Chlorination Kinetics of 11-Nor-9-carboxy-Î9-tetrahydrocannabinol

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Chlorination kinetics of 11-nor-9-carboxy-#9tetrahydrocannabinol: Effects of pH and humic acid Allison L. Mackie, Yuri Park, and Graham A. Gagnon Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.7b02234 • Publication Date (Web): 14 Aug 2017 Downloaded from http://pubs.acs.org on August 15, 2017

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Environmental Science & Technology

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Chlorination kinetics of 11-nor-9-carboxy-∆9-tetrahydrocannabinol: Effects of pH and

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humic acid

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Allison L Mackie, Yu Ri Park, Graham A Gagnon*

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Centre for Water Resources Studies, Dalhousie University, PO Box 15000, Halifax, NS, CA

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B3H 4R2

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*Corresponding author: Graham A. Gagnon Email: [email protected] Address: Department of Civil and Resource Engineering, Dalhousie University, PO Box 15000, 1360 Barrington Street, Halifax, NS, Canada B3H 4R2 Phone: +1 902 494 6070 Fax: +1 902 494 3105 1 ACS Paragon Plus Environment


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Abstract

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The main psychoactive compound in marijuana, ∆9-tetrahydrocannabinol (THC), and its

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metabolites are emerging organic contaminants that have been detected in waste and surface

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waters. As legalization of marijuana for medical and recreational use continues, the effects of

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increased use and potency of marijuana on water and wastewater treatment processes and the

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environment should be considered. This study examined degradation kinetics of the main urinary

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metabolite of THC, 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THC-COOH) with chlorine.

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THC-COOH was rapidly removed from both deionized (DI) water at pH 5.6 ± 0.2 and Suwannee

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River humic acid (SRHA) at pH 5.1 ± 0.2 using low doses of chlorine (0.1 to 0.50 mg free

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Cl2/L), with half lives calculated from second-order kinetics constants (k2) of 8 s for DI and 42 s

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for DI with SRHA. Kinetic rates increased with an increase in pH from 5 to 9 in both DI water

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and SRHA and no interference from phosphate was observed. The chlorination pathway of

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electrophilic substitution of Cl at the ortho or para position of the phenol structure of THC-

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COOH was confirmed by detection of monochlorinated by-product fragmentation ions using

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flow injection analysis with orbitrap mass spectrometry.

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Keywords: illicits, drugs of abuse, LC-MS, cannabis, THC, THC-COOH, wastewater treatment

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1

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Marijuana (Cannabis sativa) is the most commonly used illicit drug in most of the world1–5. ∆9-

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Tetrahydrocannabinol (THC) is the primary psychoactive compound found in marijuana. THC is

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adsorbed into the bloodstream through the lungs when smoked and then metabolized in the liver

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to 11-hydroxy-∆9-tetrahydrocannabinol (THC-OH), converting into 11-nor-9-carboxy-∆9-

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tetrahydrocannabinol (THC-COOH), the main metabolite excreted in human urine6,7. THC-

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COOH is not a psychoactive compound but can be generated over longer time periods as THC is

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released slowly from storage in fatty tissues and converted into metabolites. This results in an

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extended half-life of THC-COOH in the body of days or even weeks in very heavy users8,9.

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THC-COOH is widely used as biological marker of THC consumption and its detection has been

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reported in many environmental and sewage epidemiology studies6,7,10–17. THC-COOH has been

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detected in untreated wastewater up to 2500 ng/L18,19, treated WW up to 750 ng/L19, and

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untreated surface water over 500 ng/L19. One occurrence of THC-COOH in tap water has been

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reported at the detection limit in that study of 1 ng/L19.

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Marijuana is classified as an illicit drug in most countries, meaning its cultivation and use are

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prohibited20. However, legalization of marijuana for medical use and, even more recently, for

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recreational use, such as in several states in the US, is gaining popularity. There is evidence that

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medical and recreational marijuana legalization leads to increased use3,21,22 and this combined

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with Cannabis’ ever-increasing potency23,24 will lead to increased loading of THC’s metabolites

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on water treatment plants and the environment. Wastewater treatment processes have been

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shown to sometimes increase THC-COOH concentrations, leading to increased concentrations

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entering the environment, due to deconjugation of the glucuronide form of THC-COOH and/or

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its desorption from solids during treatment11,15,25–27. The toxicity of THC-COOH transformation

Introduction

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by-products, which have been detected in surface waters28, has been estimated to be higher than

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that of THC-COOH itself29 and THC-COOH has been shown to be directly toxic to aquatic

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species at concentrations above 500 ng/L30. For these reasons, a greater understanding of THC-

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COOH’s fate during water treatment processes is essential.

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Although THC-COOH has been found to be present in the aquatic environment at relatively low

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concentrations (i.e., ng/L), it may nevertheless impose serious effects on the environment30.

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Hence, the goal of this study was to determine the efficacy and kinetics of the most widely used

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drinking water treatment chemical, chlorine, on the oxidation of THC-COOH. The effect of pH

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on the degradation of THC-COOH in deionized (DI) water and DI water spiked with Suwannee

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River humic acid was investigated at unbuffered acidic condition (i.e., pH between 5 and 6), and

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phosphate buffered solutions at pH 7.0 and 9.0. The effect of phosphate was also investigated by

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adjusting pH using sodium hydroxide (NaOH) in some tests.

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2

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2.1

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11-Nor-9-carboxy-∆9-tetrahydrocannabionol (THC-COOH) and deuterated internal standard of

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THC-COOH, THC-COOH-d3, each at a concentration of 1 mg/mL in methanol were purchased

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from Cerilliant (USA). Working solutions of reference standards were prepared at a

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concentration of 1 µg/mL in methanol and stored at -20 ⁰C in the dark. LC-MS grade of formic

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acid and acetonitrile were purchased from Fisher Scientific. DI water used for all solutions was

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purified in a Milli-Q system (Reference A+, Millipore).

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Sodium hypochlorite (NaOCl) was prepared as an approximately 1% solution of free chlorine;

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actual free chlorine concentration was measured using the DPD colorimetric method (Standard

Materials and Methods Chemicals and Reagents


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Method 4500-Cl G31) on a HACH DR5000 spectrophotometer. Sodium thiosulphate (NaS2O3)

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was prepared as a 20 g/L solution. Suwanee River humic acid (SRHA) was purchased from the

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International Humic Substances Society (Colorado, USA).

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THC-COOH was spiked into different water matrices to achieve a final concentration of

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approximately 10 µg/L. Two model waters were used, DI water and DI water spiked with 4

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mg/L Suwanee River humic acid (SRHA) from a 50 mg/L stock solution of SRHA pre-filtered

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through 0.45 µm polyethersulfone (PES) filter. In addition, lake water from the intake of the

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Lake Major drinking water treatment plant in Dartmouth, NS, CA filtered through 0.45 µm PES

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filter then spiked with THC-COOH, was used in some tests. Raw water quality parameters for

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Lake Major and SRHA samples recorded during the experimental period are presented in Table

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1. Samples were filtered prior to spiking with THC-COOH because initial tests in which samples

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were filtered through 0.45 or 0.22 µm PES filters, required for LC-MS/MS testing, after spiking

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with THC-COOH resulted in complete removal of the metabolite, even from untreated samples,

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when humic acid was present. This phenomenon was not observed for THC-COOH in DI water.

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The prepared water samples were either used as is or buffered to pH 7.0 using 2.2 mM KH2PO4

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and 1.7 mM K2HPO4 or pH 9.0 using 0.18 mM KH2PO4 and 18 mM K2HPO4 added to DI water

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or SRHA samples prior to spiking with THC-COOH. Where stated, NaOH addition was used for

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pH adjustment instead of phosphate buffer to eliminate potential effects of phosphate ligands on

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oxidation processes. NaOH was added after spiking of samples with THC-COOH. Chlorine

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demand of the SRHA solution and lake water was determined using Standard Method 2350 B31

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to be 0.2 ± 0.1 and 0.5 ± 0.1 mg/L, respectively, for a 5-min reaction time.

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2.2

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Conventional oxidation tests were carried out in 200 mL batches using 600 mL borosilicate glass

Bench-scale Methods



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beakers with continuous mixing achieved via magnetic stir bar and plate. pH was monitored

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using a Thermo Scientific electrode (Orion ROSS pH/ATC triode 8157BNUMD) and Orion 4-

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Star meter with the electrode situated in the beaker. Chlorine doses tested ranged from 0.0705 to

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16.9 µM (0.005 to 1.2 mg/L), in molar excess compared to 0.029 µM THC-COOH

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concentration. All chlorine doses are reported as free chlorine added, without accounting for

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chlorine demand of the solutions (i.e., applied free chlorine). Total applied free chlorine doses

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typically range from 1 to 6 mg/L32 or 14 to 85 µM in drinking water treatment plants. A glass

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pipette was used to take 5 mL samples at t = 0, 0.5, 1, 2, 3, 4, and 5 min and oxidant was

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quenched using 1 drop of 8 g/L NaS2O3 solution added to 40 mL baked amber glass sample vials

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prior to addition of sample, giving a final NaS2O3 concentration of approximately 100 to 200

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mg/L. A recent review paper indicated that THC-COOH losses when stored in glass were

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minimal33. Samples were reacted for 0.1 s-1), which was not found for chlorination of THC-

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COOH in DI water alone. Therefore, k1 values for the slower secondary reaction are presented

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(i.e., ≥ 30 sec). This phenomenon has been previously observed for chlorination of SRHA alone

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and was attributed to highly reactive organic matter sites34. The complete removal of THC-

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COOH using 0.45 or 0.22 µm PES filters from spiked humic acid and lake water solutions, but

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not DI water, found during initial testing for this study may indicate that THC-COOH is

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attaching to these highly reactive humic acid structures strongly enough to be removed by

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filtration. The dual-stage kinetics found in this study may indicate that THC-COOH molecules

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are being oxidized with humic acid at these highly reactive sites, although no tests were run to



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verify this hypothesis. Reaction rates for tests in SRHA ranged from 6.92 x 10-4 to 1.13 x 10-2 s-1

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at pH 5.1 ± 0.1 at higher Cl2 doses from 0.1 to 1.2 mg/L (Table 2). Comparing the two model

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waters, DI water (Figure 1a) and SRHA (Figure 1b), SRHA addition to DI water resulted in

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slower THC-COOH oxidation at the same Cl2 doses. Chlorine demand of the unspiked SRHA

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solution was found to be 0.2 ± 0.1 mg/L. Spiking the solutions with 10 µg/L THC-COOH

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increased the chlorine demand by 0.09 ± 0.03 mg/L. When chlorination tests were performed

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accounting for demand of the water itself, the demand from THC-COOH, and giving a 0.2 mg/L

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free Cl2 residual after a 5 min contact time, final THC-COOH concentrations did not vary

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significantly between tests run in DI, SRHA in DI, and lake water (p-value = 0.277). Chlorine

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demand of the unspiked lake water was found to be 0.5 ± 0.1 mg/L. pH of unbuffered DI, SRHA,

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and Lake Major samples increased by approximately 0.1 over the 5-min reaction time per 0.1 mg

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free Cl2 added. A reduction in chlorine efficacy for degradation of THC-COOH in DI water to

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surface water has been previously reported28,29, however these studies did not account for the

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chlorine demand of the surface water samples.

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Second order reaction rate constants (k2; eq 3) were calculated from linear regressions of the data

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presented in Figure 2. The reaction of chlorine and THC-COOH in DI water had a k2 = 3.62 x 10-

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3

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0.1). The half life of THC-COOH upon chlorination was calculated from the second order rate

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constants (k2) to be very fast at 8 s for DI water and 42 s for DI water with SRHA. A THC-

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COOH concentration of 10 µg/L only adds approximately 0.5 (mg min)/L to the CT required for

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disinfection at pH between 5 and 6 with a typical Cl2 residual of 0.2 mg/L.

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3.2

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Chlorination resulted in increased THC-COOH oxidation with increased pH from 5.6 ± 0.2

µM-1s-1 (R2 = 0.982; pH 5.6 ± 0.2) and in SRHA k2 = 6.87 x 10-4 µM-1s-1 (R2 = 0.995; pH 5.1 ±

Effect of pH


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(unbuffered) to 9.0 (phosphate buffer) as shown in Figure 3. pH 7.0 and 9.0 tests were repeated

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in both DI water and SRHA using NaOH to adjust pH instead of phosphate buffer to ensure no

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confounding effects of phosphate ligands on the oxidation process. It was found that THC-

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COOH oxidation followed the same pattern of increasing degradation with increasing pH and

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was removed to similar concentrations at the same chlorine dose (p-value >0.05).

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At pH 9.0, adjusted using either NaOH or phosphate buffer, k1 values were substantially faster

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than at lower pH for both water matrices. At a dose of 0.10 mg Cl2/L, k1 was increased from 3.93

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x 10-3 to 7.78 x 10-2 s-1 in DI water and from 6.92 x 10-4 to 3.99 x 10-3 s-1 in SRHA. Figure 3

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compares the apparent second order rate constants, k2, for THC-COOH chlorination in DI and

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SRHA at the 3 pH values tested in this study. Kinetics were only slightly increased with pH

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increase from acidic to neutral. HOCl ⇄ OClି + H ା

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(4)

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To explain the effect of pH on the chlorination of THC-COOH, the chemistry of both chlorine

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and THC-COOH must be considered. The pKa of chlorine is 7.5 (eq 4), with HOCl having

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greater oxidizing power than OCl- due to the H+ functional group. THC-COOH contains two

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different functional groups, carboxylic acid and phenol, which results in two different pKa

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values (pKa1 = 4.7 and pKa2 = 9.3, correspondingly). At pH 9, HOCl is almost non-existent;

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however, chlorination of THC-COOH worked best at this pH (Figure 3). This is because as pH

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nears pKa2 it becomes easier for the phenol structure of the THC-COOH molecule to be

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deprotonated to phenoxide. The phenoxide ion has been shown to react faster with chlorine than

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unionized phenol35,36 and a similar pH dependency has been found for phenol37 and estrogenic

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compounds which contain phenol groups38. At unbuffered acidic condition of pH 5.1 to 5.6 (pKa1

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< pH < pKa2), THC-COOH concentration is roughly equal to THC-COO- (pKa1 = 4.7), 11 ACS Paragon Plus Environment


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carboxylic acid in THC-COOH is readily deprotonated to form carboxylate anion and hence,

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THC-COO- is predominant. However, since the main site of chlorine attack is the phenol

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structure, and that structure is still mostly protonated, it becomes more difficult for electrophilic

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substitution to occur39. The pH dependence found in the current study indicates that the phenolic

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group of the THC-COOH molecule is the main site of chlorine attack. Lower THC-COOH

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concentrations (i.e., faster reaction rates) have been previously found with chlorination at higher

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pH (i.e., 8.3), which was attributed to increased density of the electron cloud of phenoxide

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compared to phenol, such as has been found for other phenolic compounds29. This increased

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electron density can more easily repel the electrons in the OCl- molecule.

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3.3

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Chlorine has been suggested to attack the phenol ring on the THC-COOH molecule by

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electrophilic substitution, resulting in chlorinated by-products29. This site of attack has been

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validated by the pH dependence described above. First, the electron cloud of the phenol ring of

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the THC-COOH molecule repels the electrons in the HOCl molecule (or OCl- ion at basic pH),

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allowing Cl to approach the ring more closely. Next, electrons from the ring (π-bond) attach to

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Cl, forming an intermediate of the ring with H and Cl attached to a C atom. Finally, the H+

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detaches, leaving a chlorinated phenolic group on the THC-COOH molecule (Figure 4). This

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pathway is supported by the previous detection of chlorinated THC-COOH species found by

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liquid chromatography/quadropole time-of-flight mass spectrometry (LC-QTOF-MS) with the

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chlorine atom attached at the ortho or para positions relative to the phenol group29. That study

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also detected chlorination products with halogenation or hydration of the C-C π-bond in the

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cyclohexene structure below the carboxyl group (i.e., at the C10 position), which would follow a

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similar pathway to that presented in Figure 4. At pH 9.0, the phenolic structure in the THC-

Chlorination mechanisms


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COOH molecule would be as phenoxide, making the chlorine approach described above easier.

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The fragments of protonated molecules of THC-COOH (Figure S1) and THC-COOH by-

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products after chlorination (Figure S2) were detected using flow injection analysis with orbitrap

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mass spectrometry. Generated by-products of THC-COOH were evaluated by adding 2 mg/L

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free chlorine to 100 µg/L of THC-COOH in DI water at unbuffered pH 5.8 and quenching with

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NaS2O3 after a 5-min reaction time. The m/z 345.20603 fragment ion in the unchlorinated THC-

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COOH spectrum in Figure S1 corresponds to the [M+H]+ ion of THC-COOH. The fragment ion

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with m/z 257.24725, associated with the loss of propene (C3H6) from m/z 299 fragment ion, and

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the m/z 299 ion, which is associated with the loss of the carboxylic acid group from THC-COOH

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(Figure S1), were found in untreated sample but neither fragment ion was abundantly present in

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the chlorinated THC-COOH spectrum (Figure S2). The monochlorinated (either para- or ortho-

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chlorinated) product of THC-COOH, corresponding to the fragment ion with m/z 379.16675,

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was the main chlorination by-product detected in this MS/MS spectrum and this was confirmed

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by the detection of the fragment ion with a m/z 226.95134. As discussed above, a halogen (e.g.,

281

Cl) can be substituted to the active position and the para-chlorinated THC-COOH isomer is

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preferred over ortho-chlorinated29. The intense peak of m/z 292.82650 (Figure S2) is possibly

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explained by the loss of propene (C3H6) from the m/z 332.89176, but this needs to be further

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analyzed for confirmation. Minor fragment ions with m/z 260.85430 and 413.26606,

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corresponding to the species of dichlorinated THC-COOH, were also detected in the chlorinated

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THC-COOH spectrum (not apparent in Figure S2). By-products of THC-COOH prepared in

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SRHA water were also analyzed by flow injection analysis and the fragmentation ions

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corresponding to the monochlorinated products of THC-COOH were confirmed (Figure S3 and

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S4).



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3.4

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Previous studies have shown that marijuana legalization, even for medical use only, results in

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increased consumption3,19,20. Due to the recent trend of marijuana legalization, the increased

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influx of metabolites of marijuana consumption such as THC-COOH should be considered in the

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context of waste and drinking water treatment processes. A recent false positive detection of

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THC in a municipal drinking water well in Hugo, Colorado, USA, which led to an advisory to

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residents of the town not to drink, shower, or cook with tap water40,41 illustrates the need for

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more research regarding the kinetics and behaviour of THC and its metabolites after

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consumption and during water treatment processes and the need for fast, reliable detection

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methods. Considering recent legalization trends, the Hugo water advisory could just as easily

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have been from a real occurrence of THC-COOH, whose effect on humans is largely

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unknown42,43. However; this study has shown that chlorination kinetics of THC-COOH are fast

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(i.e., t1/2 = 8 s), even with interference from humic acid (i.e., t1/2 = 42 s). Thus, drinking water

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treatment plants using post-chlorination to achieve a typical distribution system residual of 0.2

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mg free Cl2/L would be expected to oxidize THC-COOH that might reach their source water or

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infiltrate into any point in the distribution system. THC-COOH has been detected in surface

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waters at over 500 ng/L19, but only one occurrence of THC-COOH in tap water has been

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reported, and this was at the detection limit of 1 ng/L19. Although organic matter characteristics

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differ from samples used in our study to other surface waters, groundwater, or wastewater,

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reactions between THC-COOH and chlorine can be expected to be similar in these matrices.

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Results from this study also indicate that THC-COOH associates with humic substances strongly

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enough to be retained on 0.45 and 0.22 µm PES filters, meaning that future research should aim

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to quantify THC-COOH concentrations associated with filtered solids to avoid underestimating

Environmental Implications


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consumption. Transformation products resulting from the chlorination of THC-COOH have been

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suggested to be more toxic than the parent compound29 and they have already been detected in

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surface waters28. The toxicity of THC-COOH and its transformation products needs to be further

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assessed through toxicological testing with the aim of reducing the threat posed to humans and

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the environment.

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4

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The authors would like to acknowledge and extend thanks for the financial support provided

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through the NSERC/Halifax Water Industrial Research Chair in Water Quality & Treatment at

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Dalhousie University. Funding partners for this Industrial Research Chair program include the

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Natural Science and Engineering Council of Canada (NSERC), Halifax Water, LuminUltra

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Technologies Ltd., Cape Breton Regional Municipality Water Utility, CBCL Ltd., AGAT

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Laboratories Ltd., and Mantech Inc. Additional funding for this work was received from the

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NSERC Discovery Grant program. Dr. Mackie would also like to acknowledge funding received

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from NSERC’s Postdoctoral Fellowship program. The authors would like to thank the

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anonymous reviewers of this manuscript for their insightful comments and suggestions as well as

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Heather Daurie, Nicole Allward, Keith Porter, and Fatou Secka for their technical support and

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experimental assistance. Finally, the authors thank Dr. Jong Sung Kim and Crystal Sweeney at

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Dalhousie University’s Health and Environments Research Centre Laboratory for their timely

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assistance with use of their flow injection analysis system.

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Supporting Information. Details of the flow injection analysis system used for fragmentation

333

ion detection and resultant fragmentation ion chromatograms of THC-COOH and THC-COOH

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chlorination by-products in the presence and absence of SRHA.

Acknowledgements



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Figures

479 480

Figure 1. Effect of chlorine dose on pseudo first-order kinetics in (a) DI water at pH 5.6 ± 0.2

481

and in (b) 4 mg/L SRHA at pH 5.1 ± 0.1

482



483 484

Figure 2: Effect of free chlorine dose on pseudo-first order reaction rate constant for degradation

485

of THC-COOH in DI water and SRHA. Note that the 5 min chlorine demand of unspiked SRHA

486

solution was 0.2 ± 0.1 mg/L and that of 10 µg/L THC-COOH was 0.09 ± 0.03 mg/L.

487


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489 490

Figure 3: Effect of pH on second-order rate constant (k2) for THC-COOH chlorination in DI

491

water and SRHA.

492



493

494 495

Figure 4: A proposed reaction mechanism of chlorine with THC-COOH at pH between 5 and 7.

496


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497

Tables

498

Table 1: Water quality parameters of Lake Major and SRHA water samples used during this

499

study. Parameters

Lake Major

SRHA

pH

5.6 ± 0.2

5.1 ± 0.1

Turbidity (NTU)

0.2 ± 0.2

0.06 ± 0.02

DOC (mg/L)

4.4 ± 0.1

1.6 ± 0.2

UV254 (cm-1)

0.22 ± 0.03

0.106 ± 0.003

Colour (PtCo)

41 ± 3

32 ± 2

Alkalinity (as mg CaCO3/L)

Chlorination Kinetics of 11-Nor-9-carboxy-Î9-tetrahydrocannabinol

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