� Basic and how the compound partitions into the water column/ pharmaceuticals, such as 17α-ethinyloestradiol (EE2) and sediments (Debsake et al�, 2004)� It should also be realised fluoroquinolone antibiotics, however, have been shown to that a large proportion of prescribed drugs are not admin- adsorb readily to sludge (Golet et al�, 2002), and can occur in istered and are disposed of directly into waste waters; an sediment at ng g−1 levels (Ternes et al�, 2002)� This facilitates estimated $1 billion of prescription drugs are discarded each their removal in WWTW and contributes to the fact that high year in the US, from hospitals, care facilities, and pharmacies proportions of these pharmaceuticals are removed from the aqueous phase as it passes from the influent to effluent (for Most human pharmaceuticals are taken orally, with rates steroidal oestrogens there is between 70% and 80% removal; of absorption ranging from under 20% for drugs such as Ternes et al�, 1999). metformin (an antidiabetic) to around 80% for fluoxetine Similarly, antidepressants readily partition into sediment 290 J. Corcoran et al. where they have been detected at ng g−1 concentrations Furthermore, there is a continuous release of pharma- ceuticals into the aquatic environment, which may result entering the aquatic environment that adsorb readily to in long-term, chronic exposure, and this, combined with a sediments in WWTWs may in turn be of greater concern for propensity, for some, to bioaccumulate (e�g�, EE2; Hill et al�, terrestrial environments where the sewage sludge is applied 2006), means there is the enhanced likelihood of adverse biological effects� Photodegradation can also be important in the environ- mental degradation of some pharmaceuticals and this proc- Evidence for biological effects of commonly
ess has been shown to play a major role in the removal of detected pharmaceuticals in fish
diclofenac in surface water (Buser et al�, 1998b) and to con-tribute significantly to the breakdown of sulfamethoxazole, Pharmaceuticals receive considerable testing to make sure propranolol, and ofloxacin (Andreozzi et al�, 2003b)� that they are not harmful to human health, and as such there is much information available relating to the physiological The susceptibility of fish to pharmaceutical
effects of drugs in mammals (e�g�, see )� However, information on the effects of these biologically active substances in nontarget animals, including fish, is lim- Pharmaceuticals are generally nonpolar ited� In this next section we review the available information, ) and are therefore able to pass through bio- both from the laboratory and the field, for the effects of vari- logical membranes by diffusion, to targets within specific ous major human and veterinary pharmaceuticals in fish� cells and tissues� The majority of drug targets are proteins, such as enzymes, receptors, carrier molecules, or ion chan- Pharmaceutical steroidal oestrogens and progestagens
nels, and it is the diverse and complex structure of these There is more information on the biological effects in fish of proteins that enables pharmaceutical selectivity, which is the synthetic oestrogen EE2 than for any other pharmaceu- the basis for the precise functioning of a drug (William and tical discharged into the aquatic environment� EE2 has fre- Cook, 2007)� Thus, as a drug is developed based on a specific quently been detected at low (ng L−1) levels in surface waters biological activity in one animal group (principally mam- and WWTW effluents ; Baronti et al�, 2000), mals) and many of these systems targeted are conserved despite the fact that only relatively small volumes are pro- amongst vertebrates, it would seem reasonable to predict duced annually (approximately 26 kg per year, worldwide, that they will target the same systems in fish� Indeed, this and 1 kg in the � Nevertheless, EE2 is has been shown to be the case for a wide range of potential extremely potent in fish, and environmentally relevant con- drug target sites, including serotonin receptors ( centrations have been shown to induce feminisation in fish, ; β-adrenergic recep- including induction of the female yolk precursor vitellogenin tors (Ruuskanan et al�, 1985), cyclooxygenase (COX) (VTG) in males (e�g�, Orn et al�, 2003, 2006; peroxisomal proliferator-activated ; formation of a female reproductive duct in the receptors ), and several testis (and induction cytomchrome P450s (CYPs) (see Siroka and Drastichova, of intersex (the presence of oocytes in the testis; e�g� 2003, for a review)� The life history of fish and some features of their physiol- et al�, 2001; )� These effects ogy potentially make them especially susceptible to phar- are documented in a wide range of species, although there maceutical uptake and effects ). Uptake appears to be differences in species sensitivity (for recent of pharmaceuticals into fish can occur via both dermal and reviews see ; )� Adding to gill surfaces for water-borne/sediment associated phar- the concern surrounding the use and discharge of EE2, life maceuticals, orally through the diet, or maternally, via the time exposure to relatively low concentrations of EE2 in the transfer of contaminants through the lipid reserve of eggs� water (5 ng L−1) has been shown to cause reproductive failure Pharmaceutical drugs are generally designed to have low in colonies of laboratory maintained zebrafish ( toxicity (possibly with the exception of cytotoxic chemothera- ), and similarly the dosing of a lake in Canada (Lake 206) peutics), but there is the potential for unintended side effects� with 4–6 ng EE2 L−1 resulted in complete failure of the fathead This is perhaps particularly in nontarget species groups, minnow (Pimephales promelas) fishery ( )� where side effects or even pharmacological effects may differ Exposure of roach (Rutilus rutilus), a species in which wide- compared with those in humans and laboratory test mam- spread sexual disruption has been shown in wild populations mals due to differences in physiology and biochemistry� For living in UK rivers downstream of WWTW discharges, to 4 ng example, fish have a lower capacity to metabolise xenobiotics L−1 EE2 for a 3-year period resulted in complete feminisation compared with mammals of the exposure populations )� Moreover, Casarett et al�, 2001), especially during early life stages physiological effects of EE2 in fish are not confined to effects on reproduction, and targeted gene expression and gene array studies have shown that EE2 also alters mitochondrial Effects of pharmaceuticals in fish 291 function, energy metabolism, and cell cycle control indomethacin, are human pharmaceuticals that are regularly detected in both WWTW effluent and surface waters at con- EE2 has a much lower solubility than natural steroid centrations in the μg L−1 range oestrogen oestradiol (E2) al�, 2004; Farre et al�, 2001; ) and it is also considerably more persistent Herberer et al�, 2002, in the aquatic environment, with an estimated half life in surface waters of between 1�5 and 17 days, depending on the amount of sunlight Jurgens et al�, 2002), and The therapeutic role of these pharmaceuticals is to reduce in soils between 3 and 7�7 days, depending on the tempera- inflammation and pain; these drugs work by inhibiting ture ()� Add to this is the fact that EE2 cyclooxygenases (COXs), enzymes that catalyse the synthe- is lipophilic and bioconcentrates in fish to high levels (over sis of prostaglandins, via the oxidation of arachidonic acid� 10,000-fold in short-term [10–21-day] exposures; There are two isozymes: COX1 is responsible for the baseline ), including in the gonads (, and levels of prostaglandins, and COX2 produces prostaglandins it is clear why this compound is of particular environmental in response to stimulation (i�e�, it is an inducible enzyme) at the site of inflammation� NSAIDs can be COX1 or COX2 Other steroidal oestrogens used in formulations for con- selective, or can inhibit both isozymes equally� traception or in hormone replacement therapy include con- This drug target is conserved across vertebrates jugated oestrone (oestrogen sulphate) and equine oestrogens ), and both COX1 and COX2 isoenzymes have (Archand-Hoy, 1998; Stevenson, 2005)� These oestrogens been characterised in a number of fish species have also been detected in WWTW effluents, at concentra- ; Buonocore et al�, 2005; tions in the ng L−1 range: oestrone sulphate 0�4–2�6 ng L−1 ; � Most NSAIDs ; , equilenin 1 ng inhibit both COX1 and COX2 isoforms, and as such, result L−1 dihydroequilenin (a product of in the nonspecific inhibition of prostaglandins� This, in turn, metabolism of equilenin) 1�45–2�51 ng L−1 ( means there is the potential for effects on any of the normal � Dihydroequilenin has also been detected in the bile physiological functions mediated by prostaglandins, which of rainbow trout downstream from a WWTW at concentra- are diverse ()� tions of 30–40 ng ml−1), which suggests In fish, prostaglandins are found in numerous cells and this compound may bioaccumulate� tissues, including red blood cells, macrophages, and oocytes Oestrone sulphate, in its conjugated form, is biologically active in fish (our own unpublished data) and is also readily and their key roles include in reproduction, where they metabolised to oestrone, which is strongly oestrogenic in fish have a paracrine role in the ovary, stimulating ovulation at environmentally relevant concentrations ( )� Similarly, equilenin and dihydroequilenin are biologi- and oestradiol production (); cally active in fish, with effective concentration inducing VTG eliciting female sexual behaviour through effects on the synthesis in rainbow trout (Oncorhynchus mykiss) of 4�2 and brain ; and as a sex pheromone, 0�6 ng−1, respectivel� stimulating male sexual behaviour (; Progestagens form a component of some contraceptive )� Consistent with the likelihood that and hormone replacement therapy (HRT) formulations, NSAID can affect reproduction in fish, indomethacin has and have been detected in the WWTW effluent and surface been shown to disrupt the process of oocyte maturation and waters at ng L−1 to μg L−1 concentrations ( ovulation in zebrafish at a concentration of 100 mg L−1 ( ) and in river sediment at a concentration ) and ibuprofen has been shown to of 6 ng g−1 (). In mammals, progestagens act alter the pattern of spawning in Japanese medaka at concen- via the progesterone receptor (PR) and regulate a number trations of µg L−1� These reported effects, of physiological effects associated with the maintenance of however, exceed those reported in any aquatic environment pregnancy, and development of the foetus� More recently it has been suggested that in humans, progestagens have COX-synthesised prostaglandins are also known to be important functions in the central nervous system ( important in cortisol biosynthesis in fish (Wendelaar Bonga, � The PR has been characterised in some fish spe- 1996; and accordingly it has been demonstrated that NSAIDs can disrupt cortisol production although there are few data on the roles of progestagens in in trout (� Cortisol is known to play fish, it is thought that they are involved in oocyte maturation an important part in osmoregulation in fish, specifically and spawning ); progesta- the development and proliferation of chloride cells in the gens also act as a precursor for oestrogen and testosterone� gills and stimulation of Na+,K+-ATPase activity for seawater adaptation � Exposure of rainbow trout to ibuprofen at a concentration of 1 mg L−1 has been shown to Nonsteroidal anti-inflammatory drugs (NSAIDs), such impair ion regulation and so the hyposmoregulatory capacity as diclofenac, naproxen, ibuprofen, ketoprofen, and in seawater ()� 292 J. Corcoran et al. Table 1. Measured environmental concentrations versus toxic effect concentrations in fish for selected pharmaceuticals.
Measured environmental Toxic effect concentration Pharmaceutical STP effluent Endpoint measured Species 0.81–33.9 μg/L 6.2 ng/L–1.8 μg/L glandin synthesis liver, and kidney Histological altera- Histological altera- Cytological altera- tions; liver, kidney, 70 ng/L–2.7 μg/L reproduction pattern Impairment of ion Disruption of oocyte Zebrafish 80 ng/L–0.52 μg/L 70 ng/L–0.39 μg/L 0.20–0.32 μg/L 0.099–0.841 μg/L 0.012–0.030 μg/L ability to catch prey Increased oestradiol Medaka changes to gonads Increased levels of 29.76 (0.056 μM) 0.0298 Inhibition of 17β- Table 1. Continued on next page Effects of pharmaceuticals in fish 293 Table 1. Continued.
Measured environmental Toxic effect concentration Pharmaceutical STP effluent Endpoint measured Species 2513.85 (9.7 μM) Inhibition of 17β- Reduced fedundity Inhibition of brain Decreased number of Fathead Inhibition of ovarian Fathead Induced testis growth Fathead 7700.00–39700.00 7.7000–39.7000 Induce oxidative 32,279.10 (133 μM) 32.2791 (EC ) Lowered sperm count Fathead Runnells et al., 2007 Lower plasma andro- Fathead Runnells et al., 2007 gen concentration 23,299.20 (96 μM) 23.2992 Inhibition of EROD Induce oxidative 19,124.52 (53 μM) 19.1245 (EC ) 9021.00 (25 μM) Inhibition of EROD Reduced testosterone Goldfish Nimeault et al., 0.048–0.052 μg/L Inhibition of CYP2M Carp 0.01–0.29 μg/L 0.012–0.59 μg/L 7002.18 (27 μM) Altered heart rate Fraysee et al., 2006 Altered blood flow Total number of eggs Medaka Number of viable eggs Medaka <10 ng/L–0.130 17.2 ng/L–0.241 Number of viable eggs Fathead 0.11–0.34 μg/L Suppressed immune Rainbow trout Grondel et al., 985 294 J. Corcoran et al. The NSAID diclofenac has been associated with a serious tissues in fish (Caamano-Tubio et al�, 2007)� As an important effect in wildlife, causing renal failure in particular species of neurotransmitter, in fish, serotonin has been implicated exposed Asian vultures that has lead to widespread popula- in several physiological functions, influencing behaviour tion crashes 2004)� The mecha- (aggression, appetite), endocrine, and reproductive param- nism of toxicity in this case (induction of visceral gout), and eters� Furthermore, serotonin is involved in social hierarchy the enhanced sensitivity, however, seem to be peculiar to a and feeding rank in some species , small number of species, and the route of exposure rather Alanara et al�, with sub- unusual (via cattle carcases on which the vultures feed)� ordinate individuals having higher brain serotonergic activity� In fish, as occurs in mammals, diclofenac hinders the stim- With this in mind, SSRIs have the potential to disrupt a wide ulation of prostaglandin synthesis in the head kidney, and in range of processes in fish, both at the level of the individual brown trout this has been shown to occur at environmentally organism, and potentially the population (by affecting social relevant concentrations of 0�5–50 μg L−1 ()� interactions and reproduction). In rainbow trout, harmful effects of diclofenac, including the To date, most research on SSRIs has focused on fluoxet- induction of glomeruloneophritis, necrosis of endothelial ine (Prozac); nevertheless, as all the SSRI drugs work via the cells, and hyaline droplet degeneration, have been shown in same basic mode of action, it is reasonable to assume that the kidney, and pillar cell necrosis, epithelial lifting, hyperpla- most will exhibit similar effects� In fish, fluoxetine has been sia, and hypertrophy of epithelial chloride cells in gills have shown to decrease territorial aggressive behaviour in male been shown to occur at exposure concentrations between 1 bluehead wrasse on introduction to an intruder male, in both and 5 μg L−1 (4)� the laboratory and field, at a concentration of 6 μg g day−1 over It is not known, however, whether the gill effects are asso- 2 weeks (). Exposure ciated with prostaglandin inhibition, or through another of striped bass to fluoxetine (23�2–100�9 μg L−1) over 6 days mechanism� In contrast, no pathological damage to the gills caused a decrease in their ability to capture prey (fathead or kidney was detected on exposure of Japanese medaka to minnow) in a concentration- and a duration-dependent man- ibuprofen, at concentrations up to 100 μg L−1 ( ner (), and fluoxetine exposure � This may be due differences in the relative potencies decreased feeding rates in fathead minnow ( of these drugs: diclofenac COX-2 IC is 0�06 μM, whereas the with an lowest observed effect level (LOEC) between IC for ibuprofen is 19 μM (� 51 and 170 μg L−1� These data indicate potential survivorship NSAID exposure has also been linked to cardiac abnor- implications; however, these concentrations far exceed meas- malities and lowered heart rate ( ured environmental concentrations� depletion of glycogen in the liver SSRIs are also implicated in alterations to reproduction in Busby et al�, 2002), teratogenicity in fish� Changes in serotonin levels are correlated with repro- zebrafish embryos , disruption of ductive phases in female fish ), the heat shock response in rainbow trout ( and it has been shown that serotonin plays an important ), and inhibition of CYP2M activity in carp stimulatory role in the regulation of gonadotropin II (GTH-II) (luteinising hormone release; ; ; ; Antidepressants (selective serotonin reuptake inhibitors)
)� GTH-II induction in turn will increase steroido- The selective serotonin reuptake inhibitor (SSRIs) antide- genesis� Accordingly, exposure of medaka to fluoxetine at pressants, such as fluoxetine, paroxetine, setraline, etc�, are 0�1 and 0�5 μg L−1 concentrations elevated oestradiol levels amongst the most commonly detected pharmaceuticals in ), presumably via an increased level of both surface water and WWTW effluents, reflecting their serotonin� In medaka, serotonin has also been shown to usage volumes in human medicine� They are generally induce oocyte maturation (Iwamatsu et al�, 1993)� Increased present at concentrations in the ng L−1 to low μg L−1 range steroidogenesis may also be associated with altered growth and developmental patterns; for example, fish may mature and have also been detected in sediment in ng g−1 concentra- in the wrong season due to impaired growth� Modification of these endpoints have indeed been reported in fathead SSRIs exert therapeutic effects by inhibiting monoamine minnow, at concentrations of between 51 and 53 μg L−1 of transporters and thus inhibiting the reuptake of the neuro- fluoxetine, and in medaka, at environmentally relevant lev- transmitter serotonin (5-hydroxytryptamine) at presynaptic els of 0�1–5 μg L−1; neuronal membranes (� This elevates the concentration of serotonin in the synaptic gap Not all studies on the effects of fluoxetine in fish, however, )� Therapeutically, this is beneficial to those have been consistent in their findings� As an example suffering with depression and related psychiatric disorders found no significant affect on fecundity, egg (Brooks et al�, 2003a)� fertilisation, or hatching success in medaka for exposures Serotonin receptors have been identified in several fish between 0�1 and 5 μg fluoxetine L−1, over a 4-week period� SSRIs are generally detected in the aquatic environment , and serotonin (5-HT) is found in several different only at very low levels (ng L−1), and many of the effects Effects of pharmaceuticals in fish 295 reported upon above far exceed likely exposure regimes for species, fadrozole significantly induced testis growth (at a fish in the wild� Wild populations of fish, however, have been concentration of 51�7 μg L−1)� found to contain detectable amounts of fluoxetine in their Ultimately, it seems that azole drugs may have the poten- body tissues (, showing this drug at least tial to affect reproduction via a number of mechanisms, as has the potential to bioaccumulate (Paterson and Metacalfe, The effective exposure concentrations for the azoles derived from laboratory studies generally appear to exceed Azoles (aromatase inhibitors)
those reported in surface waters� Nevertheless, although rarely A number of azole antifungal drugs, such as ketocona- detected above the ng L−1 level as individual compounds in zole, clotrimazole, miconazole, and fluconazole, as well the natural environment, azoles are likely to be present as a as the aromatase inhibitor fadrozole, are commonly used mixture and they are likely to have similar modes of action in human, and veterinary medicine, and some have been and be additive in their biological effects� Supporting the detected in the aquatic environment at ng L−1 concentra- statement on their presence in the environment as mixtures, studies have commonly reported the presence of propico- Peschka et al�, 2007; � Azoles nazole, used as a fungicide in agriculture, and benzotriazole act against fungi by inhibiting the enzyme CYP51, which and tolyltriazole, used as aircraft de-icer at ngL−1 to μg L−1 catalyses the 14α-demethylation of lanosterol, the main concentrations in surface waters step in the synthesis of ergosterol (Trosken et al�, 2004)� Ergosterol is required in fungal cell membrane synthesis, and as such, exposure to azoles results in structural and � Indeed, some of these compounds appear almost functional impairment of the membrane, ultimately inhib- ubiquitously present in the aquatic environment; iting fungal growth� detected benzotriazole in 94% of rivers studied in This CYP inhibition, however, is nonspecific European Union (EU) countries (out of a total 122 tested), at , and in addition to CYP51, these drugs are well known a median concentration of 226 ng L−1� The mixture issue for as potent inhibitors of other cytochrome P450s in vertebrates, azoles in the aquatic environment needs to be addressed to including in fish� For example, some azoles have been shown gain a realistic view on their (potential) impact in fish� to inhibit CYP1A and CYP3A isoforms (Hasselberg et al�, 2008), both are involved in xenobiotic and steroid metabolism� Azoles have also repeatedly been shown One of the most common classes of pharmaceuticals, in to inhibit CYP19 (aromatase), which is a key steroidal enzyme terms of detection in the aquatic environment, are the lipid involved in the synthesis of oestrogen from androgen� In fact, regulators, particularly fibrate drugs� For example, bezafi- this mechanism has been utilised in humans as the basis brate, gemfibrozil, and fenofibrate have been detected at μg of antioestrogen therapy (e�g�, for breast cancer treatment; L−1 concentrations in surface waters ; Trosken et al�, 2004)� As such, azoles have the potential to interfere with steroid biosynthesis and thus sex hormone bal- Clofibric acid is commonly reported in surface water and ance in nontarget species, including in fish� WWTW effluent at concentrations in the μg L−1 range and Drugs such as ketoconazole, clotrimazole, and fadrozole has even been detected in drinking water are known reproductive toxicants to fish and have been shown , albeit at relatively low concentrations (up to 270 ng to effect steroidogensis and reproductive success, linked to L−1). Recently, statins are being increasingly prescribed (the inhibition of steroidogenic enzymes CYP11a, CYP17, and aro- top prescription drug in the US in 2006 was a statin lipid matase, at concentrations as low as 11�1 nM ( regulator; IMS Health 2007). However in contrast with fibrate � In turn, this inhibition has been drugs, as yet there is very scarce data on the occurrence and shown to alter the production of several steroids (androsten- ecotoxicology of statins� edione, testosterone, and 17β-estr Fibrates are peroxisomal proliferators (PPs) with the ulti- ) with various knock-on reproductive mate therapeutic effect being the lowering of blood plasma effects in both male and female fish� lipid levels� PPs bind and activate the peroxisomal prolifer- In female fathead minnow, these effects include decreased ator-activated receptor alpha (αPPAR) transcription factor, egg production (), decreased plasma vitel- which in turn binds to response elements (PPREs) in the logenin concentrations , and inhibition promoter region of PP-sensitive genes (); of ovarian growth )� Effect concentrations predominantly those genes are involved in lipid metabolism, are generally in the μg L−1 range and have been demonstrated e�g�, acyl–coenzyme A oxidase (AOX), an enzyme which initi- to occur at concentrations as low as 2 μg L−1 ates peroxisomal β oxidation of fatty acids ( ). This increased enzymatic activity, coupled with In male fathead minnow exposure to fadrozole (2–50 μg L−1 increased peroxisomal volume leads to the removal of fatty over 21 days) was shown to result in elevated levels of plasma acids and cholesterol from the blood� testosterone, and this was linked to inhibition of aromatase One reported side effect of this is increased production activity (� In a separate study on the same of hydrogen peroxide (H O ) in the cell, which may lead to 296 J. Corcoran et al. oxidative stress and hepatocarcinogenesis ( prescribed classes of human pharmaceuticals and accord- � Indeed, a strong correlation has been shown between ingly, they are frequently detected in WWTW effluent and exposure to fibrates and hepatocarcinogenesis in rodents surface waters, generally at ng L−1 concentrations ( )� In addition, antioxidant system compo- nents are known to be suppressed with chronic exposure to PPs in ra), which could be expected to et al�, 2003a; ; Hilton and Thomas, 2003; exacerbate this effect� � Moreover, in some surface waters, biso- There are few studies on the effects of fibrates in fish� prolol and metoprolol have been detected at concentrations The same peroxisomal B oxidation system does exist in fish, up to the μg L−1 range ()� Beta blockers are used to treat cardiac conditions such as angina, heart failure, high blood pressure, and glaucoma, and ; and fish respond work as competitive β-adrenergic receptor (β-AR) antagonists to PPARα agonists by increasing AOX activity on cardiac muscle to decrease heart rate and contractility ; Donohue et al�, 1993)� This indicates that the PPAR pathway is an important β-ARs are relatively conserved amongst vertebrates factor in mediating enzymatic response to fibrates in fish, and this target is now known to as it is in mammals� It has further been demonstrated that be present in a number of extracardiac tissues and organs clofibrate and fenofibrate induce oxidative stress in rainbow in fish, including branchial vascular tissue, gills, liver, trout hepatocytes, at concentrations of 242�70 and 1�89 mg erythrocytes, brain, and muscles (; L−1, respectively ), indicating fish may be susceptible to the effects of fibrates� and Milsom, 1990; 1992; Interestinglreported no lipidemic- associated effects in fathead minnow exposed to clofibric � There are three subclasses of β-AR (β1, acid (0�01–1 mg L−1), but instead deleterious effects were seen β2, and β3), against which various beta blockers have dif- on the reproductive system� These included reduced sperm fering potency and efficacy, and these receptors have been count, impaired spermatogenesis, and a lowered plasma implicated in various physiological functions in fish (e�g�, androgen concentration� Similarly, it has been shown that cardiovascular regulation, growth, metabolism), reflect- exposure to gemfibrozil (1�5 mg L−1 for 96 h reduces testo- ing their wide distribution (� As such, sterone by more than 50% in goldfish testes beta blockers have the potential to impact on a range of physiological systems, and, there are a number of stud- Fibrates have additionally been shown to modify the activ- ies indicating effects in fish exposed to a number of these ity of cytochrome P450 enzymes, although there appear to be conflicting results in this regard� Bezafibrate and clofibrate In terms of acute toxicity, propranolol was shown to have induced CYP1A-associated ethoxyresorufin-O-deethlyase a LC of 24�3 mg L−1 (48 h) and caused a decreased growth (EROD) activity in fathead minnow–derived cell line PLHC-1, after 14 days' exposure to 0�5 mg L−1, in medaka ( at concentrations of 1 and 10 mM, respectively ( ; however, in another study on rainbow trout Similarly, propranolol impaired growth in juvenile rain- hepatocytes, basal EROD activity was shown to be inhibited bow trout at 10 mg L−1 after 10 days � β-ARs by these compounds (clofibrate and fenofibrate at EC of have been linked with a role in protein accretion ( 96 and 25 μM, respectively; ). Gemfibrozil , which helps regulate growth in fish, and this has been shown to inhibit the catalytic activity of CYP2M may provide a possible explanation for the effect seen on by 91% at an exposure level of 1 mM (and to a lesser extent CYP1A- and CYP3A-associated activities) in carp hepatocytes With reference to cardiovascular effects, propranolol has been shown predictably to affect the heart rate in zebrafish To our knowledge, the only published report on the acute (LOEC = 27 μM, 48 h; Fraysee et al�, 2006) as well as blood toxicity of fibrates to fish is that reported in G. Holbrooki flow through the gills, at a concentration of 10 mM ( exposed to clofibrate, where the LC was relatively high (between 7�7 and 39�7 mg L−1� Nevertheless, Additionally, showed that an gemfibrozil was reported to bioconcentrate in goldfish with exposure to 5 μM propranolol induced a 92% drop in glucose a bioconcentration factor of 113 after 14 days of exposure production in isolated liver of rainbow trout, which is most and, as such, fish may be chronically likely explained by the fact that during stress, fish respond by exposed to higher levels of these compounds than those that increasing glucose levels via an increase in hepatic β2-ARs are reported to be present in the environment� (Reid et al�, 1992)� β-ARs are also thought to be involved in oxygen chemore- Beta blockers (β-adrenergic receptor antagonists)
ception in the gills and accordingly, propranolol has been Collectively, beta blockers, such as atenolol, propranolol, shown to inhibit receptor discharge in the gills metoprolol, celiprolol, etc�, are one of the most commonly Effects of pharmaceuticals in fish 297 In addition, there are limited reports of effects of beta There is also some evidence to suggest that tetracyclines can blockers on reproductive and growth of fish� Egg production have a suppressive effect on the immune systems in fish, and hatching success were both reduced in medaka after 28 with effect concentrations overlapping with those some- days of exposure to propranolol at 5 μg L−1 times occurring in the environment (0�1–50 μg L−1 ; � Atenolol has been shown to affect growth in fathead minnow embryolarvae, after a 28-day exposure, but only at It is most likely that antibiotics may affect fish indirectly by the relatively high concentration of 10 mg L−1 ( modulating microbial function in aquatic ecosystem in turn affecting processes such as denitrification, nitrogen fixation, Propranolol has also been linked to a decreased pineal and organic breakdown , rather than function in trout ), which could having direct effects on fish physiological function per se� potentially impact on breeding cycles and activity rhythms� Many other pharmaceutical compounds outside of the main Antibiotics are a wide-ranging group of compounds of which classes outlined above are regularly detected in the aquatic there are several classes with different mechanisms of action� environment, but have received far less attention in terms The antibiotics include sulfonamides, penicillins, and tetracy- of their potential biological effects in aquatic organisms� clins, many examples of which have been detected in WWTW For example, chemotherapy drugs such as ifosamide have effluents and surface waters at ng L−1 to μg L−1 concentrations been detected in surface waters at ng L−1 levels, and in hos- pital waste waters at levels up to 4�5 μg L−1 berts and Thomas, Van der Heide and 2005; � The antiepileptic drug car- Hueck-van der Plas, 1984)� There are also reports of much bamazepine is also regularly detected at ng L−1 to μg L−1 con- higher concentrations at point discharge sources; for exam- centrations in WWTW effluent and surface water (Metcalfe ple, sulfonamide concentrations of 5 mg L−1 were detected et al�, 2003a; downstream of a landfill used for pharmaceutical produc- , seawater (Weigel et al�, 2002), tion waste disposal ) and oxytetracyclin and sediment (Thaker et al�, 2005); as are the anticonvulsant was found to be present at concentrations of up to 50 mg L−1 diazepam (van der Hoeven, 2004; in effluent from a production facility in China ( ; van der Ven et al�, 2004; and the antidiabetic metformin ()� Antibiotics are a commonly used and important group of pharmaceuticals in both human and veterinary medicine, Environmental concentrations versus
used to combat bacterial infection� Their modes of action biological effects in fish
vary according to type: penicillins impede synthesis of the bacterial cell wall; tetracyclines bind to ribosomes and impair Despite regular detection of many human and veterinary protein manufacture; and sulfonamides competitively inhibit compounds in the aquatic environment, there is still no evi- bacterial enzyme dihydropteroate synthase (DHPS)� Despite dence of any significant effects on aquatic wildlife species at the different modes of actions, however, the ultimate effect the population level� is the suppression of bacterial growth, and so they are used Various effects of pharmaceuticals have been docu- therapeutically to prevent and treat bacterial infections, as mented in fish, as described above, but these effects have well as growth promoters in farming and aquaculture� largely been confined to exposures in the laboratory, and The presence of antibiotics in the aquatic environment often at comparatively high concentrations, and few stud- has generally been investigated in terms of the develop- ies have been undertaken in the field� The most convincing ment of bacterial resistance (e�g� evidence for an association between exposure of fish to a and knock on effects regard- pharmaceutical and an adverse effect in fish is for EE2 and ing human health by the transfer of resistance to human sexual disruption� This judgement is based on combined pathogens rather than for any concern findings from extensive laboratory exposures and measured for possible toxicity to aquatic organisms� Unlike most phar- concentrations in the environment, all of which provide maceuticals, antibiotics are specifically aimed at bacterial highly persuasive data leading to the conclusion that EE2 targets avoiding possible toxicity to the infected human or contributes to the feminisation of wild roach populations liv- animal� Some classes of antibiotics are used to combat bacte- ing in the vicinity of WWTW effluent discharges in UK Rivers� rial infections in fish farms� Furthermore, both the incidence and severity of intersex in Despite the frequent occurrence of various antibiotics these feminised wild roach have been shown to be correlated in the aquatic environment, there is almost nothing in the with the predicted environmental concentration of natural literature reporting toxic effects of these drugs in fish� and synthetic oestrogens at those sampling sites ( Sulphonamides, however, are acutely toxic to fish (medaka; )� The intersex condition in the more severely Kim et al�, 2007), at high exposure concentrations (>100 mg affected fish has also been associated with reduced fertility L−1), but these are found rarely in the aquatic environment� 298 J. Corcoran et al. For all other pharmaceuticals, there is not substantive evi- ketoconazole has been shown to increase the sensitivity of dence for an adverse effect in exposed wild fish populations, rainbow trout to 17α-ethynyloestradiol exposure (Hasselberg but equally there has been little attempt to directly address et al�, 2008)� As such, where various pharmaceuticals and this question� The following section provides an overview of other contaminants occur together, there may be additional the likelihood that effects are possible in wild fish exposed to or additive effects, which could not be predicted by assess- (nonsteroidal oestrogen) pharmaceuticals� ments looking at only the concentration effects of a single shows a comparison between measured or pre- pharmaceutical� In fact, toxicity testing using combinations dicted environmental concentration and effect level con- of pharmaceuticals at low concentrations has shown that centration and in general; for most pharmaceuticals, the impacts occurred at concentrations where single compounds levels detected in the environment are at least an order of showed little or no effects e�g�, magnitude lower than those levels shown to cause any effect� diclofenac and ibuprofen have been shown to have an addi- There are however, a few exceptions, including diclofenac and tive toxic effect in daphnia ()� ibuprofen, which have been detected in WWTW effluent and As a final note, Johnston et al� (2007) used diclofenac and surface waters at concentrations in the low μg L−1 range, which propranolol in the River Tamar catchment area, UK, as a case is a concentration range that has been demonstrated to cause study to demonstrate that it may be possible to predict accu- toxic effects to fish in the laboratory rate levels of pharmaceutical exposure to aquatic life, by tak- ing into account factors such as flow rate and physiochemical Fluoxetine levels are detected in WWTW effluent, although properties of the drugs� Modelling approaches such as this, not surface waters, at concentrations shown to cause devel- combined effectively with empirical measurements, offer opmental abnormalities, and to increase circulating estradiol an attractive approach for advancing our knowledge on the concentrations in medaka )� Tetracycline likely availability and thus potential for biological effects of is also present in the environment at concentrations, which pharmaceuticals in the aquatic environment� may have some effect on immune suppression )� Declaration of interest
We need to consider also that most effect concentra- tions for pharmaceuticals in fish are reported for relatively This review was performed during the normal course of the short-term exposures (e�g�, days and weeks at most in the authors' affiliation or employment as shown on the first page� majority of cases) and the fact is that fish may be chronically JC was funded on a Biotechnology and Biological Sciences exposed to many pharmaceuticals due to continual input into Research Council Case studentship supported by AstraZeneca the aquatic environment and over time (e�g�, for months or UK Ltd� (grant reference BB/G529332/)� AstraZeneca Ltd� even possibly years), and so sufficient concentrations could develops, produces, and markets a wide range of pharma- accumulate in their bodies to cause an effect� This serves to ceutical agents� The authors have sole responsibility for the illustrate the need for more long-term chronic studies on writing and content of the manuscript� pharmaceuticals in fish to develop a greater confidence for the absence of harmful health effects� Care should also be applied in the extent to which effects of pharmaceuticals demonstrated in the laboratory in one Alanärä A, Winberg S, Brännäs E, Kiessling A, Höglund E, Elofsson U (1998). fish species can be extrapolated to another, as this is far from Feeding behaviour, brain serotonergic activity levels, and energy reserves of Arctic char (Salvelinus alpinus) within a dominance hierarchy. Can J clear� Although there is a high level of evolutionary conser- Zool 76:212–220.
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Journal of the American College of Cardiology Vol. 37, No. 7, 2001 © 2001 by the American College of Cardiology ISSN 0735-1097/01/$20.00 Published by Elsevier Science Inc. The Effect of Correction of Mild Anemiain Severe, Resistant Congestive Heart FailureUsing Subcutaneous Erythropoietin andIntravenous Iron: A Randomized Controlled StudyDonald S. Silverberg, MD, Dov Wexler, MD, David Sheps, MD, Miriam Blum, MD, Gad Keren, MD,Ron Baruch, MD, Doron Schwartz, MD, Tatyana Yachnin, MD, Shoshana Steinbruch, RN,Itzhak Shapira, MD, Shlomo Laniado, MD, Adrian Iaina, MDTel Aviv, Israel

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Author's personal copy Psychiatry Research 189 (2011) 62–66 Contents lists available at ScienceDirect Psychiatry Research Schizophrenia patients with predominantly positive symptoms have more disturbed sleep–wake cycles measured by actigraphy Pedro Afonso a,⁎, Sofia Brissos a, Maria Luísa Figueira b, Teresa Paiva ba Lisbon's Psychiatric Hospitalar Center (CHPL), Lisbon, Portugalb Hospital Santa Maria, Faculty of Medicine, University of Lisbon, (FMUL), Lisbon, Portugal