ARTICLE pubs.acs.org/est
Identifying New Persistent and Bioaccumulative Organics Among Chemicals in Commerce II: Pharmaceuticals Philip H. Howard*,† and Derek C. G. Muir‡ † ‡
SRC, Inc. Chemical, Biological, and Environmental Center (CBEC), 7502 Round Pond Road, North Syracuse, New York, and Aquatic Ecosystem Protection Research Division, Environment Canada, 867 Lakeshore Road, Burlington, Ontario
bS Supporting Information ABSTRACT: The goal of this study was to identify commercial pharmaceuticals that might be persistent and bioaccumulative (P&B) and that were not being considered in current wastewater and aquatic environmental measurement programs. We developed a database of 3193 pharmaceuticals from two U. S. Food and Drug Administration (FDA) databases and some lists of top ranked or selling drugs. Of the 3193 pharmaceuticals, 275 pharmaceuticals have been found in the environment and 399 pharmaceuticals were, based upon production volumes, designated as high production volume (HPV) pharmaceuticals. All pharmaceuticals that had reported chemical structures were evaluated for potential bioaccumulation (B) or persistence (P) using quantitative structure property relationships (QSPR) or scientific judgment. Of the 275 drugs detected in the environment, 92 were rated as potentially bioaccumulative, 121 were rated as potentially persistent, and 99 were HPV pharmaceuticals. After removing the 275 pharmaceuticals previously detected in the environment, 58 HPV compounds were identified that were both P&B and 48 were identified as P only. Of the non-HPV compounds, 364 pharmaceuticals were identified that were P&B. This study has yielded some interesting and probable P&B pharmaceuticals that should be considered for further study.
’ INTRODUCTION In 2006, we published a paper1 challenging environmental chemists to start looking for new persistent and bioaccumulative (P&B) chemicals. In 2010, we published an additional paper2 identifying 610 compounds that are potential P&B chemicals from a list of 22 000 commercial chemicals from the Canadian Domestic Substances List (DSL) or from the Toxic Substance Control Act (TSCA) with reported production ranges in 1986, 1990, 1994, 1998, 2002, and 2006 under the Inventory Update Rule (IUR). Our motivation was that analytical chemists would be more successful in identifying new P&B chemicals if they knew what they were looking for and several successes have been noted in the latter paper.2 The screening of thousands of chemicals has become possible due to the developments in Quantitative Structure Property Relationships (QSPRs) and the availability of large chemical structural databases. The approach we used to identify the 610 commercial organic chemicals relied on QSPR, expert scientific judgment, and several large databases that had production volume information on the chemicals being considered. Unfortunately, there are no large chemical structural databases with production volume information for pharmaceuticals so a different approach was necessary in addition to using QSPR and expert scientific judgment. Pharmaceuticals are different from general commercial chemicals in that they are designed to have biological effects and r 2011 American Chemical Society
be bioavailable.3 Their release to the environment varies depending upon their application. The major release of veterinary medicines is believed to be through emissions to soil and surface waters from intensive livestock treatments and aquaculture.4 The major release of human-use pharmaceuticals is from discharge to sewage treatment plants and septic systems of the pharmaceutical and its metabolites after use;5 the amount reaching the environment varies by the amount metabolized during use (90%),3 removal during sewage treatment, amount adsorbed to sewage sludge and recycled as fertilizer on soil, and amount coming to sewage treatment plants from manufacturing facilities and hospitals.3 Several investigators have evaluated the thousands of available pharmaceuticals based upon varying criteria mostly focusing on relative risk. Sanderson et al.6 developed a prioritization environmental risk assessment tool that they applied to approximately 3000 pharmaceuticals based on (1) their predicted aquatic toxicity using Quantitative Structure Activity Relationships (QSARs); (2) predicted removal in sewage treatment plants; (3) predicted potential to bioaccumulate; and (4) number of compounds in each use class. Kools and co-workers7 ranked 741 veterinary medicines Received: April 8, 2011 Accepted: July 8, 2011 Revised: July 7, 2011 Published: July 08, 2011 6938
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Environmental Science & Technology registered in the European Union using four phases: (1) usage estimation; (2) characterization of exposure to soil, dung, surface water, and aquatic organisms depending on exposure scenarios; (3) characterization of ecotoxic effects based on therapeutical doses; and (4) risk characterization, which is the ratio of exposure to effects (risk index), and ranking. If past experience is used as a guide chemicals become new emerging contaminants because of widespread detection, biomagnification, evidence for increasing trends, and high persistence, and not because much is known about their toxicity. Indeed, as noted above, of the three previous risk-based prioritizations, one used QSAR ecotoxicity values and the other two relied on therapeutic doses because of the lack of toxicity information. For some pharmaceuticals the therapeutic dose may be relevant to toxic effect in the environment especially if the effect takes place at very low concentrations (e.g., estrogenic activity and endocrine disruption effects), but most therapeutic doses for drugs (e.g., anti-inflammatory, antibiotics, beta-blockers, lipid regulators) provide little insight to carcinogenicity, mutagenicity, and reproductive and developmental effects. Even after a group of chemicals is detected in the environment, there still is a limited amount of toxicity information as illustrated by the fact that despite widespread detection of pharmaceuticals in surface waters and in biosolids,3 there is a major lack of chronic ecotoxicity data to assess impacts of pharmaceuticals in aquatic and terrestrial environments.6,8 Most human and veterinary pharmaceuticals go through wastewater treatment3,5 or land disposal4 for which biodegradation will be the determining process for persistence. Pharmaceuticals generally are not designed to bioaccumulate, but there are many drugs that are lipid soluble and therefore potentially bioaccumulative in the environment and this would be particularly important for pharmaceuticals that may have ecotoxicological effects or have human exposure through food (e.g., fish). Current guidelines require environmental fate and effects analysis if concentrations in surface waters are predicted to exceed 10 ng/L in Europe9 and g1 μg/L in WWTP effluent in the U.S.10 For the above reasons, we have focused our prioritization on pharmaceuticals that appear to be P&B chemicals to give analytical chemists targets for new emerging contaminants.
’ METHODS Development of Database of Commercial Pharmaceuticals. A list of commercial pharmaceuticals was developed by
collecting approximately 2700 drugs identified by the U.S. Food and Drug Administration (FDA)11 (this FDA database and the veterinarian database discussed below include prescription and over-the-counter drugs approved for sale as well as discontinued drugs; they do not include metabolites, dietary supplements, or drugs not approved by FDA or sold outside the U.S.) and combining it with chemicals that have significant production and use (suggest greater potential for release to the environment). We included a list of drugs in the Top 300 Rx Prescriptions from the 2005 database, available from RxList12 (as of February 2, 2010 the present Web site only lists 200 drugs). Of the Top 300, 250 were individual organic chemicals that could be added to the database. Also included was a list of the Top 200 bestselling drugs obtained from Wikipedia13 which is from MedAdNews 200 World’s Best-Selling Medicines.14 Both the order of sales (highest to lowest) and the millions of dollars in sales for 2006 were captured for 198 drugs. Also added was the
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volume of 29 pharmaceuticals sold in France (kg/yr in 2004), UK (kg/yr in 2004), and Spain (kg/yr in 2003) reported in Monteiro and Boxall.3 In addition, the Top 10 prescribed and Top 10 selling pharmaceuticals were identified in a report prepared for The Kaiser Family Foundation.15 In addition, a list of 375 veterinary drugs regulated by the U.S. FDA Center for Veterinarian Medicine16 was also included. This added 165 new drugs (210 drugs were both human and veterinary drugs) for a total of 3193 drugs in the database. Also added were chemicals that were identified as pharmaceuticals in the Hazardous Substances Data Bank (HSDB)17 (noted as HSDB Drug List in the comment field). Corresponding two-dimensional structure and simplified molecular input line entry specification (SMILES) notations were obtained from the National Library of Medicine ChemIDplus database.18 All relevant drugs available from the sources cited above were added to a substructure searchable database using ISIS/Base chemical software.19 Pharmaceuticals were entered into the database using the CAS Registry Number (CASRN) as the unique identifier. A total of 3193 were entered into the database having the following fields where the data were available or could be estimated from the structure using EPI Suite software:20 CASRN; chemical name; chemical structure; chemical formula; molecular weight; SMILES notation; KOWWIN estimated log octanol water partition coefficient (log Kow) (in many instances both the dissociated and undissociated form of pharmaceuticals was estimated); experimental log Kow; log bioconcentration factor (BCF, from the BCFBAF program); three biodegradation estimates from the BIOWIN program; an indication of whether the pharmaceutical had already been detected in the environment; comment field for informational notations for individual pharmaceuticals (Top 300 selling pharmaceuticals were noted in the comment field); rank order of sales for 2006; millions of dollars of sales for 2006; companies producing the drug; and medical use. A total of 275 pharmaceuticals in the database (and/or their metabolites) have been detected in environmental media (discussed in the Supporting Information (SI) and presented in Table S-1). Also, 10 pharmaceuticals have been detected in environmental media but are not in the database (see Table S-2); these chemicals may be registered in countries other than the U. S. and European Union. Structures were collected for 2584 chemicals in the database. Most of these drug structures that are not in the database are various naturally occurring substances such as insulin or venom isolates as well as therapeutic biologicals. Estimates of drugs without structures were not possible because the structure is necessary for EPI Suite software to work. Many of the drugs in the U.S. FDA list include free acids or bases as well as a number of salts of the parent drug. For example, there are five forms of metoprolol, a highly used beta-blocker (see SI, Table S-3).
’ RESULTS AND DISCUSSION Selection of Potential Persistent (P) and Bioaccumulative (B) Pharmaceuticals. All of the pharmaceuticals in the database
were individually examined to see if they had the potential for being persistent (P) and/or bioaccumulative (B). All the pharmaceuticals with the exception of some inorganics and metal compounds had estimated, and in some cases measured, octanol/ water partition coefficients—the estimated values were provided by the KOWWIN program from the EPI Suite software.20 6939
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Environmental Science & Technology For pharmaceuticals that had log Kow values of approximately 3 or more, the chemical was marked as potentially B. Under the proposed rule for persistent, bioaccumulative, and toxic (PBT) chemicals,21 the U.S. Environmental Protection Agency (U.S. EPA) has established a BCF range of >100 and 6. A more detailed discussion of BCF/BAF criteria is provided by Gobas and co-workers.22 Each pharmaceutical was marked as potentially persistent if (1) the BIOWIN1 or BIOWWIN5 models from EPI Suite were less than 0.5 (50% probability that biodegradation will not be fast); or (2) scientific judgment of the chemical structure identified a number of substructures that suggest persistence using the approaches of Tunkel et al.23 (e.g., persistent: highly halogenated, highly branched, nitroaromatic; biodegradable: straight-chain aliphatic compounds, esters, acids, hydroxyl functional groups). Generally pharmaceuticals with carboxylic ester functions were not give a P category unless the remaining acid appeared to be persistent (halogenated substituted, highly branched, etc.). The table of the 275 drugs detected in the environment (see Table S-1) was then examined to see if there were some properties of the pharmaceuticals that could be used to predict which other drugs may be detected in the environment. Table S-1 also included information on commercial use to see if the sales or production quantity correlated with detection in the environment. Of the 275 drugs detected in the environment, 92 were rated as potentially bioaccumulative, 121 were rated as potentially persistent, and 99 were high production volume (HPV) pharmaceuticals. HPV pharmaceuticals were either in the Top 200 pharmaceuticals in 2006 or Top 300 pharmaceuticals in 2005 or had reported production quantities in Europe.3 They are the combination of the Top 200 (198 compounds—two did not have structures that could be drawn and were left out), the Top 300 (258 compounds—the rest of the drugs were not discrete organics), and the 29 drugs with European production in France, UK, and Spain—for a total of 399 compounds (there is some overlap of chemicals within the various lists). Interestingly, 8 of the 275 chemicals were “cycline” derivatives, all of which had very low log Kow values but were predicted to be persistent—not surprising considering the four fused rings (persistent),23 but they do have several functional groups that tend to make compounds biodegradable (acids, alcohols).23 Of the 399 HPV compounds, 102 compounds have already been detected in the environment (see HPV notation as indicated in Table S-1) and these were removed from the next series of searches. The remaining 297 HPV compounds were searched for pharmaceuticals that had both P and B codes—58 compounds were found and listed in Table 1. These pharmaceuticals have the highest potential for being the next emerging
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pharmaceutical contaminants since they are produced in large quantities and are potentially persistent and bioaccumulative. The remaining 238 HPV compounds were then searched for chemicals that were P but not B—these 48 compounds were also listed in Table 1. These 48 compounds have lower potential to be emerging pharmaceutical contaminants; however, they are potentially persistent and produced in large quantities. The CASRN and names of these 106 pharmaceuticals are listed in Table 1; their structures are listed in the Supporting Information (Table S-4). This leaves 2621 pharmaceuticals that are not HPV chemicals (399) nor already detected in environmental media (275 chemicals). This list of pharmaceuticals was searched to identify which ones were both P&B chemicals. Table S-5 in the Supporting Information lists the 364 chemicals in this category. These compounds also have the potential of being new emerging pharmaceutical contaminants since they are potentially P&B, but their commercial importance is unknown. Of the 106 pharmaceuticals in Table 1, some appear to have high priority for examination. Meclizine is a HPV antihistamine that looks particularly persistent (two tertiary amines, several aromatic, and one cyclic ring) and has a high log Kow (5.87) which would suggest a BCF greater than 3000. Amiodarone is an antiarrhythmic agent that has a high estimated log Kow (8.81) and BCF (1800) and has a diiodo substituted benzene ring (which suggests persistence) and is similar to the two iodinated X-ray contrast media chemicals in Table S-2 that have been detected in environmental media but are not in the U.S. FDA databases; in fact, because the database is substructure searchable, we were able to easily identify 45 chemicals in the total database that have di- or triiodo substituted benzene rings. One of these is Levothyroxine (thyroxine), a pharmaceutical used for hypothyroidism, and is one of the Top 10 selling medications—it has recently been detected in wastewater treatment plant effluent24 (see Table S-1). It is one of the few pharmaceuticals that are a high priority from other previous studies (see next section, Comparison to Other Studies). The bicyclic structure of memantine, which is used for the treatment of Alzheimer’s disease, appears particularly persistent to microbial pathways, although the log Kow (3.34) is not particularly high. Eleven of the pharmaceuticals in Table 1 have seven member rings which are not well understood in terms of their contribution to persistence23 and would suggest the need for biodegradation studies. In fact, the environmental biodegradation of most of the selected pharmaceuticals is not well characterized. In an initial literature search conducted in 2009, we found 230 pharmaceuticals that had been detected in environmental media. Thus, the 45 pharmaceuticals that have been newly detected in the past few years indicate that this area of research is receiving considerable attention. Of these new emerging contaminant pharmaceuticals, 36 out of 45 were rated as P and 23 out of 45 were rated as B. This high percentage of P&B assessments for the newly identified pharmaceuticals provides support for our approach being used for selection. Back in 2009 none of the erectile dysfunction drugs; sildenafil, vardenafil, and tadalafil (active agents of Viagra, Levitra, and Cialis, respectively) had been detected even though we had selected them as HPV P&B or P pharmaceuticals. Recently Nieto et al.25 have detected these in wastewater or sewage sludge in Spain. In selecting potential P&B pharmaceuticals, focus was placed on chemicals whose whole structure or part of the structure would be persistent. For chemicals for which only part of the 6940
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Table 1. High Production Volume Pharmaceuticals That Have Not Been Detected in the Environment but are Estimated to be Persistent and/or Bioaccumulativea ID
name
Bb
KOWWINc
Pb
BIOWIN1d
BIOWIN5e
commentb
000058-33-3
Promethazine DM
x
2.97
x
0.3895
0.2709
Top 300
000060-87-7 000068-88-2
Promethazine Hydroxyzine
x x
4.49 2.36
x x
0.2016 0.0844
0.238 0.0633
Top 300 Top 300
000077-19-0
Dicyclomine
x
6.05
x
0.3852
0.5261
Top 300; ester might
000086-13-5
Benztropine
x
4.28
x
0.3047
0.0968
Top 300
000118-42-3
Hydroxychloroquine
x
3.03
x
0.1249
0.0746
Top 300
000846-49-1
Lorazepam
x
3.91
x
0.5982
0.114
Top 300; seven member
001095-90-5
Methadose
x
1.4
x
0.6619
0.0089
Top 300; free amine KOWWIN 4.17,
001951-25-3
Amiodarone
x
8.81
x
0.9803
1.4563
Top 300
002192-20-3
Vistaril
x
2.68
x
0.2914
0.1199
Top 300; free amine
006202-23-9
Cyclobenzaprine HCl
x
2.02
x
0.5991
0.0961
Top 300; look P, free
019794-93-5 028981-97-7
Trazodone Alprazolam
x x
3.21 3.87
x x
0.0224 0.6009
0.2729 0.1488
Top 300 Top 300
041340-25-4
Etodolac
x
3.93
x
0.2615
0.1401
Top 300
058581-89-8
Astelin
x
5.72
x
0.2327
0.3812
Top 300
061337-67-5
Mirtazapine
x
3.03
x
0.1108
0.2288
Top 300
071125-38-7
Meloxicam
x
3.5
x
1.0038
0.0375
Top 300; BIOWIN5 - P
rank 2006b
sales 2006b
130
818
metabolize - P?
ring looks P
BIOWIN1 0.47
KOWWIN 3.55 (Flexeril)
amine KOWWIN is 4.79
- amide may degrade 078246-49-8
Paxil CR
x
2.89
x
0.2138
0.4061
Top 300; log Kow slightly low for B; free amine KOWWIN 4.74
078628-80-5
Tervinafine hydrochloride
x
3.04
x
0.4075
0.1397
(Lamisil)
Top 300; P questionable with olefin and acetylenic functional groups
082640-04-8
Raloxifenehydrochloride
x
4.57
x
0.8751
0.0852
Top 300; BIOWIN5 - P
083919-23-7
Nasonex
x
3.38
x
0.1126
0.3964
Top 300; ester maybe
093479-97-1
Glimepiride (Amaryl)
x
4.7
x
0.5686
0.5467
degrade to alcohol Top 300; BIOWIN5 - P
165
567
093957-54-1
Fluvastatin sodium
x
4.85
x
0.1318
0.0346
Top 300; BIOWIN - P
141
725
158
619
50
1900
8
4364
35 54
2372 1768
(Evista)
(Lescol XL) 098319-26-7
Finasteride (Proscar)
x
3.2
x
0.4387
0.2549
Top 300
099294-93-6
Zolpidem tartrate
x
3.85
x
0.97
0.0098
Top 300; might be P,
124750-99-8
Losartan potassium
x
3.01
x
0.6856
0.3808
Top 300
124937-52-6
(Cozaar) Tolterodine tartrate
x
5.73
x
0.7406
0.1802
Top 300; tolterodine might
(Ambien)
BIOWIN5 - zolpidem
(Detrol LA)
be P but has a phenol
129722-12-9
Abilify
x
5.3
x
0.1554
0.1674
Top 300
132539-06-1
Olanzapine (Zyprexa)
x
2.56
x
0.2145
0.298
Top 300; Top 10 Sales; log Kow a little low
137071-32-0
Elidel (Pimecrolimus)
x
4.39
x
0.7732
0.4309
Top 300; P? ester, lots of
138402-11-6 139481-59-7
Irbesartan (Avapro) Candesartan cilexetil
x x
5.31 4.79
x x
0.6782 0.8466
0.1309 0.0585
Top 300 Top 300; P? BIOWIN5
OH, but highly branched
(Atacand)
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Table 1. Continued ID
name
Bb
KOWWINc
Pb
BIOWIN1d
BIOWIN5e
commentb
144689-63-4
Benicar
x
3.29
x
0.5265
0.4835
Top 300; not P ester, t-butyl alcohol
151767-02-1
Montelukast sodium
x
5.71
x
0.0456
0.4669
Top 300
x
3.19
x
0.4
rank 2006b
sales 2006b
73
1370
(Singulair) 155141-29-0
Rosiglitazone maleate
Top 300
(Avandia) 163222-33-1
Ezetimibe (Zetia)
x
3.94
x
0.5827
0.0712
Top 300
48
1929
169590-42-5
Celecoxib capsules
x
3.47
x
0.1002
0.2549
Top 300
44
2039
191114-48-4
(Celebrex) Tulathromycin
x
4.08
x
0.9827
0.5082
Top 300
219861-08-2
Lexapro (Escitalopram
x
3.74
x
0.64
0.03
Top 300
224789-15-5
Levitra
x
3.78
x
0.9316
0.407
444313-53-5
Vytorin (Ezetimibe mixture
x
3.94
x
0.58
47
1955
oxalate) Top 300 Top 300; ezetimibe - log Kow
with Simvastatin)
and BIOWIN
067392-87-4
Yasmin
x
4.02
x
0.2023
0.538
P? has an ester but quat Cs
082626-48-0 084449-90-1
Zolpidem Raloxifene
x x
3.85 6.09
x x
0.9754 0.6872
0.0098 0.0523
BIOWIN5 suggests P
106
998
31 91
2545 1159
091374-21-9
Ropinirole
x
3.03
x
0.7378
0.1405
BIOWIN5 - P
188
496
099614-02-5
Ondansetron
x
3.95
x
0.724
0.0742
P? BIOWIN5
62
1567 1499
104987-11-3
Tacrolimus
x
3.03
x
0.5
0.2336
Perhaps not P - ester
66
111025-46-8
Pioglitazone
x
3.96
x
0.7192
0.2338
BIOWIN5 - P
24
2880
114798-26-4
Losartan
x
4.01
x
0.6856
0.3808
19
3163
122320-73-4
Avandia, Avandamet,
x
3.19
x
0.4041
0.1526
23
3043
124937-51-5
Avandaryl Tolterodine
x
5.73
x
0.7406
0.1802
96
1100
128196-01-0
Escitalopram
x
3.74
x
0.6464
0.0288
29
2696
146939-27-7
Ziprasidone
x
3.6
x
0.2775
0.487
138
758
147536-97-8
Tracleer
x
3.06
x
0.8555
0.0764
145
717
152459-95-5
Imatinib
x
3.01
x
0.0215
0.8187
30
2554
HSDB Drug List
154598-52-4
Efavirenz
x
4.69
x
0.21
0.068
158966-92-8
Singulair
x
9.52
x
0.0456
0.4669
P? Carbamate may biodegrade
161973-10-0
Nexium (Esomeprazole magnesium)
x
3.4
x
0.8
0.1
Top 10 Sales; KOWWIN and BIOWIN for Esomeprazole
000050-06-6
Phenobarbital
1.33
x
0.5811
0.1798
Top 300
000059-30-3
Folic acid
2.81
x
0.4254
0.3939
Top 300
000077-36-1
Chlorthalidone
1.01
x
0.4301
0.0377
Top 300 Top 300
135
791
15
3579
4
5182
- P - BIOWIN5
000094-78-0
Phenazopyridine
2.77
x
0.0898
0.2595
000364-62-5
Metoclopramide
1.69
x
0.3254
0.1211
Top 300
000396-01-0 001622-61-3
Triamterene Clonazepam
0.8 2.53
x x
0.0538 0.3199
0.4733 0.2047
Top 300 Top 300
004205-90-7
Clonidine
1.89
x
0.2732
0.1041
Top 300
018472-51-0
Chlorhexidine
0.33
x
0.3748
0.6728
Top 300; chlorhexidine - maybe P; log Kow is 0.35;
gluconate
BIOWIN1 is 031677-93-7
Wellbutrin SR
036505-84-7 041100-52-1
Buspirone Namenda
0.33
0.75
x
0.2565
0.0565
Top 300
2.31 0.15
x x
0.0304 0.093
0.1172 0.3954
Top 300 Top 300; log Kow is for
(Budeprion SR)
N+HHH, free amine is 3.34 - could be B 051322-75-9
Tizanidine
1.07
x
0.2096
0.1442
Top 300
059803-98-4
Alphagan P
0.58
x
0.2644
0.0756
Top 300
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Table 1. Continued ID
name
063590-64-7 079559-97-0
Terazosin Sertraline hydrochloride
080474-14-2
Flonase
Bb
KOWWINc
Pb
BIOWIN1d
BIOWIN5e
commentb
1.47 2.18
x x
0.2507 0.2742
0.0033 0.2264
Top 300 Top 300; Top 10 Sales
2.49
x
0.1133
0.4086
Top 300; P questionable
rank 2006b
sales 2006b
84
1219
1843
(Zoloft) - ester and thioester, but two F’s 084057-84-1
Lamictal
0.99
x
0.2067
0.3281
Top 300
51
086386-73-4
Fluconazole
0.25
x
1.2022
0.0597
Top 300
196
435
097240-79-4
Topamax
0.33
x
1.7026
0.0209
Top 300; not stable under acid conditions O C O
45
2027
103628-48-4
Sumatriptan succinate
1.05
x
0.45
0.28
Top 300; see CASRN
42
2049
197
433
133
799
unstable in acid (Imitrex)
103628-46-2; KOWWIN and BIOWIN for Sumatriptan
111974-72-2
Quetiapine fumarate
1.94
x
0.1711
Top 300
112529-15-4
(Seroquel) Pioglitazone hydrochloride
2.11
x
0.7018
0.3516
Top 300; P questionable
(Actos) 124832-27-5
Valtrex
3.49
x
0.1688
0.1271
Top 300; P? ester
136310-93-5
Spiriva
1.76
x
0.1655
0.1379
Top 300; P? epoxide and
- P metabolite? ester, but has bicyclic ring and tertiary OH 136434-34-9 138786-67-1
Cymbalta Protonix
2.83 1.88
x x
0.7205 0.3377
0.0765 0.2148
Top 300 Top 300
161796-78-7
Esomeprazole sodium
0.7
x
0.3332
0.2065
Top 300
(Nexium) 186826-86-8
Vigamox
0.8
x
0.47
0.0678
Top 300
287714-41-4
Crestor
2.48
x
0.1531
0.165
Top 300; acid chain may biodegrade
000050-35-1
Thalidomide
0.24
x
0.6246
0.0287
HSDB Drug List; no P data in literature
028523-86-6
Sevoflurane
1.75
x
0.7359
0.2388
081403-80-7
Alfuzosin
1.86
x
0.2497
0.0671
090357-06-5
Bicalutamide
2.3
x
0.4545
0.1255
090566-53-3
Fluticasone
1.4
x
0.0342
0.1818
100286-90-6
Irinotecan
0.81
x
0.7855
0.4771
HSDB Drug List
195
443
86
1206
HSDB Drug List
164
575
P possible - several
122
903
76
1315
fused rings, but
hydrochloride
ester and carbamate functional group HSDB Drug List
103628-46-2
Sumatriptan
1.05
x
0.4563
0.2794
105102-22-5
Mometasone
2.62
x
0.242
0.3079
116
944
111974-69-7
Quetiapine
1.94
x
0.1711
0.0087
16
3560
112809-51-5
Letrozole
2.22
x
1.2257
0.0791
143
722
Two nitrile, triaryl aromatic
120511-73-1
Anastrozole
2.37
x
0.854
0.1049
P - tertiary C, nitrile
65
1508
130693-82-2
Dorzolamide
1.49
x
0.5757
0.2899
BIOWIN5 - P
148
697
137234-62-9
hydrochloride Voriconazole
1.57
x
1.978
0.1097
183
515
147127-20-6
Tenofovir
1.57
x
0.0297
0.2335
May not be P
150
689
165800-03-3
Linezolid
1.26
x
0.486
0.0888
HSDB Drug List; may not
136
782
- phosphate acid be P - carbamate 6943
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Environmental Science & Technology
ARTICLE
Table 1. Continued ID
name
Bb
KOWWINc
Pb
BIOWIN1d
BIOWIN5e
183321-74-6 186691-13-4
Erlotinib Spiriva
2.79 0.24
x x
0.1044 0.2031
0.0334 0.0968
354812-41-2
Avelox, Avalox
0.95
x
0.2988
0.0832
commentb P? ester, but bicyclic
rank 2006b
sales 2006b
155 55
649 1735
129
822
and tertiary OH a
Applies to peer-reviewed literature searched up to April 2011. b These are discussed in the Results and Discussion section. c KOWWIN: estimates the log octanol water partition coefficient (log Kow) of chemicals using an atom/fragment contribution method; a high log Kow indicates a compound will partition into organic matter rather than water. d BIOWIN1: Biodegradation Probability Program (BIOWIN) includes a linear probability model that estimates the rapid aerobic biodegradation of organic chemicals. e BIOWIN5: is the Japanese MITI (Ministry of International Trade and Industry) linear model that estimates the probability of rapid aerobic biodegradation of organic chemicals. All of the above programs are in the EPI Suite software.20
structure appears to be persistent by the “rules of thumb” for biodegradation,23 it may be desirable to use computer-aided software to predict the degradation pathways and examine the transformation products for P&B properties. This has recently been done by Kern et al. for a number of pesticides and pharmaceuticals.26,27 In addition, because of the unique way that pharmaceuticals enter the environmental (many are metabolized by humans or animals before being released), metabolites from mammalian metabolism should also be reviewed for P&B properties. Comparison to Other Studies. Although the prioritization environmental risk assessment tool by Sanderson et al.6 assessed 2986 pharmaceuticals in 51 pharmaceutical classes, the results were only presented by class not by individual chemical. Therefore, it is difficult to compare our results with theirs. Their methodology was based primarily on predicted aquatic toxicity using the ECOSAR (Q)SAR model in EPI Suite that is derived from the log Kow values (as well as chemical classes)20 as is our bioaccumulation evaluation. Thus, as the log Kow increases so will the aquatic toxicity (until it exceeds the water solubility) and predicted bioaccumulation. Kools and co-workers7 ranked 233 veterinary medicines from Europe that had sufficient information on the following exposure scenarios: intensively reared animals, pasture animals, companion animals, and aquaculture. From the treatment regimes, predicted environmental concentrations (PECs) were calculated. Because ecotoxicity data were generally lacking, the authors used a therapeutic dose (TD) as a surrogate for ecological effects. They then used a risk index by dividing the PEC by the TD in soil and water. Of the 65 veterinary medicines mentioned in the publication, 64 were in our database. However, only one chemical, Levothyroxine (thyroxine), was in their priority list and in our HPV and P&B chemicals and previously detected in the environment (see Table S-1). Thirteen of the 65 veterinary medicines were listed in the non-HPV and P&B (364), but only 2 were listed by U.S. FDA as veterinary medicines (lasalocid and moxidectin). Kostich et al.28 used marketing and pharmacology data to prioritize future research efforts. The authors started with 371 active pharmaceutical ingredients with 2004 marketing data and divided it by therapeutic dose rates. For 50 pharmaceuticals, metabolic inactivation was used. Of the 54 pharmaceuticals listed in the article, 53 were in our database, but only 3 chemicals were in Table 1 of P&B or P chemicals: linezolid, fluticasone, and ketoconazole. Kumar and Xagoraraki29 ranked 57 pharmaceuticals and 43 personal care product and endocrine disrupting chemicals detected in U.S. streamwater/source water and finished drinking water—they used a range of criteria including occurrence,
treatment, bioaccumulation/ecotoxicity, and mammalian health effects. The authors did not indicate how they had selected the pharmaceuticals other than implying that many of them had been detected in surface or drinking water. Of the 57 pharmaceuticals, 43 were in Table S-1 which lists the 275 pharmaceuticals that have already been detected in the environment. The other 13 pharmaceuticals were not found in Table S-1 or Table 1 of P&B or P chemicals which are potential targets for analytical chemists to pursue—this is probably due to ecotoxicity and mammalian health effects criteria used by the authors. However, atorvastatin and fluoxetine were in Table S-5 which includes P&B chemicals that were non-HPV pharmaceuticals. These authors were the only ones who attempted to prioritize pharmaceuticals using mammalian health effects criteria (i.e., carcinogenicity, mutagenicity, impairment of fertility, central nervous system acting, endocrine effects, immunotoxicity, and developmental effects), but the literature searches were mostly limited to the National Library of Medicine’s Hazardous Substances Data Bank and often had no data available. Conducting extensive mammalian health effects literature searches for thousand of pharmaceuticals in order to prioritize would be extremely labor intensive. Analytical Challenges. The combined 58 P&B and 48 P pharmaceuticals in Table 1 have not been reported previously in environmental samples (peer-reviewed articles searched as of April 2011). Analytical methodology to determine them at trace concentrations in water (ng/L) or in biota (ng/g) typically required for environmental impact assessment,30 has not been developed. A major challenge is the need for analytical methods encompassing structurally different pharmaceuticals and personal care products.31,32 A more difficult issue is the determination of metabolites released into the environment, which are often in the form of conjugates, as well as transformation products generated in the environment itself by biodegradation, photolysis, or hydrolysis.33,34 Nevertheless, progress in the trace analysis of pharmaceuticals and selected degradation products in environmental samples has been very rapid over the past 10 years particularly for aquatic media.31,33,35 Existing methods for the 275 individual pharmaceutical active ingredients that have been determined to date can likely be adapted and could be aided by new approaches such as computer-aided prediction of transformation products and detection with high mass resolution.26
’ ASSOCIATED CONTENT
bS
Supporting Information. Tables in the Supporting Information provide a list of 275 pharmaceuticals that have already been detected in the environment (Table S-1); a list of 10 pharmaceuticals that have been detected in the environment but are not present in the U.S. FDA or other commercial databases
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Environmental Science & Technology (Table S-2); various forms of metoprolol records found in the database (Table S-3); the CASRN, structure, and name of 106 pharmaceuticals from Table 1 (Table S-4); and 364 pharmaceuticals that are not-HPV or previously detected in the environment but are potentially P&B (Table S-5). This information is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Phone: 315-727-0679; fax: 315-452-8440; e-mail: howardp@ srcinc.com.
’ ACKNOWLEDGMENT Financial support for the study was provided by the U.S. EPA Great Lakes National Program Office (Chicago, IL) and by Environment Canada (Great Lakes 2020 program). We thank Ted Smith (U.S. EPA, GLNPO) for his interest in the project. Thanks to Joanne R. White and to Bill Meylan (SRC, North Syracuse, NY) for editorial corrections and physical chemical property estimates, respectively. ’ REFERENCES (1) Muir, D. C. G.; Howard, P. H. Are there new persistent organic pollutants? A challenge for environmental chemists. Environ. Sci. Technol. 2006, 40 (23), 7157 7166; DOI: 10.1021/es061677a. (2) Howard, P. H.; Muir, D. C. G. Identifying new persistent and bioaccumulative organics among chemicals in commerce. Environ. Sci. Technol. 2010, 44 (7), 2277 2285; DOI: 10.1021/es903383a. (3) Monteiro, S. C.; Boxall, A. B. A. Occurrence and fate of human pharmaceuticals in the environment. Rev. Environ. Contam. Toxicol. 2010, 202, 53 154; DOI: 10.1007/978-1-4419-1157-5_2. (4) Boxall, A. B. A.; Kolpin, D. W.; Tolls, J. Are veterinary medicines causing environmental risk? Environ Sci. Technol. 2003, 37 (15), 286A–294ADOI: 10.1021/es032519b. (5) Daughton, C. G.; Ruhoy, I. S. Environmental footprint of pharmaceuticals: The significance of factors beyond direct excretion to sewers. Environ. Toxicol. Chem. 2009, 28 (12), 2495 2521; DOI: 10.1897/08-382.1. (6) Sanderson, H.; Johnson, D. J.; Reitsma, T.; Brain, R. A.; Wilson, C. J.; Solomon, K. R. Ranking and prioritization of environmental risks of pharmaceuticals in surface waters. Regul. Toxicol. Pharmacol. 2004, 39, 158–183. (7) Kools, S. A. E.; Boxall, A. B. A.; Moltmann, J. F.; Bryning, G.; Koschorreck, J.; Knacker, T. A ranking of European veterinary medicines based on environmental risk. Integr. Environ. Assess. Manage. 2008, 4 (4), 399 408; DOI: 10.1897/IEAM_2008-002.1. (8) Fent, K.; Weston, A. A.; Caminada, D. Ecotoxicology of human pharmaceuticals. Aquat. Toxicol. 2006, 76 (2), 122 159. DOI 10.1016/ j.aquatox.2005.09.009. (9) Hernando, M. D.; Rodríguez, A.; Vaquero, J. J.; Fernandez-Alba, R. R.; García, E. Environmental risk assessment of emerging pollutants in water: Approaches under horizontal and vertical EU legislation. Crit. Rev. Environ. Sci. Technol. 2011, 41 (7), 699–731. (10) U.S. FDA. Guidance for Industry Environmental Assessment of Human Drug and Biologics Applications; U.S. Department of Health and Human Services, Food and Drug Administration: Silver Spring, MD, 1998; http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070561.pdf. (11) U.S. FDA. Drugs@FDA data files; U.S. Department of Health and Human Services, Food and Drug Administration: Silver Spring, MD, 2011; http://www.fda.gov/Drugs/InformationOnDrugs/ucm079750. htm.
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(12) RxList. Top 300 Rx Prescriptions; RxList; The Internet Drug Index; 2005; http://www.rxlist.com/script/main/hp.asp. (13) Wikipedia. List of bestselling drugs; Wikimedia Foundation, Inc.; 2010; http://www.rxlist.com/script/main/hp.asp. (14) MedAdNews. Med Ad News 200 World’s best-selling medicines. MedAdNews 2007, 13 (7); http://www.pharmalive.com/ magazines/medad/?date=07%2F2007. (15) Health Strategies Consultancy. Follow the pill: Understanding the U.S. commercial pharmaceutical supply chain; Henry H. Kaiser Family Foundation; Menlo Park, CA; 2005; http://www.kff.org/rxdrugs/upload/Follow-The-Pill-Understanding-the-U-S-Commercial-Pharmaceutical-Supply-Chain-Report.pdf. (16) U.S. FDA. Section 2.0 Active Ingredients; Approved Animal Drug Products; Green Book On-Line; U.S. Food and Drug Administration, Center for Veterinary Medicine: Rockville, MD: 2011; http:// www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/ucm042847.htm. (17) HSDB. Hazardous Substances Data Bank. U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine: Bethesda, MD, 2011; http://toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?HSDB. (18) NLM. ChemIDplus database. U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine: Bethesda, MD, 2011; http://toxnet.nlm.nih.gov/cgi-bin/sis/ htmlgen?CHEM. (19) MDL. ISISTM/Base 2.4. MDL Information Systems, Inc.: San Leandro, CA; 2005; http://accelrys.com/products/pdf/ISISBASE.pdf. (20) U.S. EPA. Estimation Program Interface (EPI) Suite, Version 4.00. U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics: Washington, DC, 2005; http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm. (21) U.S. EPA. 40 CFR Part 372 Persistent bioaccumulative toxic (PBT) chemicals; Proposed rule. U.S. Environmental Protection Agency: Washington, DC; Federal Register, 1999, 64 (2), 687 729. (22) Gobas, F. A.; de Wolf, W.; Burkhard, L. P.; Verbruggen, E; Plotzke, E. Revisiting bioaccumulation criteria for POPs and PBT assessments. Integr. Environ. Assess. Manage. 2009, 5 (4), 624 637; DOI: 10.1897/IEAM_2008-089.1. (23) Tunkel, J.; Howard, P. H.; Boethling, R. S.; Stiteler, W.; Loonen, H. Predicting ready biodegradability in the Japanese Ministry of International Trade and Industry test. Environ. Toxicol. Chem. 2000, 19 (10): 2478 2485. DOI: 10.1002/etc.5620191013. (24) Svanfelt, J.; Eriksson, J.; Kronberg, L. Analysis of thyroid hormones in raw and treated waste water. J. Chromatogr. A 2010, 1217 (42), 6469 6474; DOI 10.1016/j.chroma.2010.08.032. (25) Nieto, A.; Peschka, M.; Borrull, F.; Pocurull, E.; Marce, R. M.; Knepper, T. P. Phosphodiesterase type V inhibitors: Occurrence and fate in wastewater and sewage sludge. Water Res. 2010, 44 (5), 1607 1615; DOI 10.1016/j.watres.2009.11.009. (26) Kern, S.; Fenner, K.; Singer, H. P.; Schwarzenbach, R. P.; Hollender, J. Identification of transformation products of organic contaminants in natural waters by computer-aided prediction and high-resolution mass spectrometry. Environ. Sci. Technol. 2009, 43 (18), 7039 7046; DOI: 10.1021/es901979h. (27) Kern, S.; Baumgartner, R.; Helbling, D. E.; Hollender, J.; Singer, H.; Loos, M. J.; Schwarzenbach, R. P.; Fenner, K. A tiered procedure for assessing the formation of biotransformation products of pharmaceuticals and biocides during activated sludge treatment. J. Environ. Monit. 2010, 12 (11), 2100 2111; DOI 10.1039/C0EM00238K. (28) Kostich, M. S., Lasorchak, J. M. Risks to aquatic organisms posed by human pharmaceutical use. Sci. Total Environ. 2008, 389 (2-3), 329 339; doi:10.1016/j.scitotenv.2007.09.008. (29) Kumar, A.; Xagoraraki, I. Pharmaceuticals, personal care products and endocrine-disrupting chemicals in U.S. surface and finished drinking waters: A proposed ranking system. Sci. Total Environ. 2010, 408 (23), 5972 5989; DOI 10.1016/j.scitotenv.2010.08.048. (30) EMEA. Guideline on the environmental risk assessment of medicinal products for human use; European Medicines Agency: London, UK, 6945
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EMEA/CHMP/SWP/4447/00; 2006; http://www.ema.europa.eu/pdfs/ human/swp/444700en.pdf. (31) Buchberger, W. Current approaches to trace analysis of pharmaceuticals and personal care products in the environment. J. Chromatogr. A 2011, 1218 (4), 603–618DOI 10.1016/j.chroma.2010.10.040. (32) Lopez-Serna, R.; Perez, S.; Ginebreda, A.; Petrovic, M.; Barcelo, D. Fully automated determination of 74 pharmaceuticals in environmental and waste waters by online solid phase extraction-liquid chromatography-electrospray-tandem mass spectrometry. Talanta 2010, 83 (2), 410 424; DOI 10.1016/j.talanta.2010.09.046. (33) Barcelo, D. Pharmaceutical-residue analysis. TrAC Trends Anal. Chem. 2007, 26 (6), 454 455; DOI 10.1016/j.trac.2007.02.008. (34) Kosjek, T.; Heath, E.; Petrovic, M.; Barcelo, D. Mass spectrometry for identifying pharmaceutical biotransformation products in the environment. TrAC Trends Anal. Chem. 2007, 26 (11), 1076 1085; DOI 10.1016/j.trac.2007.10.005. (35) Petrovic, M.; Hernando, M. D.; Díaz-Cruz, M. S.; Barcelo, D., Liquid chromatography-tandem mass spectrometry for the analysis of pharmaceutical residues in environmental samples: A review. J. Chromatogr. A 2005, 1067 (1 2), 1 14; DOI 10.1016/j.chroma.2004.10.110.
’ NOTE ADDED AFTER ASAP PUBLICATION The last paragraph of the Introduction section was modified in the version of this paper published July 19, 2011. The correct version published July 26, 2011.
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