Excretion and ecotoxicity of pharmaceutical and personal care products in the environment

ARTICLE IN PRESS

Ecotoxicology and Environmental Safety 63 (2006) 113–130 www.elsevier.com/locate/ecoenv

Excretion and ecotoxicity of pharmaceutical and personal care products in the environment Patrick K. Jjemba Biological Sciences Department, University of Cincinnati, P.O. Box 210006, Cincinnati, OH 45221-0006, USA Received 21 April 2004; received in revised form 26 October 2004; accepted 29 November 2004 Available online 25 January 2005

Abstract The presence and fate of pharmaceutical and personal care products (PPCPs) in the environment is undergoing increasing scrutiny. The existing clinical pharmacokinetics and pharmacodynamics data for 81 common compounds were examined for cues of ecotoxicity. Of these the proportions excreted were available for 60 compounds (i.e., 74%). The compounds had a low (p0.5%), a moderately low (6–39%), a relatively high (40–69%), or a high (X70%) proportion of the parent compound excreted. More than half of the compounds evaluated have low or moderately low proportions of the parent compound excreted. However, the proportions excreted were negatively but moderately correlated (r ¼
0:50; n ¼ 13; P ¼ 0:08) with the concentrations of the compounds in the aquatic environment, suggesting that the compounds that have low proportions excreted may also have inherently low degradability in the environment. Solubility, log Kow, and pKa work well in predicting the behavior of PPCPs under clinical conditions and have been used in the environmental assessment of PPCPs prior to approval. However, these parameters did not correlate with the proportion of PPCPs excreted in the environment or their concentration in the environment, underscoring the need for research into the behavior of PPCPs in the environment. PPCPs occur in low concentrations in the environment and are unlikely to elicit acute toxicity. An ecotoxicity potential that is based on chronic toxicity, bioavailability, and duration of exposure to nontarget organisms is described as a guide in assessing the potency of these compounds in the environment. r 2005 Elsevier Inc. All rights reserved. Keywords: Bioavailability; Drug excretion; Ecotoxicity; Environmental assessment; Pharmaceuticals; Pharmacodynamics; Risk assessment; Sorption

1. Introduction A wide range of pharmaceutical and personal care products (PPCPs) are on the market. Among these, various classes, e.g., antibiotics, antiphlogistics, antiepileptics, beta-blockers, lipid regulators, vasodilators, and sympathomimetics, have been detected in drinking water, groundwater, wastewater, sewage, and manure (Halling-Sørensen et al., 1998; Kolpin et al., 2002; Ternes, 1998; Ternes et al., 2002; Golet et al. 2002a; Jjemba, 2002a; Ku¨mmerer et al., 2000). Pharmaceutical Corresponding author. Fax: +1 513 556 9299.

E-mail addresses: [email protected], [email protected] (P.K. Jjemba). 0147-6513/$ - see front matter r 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ecoenv.2004.11.011

compounds are deliberately designed to affect biochemical and physiological functions of biological systems in humans and livestock. However, they can also elicit biochemical and physiological changes in soil and aquatic dwellers. After normal application, many of these compounds and/or their metabolites are eliminated from the body mainly through the renal system (urine), biliary system (feces), or a combination of both depending on the nature of the compound and the organism in question. Thus, several sources of these compounds contained in the urine and manure in runoff from agricultural fields and in biosolids generated from sewer systems enter the environment (Ku¨mmerer et al., 1997; Ku¨hne et al., 2000). Furthermore, during sewage treatment, most of these compounds are not

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quantitatively removed and remain in the effluents that get into the surface and groundwater (Doll and Frimmel, 2003; Ternes, 1998; Mo¨hle et al., 1999). The clinical pharmacokinetics and pharmacodynamics of drugs are typically extensively studied prior to the drug’s approval for use. There are currently somewhat stringent guidelines in the US and the EU to conduct environmental assessment of pharmaceutical compounds (US FDA, 1998; EMEA, 2001). However, the ecotoxicity of a number of PPCPs that were introduced on the market prior to these guidelines is still largely unknown despite the fact that some of them are used in quantities that are equal to those of agrochemicals (Hirsch et al., 1999). There is increasing evidence that some of these compounds are persistent in the environment, impacting nontarget organisms in various ways including changes in sex ratios of higher organisms (Pascoe et al., 2003) and localized changes in biogeochemical cycles (Westergaard et al., 2001), causing subtle modifications in plant growth (Migliore et al., 1996; Jjemba, 2002b; Jjemba and Robertson, 2003), failure of larvae to molt and/or hatch (Gunn and Sadd, 1994; Strong, 1993; Ferrari et al., 2003), and varying degrees of anatomical deformities in a wide range of organisms (Watts et al., 2003). The fact that such a diverse array of organisms are affected in such divergent ways suggests that the subtle effects could be a more widespread problem than has previously been realized. A major inlet of these compounds in the environment is through excretion in both urine and feces (Jjemba, 2002a; Ku¨hne et al., 2000; Ku¨mmerer et al., 1997, 2000). There is a wealth of information about PPCPs that has been accumulated under clinical settings to determine the rate of excretion, bioavailability in the target organisms, toxicity to the target organism, mode of action, etc. In the environment, these compounds are subjected to distribution, absorption, metabolism (i.e., biodegradation), and mobility (equivalent to excretion in living organisms), the environment behaving in a manner that is somewhat analogous to how living target organisms behave when undergoing pharmaceuticalbased therapy. This analogy may, at first sight, not seem obvious but on closer examination mobility in the environment is counteracted (i.e., impeded) by physical and chemical factors such as sorption, pH, presence of heavy metals, and soil permeability, whereas excretion in the body occurs after the drug and its chiral wastes are expunged after screening through a series of membranes that vary in permeability and retention potential. The apparent difference between the body and the environment is that, once excreted, the compounds leave the body, whereas, in the environment, their movement only displaces them from one location to another. Similarly, drug metabolism in the body results in the breakdown of the compound into chemically simpler metabolites just like what biological and

chemical processes attain in the environment. When such breakdown occurs in the environment, it is typically referred to as degradation. The already existing clinical-based data have not yet been examined for potential cues about the ecotoxicity of individual compounds. The aim of this work was, therefore, to provisionally evaluate the well-studied clinical pharmacodynamic and pharmacokinetic traits of various common PPCPs and the way that some of these traits relate to ecotoxicity.

2. Evaluation framework Eighty-one PPCPs that are widely used against bone loss, inflammation, hypertension, and infectious diseases or as sedatives, contraceptives, anesthetics, immunomodulators, etc. and three fragrance compounds (i.e., acetophenone, galaxolide, and tonalide) were selected. The three fragrances are fairly widely used (Heberer et al., 2001) and have been found in the aquatic environment (Kolpin et al., 2002; Ternes et al., 2003). The selected pharmaceutical compounds are some of the most commonly used for leading disease categories and are leading in global drug sales as is reflected in Fig. 1. According to the rxlist, 28 of the 81 PPCPs were among the top 200 prescriptions in the United States in 2003 (see http://www.rxlist.com) although accurate statistics about the production and consumption of the individual compounds are not readily available because of privacy and industry competition issues. These top 200 were prescribed a total of 2,116,996,957 times within the United States in 2003, with amoxicillin being prescribed most (i.e., 3.4% times) among those included in this study, followed by atorvastatin (3.1% of the top 200 prescriptions) (Table 1). Many of the antihypertensive and cardiovascular drugs that were included in this study also made the top 200 rxlist for 2003. Tetracycline was prescribed least among the top 200 drugs included in this study, being prescribed only 0.1% of the 2,116,996,957 times. To make the study more comprehensive, even compound categories such as biophosphonates, anesthetics, and triptans that are increasingly used were included. For convenience, representative candidate drugs such as antibiotics, antifungals, antivirals, and opthalmics were combined into one category. Vaccines were not included in the analysis as most of them are deemed more biological in nature (e.g., live attenuated viruses) and/or administered occasionally on an individual basis. Various physico-chemical data such as molecular weight, solubility, octanol–water coefficient (Kow), and dissociation constants (i.e., pKa) and pharmacodynamics data such as bioavailability under clinical settings and proportions of the parent compound that are typically excreted during normal use were compiled.

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115

25

Percent of total

20

15

1998 (US$99,839 million) 1999 (US$115,001 million)

10

2000 (US$146,013 million)

5

0

1

2

3

4

5

6

7

8

9

10 11 12 13

14

Pharmaceutical categories Fig. 1. Global drug sales in 1998, 1999, and 2000 as a percentage of US $99.8 billion, $115.0 billion, and $146.0 billion, respectively. The drug categories are 1, cardiovascular and anticholesterol; 2, antibiotics and antifungal; 3, hormones (including reproductive)/endocrinology; 4, antineplast and immunosuppressants; 5, sedatives and antipsychotics (central nervous system disorders); 6, hematology; 7, antiviral; 8, respiratory; 9, gastrointestinal; 10, ophthalmic; 11, dermatological; 12, analgesics; 13, vaccines; and 14, others. (Source: Chemical Engineering News, ‘‘Chiral drug sales hurtle past $100 billion and show no sign of slowing’’ October 23:56, 2000).

Submitting information about the solubility, Kow, and pKa is currently recommended by the Food and Drug Administration as part of the environmental assessment for new PPCPs (US FDA, 1998). The elemental ratios (C/H, C/N, C/O, H/N, H/O, and N/O ratios) for each PPCP were also determined. Where available, the concentrations that have been reported in the literature within the aquatic environment were also included. A recent study by Kolpin et al. (2002) which surveyed various streams in the US was used as the primary source of the concentrations of the PPCPs in the aquatic environment. In the absence of that information for other PPCPs, data from other reknown works by Heberer (2002), Ternes et al. (2002) and Ferrari et al. (2003) were used. Where more than one such concentration was available (e.g., from more than one source), the median was determined. Bioavailability in the target organism under clinical settings and the proportions of the compound that are typically excreted were also compiled from various sources identified in Table 1, whereas log Kow and pKa values were obtained from Kasim et al. (2004) and Jjemba (2004). The solubility data were obtained from Yalkowsky and He (2003), http://chemfinder.cambridgesoft.com, and Kasim et al. (2004). Where ranges for bioavailability or proportion of PPCP excreted were given, a more conservative approach taking the lowest value for the range (indicated in boldface in Table 1) was used in the correlation analysis and subsequent classification of the PPCPs. The data generated were subjected to a multivariate analysis using SAS (Version 8.2) to determine existing correlations and their significance. The data were used to develop a quantitative ecotoxicity potential against nontarget organisms.

3. Results 3.1. Molecular composition of PPCPs All of the compounds that were evaluated are listed in Table 1 and contain C and H. A majority of them also contain N and/or O. Only the three cosmetic compounds, two of the four biophosphonates (i.e., clodronate and etidronate), two analgesics (i.e., aspirin and ibuprofen), two cardiovascular drugs (i.e., digoxin and simvastatin), both respiratory system drugs (i.e., cromoglycate and dexamethasone), and three oral contraceptives (i.e., ethinylestradiol, mestranol, and testosterone) do not contain the N atom. Of the compounds studied, the O atom is absent in only the sedative prochlorperazine, the antihypertensive drug clonidine, the immunomodulator selegiline, and the immunosupressant ifosamide. Phosphorus is present only in the immunosupressant ifosamide and all of the biophosphonates. Sulfur is present in several antimicrobial agents, the sedative temazepam, and the cardiovascular drugs chlorothiazide, hydrochlorothiazide, furosemide, and timolol. Only a few of the PPCPs contain a halogen in the form of chloride, fluoride, or bromide, the latter encountered only in the reproductive drug bromocriptine. The molecular weight of the PPCPs compared ranged between 120.2 for the fragrance acetophenone and 1155.4 for the anticholesterol drug atorvastatin (Lipitor). Molecular weight did not correlate with any of the traits of relevance in the environment, notably bioavailability of the PPCP in the body of the target organism, the proportion of the PPCP that is excreted, or the concentration of the PPCP in the aquatic environment.

C3H11NO7P2

Pamidronate (Aredia)

C17H18FN3.O3.HCl

C18H33ClN2O5S

C19H17Cl2N3O5S

C22H24N2O8

C10H24N2O2

C16H17N3O4S.H2O

C10H12N4O3

Ciprofloxacin [0.66]

Clindamycin

Dicloxacillin

Doxycycline

Ethambutol

Cephalexin (Keflex) [1.0]

Didanosine

C13H12F2N6O

C11H12Cl2N2O5

Chloramphenicol

Fluconazole (Diflucan) [0.51]

C16H19N3O4S

C16H19N3O5.3H2O

Ampicillin

Amoxicillin (Trimox; Augmentin) [3.41]

C8H11N5O3

C2H8O7P2

Etidronate (Didronel)

Antimicrobial Acyclovir (Zovirax)

Osteoporosis

CH4Cl2O6

Antifungal

Antiviral

Antibiotic

Antibiotic

Antibiotic

Antibiotic (b-lactam)

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antibiotic

Antiviral

Osteoporosis

Osteoporosis

Osteoporosis

Fragrance

C17H24O

C3H11O7P2

Fragrance

Fragrance

C18H26O

C8H8O

Common use

306.3

236.2

365.4

204.3

470.3

425

331.3

323.1

349.4

365.4

225.2

235.1

206

245

343.3

244.4

258.4

120.2

Mol wt

b


1.1

0.06


3.66

2.06

1.32


0.23


0.58


1.59

K ow

0.99

9.12

7.6

5.9

0.8

pK a

b

30–60 (Hirsch et al., 1999) 5–10 (Hirsch et al., 1999) 83.7 (Volmer et al., 1997)

0.42 (Yamashita et al., 1993) 80–90 (Hirsch et al., 1999)

0.01–0.18 (Hylastrup et al., 1993)

40–60 (Porras et al., 1999) 0.18–19 (Ylitalo et al., 1999)

c

90 (Martindale, 1999) 10 in urine; 4 in feces (Martindale, 1999) 35–76 (Donowitz 50 (Vinge et al., 1997) and Mandell, 1988) 93 (Saivin and 70 (Hirsch et al., 1999) Houin, 1988) 69–85 (Strauss and 50–80 (Breda et al., Erhardt, 1970) 1999) 89 (Padoin et al., 80 (Martindale, 1999) 1998) 20–40 (Martindale, 50 (Martindale, 1999) 1999) 90 (Martindale, 62–80 (Ripa et al., 1999) 1993)

25–75 (Triggs et al., 1980) 75–90 (Mulhall and de Louvois, 1985) 50–70 (CampoliRichards et al., 1988)

15–30 (Bras et al., 2001) 83–100 (Jones and Hill, 1974)

0.3–0.48 (Hyldstrup et al., 1993)

0.9–1.8 (Porras et al., 1999) 1.2 (Yakatan et al., 1982) 5 (Gural et al., 1985)

Bioavailability (%) to Percentage excreted the body during therapeutic use c

Effective against Mycobacterium spp.

Median concentrations of 0.02 mg/ L in 26% of US streams (Kolpin et al., 2002)

Very insoluble (0.1% w/w) in water which limits it bioavailability Appears to be easily degraded (t90o2 days) in the environment (Calamari et al., 2003)

Very poor lipophilicity and poor adsorption in body Low bioavailability and excretion as is typical of biophosphonates

Median concentration of 0.15 mg/L in 9.4% streams in the US (Kolpin et al., 2002) 0.73 mg/L found in STP effluents (Ternes et al., 2003) 0.1 mg/L found in STP effluents (Ternes et al., 2003)

Amounts detected in environment and other remarks c

116

Biophosphonates Alendronate (Fosanex) [0.97] Clodronate

Galaxolide (Musk 50; HHCB) Tonalide (AHTN)

Cosmetics Acetophenone

Pharmaceutical or personal Chemical formula care product a

Table 1 Physico-chemical properties, bioavailability, and excreted proportions of various pharmaceutical and personal care products (PPCPs) and their occurrence in the environment

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C6H9N3O3

C23H27N3O7 C16H18FN3O3

C10H11N303S

C22H24N4O8

Metronidazole (Flagyl)

Minocycline Norfloxacin

Sulfamethoxazole

Tetracycline [0.10]

C10H13N5O4

Zidovudine (AZT)

C14H10Cl2NO2

Ibuprofen (Motrin) [1.11]d C13H18O2

Diclofenac

Analgesics, antiinflammatory, and antipyretics Acetylsalicylic acid C9H8O4 (Aspirin)

C13H20N6O4

Valaciclovir (Valtrex)

C14H18N4O3

C13H15F2N3O3S

Genaconazole

Trimethoprim (Primsol/Trimpex)

C4H4FN3O

Flucytosine

Pain killer

Antiphlogistic

Antipyretic and analgesic

Antiviral

Antiviral

Antifungal

Antibiotic

Antibiotic

Antibiotic Antibiotic

Antibiotic

Antifungal

Antifungal

206.3

296.2

180.2

267.2

324.3

290.3

444.4

253.3

457.5 319.3

171.2

331.3

3.14

0.7

1.19

1.43

0.86

0.46

0.02

5.2

4.2

3.5

9.85

1.9

6.6

3.3

6.34

2.38

3.26

85–100 (Davies, 1998)

65–71 (Bochner and Lloyd, 1995)

60–65 (Guarino et al., 1998)

54 (Martindale, 1999)

90–97 (Meshi and Sato, 1971)

77 (Kramer et al., 1978)

80–90 (Lewin et al., 1973)

75–89 (Lyman and Walsh, 1992) 100 (Mojaverian et al., 1994) 90 (Freeman et al., 1997) 100 (Meyer, 1996) 30–40 (Martindale, 1999)

1–8 (Ternes, 1998)

15 (Ternes et al., 1999)

2–30 as salicylate (Martindale, 1999)

57–65 (Burnette and Demiranda, 1994)

60% (Hirsch et al., 1999)

80–90 (Ku¨hne et al., 2000)

15 (Ternes, 1998)

76–87 (Mojaverian et al., 1994) 40 (Ku¨mmerer et al., 2000) 60 (Hirsch et al., 1999) 30 in urine and feces, respectively (Martindale, 1999)

90 (Martindale, 1999)

Its primary metabolite salicyclic acid found at concentrations of 0.34 mg/L in Berlin river effluents (Heberer, 2002) Median concentrations of 0.47 mg/ L in water (Ternes et al., 2002; Ferrari et al., 2003). Readily removed by low levels of ozone or with activated C compared to flocculation which is ineffective (Ternes et al., 2002). Quite mobile in soil. Concentrations of 0.1 mg/L detected in Berlin waterways (Heberer, 2002). Median of 0.2 mg/ L in US streams (Kolpin et al., 2002).

1.4–2.42 mg/kg in untreated sewage sludge; persistent in environment, with only 80–87% removal in WWTP (Golet et al., 2002a, b). Median of 0.12 mg/L in US streams (Kolpin et al., 2002). Persistent in environment (Richardson and Bowron, 1985). Berlin effluents with 0.9 mg/L (Heberer, 2002). Median of 0.07–0.15 mg/L in US streams depending on the detection method (Kolpin et al., 2002). 0.11 mg/L in 1.2% US streams (Kolpin et al., 2002) and 9–12 mg/ kg soil in manure-treated fields (Ku¨hne et al., 2000) Median concentrations of 0.15 mg/ L in 12.5% streams in the US (Kolpin et al., 2002) Rapidly converted to acyclovir in the body (Gutierrez and Queener, 2003). Extensively and rapidly transformed in the liver to the inactive glucuronide (Gutierrez and Queener, 2003).

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C8H9NO2

C17H19NO3

Antiepileptic and antianxiety Sedative

Clonazepam (Rivotril)

C20H23NO4, HCl

Naltrexone (ReVia)

Antiepileptic

C12H14N2O2

1155.4 361.8

Lipid regulator

300.7

373.9

218.3

232.2

341.4

327.4

345.8

284.7

315.7

236.3

213.7

289.4

151.2

285.3

Mol wt

Anticholesterol

Antipsychotic and antiemetic Antianxiety

Antiepileptic

C12H12N2O3

Prochlorperazine C20H24ClN3S (Compazine) Temazepam (Restoril) C16H13ClN2O2 [0.21] Antihypertensive and cardiovascular Atorvastatin (Lipitor) C33H30D5FN2O5 [3.1] Bezafibrate C19H20ClNO4

Phenobarbitone (Nembutal) Primidone (Mysoline)

Opiod agonist

C19H21NO4

Naloxone (Narcan) Opiod agonist

Antidepressant

Fluoxentine (Prozac) [0.81]

Diazepam (Valium) [0.25] C16H13ClN2O

C15H10ClN3O3

Antiepileptic

C10H12ClNO2

Carbamazepine (Atretol) C15H12N2O

Baclofen (Lioresal)

CNS, overactive GIT, cardiac rhythm problems Agonist/spasticity

Pain relief

Painkiller

Common use

b

1.52

2.98

2.93

1.53

0.89

K ow

4.46

8.59

7.3

3.4

7

4.32

9.4

9.85

pK a

b

14 (Gibson et al., 1996) 95 (Martindale, 1999)

90 (Hosie and Nimmo, 1991)

20 (Tokola, 1988)

72 (Altamura et al., 1994) 2–10 (AAPC, 1990 86:484–85) 5–22 (Hussain et al., 1987) 70–90 (Watanabe et al., 1977) 60–80 (Watanabe et al., 1977)

95 (Naito et al., 1987) 85–100 (Reiderberg et al., 1978)

70 (Wuis et al., 1989) 60–85 (Liu and Delgado, 1994)

50 (Ellinwood Jr. et al., 1990)

20–33 (Beyssac et al., 1998) 58–68 (Muir et al., 1997)

c

5 (Prueksaritanont et al., 2002) 45 (Martindale, 1999)

15–40 (Gutierrez and Queener, 2003)

o1 (Martindale, 1999) 25 (Martindale, 1999)

2.5–11 (Altamura et al., 1994)

1 (Smith-Kielland et al., 2001)

70–85 (Gutierrez and Queener, 2003) 1–2 (Ternes, 1998)

50 (Alimelkkila et al., 1993)

71.6 (Zakowski et al., 1993) o5 (Martindale, 1999)

Bioavailability (%) to Percentage excreted the body during therapeutic use c

Undergoes extensive metabolism in body (Prueksaritanont et al., 2002) Low removal (p50%) in water except with concentrations of ozone (1.5 mg/L). However, 20%

In the environment, it can also be a metabolite of diazepam

Persistent in water even with high ozonation (3 mg/L) 10% primidone still remained in effluent. Levels of 1.08 mg/L detected in Berlin waters (Heberer, 2002)

Metabolites can be 22–43% of intake dose (Smith-Kielland et al., 2001). Drug is highly lipophilic

Median concentrations of 0.93 mg/ L reported (Heberer, 2002; Ferrari et al., 2003). Flocculation with FeCl3 was minimal. Can be effectively removed with activated C (Ternes et al., 2002)

Median concentrations of 0.11 mg/ L in US streams (Kolpin et al., 2002)

Amounts detected in environment and other remarks c

118

Anxiolytic sedatives, hypnotics, and antipsychotics Atropine C17H23NO3

Paracetamol (Acetaminophen) [0.64]d

Morphine

Pharmaceutical or personal Chemical formula care product a

Table 1 (continued )

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C9H9Cl2N3

C41H64O14

Clonidine [0.34]

Digoxin (Lanoxin) [0.34]

C19H24N2O3

C7H8ClN3O4

C23H32N2O5

Ramipril (Altace) [0.57]

Asthma; Neurological disorders

Dexamethasone (Decadron)

C22H29FO5

Asthma

C13H17N

Neurological disorders; antidementure AntiParkinsonism; antidementia

Respiratory Cromoglycate (Cromolyn) C23H16O11

Selegiline (Carbex)

Dopamirgics and Imunomodulators Nimodipine C21H26N2O7

Hematology (anticoagulants) Warfarin (Coumadin) C19H16O4 [1.15] Anticoagulant during embolism

Hypertension

Verapamil [0.49]

C27H38N2O4

Beta-blocker

Ventricular dysfunction Anticholesterol

392.5

468.4

187.3

418.4

308.3

454.6

316.4

418.6

416.5

324.4

438.5

Hypertension Antiarrhythmic

235.3

328.4

297.7

330.7

384.3

376.4

780.9

230.1

295.7

Hypertension (Betablocker) Antiarrhythmic

Antihypertension; Diabetes Antihypertension

Hypertension (Betablocker) Cardiovascular

Cardiovascular

Hypertension; agonist

Hypertension

Timolol (Blocadren) [0.15] C13H24N4O3S

Simvastatin (Zocor) [1.33] C25H38O5

C20H24N2O2

Quinidine (Quinaglute)

Procainamide (Procan C13H21N3O SR) Quinapril (Accupril) [0.60] C25H30N2O5

Hydrochlorothiazide (Vetidrex) [1.61] Labetalol (Trandate)

Felodipine (Plendil) C18H19Cl2NO4 [0.14] Furosemide (Lasix) [1.66] C12H11C1N2O5S

Enalapril (Vasotec) [0.24] C20H28N2O5

C7H6ClN3O4

Chlorothiazide (Diuril)

0.72

2.97

5.69

0.74

1.77

1.95

8.6

9

7.9

3.9

6.7

1.61 (Yeleswaram et al., 1993) 30–70 (Martindale, 1999) 2.6 (Swartz et al., 1990) 20–50 (Gutierrez and Queener, 2003) 25.2 (Meyer et al., 1995) 10–15 (Martindale, 1999)

40 (Bindschedler et al., 1997) 24 (Martindale, 1999)

2–5 (Walker et al., 25 (Yoshimi et al., 1972) 1992) 80–90 (Brophy et al., 65 (Martindale, 1999) 1983)

20 (Gordon et al., 1999)

13 (Martindale, 1999) 32 (Parnetti, 1995)

98 (Mu¨ller et al., 1988)

30–50 (Sutinen et al., 2000) 20–35 (McTavish, o4 (Martindale, 1989) 1999)

20 (Todd and Faulds, 1992) 60–67 (Ponto and Schoenwald, 1990) 60–80 (Allen et al., 1982) 30 (MacCarthy and Bloomfield, 1983) 67–99 (Koch-Weser, 1977) 50–60 (Horvath et al., 1990) 54–88 (Verme et al., 1992) 50–60 (Martindale, 1999) 5 (Grau et al., 1996)

8–20 (Adebayo and Mabadeje, 1985) 75–95 (Manhem et al., 40–60 in urine and 20 1982) in feces (Martindale, 1999) 70–90 (Martindale, 50–70 (Martindale, 1999) 1999) 60 (Martindale, 1999) 36 (Lo et al., 2000)

Mast cell stabilizer

Practically insoluble

Low bioavailability and with highly active metabolites as is typical of most statins Extensively metabolized in the liver (Martindale, 1999) About 70% and 16% excreted in urine and feces, respectively, as metabolites

Low solubility in lipids

The drug is extensively hydrolized in the liver (Martindale, 1999) About 70% excreted as metabolites (Martindale, 1999)

still remained with 3 mg ozone/L (Ternes et al., 2002)

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C19H28O2

Testosterone

C14H21N3O2S

C15H19N5 Headache

Migraine 281.4

391.5

398.4

314.4

425.9

234.3

237.7

261.1

497.5

288.4

310.4

296.4

654.6

Mol wt

4

K ow

b

3.5

7.9

7.5

4.9

pK a

b

c

20–40 (Gutierrez and 89–94 (Vyas et al., Queener, 2003) 2000) 15–20 (Gutierrez and Queener, 2003)

15–17 (Heykants et 10 (Martindale, 1999) al., 1981) 50–100 (Martindale, 30–70 (Martindale, 1999) 1999) 15 (Martindale, 1999)

20 (Clement and Nimmo, 1981) 35 (Martindale, 1999) o10 (Martindale, 1999)

12–49 (Stewart et al., 5 (Stewart et al., 1991) 1991)

40–50 (Goldzieher and Brody, 1990) 5 (Ta¨uber et al., 1986) 60 (Schumann, 1991)

5–10 (de Groot et al., 1998) 40–50 (Goldzieher and Brody, 1990)

Bioavailability (%) to Percentage excreted the body during therapeutic use c

0.01 mg/L in 1.2% of US streams (Kolpin et al., 2002)

Most of it excreted as metabolites (Martindale, 1999)

Mostly excreted in feces (Martindale, 1999) Median of 0.073 mg/L in US streams (Kolpin et al., 2002). Also a hydrolysis product of menstranol Median of 0.074 mg/L in US streams (Kolpin et al., 2002) Median detected 0.116 mg/L in 2.8% of US streams (Kolpin et al., 2002)

Amounts detected in environment and other remarks c

PPCPs shown in italic were among the top 200 most prescribed in the US in 2003 (Source: http://www.rxlist.com; last accessed on 10/14/2004). The boldface numbers in brackets are the percentages of prescriptions for that drug of the 2,116,996,957 when these top 200 drugs were prescribed that year. b Log Kow and pKa values compiled from Kasim et al. (2004) and Jjemba (2004). c Numbers shown in boldface are those used in the correlation analysis for % bioavailability, % excreted as parent compound in clinical settings, and concentrations reported in the aquatic environment. d Note that this percentage represents only the number of prescriptions. These medications are obtained mostly over the counter.

a

Sumatriptan (Imitrex) [0.21]

Triptans Rizatriptan (Maxalt)

Peptic ulcers

Sulfasalazine (Sulcolon)

C18H14N4O5S

Antacid

Ranitidine (Zantac) [0.65] C13H22N4O3S

Anaesthesia

Anaesthesia

Nausea

C14H22N2O

C13H16ClNO

C7H15Cl2N2O2P

C22H24ClN5O2

Gastrointestinal Domperidone

Lidocaine (Xylocaine)

Anesthetics Ketamine (Ketalar)

Ifosfamide

Cancer/leukemia therapy Cancer therapy

Reproductive hormone

Contraceptive

Reproductive (also Parkinson) Ovulation inhibitor

Common use

120

Antineoplast and immunosuppressants Idarubicin (Idamycin) C26H27NO9

C21H26O2

C20H24O2

Mestranol

Ethinyloestradiol (Perovex) [0.11]

Oral contraceptive and reproductive therapy Bromocriptine (Parlodel) C32H40BrN5O5

Pharmaceutical or personal Chemical formula care product a

Table 1 (continued )

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3.2. Drug bioavailability in target organism, excretion, and occurrence in the environment

121

the imunodipine nimodipine; the anesthetic lidocaine; and the gastrointestinal drugs domperidone and ranitinide (Zantac). Excreted proportions of 40–69% as parent compound can be considered relatively high and were encountered in 43% of the antimicrobial agents, alendronate, the analgesic dexamethasone, the sedative atropine, four of the cardiovascular drugs (i.e., bezafibrate, clonidine, digoxin, furosemide), and the hormone testosterone (Table 2). In contrast, 7 of the 21 antimicrobial agents (33%), the analgesic morphine, the sedative baclofen, and the antimigraine drug rizatriptan are excreted in high proportions, with 70% or more of the parent compound excreted. Table 2 also highlights (in boldface) the compounds that have been reported in the environment, with their actual concentrations in the environment reported in Table 1. It is important to point out that those that have not yet been reported in the environment may be present but have not been looked for or have lacked detection methods. It is apparent from Table 2 that even PPCPs that have been reported to have only low (i.e., p5%) proportions of the parent compound excreted have also been encountered in the environment. As a matter of fact, there was a negative though moderate correlation (r ¼
0:50; n ¼ 13; P ¼ 0:08) between the proportions of PPCPs excreted and the concentrations of PPCPs in the aquatic environment. However, it is worth noting

Bioavailability under clinical settings data were available for 76 of the 81 PPCPs and ranged from as low as 0.3% for the antiboneloss drug pamidronate to 100% for the antifungal genaconazole (Table 1). By comparison, the proportions of excreted parent compound were available for 60 of the 81 PPCPs (i.e., 74%) examined and ranged between 0.01% for pamidronate and 90% for the antifungal agent flucytosine. In general, very low (5% or less) proportions of biophosphonate compounds, except alendronate (Fosanex), are excreted as parent compound (Table 2). Low proportions of two antimicrobial agents (acylovir, chloramphenicol), three analgesics (aspirin, ibuprofen, and paracetamol), several sedatives (carbamazepine, diazepam, prozac, naltrexone), the antihypertension drugs atorvastatin, labetalol, quinapril, and verapamil, and the immunosuppressant idarubicin are excreted. Proportions of 6–39% of the parent compound excreted are categorized as moderately low. In this category are the antimicrobial agents ampicillin, clindamycin, and sulfamethoxazole; the analgesics cromoglycate and diclofenac; the sedatives phenobarbitone and primidone; the cardiovascular drugs enalapril, hydrochlorothiazide, procainamide, quinidine, ramipril, and simvastatin (Zocor);

Table 2 Categorization of 60 diverse but commonly used pharmaceutical compounds based on the proportions of the parent compound that is excreted in clinical settings Common use

Proportion of the parent compound excreted Low (p5%)

Skeletal (biophosphonates) Antimicrobial

Clodronate, Pamidronate Acylovir, Chloramphenicol

Analgesic and antiinflammatory Sedative/antipsychotic

Aspirin, Ibuprofen (Motrin), Paracetamol Carbamazepine, Valium, Fluoxentine (Prozac), Naltrexone Atorvastatin (Lipitor), Labetalol, Quinapril, Verapamil

Cardiovascular/ antihypertensive

Dopamirgics Reproductive Antineoplasts Anesthetics Gastrointestinal Triptans a

a

Moderately low (6–39%)

Relatively high (40–69%)

High (X70%)

Cromoglycate, Diclofenac

Alendronate (Fosanex) Dicloxacillin, Ethambutol, Didanosine, Fluconazole, Metronidazole, Minocycline, Norfloxacin, Trimethoprim, Valaciclovir Dexamethasone

Amoxacillin, Ciprofloxacin, Doxycycline, Cephalexin, Flucytosine, Genaconazole, Tetracycline Morphine

Phenobarbitone, Primidone

Atropine

Baclofen

Enalapril (Vasotec), Hydrochlorothiazide, Procainamide, Quinidine, Ramipril, Simvastatin (Zocor) Nimodipine

Bezafibrate, Clonidine, Digoxin, Furosemide

Ampicillin, Clindamycin, Sulfamethoxazole

Testosterone Idarubicin Lidocaine Domperidone, Rinitinide (Zantac) Rizatriptan

In boldface are some of the compounds for which occurrence in the environment has been reported at concentrations provided in Table 1.

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that the correlation was based on the small data set that is available, underscoring the need to build a larger data base of PPCPs in the environment. There was a weak positive but significant correlation (r ¼ 0:35; n ¼ 59; P ¼ 0:01) between the bioavailability of the PPCP in the target organism and the proportions of the parent compound that are excreted. On the other hand, the proportions of the parent compound that are excreted were moderately, but significantly and negatively correlated with the amount of fluorine in the parent compound (r ¼
0:74; n ¼ 8; P ¼ 0:04). However, very few of the PPCPs studied contain fluoride. The proportions of the parent PPCP excreted were weakly and negatively but significantly correlated with the C/N content of the compound (r ¼
0:29; n ¼ 52; P ¼ 0:04). Data on the occurrence in the aquatic environment were available for only 17 of the PPCPs examined and ranged between 0.01 mg/L for ranitidine and 1.08 mg/L for the antiepileptic drug primidone (Table 1). The

fragrance galaxolide (Musk 50) and the drug carbamazepine occur in concentrations of 0.7 mg/L or higher, levels that are comparatively high. In contrast, the fragrance tonalide (AHTN) and pharmaceuticals such as ciprofloxacin, tetracycline, trimethoprim, ibuprofen, paracetamol, ethinylestradiol, mestranol, and testosterone are reportedly present in low (p0.2 mg/L) concentrations. 3.3. Solubility, Kow, and pKa of the PPCPs The solubility of 58 of the 81 PPCPs ranged between 0.0002 mg/mL for morphine and 2000 mg/mL for atropine, a 107-fold difference (Table 3). The solubility of the PPCPs was arbitrarily categorized as low (p0.1 mg/mL), slightly soluble (0.2–10 mg/mL), moderately soluble (11–100 mg/mL), or highly soluble (X100 mg/mL). Of these, the PPCPs that have been reported in the aquatic environment shown in boldface

Table 3 Categorization of 58 diverse but commonly used pharmaceutical compounds based on reported solubility in water Common use

Solubility Low (p0.1 mg/mL)

Cosmetics Skeletal (biophosphonates) Antimicrobial

Analgesic and antiinflammatory

Sedative/ antipsychotic

Cardiovascular/ antihypertensive

Hematology (anticoagulant) Reproductive Anesthetics Gastrointestinal Triptans

Slightly soluble (0.2–10 mg/mL)

Moderately soluble (11–100 mg/ mL)

High (4100 mg/mL)

Acetophenone (5.5) Alendronate (33) Doxycycline (0.1), Sulfamethoxazole (0.01)

Dexamethasone (0.1), Ibuprofen (0.01), Morphine (0.0002), Paracetamol (0.1) Carbamazepine (0.01), Clonazepam (0.01), Prochlorperazine (0.015), Valium (0.01), Temazapam (0.1) Atorvastatin (0.1), Chlorothiazide (0.01), Digoxin (0.01), Furisemide (0.01), Quinidine (0.14), Simvastatin (0.03)

Acylovir (10), Amoxacillin (4), Ampicillin (1.39), Chloramphenicol (2.5), Ciprofloxacin (10), Fluconazole (1), Metronidazole (10), Norfloxacin (0.28), Trimethoprim (0.4) Aspirin (5)

Cephalexin (13.5), Clindamycin (100), Dicloxacillin (100), Didanosine (27.3), Ethambutol (100), Flucytozine (15), Tetracycline (33), Zidovudine (20.1)

Valaciclovir (174)

Baclofen (4.5), Phenobarbitone (1), Primidone (0.5)

Fluoxentine (33)

Atropine (2000)

Felodipine (4.53), Hydrochlorothiazide (1)

Enalapril (25), Quinapril (100), Ramipril (33), Timolol (33), Verapamil (83)

Warfarin (1000) Ethinylestradiol (0.01), Testoterone (0.023) Ketamine (0.2), Lidocaine (3.85) Rinitinide (1000) Rizatriptan (42), Sumatriptan (100)

a Solubility data (in parentheses; mg/ml) were mainly compiled from Yalkowsky and He (2003), http://chemfinder.cambridgesoft.com, and Kasim et al. (2004). The solubility classifications were arbitrarily set in this study to enable comparisons. In bold face are some of the compounds for which occurrence in the environment has been reported at concentrations provided in Table 1.

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in Table 3 also predominantly feature in the low or slightly soluble categories. Solubility did not correlate with the bioavailability of the PPCPs in the target organisms, the proportion of PPCPs that are excreted, or the concentration of the PPCPs in the aquatic environment. The log Kow values were available for only 28 of the 81 compounds studied and ranged between
3.66 for doxycycline and 5.69 for verapamil. Thirtytwo of the 81 compounds considered had readily available pKa values and these ranged between 0.8 for alendronate and 9.85 for zidovudine (Table 1). Neither the log Kow nor the pKa correlated with the bioavailability of the PPCPs in the target organisms, the proportion of the PPCPs that are excreted, or their concentration in the environment.

4. Discussion 4.1. Drug bioavailability, excretion, and degradability It is desirable that the half-life of the PPCP within or on the target organism be sufficiently long as to stay in contact with the intended target. In animal models, pharmacodynamics provides information on a chemical’s absorption, distribution, metabolism, and excretion, thus indicating the bioavailability of the compound in question. In other words, the bioavailability of a drug in these settings refers to the rate at which the drug becomes available and the extent to which the administered dose is ultimately absorbed. Absorption and subsequent bioavailability of pharmaceutical compounds in animal systems has also been linked to physico-chemical characteristics such as the intrinsic solubility of the molecule, the connectivity of the molecule, the electronic nature of the molecule (i.e., electron affinity, number of aromatic rings, dielectric and conformational energy), and the shape and size of the molecule (Turner et al., 2004). From such studies, it has been shown that molecular size generally limits the absorption of pharmaceutical compounds through membranes, their bioavailability changing in a cubic fashion with molar reflectivity which is based on molar mass and density. Bioavailability in the body also depends on the extent to which the drug dissolves and/ or gets metabolized at first pass. In the environment, bioavailability is influenced by the sorption kinetics, mobility (distribution), and degradability of the compound. Thus, under these conditions, it will ultimately depend on the capacity of the chemical to exchange between the liquid and the sorbent (solid) phases such as dissolved organic matter (in aquatic systems), soil, and sediments. Such exchanges depend on the sorption coefficient (Kd), hydrogen bonding, and the formation of complexes with existing particles (Tolls, 2001; Thiele-Bruhn, 2003;

123

Jjemba, 2002a, 2004). In aquatic and terrestrial environments, the physico-chemical interactions such as charge-transfer, H-bonding, and hydrophobic forces depend on the extent to which encapsulation into the humic substances occurs (Dorado and Almendros, 2001). The total molecular surface, hydrophobic molecular surface, and residual energies are also recognized as important factors in forecasting the sorptive behavior of both pesticides and herbicides (Almendros, 1995) and possibly play roles in the behavior of pharmaceutical compounds in the environment. The concentrations of the compounds in the environment correlated, albeit moderately, with the proportions of the parent compounds excreted. From an ecotoxicological perspective, because they occur in low doses, the concentrations in which these compounds occur in the environment in themselves may not be of prime importance unless they are coupled with the associated inherent biological activity (i.e., bioavailability), duration of exposure, and subsequent persistence (degradability). This contention is discussed further below (see Quantifying ecotoxicity). Surprisingly, excretion rates for the widely used reproductive compounds ethinylestradiol, mestranol, and bromocriptine are not readily available, despite the fact that some of these compounds are reported to occur very frequently in drinking water (Kolpin et al., 2002) and wastewater treatment effluents (Johnson and Sumpter, 2001). Absence of this information may stem from the possibility that these data were not required at the time that these PPCPs were approved for use. On another note, doubling the fluoride atoms in fluorinated compounds appears to reduce the proportions of the parent compound that are excreted possibly by increasing the solubility of the compound coupled with a reduced pKa. However, this particular correlation is based on only eight compounds (i.e., ciprofloxacin, fluconazole, flucytosine, genaconazole, norfloxacin, dexamethasone, fluoxentine, and atorvastatin) which have one or two fluorine atoms. The full implications of this observation are not very clear as the effects of fluorides are generally controversial (Chiba et al., 2002; Lu et al., 2000). It is logical to expect that a drug that is highly metabolized in animal systems (and therefore excreted in low proportions) is also more easily degraded in the environment. To that effect, a negative correlation between the proportions of the PPCP parent compound excreted and their concentrations in the environment is surprising and suggests that poorly excreted PPCPs may have an inherently low degradability in the environment. It is yet to be determined, as more data become available, how prevalent the poorly and moderately poorly excreted PPCPs that are not highlighted in Table 2, most of which are popular antihypertensive and antipsychotic drugs, are in the environment. When

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excreted, the metabolites are assumed to be less potent than the parent compounds. However, metabolites and early degradation products can also be of environmental concern. For example, whereas unipolar lipid regulators clofibrate, etofibrate, and fenofibrate are not detectable in sewage treatment plant effluents, their polar metabolites clofibric acid and fenofibric acid occur in effluents (Ternes, 1998; Stuer-Lauridsen et al., 2000). The metabolites may still have significant activity. For instance, although 300 -o-desmethyldoramectin and 8-ahydroxydoramectin are less toxic to daphnids than their parent compound, doramectin, both metabolites still have a high toxicity to this organism within 48 h (EC50 values of o0.0011 mg/L) (Boxall et al., 2003). Similar findings have been documented for anhydrotetracycline, a metabolite of tetracycline that had an EC50 for sludge bacteria that was threefold lower than the EC50 value for tetracycline (Halling-Sørensen et al., 2002). The anhydrotetracycline metabolite is also less susceptible to sorption, making it more likely to end up in surface and groundwater than its parent compound. This possibility has important ramifications as the few studies that have been done on the sorption and mobility of these compounds have primarily focused on the parent compounds and not their metabolites. In some instances that have not yet been well studied, the metabolites can be converted back to the parent compound once the metabolites reach the environment (Hirsch et al., 1999; Ternes et al., 1999; Ingerslev and Halling-Sørensen, 2000; Boxall et al., 2003). 4.2. Solubility and partitioning Water is an extremely important medium for transporting organic compounds in the environment (Jjemba, 2004). A clear understanding of the solubility properties of PPCPs directly relates to the partitioning of these compounds as defined by the octanol–water coefficient (Kow). Solubility refers to the maximum quantity of solute that dissolves in water at a specified temperature. It is driven by forces that determine the extent of dissolution of a compound in a liquid solvent (in this instance water). Dissolution increases the degree of entropy (i.e., randomness) or disorder in the system. It also increases the compatibility of intermolecular forces of attraction. Thus increased dissolution is accompanied by the breaking up of solute–solute and solvent–solvent intermolecular bonds and the subsequent formation of solute–solvent intermolecular bonds. The solubility values summarized in Table 3 were determined at slightly different temperatures of 20–25 1C but these temperatures fall within a range that is relevant to environmental conditions. It is clear that both the low and the highly soluble compounds make it into the environment. However, the solubility did not correlate with the bioavailability, the proportions of the PPCPs

excreted, or the concentrations of the compounds in the aquatic environment. The environment is a more open system than the body and solubility in the environment is widely influenced by a variety of factors such as pH, existing metals and salts, temperature extremes and thermoclines. Log Kow reflects the partitioning of the organic compounds between the natural organic phases and the water in addition to being an indicator of the lipophility of the compound. A high Kow is typical of hydrophobic (i.e., water-hating) compounds and, therefore, is more soluble in octanol than in water, whereas a low Kow signifies a compound that is soluble in water. An increase in the C/O and H/O ratios in practical terms implies the substitution of the oxygen atom with halogens, H or N, which in turn lowers the Kow, facilitates the transfer of the polar compound into cells, and enhances the bioaccumulation of the compound in question. Kow also affects sorption of the compound as a low Kow reduces the affinity of the compound on soils, sediments, minerals, and dissolved organic material, leading to enhanced bioavailability of the compound in the environment (Jjemba, 2004). Log Kow values of 1.72 or greater are associated with higher bioavailability in clinical settings (Kasim et al, 2004) as the respective compounds more easily penetrate fatty acid membranes. Kow and the solubility and dissociation constants are routinely used in environmental assessment to determine whether a compound is likely to amass in the environment (US FDA, 1998). However, recent studies by Tolls (2001) have indicated that Kow may not be a good descriptor of the behavior of PPCPs in the environment. 4.3. Quantifying ecotoxicity Risk assessment identifies potential hazardous consequences and determines both their likelihood to occur in a specific environment (i.e., exposure assessment) and their severity (i.e., toxicity) (NRC, 1994). It is quantitative and differs from risk management which involves weighing options to reduce the risk. Implied by this distinction is that risk assessment involves determining the probability of realizing harm as a result of exposure to a given hazard. Some jurisdictions have adapted the precautionary principle to address concerns about PPCPs in the environment (e.g., in drinking water and other food products). Implicit in adapting the principle to these compounds in the environment is the possibility that some hazards from these compounds have been identified, with the scientific evaluations yet unable to determine the degree of harm with sufficient certainty. It is important to point out that the benefits of these compounds to target organisms (e.g., human and livestock therapy) is of higher priority than their ecotoxicity. To that effect, therefore, the potential risks associated with these PPCPs in the environment need to

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meet a higher quantitative standard and guide the risk management process that is currently overly tilted to the precautionary principle. The data on prevalence and concentrations of PPCPs in the environment are comparatively more available for aquatic than for terrestrial systems. It is also apparent that their concentrations are typically quite low, i.e., nanogram and microgram ranges (Table 1), concentrations that are unlikely to elicit acute toxicity. On the contrary, the risks associated with these compounds have mostly been investigated under high doses. The occurrence of PPCPs in the environment is unique in the sense that, even though they are usually at such low concentrations, they are in most instances continuously discharging into a receiving aquatic system (Daughton and Ternes, 1999; Ferrari et al., 2003; Jjemba and Robertson, 2003). This scenario presents a sustained exposure of these compounds to nontarget organisms throughout their life cycle. This reality is at the core of the criticisms over how risk assessment for these compounds is currently done over a short duration, using high doses with lethality as the quantified outcome. Proper assessment of the risks requires considering the cumulative effects (chronic toxicity) as opposed to a one-time acute toxicity assay (Laskowski, 2001). What could be the toxicological effects of such low but sustained doses is still a poorly investigated toxicological question. Under the guidance for industry, chronic toxicity is recommended only for compounds with log Kow values p3.5 or either LC50/MEEC or EC50/MEEC ratios of X10, where MEEC is the maximum expected environmental concentration. Based on log Kow alone, the recommendation would exempt all of the PPCPs in Table 1 for which Kow values were compiled except verapamil and ethinylestradiol. Pharmaceutical compounds generally have low lipophilicity and, therefore, their log Kow values do not typically exceed 3.5. On the other hand, MEEC reflects a worstcase scenario by relying on the maximum which is not the relevant exposure at sustained low doses (i.e., chronic toxicity). The implications of the question about effects at sustained low doses can be illustrated by results from a preliminary experiment whereby increasing concentrations of three antimicrobial agents, i.e., chloroquine, quinacrine, and metronidazole, were mixed in a soil and soybean (Glycine max) was planted. While some extremely high doses of the compounds were lethal to the plants, lower doses led to the development of stunted plants (Jjemba, 2002b). In other instances, the exposure to ethylestradiol at low doses of 2 ng/L inhibited testicular growth in fish, 10 ng/L caused mouthpart deformities in Chiromonas riparius, and 100 ng/L caused changes in sex ratios from 1:1 to 2:1 females to males in Gammarus pulex (Pascoe et al., 2003). Pascoe et al. (2003) also showed an inhibition of the regeneration of

125

the digestive region in the cnidarian Hydra vulgaris to fully functional polyps by a sustained exposure for 17 days to low doses (10 mg/L) of amlodipine, diazepam, and digoxin. It is apparent from the studies summarized above that, in a number of instances, the effects from such low sustained doses can cause subtle effects. Based on the dataset in Table 4, using acute toxicity leads us to conclude that diclofenac is more toxic to Cariodaphnia dubia than carbamazepine. On the contrary, using the lowest observable effect concentration (LOEC) criteria leads us to the opposite conclusion for the same organism exposed to the same compound. EC50/NOEC ratios have also been used to assess the toxicity of compounds. For the same test organism, the larger the ratio, the less toxic is the compound to that organism. Thus, based on this ratio, carbamazepine is more detrimental than diclofenac to C. dubia (Table 4), also reinforcing the conclusions obtained when chronic toxicity is considered in the assessment process. Similarly, 17a-ethinylestradiol would be classified as less detrimental than ibuprofen and bromocyclen (to Daphnia sp.) Quantifying ecotoxicity should reflect an element of the overall residence time of the compound in question, its bioavailability, to the susceptible organisms, and its concentration in a particular environment (P.K. Jjemba and B.K. Robertson, unpublished). This important aspect is not reflected in the acute and chronic toxicity results discussed above but can be computed as an ecotoxicity potential (EP) from the relationship EP ¼ T=ðV ÞðNOECÞ; where T is the overall residence time of the compound in the environment, V is the concentration of the compound in the environment, and NOEC is the no observable effect concentration over a specific duration (e.g., the period for one life cycle). It is apparent from the above mathematical relationship that the ecotoxicity potential is a product of the fate (degradability), exposure factor (i.e., bioavailability), and the effect factor (i.e., susceptibility) of the compound in question. The lower the degradability (or the higher the persistence) and/or the higher the bioavailability of the PPCP to nontarget organisms, the higher is the magnitude of the ecotoxicity potential. Using the published data compiled in Tables 1 and 4, the ecotoxicity potentials of carbamazepine, diclofenac, ethinylestradiol, and ibuprofen on C. dubia, Danio rerio (zebrafish), and Daphnia magna were calculated by simulating a continuous discharge (concentrations in column 9 in Table 1) over 365 days. The calculated EP values presented in Table 4 provide a basis for comparison between different pharmaceutical compounds in a particular environment and show that Daphnia is very much more sensitive to ethinylestradiol than to

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1.2 0.37 — ND ND 3 — — — 3.5

Daphnia

17 aEthinylestradiol Ibuprofen

Bacitracin Bromocyclen

V. fischeri C. dubia D. rerio Diclofenac

D. magna L. machrochirus V. fischeri D. magna D. magna

ND ND ND 5000 (?) ND 9060 (48 h) ND 12,300 (5 min) 30,000 (48 h) 353 (?) Mortality ? Microtox ? Reproduction

3,000 (48 h) 10,000 ND ND 100

Halling-Sørensen Halling-Sørensen Halling-Sørensen Halling-Sørensen Halling-Sørensen

et et et et et

al. al. al. al. al.

(1998) (1998) (1998) (1998) (1998)

500 11 ND 105

10

Halling-Sørensen et al. (1998)

— 0.78 0.19 ND 23 — ND 2000 (7 days) 8,000 (10 days) 11,454 (0.5 h) 22,704 (48 h) ND

ND 1,000 (7 days) 4,000 (10 days)

Ferrari et al. (2003) Ferrari et al. (2003) Ferrari et al. (2003)

— 15.7 0.02 — 3108 — ND 100 (7 days) 50,000 (10 days) 481,000 (0.5 h) 77,700 (48 h) ND V. fischeri C. dubia D. rerio Carbamazepine

Bioluminescence (Microtox) Mobility inhibition Hatching and larval mortality Bioluminescene Mobility inhibition Hatching and larval mortality Reproduction

NOEC LOEC

Chronic criteria Acute criteria (EC50)

ND 25 (7 days) 25,000 (10 days)

Ferrari et al. (2003) Ferrari et al. (2003) Ferrari et al. (2003)

Calculated ecotoxicity potential (EP) EC50/NOEC ratio Reference Toxicity level (mg/L) Trait assayed Test organism Compound

Table 4 Acute and chronic toxicity of several pharamaceutical compounds to selected nontarget organisms

EC50, concentration which causes 50% of effect; LOEC, least observed effect concentration; NOEC, no observed effect concentration; ND, not determined. The values in parentheses indicate the duration of the assay. EP ¼ T/(V)  (NOEC) where T ¼ 365 days (i.e., all year discharge) and V is concentration in the environment that is given in Table 1.

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ibuprofen. Likewise, C. dubia is more sensitive to carbamazepine than to diclofenac, whereas D. rerio is more sensitive to diclofenac than to carbamazepine. These more informative conclusions cannot be ascertained based on acute toxicity alone and go a step further from those obtained based on LOEC as they make use of the actual concentrations that are encountered in the environment with exposure over a realistic duration.

5. Conclusion In summary, excretion is the major route through which PPCPs get into the environment. However, the drugs that have a low proportion of the parent compound excreted also display a higher concentration in the aquatic environment, suggesting that the low excretion proportions may represent higher recalcitrance in the environment. The data base on PPCP concentrations in the environment is still small but it is apparent that the concentrations are typically low. Physico-chemical characteristics such as solubility, log Kow, and pKa are used in pharmacokinetic studies in clinical settings and their use has been transplanted, seemingly wholesale, in predicting the behavior of PPCPs in environmental assessment by the FDA. The solubility, log Kow, and pKa values compared in this study did not correlate with any factor of environmental significance, notably the proportion of PPCPs excreted in the environment or their concentrations in the environment. These findings underscore the need for research into the behavior of PPCPs in the environment and their ecotoxicity. Current approaches in assessing the risks from PPCPs in the environment lay emphasis on acute toxicity but because these compounds typically occur at very low concentrations over a long time an ecotoxicity potential assessment that takes into account varying biological activity is proposed. The ecotoxicity approach enable us to develop a quantitative score that can enable comparisons across PPCPs and organisms.

Acknowledgments The author is grateful to the three anonymous reviewers for the helpful comments. Sincere help with statistical analyses and lively discussions from Jinghui Liu (Department of Environmental Health, University of Cincinnati) are also greatly appreciated. References AAPC, 1990. American Academy of Pediatrics Committee on Drugs— Naloxone and route of administration for infants and children:

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