Pharmaceutical Dispensing and Wasting In Health Care Facilities , Amounts , Costs and Evaluation of Potential Ecologic Effects Materials and Methods

Medication (12,345) and waste collection (199) records for: drugs dispensed, returned and wasted were examined. Of 2,700 drugs available, 84 drugs from 14 classes, weighing 56 kg were dispensed to patients, and 2.3 kg were wasted. Twelve drugs accounted for 80 percent of the drug waste and cost $111,000. Of the top wasted and dispensed drugs, all but ibuprofen are persistant and none were bioaccumulative. Ibuprofen, ipratropium ondansetron and oxymetazoline are ”very highly toxic” or ”highly toxic”. Environmental Risk Ratio (PEC/PNEC) for the 20 top drugs were”Insignificant” or ”Cannot Be Excluded”.

AMCH = Academic Medical Center Hospital; ASTER = Assessment Tools for the Evaluation of Risk.United States Environmental Protection Agency https://archive.epa.gov/med/med_archive_03/web/html/aster.htmlLast accessed 6/4/17; B = Bioaccumulation is the general term describing a process by which chemicals are taken up by an organism either directly from exposure to a contaminated medium or by consumption of food containing the chemical; EC50 = Effective Concentration producing an adverse effect in 50% of a test species; EbC50 or ErC50 = EC50 in terms of reduction of growth rate; EyC50 = EC50 in terms of change in biomass yield; Ecosar = Ecologic Structure Activity Relationships is a computerized predictive system that estimates aquatic toxicity.The program estimates a chemical's acute (short-term) toxicity and chronic (long-term or delayed) toxicity to aquatic organisms such as fish, invertebrates, and plants by using computerized Structure Activity Relationships (SARs).https://www.epa.gov/tsca-screening-tools/ecological-structure-activity-relationships-ecosar-predictive-model.Last accessed 6/4/17; EPA = United States Environmental Protection Agency; FDA = United States Food and Drug Administration; IC50 = Half maximal inhibitory concentration is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function; LC50 = Lethal Concentration producing 50% mortality in test species; MIC = Minimum Inhibitory Concentration is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation; MSDS = Material Safety Data Sheet.Since 2009, known as SDS or Safety Data Sheet; Neutral Organics QSAR = Subset of chemicals within Ecosar Suite; OECD = Organization for Economic Cooperation and Development; P = Persistence is the length of time a substance resides in

Introduction
Pharmaceutical and personal care product (PPCP) waste is an emerging environmental concern.Low levels of antibiotics, antiinflammatory, endocrine disruptors, psychotropics and mood altering drugs and X-ray contrast media have been detected in surface waters, soils, wastewaters and in drinking water sources of major cities, both within the USA and worldwide [1][2][3][4].Recent reviews have described the occurrence and possible effects of drug residues in tissues of aquatic organisms and wildlife [5][6][7].Pharmaceuticals are introduced into the aquatic environment from a variety of sources, such as: hospitals [2,[8][9][10][11][12]; wastewater treatment plants [13][14][15][16]; drug manufacturers [17][18][19]; livestock farms [20][21][22]; and veterinary facilities [23,24].Hospitals and patient care facilities are major dispensers of pharmaceuticals [12,25] with a number of studies and reviews evaluating hospital drug dispensing patterns and estimations of sewage outflow concentrations [12].These have led to conflicting conclusions as to the magnitude of this pollution discharge relative to other non-hospital based activities.Disposal of drugs by hospitals and healthcare facilities into the environment by flushing is a concern [26,27] and this practice needs to be reconsidered or discontinued [20,[28][29].For the general public and other unregistered end users of prescription medications, the U.S. Food and Drug Administration (FDA) has provided guidelines for disposal of excess medications.These guidelines do not apply to hospitals, pharmacies and other facilities registered with the U.S. Drug Enforcement Administration (DEA) or State regulatory authorities (for a review of the legal complexities refer to Yeh [31]).The US Environmental Protection Agency (EPA) has proposed a change to hazardous waste regulations which ban the flushing of hazardous waste pharmaceuticals and discourages the flushing of nonregulated drugs.
In addition to direct disposal of excess pharmaceuticals (e.g., discarding or wasting), up to 100% of some drugs are directly excreted by patients [32].Others may undergo significant metabolism to inactive compounds or to other active drugs prior to excretion [33][34][35].Some drugs undergo conjugation in the body to enhance water solubility [36][37][38].These conjugates may be recirculated either within the body (enterohepatic recirculation) or outside the body where the conjugates are cleaved by bacteria to reconstitute the active drug [34,39].Bathing and laundry effluents have also been proposed as pathways for the introduction of pharmaceuticals into the environment [40][41][42].
Sewage treatment plants (STPs) are not designed to remove most pharmaceuticals [60][61][62] and biodegradability tests have shown that many drugs are not totally removed during sewage treatment [63].As a result, many pharmaceuticals remain in raw sewage or are only partially removed [61,[64][65].Pharmaceuticals released from STPs flow into receiving waters, such as streams and rivers [20,61,66].Studies conducted on water quality in various countries have detected a number of antibiotics (Ab) in the low µg/L or parts per billion ranges.For example in Korea, over 95% of the Ab in the influent to a livestock wastewater treatment plant was present in the effluent [67].Laboratory analysis of water samples collected at the influent and effluent of STPs confirms that they are a primary source of pharmaceuticals, which originate from disposal or excretion [15,[68][69][70].
In prior publications [71][72][73] the patterns of wasting and potential environmental effects of propofol and other surgical drugs (e.g., lidocaine, succinylcholine, bupivacaine, ephedrine, epinephrine, atracurium, proparacaine and atropine) were reported from a surgical care center in Albany, NY.Of interest was how a small change in availability (e.g., removal of 50 and 100 mL vials of propofol from automated dispensing machines in the operating rooms) reduced propofol wastage from 29.2 to 2.8 mL for each waste receptacle per day [71].In a second communication [72], wasting of 15 controlled substance from two hospitals in Albany, New York was evaluated over a two year period.Three controlled substances (midazolam, acetaminophen-codeine and fentanyl) contributed nearly 90% by weight of the total controlled drug waste.The third publication [73] reported the patterns of antibiotic/antimicrobial drug wasting.The present study reports on the patterns of wasting and dispensing of an additional 85 pharmaceuticals in 12 pharmacologic classes given to patients at two acute care hospitals in Albany, NY.The study considered drug metabolism, excretion, disposal and toxicity to aquatic organisms (ecotoxicity).Potential strategies for drug waste minimization and possible impacts on healthcare costs are discussed.

Materials and Methods
As part of a pharmaceutical waste reduction pilot program, a total of 12,345 drug records for dispensing and waste collection were reviewed from two hospitals in Albany, NY.There were 4,889 automated drug dispensing machine (PYXIS®) records which were collected and tabulated at the Albany Medical Center Hospital (AMCH; 630-bed, acute care) and 7,257 PYXIS® records from the South Clinical Campus (SCC; 20 bed surgical care center).Additionally, the contents of 199 pharmaceutical waste collection containers placed at SCC were sorted by hand and their contents tabulated.
Data were recorded by location, medication form, weight and number of units dispensed, returned, "bedside wasted" or discarded (e.g., a 1g dose of phenylephrine was recorded as 1g regardless of the total weight of the drug formulation.).No human subject or patient identifier information was accessed; all data were recorded as summary aggregates.The funding agency (US EPA) did not participate in the design, conduct, or analysis of the study.All numeric data were entered and archived on a Windows® based personal computer and analyzed by standard software packages (Microsoft Access®, Excel®).N.b., Bedside wasted at health care facilities refers to the discharge of excess drug withdrawn for patient administration, but only partially given to a patient.The leftover medication is then discarded by a healthcare professional who documents the wasting in the medication record.
Table 1 (and Supplemental Table 1) provides a summary of ecotoxicity information for the pharmaceuticals of interest.Inhibitory and lethal concentration data were considered to be the same for our review (e.g., EC50 = IC50 = LC50).These values (EC50, IC50, and LC50) were selected as they represent the most reproducible point on the doseresponse curve.
In addition to the laboratory derived toxicity information presented in the MSDS/SDS (Material Safety Data Sheet/Safety Data Sheet) and outside literature, mathematically modeled values are provided in  For those drugs for which no data (designated as ND) were found for PBT, environmental risk ratio, ecotoxicity or pharmacokinetics, a computerized search of the available primary literature was conducted (http://www.ncbi.nlm.nih.gov/pubmed) and referenced in footnotes to Tables 1 and 2 (and Supplemental Tables 1 and 2).

Formulary Overview
As part of our evaluation of drug dispensing and disposal, the formulary for the academic medical center hospital and surgical care center was evaluated by a commercial contractor.As depicted in the pie chart (Figure 1), of 2,700 drug formulations (represented by unique National Drug Codes -NDCs), most (90%) are not regulated but include such major therapeutic drug classes as: endocrine disruptors, steroids, antibiotics, mood altering drugs, heart and blood pressure medications, antiinflammatory drugs, and cholesterol lowering drugs as well as innocuolus salts, buffers, nutritionals and emmolients.The remaining drug formulations possess one or more hazardous or regulated characteristics.Controlled substances are the more numerous at 4.8% of the drugs; followed closely by those whose wastes are regulated by the US EPA (so called "RCRA" -Resource Conservation and Recovery Act or hazardous chemicals; e.g., flammable, corrosive, reactive, mercury containing, etc.) at 4.4%; cytotoxic and antimetabolite drugs (used in treating cancer patients) regulated by the US Occupational Safety and Health Administration (US OSHA) or the National Institutes of Occupational Safety and Health (NIOSH) comprise 3.2%; vaccines and biologicals (biohazardous, infectious or recombinant DNA) at 2.7%; and aerosols (inhalers, pressurized dispensers) regulated by the US Department of Transportation (US DOT) at but 0.3% of the hospital's formulary.Please note that the total exceeds 100% as a number of drug formulations have multiple hazard characteristics, e.g. a RCRA hazardous waste and a controlled substance -(paraldehyde, chloral hydrate), a RCRA hazardous waste and a cytotoxic (cyclophosphamide, actinomycin), a RCRA hazardous waste and biohazardous infectious drug (vaccines with preservatives), etc.The current communication focuses upon unregulated drugs and those few pharmaceuticals which meet the criteria for regulation under current state and federal hazardous waste laws ("RCRA").As noted in figure 1, these comprise nearly 90% of the "On Formulary" NDC's (Not Currently Regulated) and about 4.4% of the "On Formulary" NDC's (RCRA regulated).e. PBT : persistence, bioaccumulation, and toxicity (0 -3 range for each, with zero being the most benign).

Pharmaceutical Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
f. Risk: defined as -cannot be excluded, insignificant, low, moderate, and high g.Disposal -from MSDSs -n.b., does not apply to consumers or end users -refer to US FDA guidelines and office of national drug control policy (ONDCP, 2007).
h. ND = no data available or not determined.

Pharmaceutical Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
WikiPharma: A total of 12,345 drug records for dispensing and waste collection were reviewed; 4,889 records from the 630 bed Albany Medical Center Hospital and 7,257 records from the 20 bed South Clinical Campus of Albany Medical Center.The contents of 199 pharmaceutical waste collection containers placed at SCC were sorted by hand and the results tabulated by location, medication form and weight of units discarded.Weights are for active ingredient, e.g. a 1 g dose of acetazolamide was recorded as 1 g regardless of the total weight of the drug formulation.e. Risk: defined as -cannot be excluded, insignificant, low, moderate, and high f.Disposal -from MSDSs -n.b., does not apply to consumers or end users -refer to US FDA guidelines and office of national drug control policy (ONDCP, 2007).
g. ND = no data available or not determined.h.Daphnia: crustacean, water flea.i. EC50: concentration of a material which is expected to cause an adverse biological effect on 50% of the test organisms -acute toxicity.e. Active Metabolites: indicates the drug is changed in the body to pharmacologically active compounds prior to excretion, thus the risk to the environment from the excreted drug may reside in its metabolites and not in the parent compound.
f. Excretion of Parent Compound: indicates that the drug, or a portion of the dose, is excreted unchanged.
i. Value within parentheses: the percent of the drug that is excreted unchanged or the percent of the drug that is metabolized unchanged.Y (fecal and 10 -40% urine) indicates that some fraction of the drug is excreted in the feces unchanged and from 10 to 40% of the drug is also excreted in the urine unchanged.Y (<5%) indicates that less than 5% of the drug is metabolized, more than 95% tabulated by location, medication form and weight of units discarded.Weights are for active ingredient, e.g.A 1 g dose of acetazolamide was recorded as 1 g regardless of the total weight of the drug formulation.
zz. CAS# -Chemical Abstracts Services unique chemical identification number.
aaa.Metabolism: indicates the drug undergoes change in the body.
bbb.Active Metabolites: indicates the drug is changed in the body to pharmacologically active compounds prior to excretion, thus the risk to the environment from the excreteddrug may reside in its metabolites and not in the parent compound.
Overall, drug wasting averaged 3% but was not uniform, varing from over 57% for insulin to about 0.2% for vasopressin (Figure 5).
As depicted in the bar graph (Figure 6), almost 56 kg of drugs were dispensed with 5 therapeutic classes (NSAID, CVS, GI, RCRA and ED) accounting for almost 80% of the drug dispensed.In each therapeutic class, one drug contributed the majority of the waste.
As depicted in Figure 7; 56 kg of 85 drugs were dispensed.Fifteen drugs accounted for over 80% of the total weight of drug dispensed while

Pharmaceutical Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
department, the value represented by the wasted and discarded drugs exceeded $111,000.As depicted in Figure 8, the most costly drug wasting was associated with neostigmine, which accounted for nearly 30% of the discarded value ($31,692).Acetazolamide, dexamethasone,nitroglycerine, ondansetron, phenylephrine and tetracaine accounted for the rest of the 68 drugs comprised the remaining 20% (note one drug was dispensed but not wasted).

Cost of Wasting
Based on pricing data provided by the particpating pharmacy is "very highly toxic" (EC50, IC50 or LC50<1.0mg/L), ibuprofen "highly toxic" and albuterol, ketorolac and metoprolol are "moderately toxic".The environmental risk ratio for ibuprofen, ipratropium, ketorolac and metoprolol are "Insignificant" while albuterol and prednisone are considered "Cannot Be Excluded".

Ecotoxicity of the Most Frequently Wasted and Discarded Drugs Invertebrates
As depicted in Table 1, four drugs (dexamethasone, ibuprofen, neostigmine and nitroglycerine) are very hughly toxic to invertebrates (EC50, IC50 or LC50 values of <1.0 mg/L).Dexamethasone has the greatest chronic toxicity to Ceriodaphnia of 0.05 ppm (or mg/L; 7 d EC50).Ibuprofen is extremely chronically toxic (28d EC50 of 0.0007 mg/L) to the crab (Carcinus) and very highly toxic (96hr EC50 of 0.4 mg/L) to zebra mussel (Dreisssena).Ibuprofen toxicity was variable from high to moderate (96 hr EC50, IC50 and LC50 of 1.7 mg/L to 22 mg/L) to Hydra.Neostigmine is very highly acutely toxic to Daphnia with a 24 hr EC50 of less than 1 mg/L.Nitroglycerine is predicted to be very highly toxic to Daphnia (EC50 of 0.0000156 mg/L, Topkat software program).Mepivacaine, metoprolol, neostigmine and prednisone are highly toxic (acute and chronic) to Daphniaor Hydrawith EC50 or LC50 values of from >1 mg/L to 10 mg/L.Metopropol is highly toxic to Ceriodaphnia (24 and 48 hr LC50 top 80% of drugs wasted, for an aggregate total of almost $91,000.

Fish
Acetazolamide is very high toxicity to fish (<1 mg/L) with a value of 0.001 mg/L for 120hr LC83, but is predicted to be of low toxicity (LC50 value of >1000 mg/L, Ecosar, Aster, PNN and Neutral Organics QSAR computer programs).Ibuprofen is predicted to be very highly toxic to fish (LC50<1 mg/L, Neutral Organics QSAR in the ECOSAR computer program).However, the 96 hr LC50 for ibuprofen was variable from moderately toxic (89 mg/L) for Oryzias to low toxicity (>100mg/L) for Lepomis.Mepivacaine, ondansetron are highly toxic to fish (EC50 or LC50values of <10mg/L).Nitroglycerine is highly toxic to fish with a LC50 of 1.4 mg/L as reported by the MSDS/SDS and predicted by Neutral Organics QSAR (LC50 of 4.8 mg/L) but is essentially non-toxic (LC50>100 mg/L) as predicted by Aster, Ecosar, Oasis Forecast and PNN computer programs.Ketorolac, metoprolol, oxymetazoline and phenylephrine are essentially non toxic to fish with EC50 or LC50 values >100 mg/L, despite one value for metoprolol reported at 31 mg/L for a 72hr EC50.Albuterol, dexamethasone, diatrizoate meglumine, gadodiamide, glycopyrrolate, insulin, iopamidol, ipratropium, neostigmine and nicardipine have no ecotoxicity data available for fish as depicted in Table 1.

Other
Ondansetron is very highly toxic to green algae (Pseudokirchneriella) with a 24 hr IC50 of less than 1 mg/L (Table 1).Insulin is moderately toxic (EC50 10-100 mg/L) to algae (72 h EC50 of 19 to 33 mg/L).Ibuprofen had high to low toxicity values for algae and other organisms ranging from a high toxicity (7d EC50 of 1.0 mg/L) for the vascular plant duckweed (Lemna); moderate toxicity (5d EC50 of 40 mg/L) for the algae Skeletonema and bacteria Vibrio (15 min EC50 values of 11 to 19 mg/L) to low toxicity (96 h EC50 of >100 mg/L) for the algae Pseudokirchnerella and Desmodesmus (3d EC50).Ibuprofen was moderately toxic to African clawed frog Xenopus tadpoles 3 (96h EC50 of 40 mg/L and 57 mg/L).Mepivacaine is predicted to be highly toxic (EC50 or LC50 of 5.3 mg/L, Ecosar) to algae.Metoprolol was high to moderately toxic to Desmodesmus (3d EC50 of 7.3 mg/l; 48 h EC50 of 7.9 mg/L; and 24 h EC50 of 40 mg/L) or green algae (72 h ErC50 value of 58.3 mg/L); moderate (EC50 value of 14.5 mg/L) to low toxicity (30 min EC50 value of >100 mg/L) to Vibriobacteria; and low toxicity to Lemna (7 d EC50 value of >100 mg/L or >320 mg/L).Nitroglycerine is predicted to have moderate chronic toxicity (EC50 21 mg/L, Ecosar) and low acute toxicity EC50 or LC50>100 mg/L, Ecosar) to algae.Prednisone was moderately toxic to algae (Pseudokirchnerella with a 72h IC50 of 31 mg/L) while acetazolamide (Ecosar, acute and chronic EC50 or LC50>100 mg/L), dexamethasone (Pseudokirchnerella 72 h EC50>100 mg/L) and ketorolac (Chlorella EC50>1000 mg/L) had low toxicity to algae.Activated sludge toxicity was extremely low and recorded at >1000 mg/L for insulin and ondansetron.Albuterol, diatrizoate meglumine, gadodiamide, glycopyrrolate, iopamidol, ipratropium, neostigmine and nicardipine have no ecotoxicity data available for algae or other aquatic organisms.

Recommended Disposal
Incineration was recommended by the MSDS/SDS for dexamethasone, insulin, nicardipine and prednisone.Iopamidol is accompanied by a warning in the MSDS/SDS not to dispose in household garbage or into the sewer system.No method of disposal was recommended by the MSDS/ SDS for 15 of the top wasted or dispensed pharmaceuticals (Table 1).

Metabolism and Excretion
As depicted in Table 2, all but 2 (insulin and nitroglycerine) of the "wasted", discarded or dispensed pharmaceuticals were excreted as parent compound in the urine and or feces of human patients, at levels from 5 to 100% of the administered dose.Fourteen of these underwent metabolism in vivo but active metabolites were formed from only two (nitroglycerine and prednisone).Nicardipine, ondansetron and prednisone formed potentially reversible drug conjugates (predominantly glucuronides) which were excreted in the urine, feces or underwent enterohepatic recirculation (Table 2).

Discussion
The present communication found that over 56 kg of 84 drugs from 14 therapeutic classes were dispensed in two Albany, New York hospitals.Of this 56 kg, only 2.3 kg of drug (as active ingredient) worth in excess of $111,000 was discarded.Others have reported detectable levels of drug waste in effluents of healthcare facilities [16,60,74].Sim et al. [16] assayed twenty-four (24) different drugs in Korean wastewater finding ug/L levels of pharmaceuticals in hospital effluent.Olivera et al. [71] measured 185 pharmaceutical and personal care products by liquid chromatographymass spectroscopy (LC-MS) in hospital effluent and wastewater in Suffolk County, USA finding very low levels ranging from undetectable (most) to 1.4 ug/L for erythromycin.
In previous studies [71,72], wasting of propofol, other injectable drugs, and controlled substances (CS) was generally higher (4.1%) at the same facilities as reported herein.For example; Mankes [71] found that 41 liters of propofol emulsion and other liquid injectable surgical drugs were wasted of 150 liters dispensed.Mankes and Silver [72] reported that 8.5 kg of CS were wasted of 38 kg dispensed and 2.3 kg wasted of 56 kg dispensed in the present study.This contrasts to much lower (1.7%) wasting of antibiotic/antimicrobial drugs (Ab), found to be 1.3 kg wasted of 77 kg dispensed [73].This disparity between Ab wasting and other pharmaceuticals [71][72][73][74] may be due to the longstanding process of antibiotic stewardship [75].
Others [76] have concluded hospitals are not the main source of pharmaceutical waste in municipal sewage in Germany, with community use reported to be 70-75%, (on a defined daily dose or DDD basis).Application of the Pareto Principle (or 80-20 rule [77]) has been previously reported for propofol, controlled substances [71,72] and other hospital processes [78][79][80].For example, a process improvement team consisting of representatives from nursing, anesthesiology, and pharmacy could be charged with targeting the wasting of the top drugs as illustrated by "Lean-Six Sigma" [81].Reduction in dispensing, sizes and strengths stocked, etc. could be enforced with a reduction in wasting [41,71,79].
In the present study, all but two of the wasted, discarded or dispensed drugs were excreted in whole or in part as active drug [18] or drug conjugates [3].Kummerer [76] found that nearly 70% of drugs evaluated were excreted unchanged.We previously reported that injectable drugs [71], CS [72], or Ab [73] were metabolized in vivo or were highly biodegradable (e.g., propofol).In the case of Ab [73], the total drug discharged was representative of the total drug dispensed (77 kg) rather than just that which was wasted, thus complicating estimations of hospital discharge of drugs [82].
Others have assumed drug loads in hospital wastewater to be proportional to total dispensing [12] while Escher et al. [9] have advocated more complex computer simulations.In this report, Escher et al., [9] evaluated 100 drugs expected to occur in 2 hospitals' wastewater.One was a 338 bed general hospital and the second a 211 bed psychiatric center.In the general hospital, the top-100 drugs dispensed totaled 1137 kg consumed and 777 kg excreted.X-ray contrast media was 58% of the excreted load, 19% from laxatives, 16% from antibiotics, and 8% from others.
As seen in our earlier studies, drug waste, although an overall average of 3%, was not uniform and varied from 0.2% (vasopressin) to as high as 57% (insulin).In previous studies, wasting of injectable surgical drugs varied from 12 to 48% of dispensed drug [71]; wasting of CS ranged from less than 0.1% to 49.5% of drug dispensed [72]; and wasting of Ab varied from 0.1% to 45% [73].In the present study, the highest percentage of wasted drugs were not among those with the greatest absolute wasting (in grams).For example: insulin at 57.4% wasting accounted for only 140g of 2.3 kg wasted, while phenylephrine accounted for the most (329g) drug wasted but only 8.75% of the phenylephrine dispensed.
As noted, the costs of drug wasting in the present study exceeded $111,000 and were primarily due to seven of 46 pharmaceuticals (acetazolamide, dexamethasone, neostigmine, nitroglycerine, ondansetron, phenylephrine and tetracaine).Others [83][84][85][86] have found that costs of drug wasting can be significant, ranging from $185,000 for 543 surgical cases [83] up to $30 billion annually [87].In an earlier study, Mankes [71], found eliminating larger vial sizes of propofol, by stocking only 20 mL size had a significant reduction in propofol waste.Others also have advocated: reductions in vial sizes [84,86,88]; mandating drug take back and reissue programs [84]; use of prefilled syringes for surgical cases [83]; use of sophisticated drug management software to increase reuse of anti-cancer drugs [85] or better managed short-stability and titratable products [89].In any event, it is clear that small changes in pharmaceutical waste management can have a significant impact on pharmaceutical waste costs.

PBT, Environmental Risk Ratio and Ecotoxicity Analysis
As noted earlier, the PBT Index was developed in 2003 by the Stockholm County Council to rank the environmental impact of pharmaceuticals (http://www.janusinfo.se/Beslutsstod/Miljo-ochlakemedel/About-the-environment-and-pharmaceuticals).The PBT (persistence, bioaccumulation and toxicity) and environmental risk ratio system of drug comparison [90] is used by European governments (REACH -http://ec.europa.eu/environment/water/water-dangersub/pri_substances.htm)[91] as well as adopted by one US State (Oregon) [92][93][94][95].One of our objectives is to determine if such data provides the hospital environmental professional with a method of ranking damaging drug wastes.
Persistence (as determined by OECD Test 301) [96] is important when evaluating the environmental impact of a contaminant.In the present study, we found eight drugs were considered "not readily biodegradable" or highly persistent (3/3) while only one (ibuprofen) was rated "readily biodegradable" (0/3 for persistence) and thus would not be expected to be long lived in the environment.Similarly, bioaccumulation (OECD Tests 107 and 111) [97][98] is a function of amplification within the environment and is seen with increasing concentrations (generally Log KOW or the log oil/water partition coefficient).None of the top wasted / dispensed drugs in the present study were considered potentially bioaccumulative.
The REACH PBT toxicity designations are based upon OECD Tests 201, 202 and 203) [99][100][101].Four drugs (ibuprofen, ipratropium, ondansetron and oxymetazoline) were "very high" or "high" toxicity.Five drugs were considered "moderate" or "low" toxicity.In contrast, the toxicity values derived from the laboratory test results for crustaceans (Daphnia, Ceriodaphnia, Thamnocephalus, etc.), fish (Cyprinodon, Oryzias, Lepomis, etc.) and other (Pseudokirchneriella, Desmodesmus, Lemna, Xenopus, etc.) revealed that only 2 (neostigmine and ondansetron) were very highly toxic to Daphnia (neostigmine) or algae (ondansetron).Dexamethasone is very highly toxic to Ceriodaphnia (0.05 ppm or mg/L) after 7 days, while ibuprofen is very highly toxic to Dreissena (EC50 0.4 mg/L).Four drugs (ibuprofen, mepivacaine, nitroglycerine and ondansetron) are highly toxic to fish.Thus there appears to be poor correlation between the laboratory toxicity test results and the REACH PBT toxicity scoring.Recently, Mendoza et al. [102] analyzed 25 drugs and radiocontrast agents in effluents from a hospital.PBT and environmental risk values from the Stockholm County Council were presented.These values were not correlated to the results of the ecotoxicity reviews regardless of species.As noted in our previous communications for controlled substances and antimicrobial drugs [72][73], we recommend more complete laboratory derived aquatic toxicity data (e.g., EC50 or LC50 values for Daphnia, fish, algae and bacteria) be included in manufacturer MSDSs/SDSs for the most frequently wasted drugs, rather than an over reliance on PBT or the environmental risk ratio.
In general, toxicity values for pharmaceuticals are determined by laboratory testing or predicted by models.Some sources of toxicity values such as MSDSs/SDSs, Wikipharma, and literature reviews [59] present both lab test and predicted data.In some instances lab testing results are dissimilar and appear contradictory.For example, acute lab data results for Daphnia (magna) for ibuprofen range from 31 mg/L to 132.6 mg/L) [51,[103][104][105], an order of magnitude different.In other instances, lab data and predicted data can be dissimilar.Using ibuprofen as an example again, the acute laboratory toxicity result for fish (Oryzias) is 89 mg/L, while the predicted acute data for fish is 0.0318 mg/L (Neutral Organics QSAR in Ecosar), a difference of almost 2,800.These wide ranges can be problematic when applying a toxicity scale of <1 mg/L to indicate that a pharmaceutical is very highly toxic, 1-10 mg/L as very toxic, 11-99 mg/L as moderately toxic, and >100 mg/L as not toxic.Pharmaceuticals in this paper other than ibuprofen that present these potential data interpretation issues include insulin, metoprolol and nitroglycerine.We recommend more complete laboratory derived aquatic toxicity data rather than relying solely upon modeled data.

Metabolism and Excretion
Excretion of drugs has been considered a major source of pharmaceuticals in wastewaters [30,40].Hospital effluents are recognized as major sources of drugs [2,60,74,102].For most of the drugs studied herein, the official (FDA) manufacturer label provided adequate insight into the urinary and fecal excretion of the drug and its metabolites.For the top drugs that were both wasted and dispensed, 18 were excreted in urine and feces, 3 (nicardipine, ondansetron and prednisone) formed drug conjugates, while 2 (insulin, nitroglycerine) were not excreted, in whole or in part.
As noted by others [30,40], our data suggest that for these 18 pharmaceuticals, excretion from patients, with or without direct hospital wasting, would be a major source in hospital effluent.Unfortunately, little data are available in the open literature for wastewater concentrations of these 18 pharmaceuticals [12,45,82].Albuterol levels varied from 0.08-0.28ug/L in hospital wastewater systems from Suffolk County, New York [74] while an average of 23 ng/L (range of 3.7-110 ng/L) was reported by Bernot et al. [106].Santos et al. [60] found dexamethasone levels in hospital effluents ranging from undetectable to 352 ng/L.Ibuprofen is commonly detected in hospital effluents at ng/L levels (119 to 7090) [13,102], or at ug/L levels (3.11) [107].Metoprolol was found at levels from 1.57 to 32.8 ug/L in Suffolk County, NY [74]

Disposal and Destruction
The traditional method for "left over" drug disposal is to squirt any remaining liquid drug into a waste receptacle, sink or toilet [27,68,108].The first federal (US) guidance for consumer disposal of drugs, issued in 2007, recommended discarding them in the household trash [108].US consumers have been offered scheduled national "Drug Take Back Days" by the US Drug Enforcement Administration where excess drugs may be dropped off with drug enforcement officials prior to the drugs being disposed of responsibly.In healthcare facilities, pills are usually crushed and mixed with water and flushed or put into sharps containers [109].Excluding disposal in a sharps container [110], these procedures increase the likelihood that drugs will be released into the environment, as WWTP do not fully remove them [61,62].Recently, Phillips et al. [111] found septic systems in New York and New England contribute a wide variety of micropollutants, including pharmaceuticals, to shoreline wells.In the present study, drugs were discarded into pharmaceutical waste containers which were then sorted and shipped via commercial waste transporter to a secure incineration facility.
Recommendations for disposal methods are confusing and conflicting [27,31,112].In the present study, only 5 of the twenty frequently wasted or discarded drugs had disposal recommendations provided by the MSDSs/SDSs.Incineration was recommended for 4 drugs (dexamethasone, insulin, nicardipine and prednisone) and one drug (iopamidol) it is not to be disposed of in the trash nor in the sewage.The MSDS/SDS for the other fifteen drugs provide no guidance regarding disposal.Seehusen and Edwards [113] surveyed disposal of medication practices and found incineration to be the best disposal option currently available.In any event, clear and detailed disposal recommendations are needed and should be included in a manufacturer's MSDS/SDS.This would provide guidance and clarity to healthcare environmental professionals and pharmacy staff alike in designing and implementing pharmaceutical waste programs.In the study reported herein, all residual drugs were disposed offsite, in a permitted hazardous waste incineration facility and appropriate documentation was maintained throughout.

Conclusions
Pharmaceutical wasting in healthcare facilities, represented by two hospitals in Albany, New York, USA, can be identified and quantified by drug class, individual drug and costs of wasting.The 80-20 rule is applied to the data to focus remediation efforts upon the drugs accounting for the greatest waste in weight and costs.Potential for ecological damage by wasted drug is assessed by using MSDS/SDS, WikiPhama and open literature data for ecotoxicity, drug metabolism and bioaccumulation.We find that information on drug ecotoxicity should be more readily available to pharmacists and healthcare environmental personnel in MSDS/SDS provided by drug suppliers.We also find that wasted drugs should be centrally collected for destruction by incineration and not disposed in sinks or toilets.
ccc.Excretion of Parent Compound: indicates that the drug, or a portion of the dose, is excreted unchanged.ddd.Drug Conjugates (glucuronides) Excreted: indicates excretion (urine or feces) of drug as conjugate.eee.Y=yes.fff.N=no.ggg.ND=not determined, no data available.hhh.Value within parentheses: the percent of the drug that is excreted unchanged [e.g., Y (5%) indicates that 5% of the drug is excreted unchanged, 95% is not].

Figure 2 :
Figure 2: Wasting of 84 Drugs by 14 Therapeutic Classes

Figure 4 :
Figure 4: Bar graph of cumulative drug waste (in grams) from two healthcare facilities A total of 12,345 drug records for dispensing and waste collection were reviewed.There were 4,889 records at the 630 bed Albany Medical Center Hospital and 7,257 records for the 20 bed South Clinical Campus of Albany Medical Center.The contents of 199 pharmaceutical waste collection containers placed at SCC were sorted by hand and the results tabulated by location, medication form and weight of units discarded.Weights are for active ingredient, e.g., a 1g dose was recorded as 1g regardless of the total weight of the drug formulation.In this study, 12 drugs accounted for over 80% of the drug waste.

Figure 5 :
Figure 5: Bar graph of drug wasting as a percentage of drugs dispensed from two healthcare facilities A total of 12,345 drug records for dispensing and waste collection were reviewed.There were 4,889 records at the 630 bed Albany Medical Center Hospital and 7,257 records for the 20 bed South Clinical Campus of Albany Medical Center.The contents of 199 pharmaceutical waste collection containers placed at SCC were sorted by hand and the results tabulated by location, medication form and weight of units discarded.

Figure 6 :
Figure 6: Weight of Drugs Dispensed by Therapeutic Class A total of 12,345 drug records for dispensing and waste collection were reviewed; 4,889 records from the 630 bed Albany Medical Center Hospital and 7,257 records from the 20 bed South Clinical Campus of Albany Medical Center.The contents of 199 pharmaceutical waste collection containers placed at SCC were sorted by hand and the results tabulated by location, medication form and weight of units discarded.Weights are for active ingredient, e.g. a 1 g dose of acetazolamide was recorded as 1 g regardless of the total weight of the drug formulation.Class -pharmaceutical is used to treat disease (e.g., Optho = eye; Pulmonary -lung function; Psy = mood altering; CVS = cardiovascular; CNS = central nervous system; ED = endocrine; Mus = musculo-skeletal; NS -nervous system, GI -gastrointestinal; Renal -kidney; Radiology -imaging, LA = local anesthetic).

Figure 7 :
Figure 7: Bar graph of cumulative drugs dispensed (in grams) from two healthcare facilities A total of 12,345 drug records for dispensing and waste collection were reviewed from 2008 and 2009.There were 4,889 records for a one week period in April, 2009 at the 630 bed Albany Medical Center Hospital and 7,257 records from August, 2008 through February, 2009 for the 20 bed South Clinical Campus of Albany Medical Center.The contents of 199 pharmaceutical waste collection containers from August, 2008 through February, 2009 placed at SCC were sorted by hand and the results tabulated by location, medication form and weight of units discarded.Weights are for active ingredient, e.g., a 1g dose was recorded as 1 g regardless of the total weight of the drug formulation.In this study, 15 drugs accounted for over 80% of the drug dispensed.

Figure 8 :
Figure 8: Bar graph of the cumulative cost of drug wasting from two healthcare facilities Values were based on pricing data provided by the participating pharmacy department.A total of 12,345 drug records for dispensing and waste collection were reviewed; 4,889 records from the 630 bed Albany Medical Center Hospital and 7,257 records from the 20 bed South Clinical Campus of Albany Medical Center.The contents of 199 pharmaceutical waste collection containers placed at SCC were sorted by hand and the results tabulated by location, medication form and weight of units discarded.Note that seven drugs accounted for over 80% of the costs of drugs wasted.

Table 1 :
Summary of the Most Frequently Wasted, Discarded or Dispensed Pharmaceuticals and Potential Ecotoxic Effects from an Academic Medical Center and a Surgical Care Center over a Two

ND Pharmaceutical Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
ND Citation: Russell F Mankes, Charles D Silver (2017) Pharmaceutical Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects.SOJ Pharm Pharm Sci.4(4), 1-32.

Page 6 of 32 Pharmaceutical Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects Copyright: © 2017 Mankes RF,et al.
total of 12,345 drug records for dispensing and waste collection were reviewed; 4,889 records from the 630 bed Albany Medical Center Hospital and 7,257 records from the 20 bed South Clinical Campus of Albany Medical Center.The contents of 199 pharmaceutical waste collection containers placed at SCC were sorted by hand and the results tabulated by location, medication form and weight of units discarded.Weights are for active ingredient, e.g. a 1 g dose of acetazolamide was recorded as 1 g regardless of the total weight of the drug formulation. A

Pharmaceutical Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
NDPharmaceutical Dispensing

and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
Pharmaceutical Dispensing

and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
NDPharmaceutical Dispensing

and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
Pharmaceutical Dispensing

Pharmaceutical Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects dd
j. LC50: lethal concentration that kills 50% of the test organisms -acute toxicity. .IC50: concentration of a material in water which is expected to cause an inhibitory effect on 50% of the test organisms -acute toxicity.ee.Leuciscus: orfe,fish.ff.Eisenia: common earthworm.gg.Eisenia: common earthworm.hh.EbC50: is the EC50 of the reduction in biomass growth in 72 hours, acute toxicity.

Table 2 :
Summary of Metabolism and Excretion of the Most Frequently Wasted and Discarded Pharmaceuticals at an Academic Medical Center Hospital and a Surgical Care Center in Albany, NY

Table 2 :
Summary of Metabolism and Excretion of Wasted and Discarded Pharmaceuticals at an Academic Medical Center Hospital and a Surgical Care Center in Albany, NY.
is not].j.Y: yes.k.ND: not determined, no data available.Supplemental

Dispensing and Wasting In Health Care Facilities, Amounts, Costs and Evaluation of Potential Ecologic Effects
12,345 drug records for dispensing and waste collection were reviewed.These were 4,889 records at the 630 bed Albany Medical Center Hospital and 7,257 records for the 20 bed South Clinical Campus of Albany Medical Center.The contents of 199 pharmaceutical waste collection containers placed at SCC were sorted by hand and the results