Degradation of Pharmaceuticals and Metabolite in Synthetic Human

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Degradation of Pharmaceuticals and Metabolite in Synthetic Human Urine by UV, UV/H2O2 and UV/PDS Ruochun Zhang, Peizhe Sun, Treavor H Boyer, Lin Zhao, and Ching-Hua Huang Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/es504799n • Publication Date (Web): 27 Jan 2015 Downloaded from http://pubs.acs.org on February 8, 2015

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Environmental Science & Technology

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Degradation of Pharmaceuticals and Metabolite in Synthetic

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Human Urine by UV, UV/H2O2 and UV/PDS

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Ruochun Zhang1,2, Peizhe Sun2, Treavor H. Boyer3, Lin Zhao1,*, and Ching-Hua Huang2,*

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School of Environmental Science and Engineering, Tianjin University, Tianjin 300072, China 2

School of Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, United States

8 9 10

3

Department of Environmental Engineering Sciences, University of Florida, Gainesville, Florida 32611, United States

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* Corresponding Authors. Phone: 404-894-7694; Fax: 404-358-7087.

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E-mail: [email protected]; Phone: 86-22-27401154; Fax: 86-22-27401797. E-mail:

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[email protected]

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Revised manuscript submitted to

17


18 19

January 23, 2015

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1 ACS Paragon Plus Environment


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ABSTRACT

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To minimize environmental pharmaceutical micropollutants, treatment of human urine could be

23

an efficient approach due to the high pharmaceutical concentration and toxic potential excreted

24

in urine. This study investigated the degradation kinetics and mechanisms of sulfamethoxazole

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(SMX), trimethoprim (TMP) and N4-acetyl-sulfamethoxazole (acetyl-SMX) in synthetic fresh

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and hydrolyzed human urines by low-pressure UV, and UV combined with H2O2 and

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peroxydisulfate (PDS). The objective was to compare the two advanced oxidation processes

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(AOPs) and assess the impact of urine matrices. All three compounds reacted fast in the AOPs,

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exhibiting rate constants of (6.09−8.53) × 109 M-1⋅s-1 with hydroxyl radical, and (2.35−16.1) ×

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109 M-1⋅s-1 with sulfate radical. In fresh urine matrix, the pharmaceuticals’ indirect photolysis

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was significantly suppressed by the scavenging effect of urine citrate and urea. In hydrolyzed

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urine matrix, the indirect photolysis was strongly affected by inorganic urine constituents.

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Chloride had no apparent impact on UV/H2O2 but significantly raised hydroxyl radical

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concentration in UV/PDS. Carbonate species reacted with hydroxyl or sulfate radical to generate

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carbonate radical, which degraded SMX and TMP primarily due to the presence of aromatic

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amino group(s) (k = 2.68 × 108 and 3.45 × 107 M-1⋅s-1) but reacted slowly with acetyl-SMX.

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Ammonia reacted with hydroxyl or sulfate radical to generate reactive nitrogen species that

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could react appreciably only with SMX. Kinetic simulation of radical concentrations, along with

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products analysis, helped elucidate the major reactive species in the pharmaceuticals’

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degradation. Overall, the AOPs’ performance was higher in the hydrolyzed urine than fresh urine


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matrix with UV/PDS better than UV/H2O2, and varied significantly depending on

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pharmaceutical’s structure.

43



44

INTRODUCTION

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The U.S. population spent nearly $325.8 billion on medication in 2012.1 A large portion of

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the prescribed pharmaceuticals are excreted unchanged or as metabolites in urine and feces

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which follow municipal wastewater streams. Unless wastewater treatment plants (WWTPs) are

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equipped with highly advanced treatment processes, most pharmaceuticals and metabolites are

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not removed and eventually end up in the natural environment, threatening the aquatic ecosystem

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because of their toxicity and potential to induce drug resistance.2 Numerous studies have

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reported detection of pharmaceuticals in drinking water, surface water, groundwater and

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wastewater at ng⋅L-1 to µg⋅L-1 levels.3-6 The extensive occurrence of pharmaceuticals in aquatic

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environments and potable water demands more efficient treatment of these micropollutants from

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the source.

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Human urine accounts for less than 1% of municipal wastewater by volume7 but contains

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pharmaceuticals at 2-3 orders of magnitude higher concentrations.8,9 Lienert et al. estimated that,

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on average, pharmaceuticals are excreted at 64(±27)% via urine and 35(±26)% via feces, and for

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excretion in urine, about 42(±28)% of the pharmaceuticals are excreted as metabolites.10

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Moreover, Escher, Lienert and co-workers estimated that nearly 67% of 42 pharmaceuticals

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(selected from 22 therapeutic groups) retained at least half of their toxicity after being excreted

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in urine, and 24% of the investigated pharmaceuticals excrete toxicity exclusively via urine.7,11,12

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Thus, urine not only contains a greater portion of the excreted pharmaceuticals but also carries

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greater pharmaceutical toxic potential to aquatic organisms, suggesting that urine treatment


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would be an efficient way to minimize the harm of excreted pharmaceuticals. Furthermore,

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recovering nutrients, in particular nitrogen and phosphorus, in source-separated urine to produce

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fertilizers is creating a new wastewater management and resource recovery strategy.13 Source

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separation is especially favorable in rural areas, densely populated areas in developing countries,

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and coastal areas without wastewater infrastructure.14 Demonstration projects of source

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separation have been under way in residential and workplace locations for extended periods of

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time, notably in Sweden, Denmark, South Africa,15 Germany,16 and Switzerland,17 and the

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technology has been increasingly viewed as a realistic alternative to conventional nutrient

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elimination. However, although liquid urine can be applied directly as fertilizer,18-21 the

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micropollutants such as pharmaceuticals in urine may accumulate in the soil and plants and exert

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hazard,22,23 or contaminate the nutrients to be separated from urine.24 Thus, the removal of

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micropollutants becomes a necessary prerequisite to feasibly utilize urine-based fertilizer.

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To date, research regarding the removal of pharmaceuticals and their metabolites in urine is

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still quite limited. Nanofiltration (NF) membranes,24 strong-base anion exchange polymer

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resins,25 electrodialysis, and struvite precipitation11,26 have been investigated; however, all the

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above methods only physically separate pharmaceuticals from urine and generate pharmaceutical

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wastes that still need to be handled. Ozonation is so far the only technology investigated for

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destruction of pharmaceuticals in urine; however, very high doses of ozone were needed to

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achieved 50% reduction of pharmaceutical concentrations in source-separated urine.27 Thus,

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more effective treatment processes, either stand-alone or in conjunction with other processes, are



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needed for eliminating pharmaceuticals and metabolites in urine.

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Advanced oxidation processes (AOPs) are attractive and promising technology to destruct

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organic pollutants by highly oxidizing agents. Hydroxyl radical (·OH)-based AOPs, such as

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UV/H2O2, are among the most frequently employed to degrade recalcitrant organic contaminants,

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and have been demonstrated to effectively remove pharmaceuticals in various systems.28-34

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Reports have shown that many pharmaceuticals react rapidly with ·OH (k = 108−1010 M-1⋅s-1).35

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Meanwhile, AOPs based on sulfate radical (SO4· -) are gaining more interest owing to similar

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oxidizing power (E° (SO4· -/SO42-) = 2.5−3.1 V)36 to ·OH (E° (·OH/H2O) = 1.9−2.7 V).37

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Generated from activation of peroxydisulfate (S2O82-, PDS) or peroxymonosulfate (HSO5-, PMS)

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by UV light, heat, alkaline or metal catalysts, SO4· - has been shown effective in treating

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pharmaceuticals.38-42 While the reaction rates of pharmaceuticals with SO4· - have not been

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extensively studied, many pharmaceuticals, except for a few cases (e.g., iopromide),43 react with

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SO4· - at comparable rates as with ·OH.44,45

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Human urine is a complex matrix different from wastewater and drinking water, where

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UV/H2O2 and UV/PDS have been successfully applied. Urine is typically classified as fresh

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urine (i.e., the urine just left the human body) and hydrolyzed urine (i.e., the stored urine that the

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original composition has changed due to hydrolysis of urea, which is catalyzed by

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urease-positive bacteria).25 Urea, inorganic salts and organic compounds (e.g., citrate)46 in fresh

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urine may bring about scavenging and shielding effects in AOPs. On the other hand, high

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concentrations of ammonia and bicarbonate in hydrolyzed urine, may act not merely as radical


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scavengers47 because their reactions with ·OH and SO4· - can generate new reactive species, such

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as carbonate radical (CO3· -) and amino radical (·NH2). Carbonate radical (Eº (CO3· -/CO32-) =

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1.63 V at pH 8.4)48 is electrophilic and also sufficient to degrade pharmaceuticals, but is more

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selective than ·OH and SO4· -. Reactivity of CO3· - towards some pesticides and biochemical

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compounds49,50 has been investigated but little research has been conducted towards

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pharmaceuticals. Amino radical is a relatively weak oxidant (E° (·NH2/NH3) = 0.6 V)36 and may

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react with aromatic compounds that contain strong electron-donating substituents by electron

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transfer.51

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Both pharmaceuticals and their metabolites should be considered in urine treatment. In fresh

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urine, the concentration ratio between pharmaceutical and its metabolites varied widely.52,53 For

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example, 77.5% of trimethoprim (TMP) was excreted in unchanged form54 whereas it was 9.5%

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for sulfamethoxazole (SMX).55 Currently, information is scarce regarding the concentrations of

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pharmaceuticals versus metabolites in hydrolyzed urine. However, considering microbial and

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enzymatic activities in WWTPs can transform some pharmaceutical metabolites back to the

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parent compounds,56 such transformation may also occur in hydrolyzed urine due to microbial

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activities in real urine. To date, few studies have investigated the removal of pharmaceutical

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metabolites by AOPs.

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The objective of this study was to evaluate the efficacy of UV/H2O2 and UV/PDS processes

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in eliminating pharmaceuticals and metabolites in synthetic human urine. UV/H2O2 and UV/PDS

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were selected because they are among the most common ·OH- and SO4· --based AOPs and allow



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for comparison between the two radical systems. SMX and TMP, two widely co-prescribed

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antibiotics, were selected because they are frequently detected in the environment.3

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N4-acetyl-sulfamethoxazole (acetyl-SMX), the most prominent metabolite of SMX,57 was

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studied as an example of human pharmaceutical metabolites. Because urine presents challenging

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matrices that can significantly impact AOPs’ performance, this study focused on assessing such

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influence through experimental and kinetic modeling approaches. The experiments employed

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synthetic human urine to allow evaluation of individual major urine constituents. The study goal

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was to gain mechanistic insight that can help develop better AOP urine treatment strategies. To

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the authors’ best knowledge, this study is among the first to investigate the degradation of

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pharmaceuticals in urine matrices by UV/H2O2 and UV/PDS, and systematically evaluate the

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impact of major urine constituents. Several reaction rate constants were also determined for the

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first time for the pharmaceuticals and urine constituents with radical species, thereby making the

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comprehensive kinetic simulation for the SO4· --, CO3· -- and reactive nitrogen species

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(RNS)-dominated systems possible. Overall, the evaluation of the different major reactive

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species in the AOPs significantly improves the understanding of the unique matrix impacts of

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urine on UV/H2O2 and UV/PDS in general and for destruction of pharmaceutical

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micropollutants.

141 142

MATERIALS AND METHODS

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Chemicals. Sources of chemicals and reagents are provided in the Supporting Information (SI)


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Text S1. Structures and chemical properties of the target compounds are shown in SI Table S1.

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Synthetic urine matrices. Two types of synthetic human urine, fresh (pH 6) and hydrolyzed (pH

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9), were prepared by adopting recipes from previous literature25,58 (Table 1). The main

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differences included different pHs and that the urea and citrate in fresh urine were replaced by

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ammonia and bicarbonate in hydrolyzed urine. Though citrate may not be removed completely as

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urea, it was neglected in hydrolyzed urine. The high concentrations of ammonia and bicarbonate

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dominate in the scavenging effects in hydrolyzed urine; inclusion of citrate at a possible

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concentration (approximately 1 mM) would barely influence the concentrations of main reactive

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species as indicated by kinetic modeling (see description about kinetic modeling below).

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Concentrated solutions of NaOH and H3PO4 were used to adjust the urine pH. As a baseline

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matrix compared to the synthetic urine, phosphate buffer (PB) (10 mM) solutions at pH 6 and 9

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were also employed.

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Experimental setup and analysis. Direct Photolysis. Photolysis experiments were conducted in

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a 100-mL magnetically stirred cylindrical quartz reactor with a 4-W low pressure (LP) UV lamp

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(G4T5 Hg lamp, Philips TUV4W) peaking at 254 nm (SI Figure S1). The light intensity was

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measured to be 2.57 × 10-6 Einstein⋅L-1⋅s-1, using potassium ferrioxalate as chemical

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actinometer.59 Solutions were prepared with 10 µM of each target compound in 50 mL fresh

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urine, hydrolyzed urine or PB solution at pH 6 or 9. Reaction was initiated by exposing the

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solution to UV light. The degradation of target compounds was monitored by HPLC-DAD and

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the transformation products were studied using LC/MS. Detailed analytical methods are



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described in SI Text S2. Quantum yield calculation is described in SI Text S3.

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UV/H2O2 and UV/PDS AOPs. Advanced oxidation conditions were created with similar

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procedures described above with the addition of 294 µM (the same as the commonly used 10

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mg/L H2O2 dose in UV/H2O2)29,60 H2O2 or sodium PDS. Control experiments with H2O2 or PDS

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were conducted without UV irradiation. Competition kinetic approaches (SI Text S4-6) were

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used to determine the second-order rate constants of the target compounds and urine constituents

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with ·OH, SO4· - and CO3· - using nitrobenzene (NB), anisole and para-nitroaniline (PNA) as

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chemical probes, respectively.49,61

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Kinetic modeling. To evaluate the reactive species under different conditions, radical

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concentrations after 5 min (close to the pseudo-steady state of most reactive species) of UV/H2O2

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or UV/PDS treatment were simulated by kinetic modeling using Gepasi 3.0. The rate constants

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for reactions considered in the kinetic modeling were obtained or calculated from literature (SI

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Table S2)62-64. On the basis that the concentration of pharmaceuticals is much lower than the

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concentrations of urine constituents, the kinetic modeling first neglected target pharmaceuticals

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in the solutions so that a general perspective could be obtained. Meanwhile, additional

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simulations with each pharmaceutical in the system were also performed and shown in SI Table

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S3. For most scenarios, both methods yielded similar trends of radical concentrations (detailed

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comparison discussed in SI Text S7). Thus, for simplicity and clarity, the discussion is mainly

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based on the kinetic modeling without considering target pharmaceuticals.

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RESULTS AND DISCUSSION

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Direct Photolysis. The degradation of pharmaceuticals in UV/H2O2 and UV/PDS processes

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included two parts, direct photolysis and indirect photolysis:

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kobs = kd + ki

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where kobs was the observed pseudo-first-order degradation rate constant (s-1), kd was the

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measured pseudo-first-order direct photolysis rate constant (s-1), and ki was the indirect

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photolysis rate constant (s-1), primarily due to reactive species such as ·OH and SO4· -, which

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could be derived from ki = kobs − kd.

(1)

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Before investigating the AOPs, the direct photolysis of target compounds under LPUV only

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was studied in PB (pH 6 and 9) and synthetic fresh and hydrolyzed urine. Noted that the

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synthetic urine components did not have significant influence on the direct photolysis rates

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(Table 2), likely due to their low light absorption at 254 nm. The light absorption spectra of SMX,

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acetyl-SMX and TMP were obtained in PB (pH 3.5, 6 and 9; SI Figure S2) based on their pKa

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values57,65,66 and urine pHs. The molar absorption coefficients (ε) of the three compounds at 254

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nm are summarized in Table 2. For SMX and acetyl-SMX, their anionic forms (dominant at pH 9)

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exhibited slightly higher ε254nm than their neutral forms (dominant at pH 3.5), and their ε254nm

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values were about 4−8 times of those of TMP.

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Under LPUV irradiation, SMX was rapidly photodegraded with kd of 1.22−1.24 × 10-2 (pH 6)

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and 6.30−6.50 × 10-3 (pH 9) s-1 (Table 2). Previous research also observed faster

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photodegradation of the neutral form than the anionic form of SMX.30 The fraction of SMX in



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the neutral form is about 30% at pH 6, but less than 0.1% at pH 9 (Figure S2). As a result, the

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direct photolysis rate of SMX was faster at pH 6. Such pH dependence of the photochemical

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behavior may be related to SMX’s functional groups but requires further study to delineate. The

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direct photolysis rate of acetyl-SMX was about 1/6 of that of SMX, and was also faster at pH 6

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than at pH 9 (Table 2). In comparison, TMP underwent direct photolysis much more slowly.

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Quantum yields were calculated from the direct photolysis rates (SI Text S3) and were

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comparable to the previous literature.30,57 The quantum yield of SMX was 5.5−6.5 times of that

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of acetyl-SMX and more than 24 times of that of TMP (Table 2). The low light absorption ability

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and quantum yield of TMP indicate LPUV alone is not sufficient to remove all the

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pharmaceuticals.

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UV/H2O2 and UV/PDS AOPs in Synthetic Fresh Urine. The target compounds were treated by

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LPUV with 294 µM of H2O2 or PDS in pH 6 PB or synthetic fresh urine. No degradation of the

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target compounds was observed in the dark experiments with either H2O2 or PDS for up to 1 h.

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From this point on, the discussion focuses on the indirect photolysis (ki shown in Figures 1 and 2)

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for a more straightforward comparison on reactive species’ contributions under different

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conditions. Also noted is that the kinetic modeling, in conjunction with the experiments, was

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aimed to illustrate how the target compound degradation was driven by different radicals, rather

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than to draw a definitive conclusion on the concentration of the radicals.

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Compared to UV only (Table 2), UV/H2O2 increased the degradation rate constants (kobs) of


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SMX, acetyl-SMX and TMP to 1.78 × 10-2, 8.20 × 10-3 and 9.40 × 10-3 s-1, respectively, in PB.

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Radical species importantly contributed to the increased degradation. A competition kinetic

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method (SI Text S4) was employed to determine the second-order rate constants of the target

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compounds with ·OH and yielded similarly large rate constants (k·OH = 6.09−7.02 × 109 M-1⋅s-1,

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Table 3), comparable to the literature values where available.33,35,37,41,67

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Compared to that in PB, the degradation rate of the three compounds by UV/H2O2 in

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synthetic fresh urine was inhibited by approximately 90% (Figure 1). Kinetic modeling indicated

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that the ·OH concentration decreased from 1.36 × 10-11 M in PB to 1.29 × 10-13 M in synthetic

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fresh urine (Table 4). The decrease in ·OH concentration was due mainly to the competing

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reactions by citrate and urea. The second-order rate constants of citrate and urea with ·OH were

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reported to be 2.4 × 108 M-1⋅s-1 67 and 7.9 × 105 M-1⋅s-1 37, which made them strong scavengers at

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their concentrations in fresh urine (Table 1).

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UV/PDS treatment led to a slightly faster degradation of the target compounds in PB than

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UV/H2O2 (Figure 1). The second-order rate constants of the target compounds with SO4· - were

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determined using a competition kinetic method (SI Text S5), and revealed different reactivity of

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the compounds (kSO4· - = 3.01−16.1 × 109 M-1⋅s-1, Table 3). The rate constant of SMX was two

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times of that of TMP and 5 times of that of acetyl-SMX, demonstrating a higher selectivity of

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SO4· -. Considering the electrophilic nature of SO4· -,68 aromatic compounds with a stronger

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electron-donating substituent are probably more reactive toward SO4· -, which explains the higher

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reactivity of SMX than acetyl-SMX because -NH2 is a stronger electron-donating substituent



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than -NHCOCH3. While SO4· - can react with OH- anion to generate ·OH,69 the concentration

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of ·OH was not significant compared to the concentration of SO4· - in the pH 6 PB (Table 4).

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Furthermore, compared to UV/H2O2, UV/PDS had a better radical quantum yield (Table 4),

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which contributed to the faster degradation of SMX and TMP by UV/PDS in addition to their

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higher reactivity with SO4· -. The higher radical quantum yield of UV/PDS particularly played a

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role in the faster degradation of acetyl-SMX, considering that the rate constant of acetyl-SMX

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with ·OH is twice as much with SO4· -.

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UV/PDS treatment in synthetic fresh urine also experienced strong suppression effect; the

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indirect photolysis rate (ki) of all three compounds was decreased to around 4 × 10-4 s-1 (Figure 1).

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Meanwhile, both ·OH and SO4· - concentrations decreased in fresh urine compared to the PB

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matrix (Table 4). By using competition kinetic method, the rate constants of citrate and urea with

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SO4· - were determined to be 1.9 × 108 M-1⋅s-1 and 6.35 × 105 M-1⋅s-1 (Table 3), slightly lower than

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those with ·OH. The kinetic modeling indicated that in fresh urine, in contrast to the case in PB,

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the role of ·OH probably outweighed that of SO4· - in pharmaceutical degradation since ‧OH

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concentration was more than 15 times higher than SO4‧- (Table 4, SI Table S3). This result can

259

be further explained by the discussion of the effect of chloride in a later section.

260 261

UV/H2O2 and UV/PDS AOPs in Synthetic Hydrolyzed Urine. The target compounds were

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treated by LPUV with 294 µM of H2O2 or PDS in pH 9 PB or synthetic hydrolyzed urine. The

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target compounds did not degrade in the dark with either H2O2 or PDS for up to 1 h.


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In pH 9 PB with UV/H2O2, lower ki of all three target compounds were observed compared

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to those at pH 6 (Figure 2a), which can be verified by the kinetic modeling because the ·OH

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concentration decreased to 4.57 × 10-12 M compared to that at pH 6 (1.36 × 10-11 M, Table 4) .

267

On the other hand, the target compounds mostly existed in their anionic form at pH 9 (SI Figure

268

S3). As a result, the second-order rate constants with ·OH were always slightly higher than those

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at pH 6 (Table 3), benefiting from the relatively electron-richer form of the compounds.

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In hydrolyzed urine with UV/H2O2, no degradation of acetyl-SMX due to indirect photolysis

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was observed (Figure 2a), which could be expected because the ·OH concentration of 5.41 ×

272

10-15 M was insufficient to yield an observable indirect photolysis rate. However, for SMX and

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TMP, the ki was 3.10 × 10-3 s-1 and 1.34 × 10-3 s-1, respectively. Even though SMX and TMP

274

have comparable rate constants with ·OH as acetyl-SMX, yet their degradation was achieved,

275

indicating that other reactive species played an important role in degrading these compounds.

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In pH 9 PB with UV/PDS, the ki of TMP and acetyl-SMX were lower than those in pH 6 PB,

277

which were consistent with the decreased concentrations of SO4· - and ·OH (Table 4). As for

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SMX, ki in pH 9 PB was similar to that in pH 6 PB, which was consistent with what the model

279

predicted. Furthermore, unlike ·OH which is neutral, SO4· - is negatively charged. Thus, SO4· - is

280

prone to react with more positively charged species, whose concentration decreases as pH

281

increases (SI Figure S3). This resulted in the slightly decreased rate constants of the target

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compounds with SO4· - at pH 9 versus pH 6 (Table 3). Moreover, according to the simulated

283

SO4· - and ·OH concentrations (SI Table S3) and the measured rate constants with the radicals



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(Table 3), UV/PDS was supposed to lead to greater indirect photolysis of the target compounds

285

than UV/H2O2 in pH 9 PB; however, this was only true for SMX (Figure 2). Further study will

286

be needed to evaluate if there was any unknown scavenger of SO4· - (such as persulfate radical)

287

or any underestimated rate constant for reaction with SO4· -, bringing about a lower SO4· -

288

concentration than predicted.

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In hydrolyzed urine with UV/PDS, there was also no measurable indirect photolysis of

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acetyl-SMX, which could be expected based on the low SO4· - (4.15 × 10-15 M) and ·OH (3.17 ×

291

10-18 M) concentrations (Table 4). In contrast, ki of 5.35 × 10-3 s-1 was achieved for SMX, which

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was 1.7 times higher than that by UV/H2O2 in hydrolyzed urine. For TMP, ki was 1.30 × 10-3 s-1,

293

which was comparable to that by UV/H2O2 in hydrolyzed urine (Figure 2). Although the rate

294

constant of acetyl-SMX with SO4· - was lower than those of SMX and TMP, they were still on the

295

same order of magnitude and should not result in such a large difference in the degradation. The

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observable indirect photolysis of SMX and TMP also suggested that other radicals were

297

involved.

298 299

Impact of Constituents in Hydrolyzed Urine. Chloride, bicarbonate and ammonia are the most

300

abundant constituents in hydrolyzed urine and their reactions with ·OH and SO4· - can generate

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new radicals:

302

Cl − + ⋅OH → ClOH ⋅−

k = 4.3 × 109 M-1⋅s-1

(2) 62

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Cl − + SO4 ⋅− → Cl ⋅ + SO4 2−

k = 3.0 × 108 M-1⋅s-1

(3) 62


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ClOH ⋅− + H + → Cl ⋅ + H 2O

k = 2.1 × 1010 M-1⋅s-1

(4) 62

305

ClOH ⋅− +Cl − → Cl2 ⋅− +OH −

k = 1.0 × 104 M-1⋅s-1

(5) 62

306

HCO3− + ⋅OH → CO3 ⋅− + H 2 O

k = 8.5 × 106 M-1⋅s-1

(6) 70

307

CO32− + ⋅OH → CO3 ⋅− +OH −

k = 3.9 × 108 M-1⋅s-1

(7) 70

308

HCO3− + SO4 ⋅− → HCO3 ⋅ + SO4 2−

k = 2.8 × 106 M-1⋅s-1

(8) 62

309

CO32− + SO4 ⋅− → CO3 ⋅− + SO4 2−

k = 6.1 × 106 M-1⋅s-1

(9) 42

310

NH 3 + ⋅OH → ⋅ NH 2 + H 2O

k = 9 × 107 M-1⋅s-1

(10) 64

311

NH 3 + SO4 ⋅− → ⋅ NH 2 + SO4 2− + H +

k = 1.4 × 107 M-1⋅s-1

(11) 36

312

The high concentrations of chloride, bicarbonate and ammonia in hydrolyzed urine guaranteed

313

the abundant sources for the corresponding radicals (Table 4). Investigating the reactivity of the

314

target compounds towards these radicals will help understand their degradation in hydrolyzed

315

urine matrix by AOPs.

316

Effect of chloride. As shown in Figure 2, in UV/H2O2 treatment, ki of the pharmaceuticals was

317

not impacted by the addition of 0.1 M chloride compared to that in PB. The ·OH concentration

318

hardly changed (Table 4). Although the reaction rate of ·OH with Cl- is high (Equation (2)), there

319

is also a fast backward reaction (ClOH•- → Cl- + ·OH, k = 6.1 × 109 M−1⋅s−1),62 leading to a

320

stable ·OH concentration. Furthermore, when chloride was added into solution together with

321

bicarbonate or ammonia, because the ·OH concentration would be nearly the same as when there

322

was no chloride, all other radicals generated from ·OH would also change little by chloride

323

(Table 4). Comparing any two samples whose only difference was the presence of chloride (e.g.,



324

“bicarbonate” vs. “chloride & bicarbonate”), it suggests that chloride reactive species did not

325

contribute to the pharmaceuticals’ degradation, which may be due to either low reactivity or low

326

concentration.

Page 18 of 42

327

In UV/PDS treatment, chloride addition also did not influence ki signifincatly (Figure 2) but,

328

according to the kinetic modeling, decreased the SO4· - concentration because of scavenging

329

effect (Equation (3)). Unlike ClOH•-, the generation of SO4·- from the reaction of chlorine atom

330

(Cl·) and sulfate ion was slow due to both the lower reaction rate constant and the lower

331

concentration of sulfate. Instead, the reactions of Cl· with H2O and OH- (SI Table S2) produced

332

ClOH•- and ultimately led to a higher ·OH concentration (Table 4). The high reactivity of the

333

pharmaceuticals towards ·OH compensated the decrease in SO4· - and maintained high ki of 6.5 ×

334

10-3, 5.7 × 10-3, and 6.5 × 10-3 s-1 for SMX, acetyl-SMX and TMP, respectively.

335

Effect of bicarbonate. The presence of 0.25 M bicarbonate impacted ki of the pharmaceuticals to

336

different extent in the UV/H2O2 process (Figure 2a). For SMX and TMP, the ki dropped by

337

approximately half when PB solution was added with bicarbonate, although the rate should have

338

been close to zero if only taking the oxidation by ·OH into consideration (Table 4). This

339

suggested SMX and TMP can react with CO3· -. Meanwhile, the negligible indirect photolysis

340

rate of acetyl-SMX showed its low reactivity to CO3· -. Indeed, the second-order rate constants of

341

SMX and TMP with CO3· - were determined (SI Text S6) to be 2.68 × 108 M-1⋅s-1 and 3.45 × 107

342

M-1⋅s-1, respectively. Although the rate constants with CO3· - were lower than those with ·OH

343

(Table 3), the higher selectivity of CO3· - also rendered it less susceptable to scavenging effects


Page 19 of 42


344

by the solution matrix. This could be seen from the kinetic modeling that the CO3· - concentration

345

was 3-4 orders of magnitude higher than that of ·OH in the different matrices (Table 4).

346

In UV/PDS treatment, the ki for SMX and TMP in PB added with bicarbonate were

347

significantly higher than those in PB only and were also much higher than those by UV/H2O2

348

(Figure 2b). This result could be partially explained by the lower scavenging effect of

349

HCO3-/CO32- on SO4· - than ·OH, which maintained relatively high SO4· - concentration in the

350

solution (Table 4). However, it should be noted that the simulated radical concentrations

351

(SO4· -, ·OH, and CO3· -) could not fully account for the SMX and TMP degradation rates

352

observed in the experiments. One possible reason could be the overestimated scavenging effect

353

of PDS on CO3· -. The rate constant of 3 × 107 M-1⋅s-1 assumed by Yang et al.62 for the reaction

354

between PDS and CO3· - was used in the kinetic modeling; however, we found that a 1-2 orders

355

of magnitude lower k value would match the experimental results better.

356

Previous work by Chen and Hoffman found that sulfur-containing compounds can react fast

357

with CO3· -.50 Huang and Mabury proposed the reaction pathway to be conversion to sulfoxide,

358

followed by production of sulfone.71 The drastically different reactivity of SMX and acetyl-SMX

359

towards CO3· -, as well as their already oxidized sulfanilamide form, excluded the possibility of

360

CO3· - attack on the sulfur atom. Because the only structural difference between SMX and

361

acetyl-SMX is the phenylamino group, its presence must play a critical role. Based on previous

362

research, the -NH2 substituted benzene derivative is much more reactive to CO3· - than the

363

-NHCOCH3 benzene derivative.72 Furthermore, the addition of CO3· - to the aromatic compounds



Page 20 of 42

364

is the rate-determining step.72 The interaction of CO3· - with protonated or deprotonated amino

365

group holds the radical in proximity to the aromatic system longer than random collision and

366

thus the reaction can occur at a higher rate.73 This may explain why there was significant

367

degradation of SMX by CO3· - but not acetyl-SMX. To probe the specific functional group(s) responsible for the reactivity of TMP toward CO3· -,

368 369

the

degradation

of

two

moieties

of

TMP,

3,4,5-trimethoxytoluene

370

2,4-diamino-5-methylpyrimidine (DAMP), was investigated. DAMP was degraded with a

371

comparable rate constant (ki = 2.28 × 10-3 s-1) as TMP (ki = 3.98 × 10-3 s-1), whereas the

372

degradation of TMT was much slower (ki = 4.48 × 10-4 s-1) (SI Figure S4). This indicated that the

373

DAMP moiety was primarily responsible for TMP’s reaction with CO3· -, which was consistent

374

with the hypothesis that amino group on aromatic moieties plays an important role in reaction

375

with CO3· -.

376

Effect of ammonia. In UV/H2O2 treatment, addition of 0.5 M ammonia to PB nearly completely

377

inhibited the indirect photolysis of acetyl-SMX, and decreased the ki of SMX and TMP to 9 ×

378

10-4 and 3.5× 10-5 s-1, respectively. Amino radical (·NH2) would first be generated from the

379

reaction of ammonia and ·OH (Equation (10)). Then, after a series of reactions including with

380

oxygen and H2O2 (SI Table S3), nitrogen dioxide radical (·NO2), nitric oxide radical (·NO) and

381

ONOOH/ONOO- would also be produced, together with a few reactive intermediates. Although

382

the rate constants between RNS and target compounds were not previously determined, the

383

reactions are expected, considering that RNS are reactive toward electron-rich aromatic


(TMT),

and

Page 21 of 42


384

moieties.51 In addition, the preliminary product analysis proved that ·NH2 reacted TMP (details

385

are discussed in the transformation product analysis section), and the degradation rate of SMX in

386

the ammonia-containing matrix could not be attributed to ·OH (Table 4 and Figure 2(a)).

387

The major RNS responsible for the degradation of SMX and TMP may be discerned based

388

on the comparison between the ammonia-alone matrix and the bicarbonate+ammonia.matrix.

389

The ki of SMX in PB amended with bicarbonate and ammonia was equivalent to the sum of ki in

390

PB amended with bicarbonate only and in PB amended with ammonia only (Figure 2a). For TMP,

391

the ki in PB amended with bicarbonate and ammonia was approximately half of the ki in PB

392

amended with bicarbonate only (Figure 2a). However, the kinetic modeling indicated that, while

393

the concentrations of ·NH2 and ·NO remained similar, the CO3· - concentration would drop

394

notably when bicarbonate and ammonia were added together in PB (Table 4), due to competition

395

between bicarbonate and ammonia for reaction with ·OH and the combining reaction between

396

CO3· - and ·NH2, and the CO3· - concentration became inadequate to retain significant degradation

397

rates. Although the ·NO2 concentration was increased by an order of magnitude in PB amended

398

with bicarbonate and ammonia compared to PB amended with ammonia only (Table 4), the

399

concentration was still quite low (6.54 × 10-15 M) and thus there were probably other RNS

400

reacting with SMX and TMP. On the other hand, ONOOH concentration was one order of

401

magnitude higher when bicarbonate and ammonia were added together than they were added

402

separately (Table 4). It has been reported that ONOOH itself may induce nitration of naphthalene

403

and benzene.74 Considering the reactivity of aromatic moieties (with electron-donating



404

substituents) of SMX and TMP, they likely have the potential to react with ONOOH. As for ·NO,

405

due to the limited knowledge, the modeled concentration may be inaccurate. Based on the

406

current simulation, ·NO probably degraded SMX and TMP to some extent due to its high

407

concentration, but no evidence exists yet to prove its role.

Page 22 of 42

408

In UV/PDS treatment, the ki of SMX in PB amended with ammonia is comparable to that by

409

UV/H2O2 (Figure 2b). The quenching effect of ammonia on SO4· - was lower than on ·OH due to

410

slower reaction (Equation 11). Thus, a significant concentration of SO4· - together with RNS

411

provided a comparable removal rate for SMX as by UV/H2O2. Note that ·NO2 and ONOOH

412

concentrations were much lower in UV/PDS than UV/H2O2 because H2O2 was essential in their

413

generation process (SI Table S2). Notably, the ki of SMX and TMP was significantly lower in PB

414

amended with bicarbonate and ammonia together than that in PB amended with bicarbonate only

415

(Figure 2b), because SO4· - was consumed by ammonia resulting in less CO3· - production.

416

However, in hydrolyzed urine, the CO3· - concentration increased (Table 4) due to the presence of

417

chloride and thus the overall ki was enhanced (Figure 2b).

418 419

Transformation Product Analysis. Preliminary transformation product analysis was conducted

420

for TMP and SMX under different reaction conditions (SI Table S4) and showed product

421

variations because different reactive radicals were involved. The oxidation of TMP by ·OH (by

422

UV/H2O2 in PB) produced mainly two products both with m/z M-14 (loss of 14 Dalton from the

423

molecular weight), whose retention times were only 0.4 min apart, suggesting close similarity in


Page 23 of 42


424

structures. The loss of 14 in m/z was probably due to ipso attack of ·OH to replace the –OCH3 by

425

-OH.75 By SO4· - (by UV/PDS in PB), two primary products with m/z M+14 and M+16 were

426

generated. The M+14 product was speculated to be a ketone compound and the M+16 product

427

was probably due to hydroxylation. By CO3· - (generated by adding excess bicarbonate into pH 9

428

PB in the UV/H2O2 process), the products were similar to those by SO4· -. In general, SO4· - most

429

likely reacts by electron-transfer mechanism,68 whereas for ·OH, the mechanism of radical

430

adduct formation, hydrogen atom abstraction, and single electron transfer are commonly

431

considered.76 The similar products by SO4· - and CO3· - suggest that these two radicals may react

432

with TMP via similar mechanisms. In the ·NH2-dominated system (by adding excess ammonia

433

into pH 9 PB in the UV/PDS process), a product with m/z M+15 was observed and likely due to

434

-NH2 addition. In addition, pH had no significant influence on the TMP product variety. In terms

435

of synthetic urine matrices, in fresh urine by UV/H2O2, the M-14 products indicated ·OH was

436

dominant, whereas the products were different by UV/PDS from those under any other

437

conditions. This may be due to the presence of urea and citrate generating new reactive species

438

that led to different products formation. In hydrolyzed urine by either oxidant, in addition to the

439

products by CO3· - (or remaining SO4· - by UV/PDS), the product with m/z M+15 was found,

440

indicating ·NH2 played a role in the TMP degradation when ammonia was present.

441

For SMX, because of its high direct photolysis rate, a large portion of SMX was degraded by

442

direct photolysis so that the products of indirect photolysis were not as prominent in the system

443

as in the case of TMP. An isomer of SMX was produced by direct photolysis, which has been



Page 24 of 42

444

reported due to photoisomerization of the isoxazole ring.77 A m/z M+16 product was also found

445

in the direct photolysis system and its concentration increased significantly in the UV/H2O2

446

system, indicating it was a product by ·OH oxidation possibly from hydroxylation. The

447

abundance of this M+16 product suggested radical addition was a primary mechanism of ·OH

448

oxidation of SMX.78 There was a big difference in the products by SO4· - under different pHs. At

449

pH 6, only the isomer of SMX (due to direct photolysis) was found but at pH 9, several products

450

with relatively higher molecular weights were observed (SI Table S4), which may partly be due

451

to addition of the sulfate moiety to the parent compound and intermediates. A particular

452

observation was that in the UV/PDS process at pH 9 (both in PB and hydrolyzed urine matrices),

453

no direct photolysis product of SMX was found. Separate experiments showed that UV/PDS did

454

not react with the SMX isomer product (results not shown); thus, we speculated that UV/PDS

455

might destruct some intermediates that were important for formation of the isomer product at pH

456

9, but further research is needed to assess this hypothesis. Furthermore, a m/z M-155 product

457

was detected under every tested condition by both processes, which was likely

458

3-amino-5-methylisoxazole.77

459 460

Environmental Significance. Direct photolysis rates of the pharmaceuticals vary in a large

461

range based on their molar absorption coefficient and quantum yield. In general, UV irradiation

462

alone is not sufficient to remove the pharmaceuticals in urine matrix. Results of this study show

463

that for both UV/H2O2 and UV/PDS AOPs, hydrolyzed urine is a better matrix than fresh urine to


Page 25 of 42


464

be treated, which will also be a more easily implemented stage for source-separated urine due to

465

the natural tendency of urea hydrolysis to occur. However, the AOP performance will highly

466

depend on the specific structure of pharmaceuticals. Aromatic pharmaceuticals with

467

electron-donating substituents, such as SMX and TMP, will be relatively easy targets to destruct

468

by the AOPs. However, for the acetylated SMX metabolite, UV/H2O2 and UV/PDS were unable

469

to achieve satisfactory degradation in hydrolyzed urine in which ·OH and SO4· - were

470

transformed to less reactive species. With regard to the hydrolyzed urine treatment, ammonia is

471

the principal obstacle of a higher removal rate in the urine matrix. Thus, based on the

472

experimental data, elimination of ammonia prior to the AOPs will markedly improve the AOP

473

treatment efficiency. Moreover, because the isomer of SMX is of higher toxicity than the parent

474

SMX,77 PDS would be a better oxidant when treating hydrolyzed urine because there was no

475

SMX isomer found in the transformation products. The kinetic simulation conducted in this

476

study provides trend comparison of radical concentrations under different conditions, which

477

illustrates the variation in main reactive species and reveals the difference of AOPs conducted in

478

urine matrices from other more conventional water matrices. To comprehensively evaluate the

479

performance of UV/H2O2 and UV/PDS processes in destructing pharmaceuticals in human urine,

480

future research should be conducted to evaluate other urinary organic metabolites to minimize

481

the knowledge gaps between synthetic urine and real urine, and to validate the reactions in real

482

urine samples.

483



484

ASSOCIATED CONTENT

485

Supporting Information. Text S1-S6, Tables S1-S4 and Figures S1−S4. This material is

486

available free of charge via the Internet at http://pubs.acs.org.

487 488

ACKNOWLEDGMENTS

489

R. Zhang gratefully acknowledges financial support from the China Scholarship Council.

490 491

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492

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Page 37 of 42


Table 1. Composition of synthetic fresh urine and hydrolyzed urine matrices Concentration (mol⋅L-1) Species

-1

MW (g⋅mol ) fresh urine

hydrolyzed urine

Urea

60.06

0.25

-

NaCl

58.44

0.044

0.06

Na2SO4

142.04

0.015

0.015

KCl

74.55

0.04

0.04

NH4OH (conc.)

35.04

-

0.25

MgCl2·6H2O

203.31

0.004

-

NaH2PO4

119.98

0.02

0.0136

CaCl2·2H2O

147.02

0.004

-

NH4HCO3

79.06

-

0.25

Na3Citrate·2H2O

294.1

0.0027

-

6

9

pH



Page 38 of 42

Table 2. Molar absorption coefficients, quantum yields, and direct photolysis rate constants for SMX, acetyl-SMX and TMP Synthetic fresh urine

Synthetic hydrolyzed urine

(pH 6)

(pH 9)

SMX

ε254nm (M-1⋅cm-1)b

16120

17843

pKa1 = 1.7

Φ (mol⋅Einstein-1)c

(7.20 ± 0.17) × 10-2

(3.40 ± 0.01) × 10-2

pKa2 = 5.6a

kd (s-1) (in PB)d

(1.24 ± 0.03) × 10-2

(6.50 ± 0.01) × 10-3

kd (s-1) (in urine)

(1.22 ± 0.06) × 10-2

(6.30 ± 0.05) × 10-3

ε254nm (M-1⋅cm-1)

16260

16665

Φ (mol⋅Einstein-1)

(1.10 ± 0.5) × 10-2

(6.10 ± 0.51) × 10-3

kd (s-1) (in PB)

(2.0 ± 0.1) × 10-3

(1.2 ± 0.1) × 10-3

kd (s-1) (in urine)

(2.0 ± 0.2) × 10-3

(9.0 ± 0.5) × 10-4

ε254nm (M-1⋅cm-1)

3899

2179

Φ (mol⋅Einstein-1)

(2.0 ± 0.22) × 10-4

(1.4 ± 0.11) × 10-3

kd (s-1) (in PB)

(1.8 ± 0.2) × 10-5

(9.0 ± 0.7) × 10-5

kd (s-1) (in urine)

(1.5 ± 0.3) × 10-5

(8.0 ± 0.8) × 10-5

acetyl-SMX pKa = 5.07e

TMP pKa1 = 3.2 pKa2 = 7.1f

a

From Ref (55). bMeasured in 10 mM PB; cQuantum yield was calculated using the kd value measured

in 10 mM PB, the errors represent the standard deviations (n ≥ 2); dMeasured in 10 mM PB; eFrom Ref (48); fFrom Ref (56).


Page 39 of 42


Table 3. Second-order rate constantsa of the compounds with hydroxyl, sulfate and carbonate radicals determined in pH 6 and 9 PB solutions. pH 6

SMX

acetyl-SMX

TMP

pH 9 -

k·OH

kSO4· -

kCO3· -

(7.89 ± 0.07) × 109

(1.17 ± 0.13) × 1010

(2.68 ± 0.71) × 108

(3.01 ± 0.32) × 109

(6.93 ± 0.22) × 109

(2.35 ± 0.19) × 109

-

(7.71 ± 0.29) × 109

(8.53 ± 0.12) × 109

(5.85 ± 0.13) × 109

(3.45 ± 0.49) × 107

k·OH

kSO4·

(7.02 ± 0.20) × 109

(1.61 ± 0.17) × 1010

(6.19 ± 0.67) × 109b

(1.25 ± 0.19) × 1010c

(6.09 ± 0.17) × 109 (6.99 ± 0.11) × 109 (7.2 ± 1.53) × 109b

citrate

2.40 × 108d

(1.90 ± 0.25) × 108

-

-

-

urea

7.90 × 105e

(6.35 ± 0.76) × 105

-

-

-

a

All the rate constants unit = M-1⋅s-1, errors represent standard deviation (n ≥ 2); bMean value reported in previous literatures measured at pH

7.8,from Ref (23) and Ref(25); cValue reported in previous literatures, measured at pH7, from Ref (31); dFrom Ref(55); eFrom Ref (27).



Page 40 of 42

Table 4. Simulated molar concentrations (in M) of inorganic radicals with various components in solutions or synthetic urine. UV/H2O2 pH = 6

[·OH]

pH = 9

phosphate buffer

fresh urine

phosphate buffer

chloride

bicarbonate

ammonia

chloride & bicarbonate

chloride & ammonia

bicarbonate & ammonia

hydrolyzed urine

1.36×10-11

1.29×10-13

4.57×10-12

4.57×10-12

1.55×10-14

7.81×10-15

1.55×10-14

7.81×10-15

5.41×10-15

5.41×10-15

2.88×10-23

5.16×10-20

5.33×10-20

7.31×10-16

[Cl·]

4.38×10-17

6.93×10-18

[Cl2· -]

6.17×10-13

9.82×10-14

[CO3· -]

3.93×10

-10

3.93×10

-10

1.00×10-23 1.86×10-20 7.03×10

-12

7.03×10-12

[·NH2]

3.85×10-13

3.85×10-13

3.82×10-13

3.82×10-13

[·NO2]

6.82×10-16

6.82×10-16

6.54×10-15

6.61×10-15

[·NO]

3.36×10-05

3.36×10-05

3.30×10-05

3.30×10-05

[ONOOH]

6.47×10-11

6.47×10-11

6.78×10-10

6.85×10-10

-08

-08

-07

1.71×10-07

[ONOO-]

1.62×10

1.62×10

1.70×10

UV/PDS pH = 6 phosphate buffer -

-11

[SO4· ]

7.17×10

[·OH]

1.24×10-11

pH = 9

fresh urine 1.05×10

-14

1.75×10-13

phosphate

chloride

buffer 1.13×10

-11

2.94×10-12

4.49×10

-15

2.78×10-11

bicarbonate 1.71×10

-13

3.49×10-17

ammonia 6.51×10

-14

5.90×10-18

chloride

chloride

bicarbonate

hydrolyzed

&bicarbonate

&ammonia

&ammonia

urine

-15

-14

4.18×10-15

3.02×10-18

3.17×10-18

4.17×10

-15

4.70×10

1.03×10-17

9.39×10-15

4.82×10

[Cl·]

4.50×10-14

1.40×10-14

1.38×10-16

1.45×10-14

1.38×10-16

[Cl2· -]

6.35×10-10

1.97×10-10

5.60×10-15

2.03×10-10

5.59×10-15

[CO3· -]

1.84×10-11

1.87×10-11

2.76×10-12

1.04×10-11

[·NH2]

5.42×10-13

5.42×10-13

4.51×10-13

2.20×10-13

[·NO2]

3.68×10-23

0

2.89×10-28

0

-05

4.75×10

-05

3.99×10

-05

1.93×10-05

[·NO]

4.75×10

[ONOOH]

1.56×10-28

3.81×10-21

0

4.42×10-26

[ONOO-]

3.89×10-26

9.51×10-19

0

1.10×10-23

Note: Oxidant concentration was 294 µM; concentration of phosphate buffer was 10 mM; the pharmaceuticals were not included in the system when performing the calculation; total simulation time was 300 s.


Page 41 of 42


0.014 0.012

SMX acetyl-SMX TMP

k i (s-1 )

0.010 0.008 0.006 0.004 0.002 0.000 PB (pH 6) UV/H2O 2

fresh urine UV/H2O 2

PB (pH 6) UV/PDS

fresh urine UV/PDS

Figure 1. Measured indirect photolysis rate constants (ki) of SMX, acetyl-SMX, and TMP in phosphate buffer (PB) (10 mM) and synthetic fresh urine (composition in SI Table S2) at pH 6 by UV/H2O2 and UV/PDS. Errors represent the standard deviation (n ≥ 2).



0.014

(a) UV/H2O2

Page 42 of 42

SMX acetyl-SMX TMP

0.012

k i (s-1 )

0.010 0.008 0.006 0.004 0.002

0.014

NH hy dr 3 ol yz ed ur in e

HC

O 3 +

C l +

NH 3

O 3 HC

NH 3

O 3 -

C l +

PB

HC

C l

(p H

9)

0.000

(b) UV/PDS

SMX acetyl-SMX TMP

0.012

k i (s-1 )

0.010 0.008 0.006 0.004 0.002

NH hy dr 3 ol yz ed ur in e

O 3 + HC

C l +

NH 3

O 3 HC

NH 3 C l +

C l

O 3 HC

PB

(p H

9)

0.000

Figure 2. Measured indirect photolysis rate constants (ki) of SMX, acetyl-SMX, and TMP in PB (10 mM), PB + various urine inorganic components, and synthetic hydrolyzed urine (composition in SI Table S2) at pH 9 by (a) UV/H2O2 and (b) UV/PDS. Concentrations of urine inorganic components used were the same as in the hydrolyzed urine recipe. Errors represent the standard deviation (n ≥ 2).


Degradation of Pharmaceuticals and Metabolite in Synthetic Human

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