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.
vation in some drug targets, sensitivity between fish species Andersen Ø, Eijsink VGH, Thomassen M (2000). Multiple variants of the peroxi- to some pharmaceuticals may differ (as it does with many some proliferator-activated receptor (PPAR) γ are expressed in the liver of Atlantic salmon (Salmo salar). Gene 255:411–418 other environmental contaminants)� This has been shown, Andersson T, Förlin L (1992). Regulation of the cytochrome P450 enzyme system albeit in vitro, in the responses of a PLHC-1 cell line, derived in fish. Aquat Toxicol 24:1–19 from fathead minnow, compared to RTG-2 cell lines, from Andreozzi R, Raffaele M, Paxéus N (2003). Pharmaceuticals in STP effluents and their solar photodegradation in aquatic environment. Chemosphere rainbow trout, where the latter was far less responsive to a range of different pharmaceuticals )� Ankley G, Brooks B, Huggett D, Sumpter J (2007). Repeating history: The ecological niche of a fish species will also put some fish Pharmaceuticals in the environment. Environ Sci Technol 41:8211–8217 Ankley GT, Daston GP, Degitz SJ, Denslow ND, Hoke RA, Kennedy SW, species at greater exposure risk compared with others� For Miracle AL, Perkins EJ, Snape J, Tillitt DE, Tyler CR, Versteeg D (2006). example, benthic species are more likely to be exposed to Toxicogenomics in regulatory ecotoxicology. Environ Sci Technol pharmaceuticals bound to sediment than pelagic species� Ankley GT, Kahl MD, Jensen KM, Hornung MW, Korte JJ, Makynen EA, Leino Adding to the possible environmental concern, some phar- RL (2002). Evaluation of the aromatase inhibitor fadrozole in a repro- maceuticals could have interactive (mixture) effects, espe- duction assay with fathead minnow (Pimephales promelas). Toxicol Sci cially if sharing a common mode of action (as for some of the Arcand-Hoy LD, Nimrod AC, Benson WH (1998). Endocrine modulating sub- azoles)� Additive effects of chemicals (including for pharma- stances in the environment—Estrogenic effects of pharmaceutical prod- ceutical oestrogens) have been shown in fish ( ucts. Int. J. Toxicol 17:139−158.
and some pharmaceuticals have Ashton D, Hilton M, Thomas KV (2004). Investigating the environmental trans- port of human pharmaceuticals to streams in the United Kingdom. Sci been shown to modify the toxicity of others� As an example, Total Environ 333:167–184 Effects of pharmaceuticals in fish 299 Atsuko S, Sanae F, Shigeki M (2004). Occurrence of pharmaceuticals used in Choe KP, Havird J, Rose R, Hyndman K, Piermarini P, Evans DH (2006). COX2 human and veterinary medicine in aquatic environments in Japan. J Jap in a euryhaline teleost, Fundulus heteroclitus: Primary sequence, distribu- Soc wat environ 27:685–691 tion, localization and potential function in gills during salinity acclima- Auriol M, Filali-Meknassi Y, Tyagi RD, Adams CD, Surampalli RY (2006). tion. J Exp Biol 209:1696–1708 Endocrine disrupting compounds removal from wastewater, a new chal- Choi K, Kim Y, Park J, Park C.K, Kim M, Kim HS, Kim P (2008). Seasonal lenge. Process Biochem 41:525–539 variations of several pharmaceutical residues in surface water and Barber LB, Murphy SF, Verplanck PL, Sandstrom MW, Taylor HE, Furlong ET sewage treatment plants of Hans River Korea. Sci Total Environ (2006). Chemical loading into surface water along a hydrological, biogeo- chemical, and land use gradient: A holistic watershed approach. Environ Clara M, Strenn B, Kreuzinger N (2004). Carbamazepine as a possible anthro- Sci Technol 40:475–486 pogenic marker in the aquatic environment: Investigations on the behav- Bartelt-Hunt SL, Snow DD, Damon T, Shockley J, Hoagland K (2009). The occur- iour of carbamazepine in wastewater treatment and during groundwater rence of illicit and therapeutic pharmaceuticals in waste water effluent infiltration. Water Res 38:947–954 and surface waters in Nebraska. Environ Pollut 157:786–791 Cleuvers M (2003). Aquatic ecotoxicity of pharmaceuticals including the assess- Belfroid AC, Van der Horst A, Vethaack AD, Schäfer AJ, Rijs GB, Wegener J, ment of combination effects. Toxicol. Lett 142:185–194 Cofino WP (1999). Analysis and occurrence of estrogenic hormones and Cleuvers M (2004). Mixture toxicity of the anti-inflammatory drugs diclofenac their glucuronides in surface water and waste water in the Netherlands. ibuprofen naproxen and acetylsalicyclic acid. Ecotoxicol Environ Saf Sci Total Env 225:101–108 Blain H, Boileau C, Lapicque F, Nédélec E Loeuille D, Guillame C, Gaucher Colucci M.S, Topp E (2001). Persistence of estrogenic hormones in agricultural A, Jeandel C, Netter P, Jouzeau JY (2002). Limitation of the in vitro whole soils: II. 17α-Ethinylestradiol. J Environ Qual 30:2077–2080 blood assay for predicting the COX selectivity of NSAIDs in clinical use. Constanzo SD, Murby J, Bates J (2004). Ecosystem response to antibiotics enter- Br J Clin Pharmacol 53:255–265 ing the aquatic environment. Mar Pollut Bull 51:218–223 Bound JP, Voulvoulis N (2005). Household disposal of pharmaceuticals as a Crocket EL, Sidell BD (1993). Peroxisomal β-oxidation is a significant path- pathway for aquatic contamination in the United Kingdom. Environ way for catabolism of fatty acids in a marine teleost. Am J Physiol Health Perspect 113:1705–1711.
Brinton RD, Thompson RF, Foy MR, Baudry M, WangJ, Finch CE, Morgan TE, Daughton C.G, Ternes T (1999). Special report: Pharmaceuticals and personal Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J (2008). Progesterone receptors: care products in the environment: Agent of subtle change? Environ Health Form and function in the brain. Front Neuro-endocrinol 29:313–339 Perspect 33:2529–2535 Brooks BW, Chambliss CK, Stanley JK, Ramirez A, Banks KE, Johnson RD, Lewis David A, Pancharatra K (2009). Developmental anomalies induced by a non- RJ (2005). Determination of select antidepressants in fish from an effluent- selective COX inhibitor (ibuprofen) in zebrafish (Danio rerio). Environ dominated stream. Environ Toxicol Chem 24:464–469 Toxicol Pharmacol 27:390–395 Brooks BW, Foran CM, Richards SM, Weston J, Turner PK, Stanley JK, Solomon De Lucchini S, Marracci S, Nardi I (2001). The serotonin 5-HT2B receptor from KR, Slattery M, La Point TW (2003). Aquatic ecotoxicology of fluoxetine. the puffer fish Tetraodon fluviatilis: cDNA cloning, genomic organization Toxicol Lett 142:169–183 and alternatively spliced variants. Mol Brain Res 97:89–93 Brown KD, Kulis J, Thomson B, Chapman TB, Mawhinney DB (2006). Occurrence Desvergne B, Wahli W (1999). Peroxisome proliferator-activated receptors: of antibiotics in hospital, residential and dairy effluent, municipal waste- Nuclear control of metabolism. Endocr Rev 20(Suppl):649–688 water, and the Rio Grande in New Mexico. Sci Total Environ 366:772–783 Dietrich DR, Prietz A (1999). Fish embryotoxicity and teratogenicity of pharma- Burleson ML, Milsom WK (1990). Propranolol inhibits O -sensitive chemore- ceuticals detergents and pesticides regularly detected in sewage treatment ceptor activity in trout gills. Am J Physiol R258:1089–1091 plant effluents and surface waters. Toxicologist 48(1–s):151.
Buser HR, Poiger T, Müller MD (1998). Occurrence and fate of the pharmaceuti- Domagalski J, Belitz K, Furlong ET (2007). Occurrence of pharmaceuti- cal drug diclofenac in surface waters: Rapid photodegradation in a lake. cal and other organic compounds in groundwater in ten regions of Environ Sci Technol 32:3449–3456 California, USA. Presented at the American Geophysical Union Spring Buser HR, Poiger T, Müller MD (1999). Occurrence and environmental behav- meeting.22-25 May 2007, Acapulco, Mexico iour of the chiral pharmaceutical drug ibuprofen in surface waters and in EMEA (2006). Committee for Medicinal Products for Human Use (CHMP). wastewater. Environ Sci Technol 33:2529–2535 Guideline on the Environmental Risk Assessment of Medicinal Products for Caamaño-Tubío RI, Pérez J, Ferreiro S, Aldegunde M (2007). Peripheral sero- tonin dynamics in the rainbow trout (Oncorhynchus mykiss). Comp Biochem Physiol C 145:245–255 Erickson RJ, Nichols JW, Cook PM, Ankley GT (2008). Bioavailability of chemical Calamari D (2003). Assessment of persistent and bioaccumulating chemicals contaminants in aquatic systems. In: Di Giulio RT, Hinton DE, eds. The in the aquatic environment. Toxicology 181–182:163–186.
toxicology of Fishes New York: CRC Press, 9–54.
Caminada D, Escher C, Fent K (2006). Cytotoxicity of pharmaceuticals found in Farre M, Ferrer I, Ginebreda A, Figueras M, Olivella L, Tirapu L, Vilanova M, aquatic systems: comparison of PLHC-1 and RTG-2 fish cell lines. Aquat Barcelo D (2001). Determination of drugs in surface water and wastewa- Toxicol 79:114–123 ter samples by liquid chromatography-mass spectrometry: Methods and Cancilla D.A, Martinez J, van Aggelen GC (1998). Detection of aircraft deicing/ preliminary results including toxicity studies with Vibrio fischeri. J chro- antiicing fluid additives in a perched water monitoring well at an inter- matogr A 938:187–197 national airport. Environ Saf Technol 32:3834–3835 Fent K, Weston AA, Caminada D (2006). Ecotoxicology of human pharmaceu- Carlsson G, Örn S, Larsson DGJ (2009) Effluent from bulk drug production is toxic to ticals. Aquat Toxicol 76:122–159 aquatic vertebrates. Environ Toxicol Chem In press. DOI: 10.1897/08-524.1.
Ferrari B, Mons R, Vollat B, Fraysee B, Paxeus N, Lo Giudice R, Pollio A, Garric Castiglioni S, Fanelli R, Calamari D, Bagnati R, Zuccato E (2004). Methodological J (2004). Environmental risk assessment of six human pharmaceuticals: approaches for studying pharmaceuticals in the environment by compar- Are the current environmental risk assessment procedures sufficient ing predicted and measured concentrations in river Po, Italy. Reg Toxicol for the protection of the aquatic environment? Environ Toxicol Chem Pharmacol 39:25–32 Castillo M, Martinez E, Ginebreda A, Tirapu L, Barcelo D (2000). Determination Filby AL, Thorpe KL, Maack G, Tyler CR (2007). Gene expression profiles reveal- of non-ionic surfactants and polar degradation products in influent and ing the mechanisms of anti-androgen- and estrogen-induced feminisa- effluent water samples and sludges of sewage treatment plants by a generic tion in fish. Aquat Toxicol 81:219–223 solid-phase extraction protocol. The Analyst 125:1733–1739 Flippin JL, Huggett D, Foran CM (2007). Changes in the timing of reproduction Chee-Sandford JC, Aminov RI, Krapac IJ, Garrigues-Jeanjean N, Mackie RI following chronic exposure to ibuprofen in japanese medaka (Oryzias lat- (2001). Occurrence and diversity of tetracycline resistance genes in ipes). Aquat Toxicol 81:73–83 lagoons and groundwater underlying two swine production facilities. Flores A, Hill E.M (2008). Formation of estrogenic brominated ethinylestradiol Appl Environ Microbiol 67:1494–1502 in drinking water: Implications for aquatic toxicity testing. Chemosphere Cherkaoui-Malki M, Meyer K, Cao WQ, Latruffe N, Yeldandi AV, Rao MS, Bradfield CA, Reddy J.K (2001). Identification of novel peroxisome prolif- Foran CM, Weston J, Slattery M, Brooks BW, Huggett DB (2004). Reproductive erator-activated receptor α (PPARα) target genes in the mouse liver using assessment of Japanese medaka (Oryzias latipes) following a four week cDNA microarray analysis. Gene Expr 9:291–304 fluoxetine (SSRI) exposure. Arch Env Contam Toxicol 46:511–517 Chikae M, Ikeda R, Hasan Q, Morita Y, Tamiya E (2003). Effects of alkylphenols Fraysse B, Mons R, Garric J (2006). Development of a zebrafish 4-day embryo- on adult male medaka: Plasma vitellogenin goes up to the level of estrous larval bioassay to assess toxicity of chemicals. Ecotoxicol Environ Saf female. Environ Toxicol Pharmacol 15:33–36 300 J. Corcoran et al. Furlong ET, Kinney CA, Burkhardt MR, Zaugg SD, Werner SL (2003). Organic Herberer T (2002). Occurrence, fate, and removal of pharmaceutical residues wastewater contaminants in biosolids and biosolid-derived products. In: in the aquatic environment: A review of recent research data. Toxicol Lett Abstracts with Programs. Vol. 35. Wsshington, DC: Geological Society of America, 149.
Herberer T, Stan HJ (1997). Determination of clofibric acid and Gamperl, AK, Wilkinson M, Boutilier R.G (1994). β-Adrenoceptors in trout N-(phenylsulfonyl)-sarcosine in sewage, river and drinking water. Intl J (Oncorhynchus mykiss) heart: Characterization, quantification and effects Environ Anal Chem 67:113–124 of repeated catecholamine exposure. Gen Comp Endocrinol 95:227–259 Hernandez-Rauda R, Rozas G, Rey P, Otero J, Aldegunde M (1999). Changes in Garrison A, Pope J, Allen F (1976). GC/MS analysis of organic compounds in the pituitary metabolism of monoamines (dopamine, norepinephrine, domestic waste waters. In: Keith C, ed. Identification and Analysis of and serotonin) in female and male rainbow trout (Oncorhyncus mykiss) Organic Pollutants in Water. Ann Arbor, Michigan: Ann Arbor, Michigan during gonadal recrudsecence. Physiol Biochem Zool 72:352–359 Science, 517–566.
Hiemke C, Härtter S (2000). Pharmacokinetics of selective serotonin re-uptake Gaworecki KM, Klaine SJ (2008).Behavioural and biochemical responses of inhibitors. Pharmacol Therapeut 85:11–28 hybrid striped bass during and after fluoxetine exposure. Aquat Toxicol Hinfray N, Porcher JM, Brion F (2004). Inhibition of rainbow trout (Oncorhynchus mykiss) P450 aromatase activities in brain and ovarian Gervois P, Torra IP, Fruchart J-C, Staels B (2000). Regulation of lipids and lipo- microsomes by various environmental substances. Comp Biochem protein metabolism by PPAR activators. Clin Chem Lab Med 38:3–11 Physiol C 144:252–262 Gibson R, Smith MD, Spary CJ, Tyler CR, Hill EM (2005). Mixtures of estrogenic Hinkle SR, Weick RJ, Johnson JM, Cahill JD, Smith SG, Rich BJ (2005). Organic contaminants in bile of fish exposed to wastewater treatment works efflu- wastewater compounds, pharmaceuticals, and coliphage in groundwa- ents. Environ Sci Technol 39:246–271 ter receiving discharge from onsite wastewater treatment systems near Giger W, Schaffner C, Kohler HE (2006). Benzotriazole and tolyltriazole as La Pine, Oregon: Occurrence and implications for transport. Scientific aquatic contaminants. 1. Input and occurrence in rivers and lakes. Environ Investigations Report 5055. U.S. Geological Survey Scientific Investigations Sci Technol 40:7186–7192 Report 5055.
Gimeno S, Gerritsen A, Bowmer T, Komen H (1996). Feminization of male carp. Hirsch R, Ternes T, Haberer K, Kratz K-L (1999). Occurrence of antibiotics in Nature 384:221–222 the aquatic environment. Sci Total Environ 225: 109–118 Goetz FW, Theofan G (1979). In vitro stimulation of germinal vesicle break- Hoeger BA, Köllner B, Dietrich DR, Hitzfeld B (2005). Water-borne diclofenac down and ovulation of yellow perch (Perca flavescens) ooytes: Effects of affects kidney and gill integrity and selected immune parameters in brown 17α-hydroxy-20β-dihydroprogesterone and prostaglandins. Gen Comp trout (Salmo trutta f. fario). Aquat Toxicol 75:53–64 Holford NHG (2001). Pharmacokinetics and pharmacodynamics: Rational dos- Golet E. M, Alder A. C, Hartmann A, Ternes T, Giger W (2001). Trace determina- ing and the time course of drug action. In: Katzung BG, ed. Basic and tion of fluoroquinolone antibacterial agents in urban wastewater by solid- Clinical Pharmacology New York: McGraw-Hill Professional, Chapter 3: phase extraction and liquid chromatography with fluorescence detection. Anal Chem 73:3632–638.
Holloway AC, Leatherland JF (1997). Effect of gonadal steroid hormones on Gonzalez FJ, Peters JM, Cattley RC (1998). Mechanism of action of the nong- plasma growth hormone concentrations in sexually immature rainbow enotoxic peroxisome proliferators; role of the peroxisome proliferator- trout (Oncorhynchus mykiss). Gen Comp Endocrinol 102:246–254 activated receptor α. J Natl Cancer Inst 90:1702–1709 Holm JV, Rügge K, Bjerg PL Christensen TH (1995). Occurrence and dis- Gravel A, Vijayan MM (2007). Salicylate impacts the physiological responses to tribution of pharmaceutical organic compounds in the groundwater an acute handing disturbance in rainbow trout. Aquat Toxicol 85:87–95 downgradient of a landfill (Grindsted, Denmark). Environ Sci Technol Gravel A, Wilson JM, Pedro DFN, Vijayan MM (2009). Non-steroidal anti- inflammatory drugs disturb the osmoregulatory, metabolic and cortisol Huggett DB, Brooks BW, Peterson B, Foran CW, Schlenk D (2002). Toxicity of responses associated with seawater exposure in rainbow trout. Comp select beta-adrenergic receptor blocking pharmaceuticals (β blockers) on Biochem Physiol C 149:481–490 aquatic organisms. Arch Environ Contam Toxicol 43:229–235 Grondel JL, Gloudemans AG, Van Muiswinkle WB (1985). The influence of anti- Huggett DB, Khan IA, Foran CM, Schlenk D (2003). Determination of beta- biotics on the immune system II. Modulation of fish leukocyte responses adrenergic receptor blocking pharmaceuticals in United States wastewater in culture. Vet immunol Immunopathol 9:251–260 effluent. Environ Pollut 121:199–205 Gross B, Montgomery-Brown J, Naumann A, Reinhard M (2004). Occurrence and Ibabe A, Grabenbauer M, Baumgart E, Fahimi DH, Cajaraville MP (2002). fate of pharmaceuticals and alkylphenol ethoxylate metabolites in an efflu- Expression of peroxisome proliferator-activated receptors in zebrafish ent-dominated river and wetland. Environ Toxicol Chem 23:2074–2083 (Danio rerio). Histochem Cell Biol 118:231–239 Guiguen Y, Baroiller J-F, Ricordel M-J, Iseki K, McMeel O.M, Martin SAM, Fostier Ikeuchi T, Todo T, Kobayashi T, Nagahama Y (2001). Two subtypes of andro- A (1999). Involvement of estrogens in the process of sex differentiation in gen and progestogen receptors in fish testes. Comp Biochem Physiol B two fish species: The rainbow trout (Oncorhynchus mykiss) and a tilapia (Oreochromis niloticus). Mol Reprod Dev 54:154–162 Ikeuchi T, Todo T, Kobayashi T, Nagahama Y (2002). A novel progestogen Gunnarsson L, Jauhiainen A, Kristiansson E, Nerman O, Larsson D.G (2008). receptor subtype in the Japanese eel Anguilla japonica. FEBS Lett Evolutionary conservation of human drug targets in organisms used for environmental risk assessments. Environ Sci Technol 42:5807–5813 IMS Health. Available at: Hamscher G, Sczesny S, Höper H, Nau H (2002). Determination of persistent tetracycline residues in soil fertilized with liquid manure by high-perform- Ingerslev F, Halling-Sørensen B (2001). Biodegradability of metronidazole ance liquid chromatography with electrospray ionization tandem mass olaquindox and tylosin and formation of tylosin degradation products in spectrometry. Anal Chem 74 1509–18.
aerobic soil-manure slurries. Ecotoxicol Environ Saf 48:311–320 Harris CA, Routledge EJ, Schaffner C, Brian JV, Giger W, Sumpter JP (2007). Ishikawa TO, Herschman HR, (2007). Two inducible, functional cyclooxyge- Benzotriazole is antiestrogenic in vitro but not in vivo. Environ Toxicol nase-2 genes are present in the rainbow trout genome. J Cell Biochem Chem 26:2367–2372 Hartig C, Storm T, Jekel M (1999): Detection and identification of sulphona- IwamatsuT, Toya Y, Sakai N, Yasutaka T, Nagata R, Nagahama Y (1993). Effect mide drugs in municipal wastewater by liquid chromatography coupled of 5-hydroxytryptamine on steroidogenesis and oocyte maturation in with electrospray ionisation tandem mass spectrometry. J Chromatogr pre-ovulatory follicles of the medaka Oryzias latipes. Dev Growth Differ Hasselberg L, Grøsvik B-E, Goksøyr A, Celander MC (2005). Interactions Jakoby WB, Ziegler DM (1990). The enzymes of detoxification. J Biol Chem between xenoestrogens and ketoconazole on hepatic CYP1A and CYP3A in juvenile Atlantic cod (Gadhus mortiua). Comp Hepatol 4(1):2.
Jobling S, Coey S, Whitmore JG, Kime DE, Van Look KJW, McAllister BG, Havird JC, Miyamoto MM, Choe KP, Evans DH (2008). Gene duplications and Beresford N, Henshaw AC, Brighty G, Tyler CR (2002). Wild intersex roach losses within the cyclooxygenase family of teleosts and other chordates. (Rutilus rutilus) have reduced fertility. Biol Reproduct 67:515–524 Mol Biol Evol 25:2349–2359 Jobling S, Nolan M, Tyler CR, Brighty G, Sumpter JP (1998). Widespread sexual Haywood GP, Isaia J, Maetz J (1977). Epinephrine effects on branchial water and disruption in wild fish. Environ Sci Technol 32:2498–2506 urea flux in rainbow trout. Am J Physiol 232:R110-R115 Jobling S, Tyler CR (2003). Endocrine disruption, parasites and pollutants in Hegelund T, Ottosson K, Rådinger M, Tomberg P, Celander M.C (2004). Effects wild fish. Parasitology. 126:S103–S108 of the antifungal imidazole ketoconazole on CYP1A and CYP3A in rainbow Jobling S, Williams R, Johnson A, Taylor A, Gross-Sorokin M, Nolan M, Tyler trout and killifish. Environ Toxicol Chem 23:1326–1334 CR, van Aerle R, Santos E, Brighty G (2006). Predicted exposures to steroid Effects of pharmaceuticals in fish 301 oestrogens in UK rivers correlate with widespread sexual disruption in Loos R, Gawlik BM, Locoro G, Rimaviciute E, Contini S, Bidoglio G (2009). wild fish populations. Environ Health Perspect 114(S1):32–39 EU-wide survey of polar organic persistent pollutants in European river Johnson AC, Belfroid A, Di Corcia A (2000). Estimating steroid oestrogen inputs waters. Environ Pollut 157:561–568 into activated sludge treatment works and observations on their removal Lortie MB, Moon TW (2003). The rainbow trout skeletal muscle β-adrenergic from the effluent. Sci Total Environ 256:163–173 system: characterization and signaling. Am J Physiol 284:R689–R697 Johnson AC, Keller V, Williams RJ, Young A (2007). A practical demonstration in Lovy J, Speare DJ, Wright GM (2007). Pathological effects caused by chronic modelling diclofenac and propranolol river water concentrations using a treatment of rainbow trout with indomethacin. J Aquat Anim Health GIS hydrology model in a rural UK catchment. Environ Pollut 146:155–165 Johnson AC, Williams RJ (2004). A model to estimate influent and effluent con- Ma X, Ortolano L (2000). Environmental Regulation in China: Institutions, centration of estradiol, estrone and ethinylestradiol at sewage treatment Enforcement and Compliance. Lanham: Rowman & Littlefield.
works. Environ Sci Technol 38:3649–3658 Martin C.H, Meissl H (1992). Effects of dopaminergic and noradrenergic mech- Jones OAH, Voulvoulis N, Lester JN (2001). Human pharmaceuticals in the anisms on the neuronal activity of the isolated pineal organ of the trout aquatic environment: A review. Environ Technol 22:1383–1395 (Oncorhynchus mykiss). J Neural Transm 88:37–51 Jones OAH, Voulvoulis N, Lester JN (2002). Aquatic environmental assess- McCormick S.D (2001). Endocrine control of osmoregulation in teleost fish. ment of the top 25 English prescription pharmaceuticals. Water Res Am Zool 41:781–794 McKinley SJ, Hazel JR (1993). Epinephrine stimulation of glucose release from Jürgens MD, Holthaus KIE, Johnson AC, Smith JJL, Hetheridge M, Williams perfused trout liver: Effects of assay and acclimation temperature. J Exp RJ (2002). The potential for estradiol and ethinylestradiol degradation in English rivers. Environ Toxicol Chem 21:480–488 Mehrle PM, Buckler DR, Little EE, Smith LM, Petty JD, Peterman PH, Stalling Khan A, Thomas P (1992). Stimulatory effects of serotonin on maturational DL, De Graeve GM, Coyle JJ, Adams WJ (1988). Toxicity and bioconcentra- gonadotropin release in the Atlantic croaker, Micropogonias undulates. tion of 2,3,7,8-tetrachlorodibenzodioxin and 2,3,7,8-tetrachlorodibenzo- Gen Comp Endocrinol 88:388–396 furan in rainbow trout. Environ Toxicol Chem 7:47–62 Khetan SK, Collins TJ (2007). Human pharmaceuticals in the aquatic environ- Mercure F, Van der Kraak G (1996). Mechanisms of action of free arachidonic ment: A challenge to green chemistry. Chem Rev 107:2319–2364 acid on ovarian steroid production in the goldfish. Gen Comp Endocrinol Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evans RE, Lazorchak JM, Flick RW (2007). Collapse of a fish population after exposure to a synthetic oestro- Metcalfe CD, Koenig BG, Bennie DT, Servos M, Ternes TA, Hirsch R (2003). gen. Natl Acad Sci 104:8897–8901 Occurrence of neutral and acidic drugs in the effluents of Canadian sew- Kim Y, Choi K, Jung J, Park S, Kim PG, Park J (2006). Aquatic toxicity of aceta- age treatment plants. Environ Toxicol Chem 22:2872–2880 minophen, carbamazepine, cimetidine, diltiazem, and six major sul- Miao X-S, Koening BG, Metcalfe C.D (2002). Analysis of acidic pharmaceutical fonamides and their potential ecological risks in Korea. Environ Int drugs in the aquatic environment using liquid chromatography-electro- spray tandem mass spectrometry. J Chromatogr 95A:139–147 Kolpin D, Furlong ET, Meyer MT, et al. (2002). Pharmaceuticals, hormones, Mimeault C, Woodhouse AJ, Miao X-S, Metcalfe CD, Moon TW, Trudeau VL and other organic wastewater contaminants in U.S. streams, 1999–2000: (2005). The human lipid regulator, gemfibrozil, bioconcentrates and A national reconnaissance. Environ Sci Technol 36:1202–1211.
reduces testosterone in the goldfish Carassius auratus. Aquat Toxicol Kuster M, López de Alda MJ, Hernando MD, Petrovic M, Martin-Alonso J, BarcelóD (2008). Analysis and occurrence of pharmaceuticals, estrogens, Minier C, Caltot G, Leboulanger F, Hill EM (2000). An investigation of the inci- progestogens and polar pesticides in sewage treatment plant effluents, dence of intersex fish in Seine—Maritime and Sussex regions. Analysis river water and drinking water in the Llobregat river basin (Barcelona, Spain). J Hydrol 358:112–123.
Mommsen TP, Vijayan MM, Moon TW (1999). Cortisol in teleosts: Dynamics Kwon JW, Armbrust KL (2003). Hydrolysis and photolysis of sertraline a selective mechanisms of action and metabolism regulation. Rev Fish Biol Fisheries serotonin reuptake inhibitor in aqueous solutions. In: Abstracts, SETAC 24th Annual Meeting, Austin, Texas, USA, November 9– 13, p. 204.
Monteiro PRR, Reis-Henriques MA, Coimbra J (2000). Polycyclic aromatic Lai KM, Johnson KL, Scrimshaw MD, Lester JN (2000). Binding of waterborne hydrocarbons inhibit in vitro ovarian steroidogenesis in the flounder steroid estrogens to solid phases in rivers and estuarine systems. Environ (Platichthyus flesus L.). Aquat Toxicol 48:549–559 Sci Technol 34:3890–3894 Moore A, Waring C (1996). Electrophysiological and endocrinological evidence Lange A, Paull GC, Coe TS, Katsu Y, Urushitani H, Iguchi T, Tyler CR (2009). that F-series prostaglandins function as priming pheromones in matrure Sexual reprogramming and estrogenic sensitisation in wild fish exposed male Atlantic salmon (Salmo salar) parr. J Exp Biol 199:2307–2316 to ethinylestradiol. Environ Sci Technol 43:1219–1225 Mori T, Matsumoto H, Yokota H (1998). Androgen-induced vitellogenin gene Langhammer JP, Führ F, Büning-Pfaue H (1990). Verbleib von sulfonamid- expression in primary cultures of rainbow trout hepatocytes. J Steroid rückständen aus der gülle, in boden und nutzpflanze. Lebensmittelchemie Biochem Mol Biol 67:133–141 Mustafa T, Srivastava K.C (1989). Prostaglandins (eicosanoids) and their role in Larsson DGJ (2008). Drug production facilities—an overlooked discharge ectothermic organisms. Adv Comp Env Physiol 5:157–207 source for pharmaceuticals to the environment. In: Kummerer K, ed. Nagahama Y (1994). Endocrine regulation of gametogenesis in fish. Int J BioI Pharmaceuticals in the Envrionment: Sources, Date, Effects and Risks Berlin: Springer, 37–42.
Nakata H, Kannan K, Jones PD, Giesy J.P (2005). Determination of fluo- Larsson D.G.J, Adolfsson-Erici M, Parkkonen J, Pettersson M, Berg A.H, Olsson roquinolone antibiotics in wastewater effluents by liquid chromatog- P-E, Förlin L (1999). Ethinyloestradiol—An undesired fish contraceptive? raphy-mass spectrometry and fluorescence detection. Chemosphere Aquat Toxicol 45:91–97 Larsson DGJ de Pedro C, Paxéus N (2007). Effluent from drug manufactures Nash JP, Kime DE, Van der Ven LTM, Wester PW, Brion WF, Maack G, contains extremely high levels of pharmaceuticals. J Hazard. Mater Stahlschmidt-Allner P, Tyler CR (2004). Long-term exposure to environ- mental concentrations of the pharmaceutical ethynylestradiol causes Laville N, Aït-Aïssa S, Gomez E, Casellas C, Porcher J.M (2004). Effects of human reproductive failure in fish. Environ Health Perspect 112:1725–1733 pharmaceuticals on cytotoxicity, EROD activity and ROS production in Nickerson JG, Dugan SG, Drouin G, Moon TW (2001). A putative beta2-adren- fish hepatocytes. Toxicology 196:41–55 oceptor from the rainbow trout. Eur J Biochem 268:6465–6472 Leaver MJ, Wright J, George SG (1998). A peroxisomal proliferator-activated Nickerson JG, Dugan SG, Drouin G, Penny SF, Moon TW (2003). Activity of receptor gene from the marine flatfish the plaice (Pleuronectes platessa). the unique β-adrenergic Na+/H+ exchanger in trout erythrocytes is Mar Environ Res 46:75–79 controlled by novel β 3-adrenergic receptor subtype. Am J Physiol. Lehmann M (2000). Arzneimittel und hormonell wirksame Stoffe in fließgewässern Baden-wüttembergs. In: 25 Jahre LFU.jahresbericht Nunes B, Carvalho F, Guilhermino L (2004). Acute and chronic effects of clofi- 1998/99. Baden-wüttemberg: LFU.
brate and clofibric acid on the enzymes acetylcholinesterase, lactate Lindqvist N, Tuhkanen T, Kronberg, L (2005). Occurrence of acidic pharma- dehydrogenase and catalase of the mosquitofish Gambusia holbrooki. ceuticals in raw and treated sewages and in receiving waters. Water Res Oaks JL, Gilbert M, Virami MZ, Watson RT, Meteyer CU, Rideout BA, Lister A, Van der Kraak G (2008). An investigation into the role of prostaglandins Shivaprasad HL, Ahmed S, Chaudhry MJI, Arshad M, Mahmood S, Ali A, in zebrafish oocyte maturation and ovulation. Gen Compara Endocrinol Khan AA (2004). Diclofenac residues as the cause of vulture population decline in Pakistan. Nature 427:630–633 302 J. Corcoran et al. O'Brien ML, Twaroski TP, Cunningham ML, Glauert HP, Spear B (2001). Effects structural, pharmacological and functional properties among the three of peroxisome proliferators on antioxidant enzymes and antioxidant vita- human and five zebrafish α -adrenoceptors. Br J Pharmacol 144:165–177 mins in rats and hamsters. Toxicol Sci 60:271–278 Ruyter B, Andersen O, Dehli A, Östlund Farrants A-K, Gjøen T, Thomassen MS Örn S, Holbech H, Madsen TH, Norrgren L, Petersen GI (2003). Gonad develop- (1997). Peroxisome proliferator activated receptors in Atlantic salmon ment and vitellogenin production in zebrafish (Danio rerio) exposed to (Salmo salar): Effects on PPAR transcription and acyl-coA oxidase activ- ethinylestradiol and methyltestosterone. Aquat Toxicol 65(4):397–411 ity in hepatocytes by peroxisome proliferators and fatty acids. Biochim Örn S, Yamani S, Norrgren L (2006). Comparison of vitellogenin induction sex Biophys Acta Lip Lip Metab 1348: 331–338 ratio and gonad morphology between zebrafish and Japanese medaka Sacher F, Lange FT, Brauch H-J, Blankenhorn I (2001). Occurrence of antibiotics after exposure to 17α-ethinylestradiol and 17β-trenbolone. Arch Environ in groundwater in Baden-Württemberg, Germany—Results of a compre- Contam Toxicol 51:237–243 hensive monitoring program. In: Abstracts of the 11th Annual Meeting Overli O, Winberg S, Damsgård B, Jobling M (1998). Food intake and spontane- of SETAC Europe (Society of Environmental Toxicology and Chemistry), ous swimming activity in Arctic char (Salvelinus alpinus): Role of brain Madrid, Spain, 2001. Abstract M/EH056, p. 112. SETAC Europe, Brussels, serotonergic activity and social interactions. Can J Zool. 76:1366:1370 Owen SF, Giltrow E, Huggett DB, Hutchinson TH, Saye J, Winter MJ, Sumpter Sacher F, Lochow E, Bethmann D, Brauch H-J (1998). Occurrence of drugs in J.P (2007). Comparative physiology, pharmacology and toxicology of surface waters. Vom Wasser 90:233–243 β-blockers: Mammals versus fish. Aquat Toxicol 82:145–162 Santos EM, Paull GC, Van Look KJW, Workman VL, Holt WV, van Aerle R, Kille P, Panter GH, Hutchinson TH, Hurd KS, Sherren A, Stanley RD, Tyler CR (2004). Tyler CR (2007). Gonadal transcriptome responses and physiological con- Successful detection of (anti-)androgenic and aromatase inhibitors in sequences of exposure to oestrogen in breeding zebrafish (Danio rerio). pre-spawning adult fathead minnows (Pimephales promelas) using easily Aquat Toxicol 83:134–142 measured end points of sexual development. Aquat Toxicol 70:11–21 Scarano LJ, Calabrese EJ, Kostecki PT, Baldwin LA, Leonard DA (1994). Parkinson A (1996). Biotransformation of xenobiotics. In: Casarett LJ, Klaassen Evaluation of a rodent peroxisome proliferator in two species of freshwater CP, Doull J, eds. Casarett and Doull's Toxicology New York: McGraw-Hill.
fish: Rainbow trout (Oncorhynchus mykiss) and Japanese medaka (Oryzias Payan P, Girard J-P (1977). Adrenergic receptors regulating patterns of blood flow latipes). Ecotoxicol Environ Saf 29:13–19 through the gills of trout. Am J Physiol Heart Circ Physiol 232:H18–H23 Scholz S, Kordes C, Hamann J, Gutzeit HO (2004). Induction of vitellogenin Perreault HAN, Semsar K, Godwin J (2003). Fluoxetine treatment decreases in vivo and in vitro in the model telesot medaka (Oryzias latipes): territorial aggression in a coral reef fish. Physiol Behav 79:719–724 Comparison of gene expression and protein levels. Marine Environ Res Pinter J, Thomas P (1995). Characterization of a progestogen receptor in the ovary of the spottted sea trout (Cynoscian nebulosus). Biol Reprod Schwaiger J, Ferling H, Mallow U, Wintermayr H, Negele RD (2004). Toxic effects of the non-steroidal anti-inflammatory drug diclofenac: Part I. Priyadarshini K, Gupta OK (2003). Compliance to environmental regulations: Histopathological alterations and bioaccumulation in rainbow trout. The indian context. Int J Bus Econ 2:9–26 Aquat Toxicol 68:141–150 Qiting J, Xiheng Z (1988) Combination process of anaerobic digestion and ozo- Seki M, Yokota H, Matsubara H, Tsuruda Y, MaedaM, Tadokoro H, Kobayashi nization technology for treating wastewater from antibiotics production. K (2002). Effect of ethinylestradiol on the reproduction and induction of Wat Treat 3:285–291 vitellogenin and testis-ova in medaka (Oryzias latipes). Environ Toxicol Radford MG Jr, Holley KE, Grande JP, Larson TS, Wagoner RD, Donadio JV, Chem 21:1692–1698 McCarthy JT (1996). Reversible membranous nephropathy associated with Semsar K, Perreault HAN, Godwin J (2004). Fluoxetine-treated male wrasses the use of nonsteroidal anti-inflammatory drugs. JAMA 276:466–469 exhibit low AVT expression. Brain Res 1029:141–147 Reddy JK, Hashimoto T (2001). Peroxisomal β-oxidation and peroxisome pro- Senthilkumaran B, Yoshiura Y, Oba Y, Sudhakumari CC, Wang DS, Kobayashi liferator-activated receptor α: An adaptive metabolic system. Annu Rev T, Yoshikuni M, Nagahama Y (2001). Steroidogenic shift is a critical event Nutri 21:193–230 for ovarian follicles to undergo final maturation. Fish Physiol Biochem Reemtsma T, Weiss S, Mueller J, Petrovic M, González Blanco S, BarcelóD, Ventura F, Knepper TP (2006). Polar pollutants entry into the water cycle Shved N, Berishvili G, Baroiller JF, Segner H, Reinecke M (2008). Environmentally by municipal wastewater: A European perspective. Environ Sci Technol relevant concentrations of 17α-ethinylestradiol interfere with the growth hormone (GH)/insulin-like growth factor (IGF)-I system in developing Reid SD, Moon TW, Perry SF (1991). Characterization of β-adrenoreceptors bony fish. Toxicol Sci 106:93–102 of rainbow trout (Oncorhynchus mykiss) erythrocytes. J Exp Biol ŠirokáZ, DrastichováJ (2004). Biochemical markers of aquatic environment contamination—Cytochrome P450 in fish. A review. Acta Vet Brno Richardson ML, Bowron JM (1985). The fate of pharmaceutical chemicals in the aquatic environment. J Pharm Pharmacol 37:1–12 Somoza GM, Peter RE (1991). Effects of serotonin on gonadotropin and growth Rijkers GT, van Oosterom RV, Van Muiswinkle WB (1981). The immune system hormone release from in vitro perfused goldfish pituitary fragments. Gen of cyprinid fish: Oxytetracycline and the regulation of humoral immunity Comp Endocrinol 82:103–110 in carp (Cyprinus carpio). Vet Immunol Immunopathol 2:281–290 Somoza GM, Yu KL, Peter RE (1988). Serotonin stimulates gonadotropin release Roberts PH, Bersuder P (2006). Analysis of OSPAR priority pharmaceuticals in female and male goldfish, Carassius auratus L. Gen Comp Endocrinol using high-performance liquid chromatography-electrospray ionisation tandem mass spectrometry. J Chromatog A 1134:143–150 Sorbera LA, Asturiano JF, Carrillo M, Zanuy S (2001). Effects of polyunsatu- Roberts PH, Thomas KV (2006). The occurrence of selected pharmaceuticals in rated fatty acids and prostaglandins on oocyte maturation in a marine wastewater effluent and surface waters of the lower Tyne catchment. Sci teleost, the European sea bass (Dicentrarchus labrax). Biol Reprod Total Environ 356:143–153 Roberts SB, Langenau DM, Goetz FW (2000). Cloning and characterisation of Sorensen PW, Goetz FW (1993). Pheromonal and reproductive function of prostaglandin endoperoxide synthase-1 and -2 from the brook trout ovary. F prostaglandins and their metabolites in teleost fish. J Lipid Mediat Mol Cell Endocrinol 160:89–97 Rogers IH, Birtwell IK, Kruznyski GM (1986). Organic extractables in munici- Sorensen PW, Hara T.J, Stacey NE, Goetz F. (1988). F prostaglandins function pal wastewater, Vancouver, British Columbia. Wat Pollut Res J Can as potent olfactory stimulants that comprise the postovulatory female sex pheromone in goldfish. Biol Reprod 39:1039–1050 Rose J, Holbech H, Lindholst C, Norum U, Povlsen A, Korsgaard B, Stacey WE, Goetz FW (1982). Role of prostaglandins in fish reproduction. Can Bjerregaard P (2002). Vitellogenin induction by 17β -estradiol and 17α- J Fish Aquat Sci 39:92–98 ethinylestradiol in male zebrafish (Danio rerio). Comp Biochem Physiol Stanley JK, Ramirez AJ, Chambliss CK, Brooks BW (2007). Enantiospecific suble- thal effects of the antidepressant fluoxetine to a model aquatic vertebrate Ruhoy IS, Daughton CG (2007). Types and quantities of leftover drugs entering and invertebrate. Chemosphere 69:9–16 the environment via disposal to sewage—Revealed by coroner records. Steger-Hartmann T, Kümmerer K, Hartmann A (1997). Biological degradation Sci Total Environ 388:137–148 of cyclophosphamide and first occurrence in sewage water. Ecotoxicol Runnalls TJ, Hala DN, Sumpter JP (2007). Preliminary studies into the effects of Environ Saf 36:174–179 the human pharmaceutical clofibric acid on sperm parameters in adult Stensløkken KO, Sundin L, Nilsson GE (2002). Cardiovascular effects of pros- fathead minnow. Aquat Toxicol 84:111–118 taglandin F2a and prostaglandin E2 in Atlantic cod (Gadus morhua). J Ruuskanen JO, Laurila J, Xhaard H, Rantanen VV, Vuoriluoto K, Wurster S, Comp Physiol B 172:363–369 Marjamäki A, Vainio M, Johnson MS, Scheinin M (2005). Conserved Stevenson JC (1997). Gonadal hormones. Oesteopor Int 7(Suppl 1):58–60 Effects of pharmaceuticals in fish 303 Strom S (2005). Old pills finding new medicine cabinets. The New York Times Velicu M, Suri R (2008). Presence of steroid hormones and antibiotics in surface Technology News 18 May 2005.
waters of agricultural suburban and mixed use areas. Environ Monitor Stumpf M, Ternes TA, Haberer K, Seel P, Baumann W (1996). Determination Assess 154(1–4):349–59 (Epub 2008 Jun 21).
of drugs in sewage treatment plants and river water. Vom Wasser ViganòL, Arillo A, Bottero S, Massari A, Mandich A (2001). First observation of intersex cyprinids in the Po River (Italy). Sci Total Environ 269:189–194 Stumpf M, Ternes TA, Wilken R-D, Rodrigues SV, Baumann W (1999). Polar Villeneuve DL, Ankley GT, Makynen EA, Blake LS, Greene KJ, Higley EB, drug residues in sewage and natural waters in the state of Rio de Janeiro Newsted JL, Giesy JP, Hecker M (2007). Comparison of fathead minnow in Brazil. Sci Total Environ 225:135–141 ovary explant and H295R cell-based steroidogenesis assays for identifying Ternes T (1998). Occurrence of drugs in German sewage treatment plants and endocrine-active chemicals. Ecotoxicol Environ Saf 68:20–32 rivers. Water Res 32:3245–3260 Voutsa D, Hartmann P, Schaffner C, Giger W (2006). Benzotriazoles alkylphenols Ternes TA, Herrmann N, Bonerz M, Knacker T, Seigrist H, Joss A (2004). A and bisphenol A in municipal wastewaters in the Glatt river, Switzerland. rapid method to measure the solid-water distribution coefficient (K ) Environ Sci Pollut Res 13:333–334 for pharmaceuticals and musk fragrances in sewage sludge. Water Res Vulliet E, Baugros J-B, Flament-Waton M-M, Grenier-Loustalot M-F (2007). Analytical methods for the determination of selected steroid sex hormones Ternes TA, Kreckel P, Mueller J (1999a). Behaviour and occurrence of estrogens and corticosteriods in wastewater. Anal Bioanal Chem 387:2143–2151 in municipal sewage treatment plants—II. Aerobic batch experiments Walker MK, Peterson RE (1991). Potencies of polychlorinated dibenzo-p-dioxin with activated sludge. Sci Total Environ 225:91–99 dibenzofuran and biphenyl congeners relative to 2,3,7,8-tetrachlorod- Ternes TA, Meisenheimer M, McDowell D, Sacher F, Brauch HJ, Haist- ibenzo-p-dioxin for producing early life stage mortality in rainbow trout Gulde B, Preuss G, Wilme U, Zulei-Seibert N (2002). Removal of phar- (Oncorhynchus mykiss). Aquat Toxicol 21:219–238 maceuticals during drinking water treatment. Environ Sci Technol Walraven N, Laane RWPM (2009). Assessing the discharge of pharmaceuticals along the Dutch coast of the North Sea. Rev. Environ Contam Toxicol Ternes TA, Stüber J, Hermann N, McDowell D, Ried A, Kampmann M, Teiser B (2003). Ozonation: A tool for removal of pharmaceuticals, Watts C, Craythorne M, Fielding M, Steel CP (1983). Identification of non- contrast media and musk fragrances for wastewater? Water Res volatile organics in the water using field desorption mass spectrometry and high performance liquid chromatography. In: Angletti G, et al., eds. Ternes TA, Stumpf M, Mueller J, Haberer K, Wilken R.D, Servos M (1999b). Analysis of Organic Micropollutants in Water Dordrecht, Netherlands: Behaviour and occurrence of estrogens in municipal sewage treatment D.Reidel Publishing Company, 120–131.
plants—I: Investigations in Germany, Canada and Brazil. Sci Total Environ Watts C, Maycock D, Crane M, Fawell J, Goslan E (2007). Desk based review of current knowledge on pharmaceuticals in drinking water and estimation Thaker PD (2005). Pharmaceutical data eludes researchers. Environ Sci Technol of potential levels. Final report. Defra project code CSA 7184/WT02046/ Thibaut R, Porte C (2008). Effects of fibrates anti-inflammatory drugs and anti- Weiss S, Reemtsma T. 2005. Determination of benzotriazole corrosion inhibitors depressants in the fish hepatoma cell line PLHC-1: Cytotoxicity and inter- from aqueous environmental samples by liquid chromatography– electrospray actions with cytochrome P450 1A. Toxicol In Vitro 22:11128–1135 ionization–tandem mass spectrometry. Anal Chem 77:7415–7420 Thibaut R, Schnell S, Porte C (2006). The interference of pharmaceuticals with Wiegel S, Aulinger A, Brockmeyer R, Harms H, Löffler J, Reincke H, Schimdt R, endogenous and xenobiotic metbolizing enzymes in carp liver: An in vitro Stachel B, von Tümpling W, Wanke A (2004). Pharmaceuticals in the River study. Environ Sci Technol 40:5154–5160 Elbe and its tributaries. Chemosphere 57:107–126 Thomas PM, Foster GD (2004). Determination of nonsteroidal anti- inflammatory Weigel S, Berger U, Jensen E, Kallenborn P, Thoresen H, Hühnerfuss H (2004). drugs caffeine and triclosan in wastewater by gas chromatography–mass Determination of selected pharmaceuticals and caffeine in sewage and spectrometry. J Environ Sci Health A 39(8):1969–1978 seawater from Tromsø/Norway with emphasis on ibuprofen and its Thomas KV, Hilton MJ (2004). The occurrence of selected human pharmaceuti- metabolites. Chemosphere 56:583–592 cal compounds in UK estuaries. Mar Pollut Bull 49:436–444 Wiegel S, Kuhlmann J, Hühnerfuss H (2002). Drugs and personal care products Thorpe KL, Cummings RI, Hutchinson TH, Scholze M, Brighty G, Sumpter JP, as ubiquitous pollutants: Occurrence and distribution of clofibric acid Tyler CR (2003). Relative potencies and combination effects of steroidal caffeine and DEET in the North Sea. Sci Total Environ 295:131–141 estrogens in fish. Environ Sci Technol 37:1142–1149 Williams RT, Cook JC (2007). Exposure to pharmaceuticals present in the envi- Triebskorn R, Casper H, Heyd A, Eikemper R, Köhler H-R, Schwaiger J (2004). ronment. Drug Inform J 41:133–141 Toxic effects of the non-steroidal anti-inflammatory drug diclofenac. Part Winberg S, Nilsson A, Hylland P, Söderstöm V, Nilsson GE (1997). Serotonin as II. Cytological effects in liver kidney gills and intestine of rainbow trout a regulator of hypothalamic-pituitary-interrenal activity in teleost fish. (Oncorhynchus mykiss). Aquat Toxicol 68:151–166 Neurosci Lett 230:113–116 Trösken ER, Scholz K, Lutz RW, Völkel W, Zarn J.A, Lutz WK (2004). Comparative Winberg S, Nilsson GE (1993). Roles of brain monoamine neurotransmitters in assessment of the inhibition of recombinant human CYP19 (aromatase) agonistic behaviour and stress reactions with particular reference to fish. by azoles used in agriculture and as drugs for humans. Endocrine Res Comp Biochem Physiol C 106:597–614 Winberg S, Nilsson GE, Olsén KH (1991). Social rank and brain levels of Trudeau VL, Metcalfe CD, Mimeault C, Moon TW (2005). Pharmaceuticals monoamines and monoamine metabolites in arctic char Salvelinus alpi- in the environment: Drugged fish? In: Mommsen TP, Moon TW, eds. nus (L). J Comp Physiol A 168:241–246 Biochemistry and Molecular Biology of Fishes Vol. 6. Amsterdam: Elsevier, Winckler C, Grafe A. 2001. Use of veterinary drugs in intensive animal produc- tion. J Soil Sedi 1:66–70.
Tyler CR, Filby AL, Bickley LK, Cumming RI, Gibson R, Labadie P, Katsu Y, Winker M, Clemens J, Reich M, Gulyas H, Otterpohl R. (2008a). Behaviour of Liney KE, Shears JA, Silva-Castro V, Urushitani H, Lange A, Winter MJ, three pharmaceuticals in soil applied by urine fertilisation. Presented at Iguchi T, Hill EM (2009). Environmental health impacts of equine estro- International Symposium: Coupling Sustainable Sanitation & Groundwater gens derived from hormone replacement therapy. Environ Sci Technol Protection, 14–17 October 2008, Hanover, Germany.
Winker M, Tettenborn F, Faika D, Gulyas H, Otterpohl R, 2008b. Comparison of Tyler CR, van Aerle R, Hutchinson TH, Maddix S, Trip H (1999) An in vivo testing analytical and theoretical pharmaceutical concentrations in human urine system for endocrine disruptors in fish early life stages using induction of in Germany. Wat Res 42 3633–3640.
vitellogenin. Environ Toxicol Chem 18:337–347.
Winter MJ, Caunter JE, Glennon Y, Hutchinson TH (2006). Atenolol: 28 day Urase T, Kikuta T (2005). Separate estimation of adsorption and degradation of assessment of survival and growth in fathead minnow (Pimephales prom- pharmaceutical substances and estrogens in the activated sludge process. las) embryo-larvae. AstraZeneca Brixham Environmental Laboratory, Wat Res 39:1289–1300 Report Number BL8269A.
van Aerle R, Nolan TM, Jobling S, Christiansen LB, Sumpter JP, Tyler CR (2001). Winter MJ, Owen SF, Murray-Smith RM, Panter GH, Hetheridge MJ, Kinter Sexual disruption in a second species of wild cyprinid fish (the gudgeon, LB (2009). Using data from drug discovery and development to aid the Gobio gobio) in United Kingdom freshwaters. Environ Toxicol Chem aquatic Environmental Risk Assessment of human pharmaceuticals: Concepts, considerations and challenges. IEAM (Integr Environ Assess Van der Heide EF, Hueck-Van der Plas EH (1994). Geneesmiddelen en milieu. Manag), (June 26 Epub ahead of print).
Pharmaceutisch Weekblad 119:936–1647 Wishkovsky A, Roberson BS, Hetrick FM (1987). In vitro suppression of the Van der Hoeven N (2004). Current issues in statistics and models for ecotoxi- phagocytic response of fish macrophages by tetracyclines. J Fish Biol cological risk assessment. Acta Biotheor 52:201–217 304 J. Corcoran et al. Witte W, Klare I, Werner G (1999). Selective pressure by antibiotics as feed addi- teleost the red porgy (Pagrus pagru Ssparidae). J Comp Neurol tives. Infection. 27(Suppl 2):S35–S38 Wolf JC, Wolfe MJ (2005). A brief overview of nonneoplastic hepatic toxicity in Zou J, Neumann NF, Holland JW, Belosevic M, Cunningham C, Secombes CJ, fish. Toxicol. Pathol 33:75–85 Rowley AF (1999). Fish macrophages express a cyclo-oxygenase-2 homo- Yamaguchi F, Brenner S (1997). Molecular cloning of 5-hydroxytryptamine logue after activation. Biochem J 340:153–159 (5-HT) type 1 receptor genes from the Japanese puffer fish, Fugu rubripes Zuccato E, Calamari D, Natangelo M, Fanelli R (2000). Presence of therapeutic Gene 191:219–223 drugs in the environment. Lancet 335:1789–90.
Yang JH, Kostecki PT, Calabrese EJ, Baldwin LA (1990). Induction of peroxi- Zuccato E, Castiglioni S, Fanelli R (2005). Identification of the pharmaceuticals some proliferation in rainbow trout exposed to ciprofibrate. Toxicol Appl for human use contaminating the Italian aquatic environment. J Hazard Pharmacol 104:476–482 Mater 122:205–209 Zikopoulos B, Dermon CR (2005). Comparative anatomy of alpha(2) and Zuo Y, Zhang K, Deng Y (2006). Occurrence and photochemical degradation of 17α- beta adrenoceptors in the adult and developing brain of the marine ethinylestradiol in Acushnet River estuary. Chemosphere 63:1583–1590a Copyright of Critical Reviews in Toxicology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.


Pii: s0735-1097(01)01248-7

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

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