Phthalate Metabolites, Hydroxy-Polycyclic Aromatic Hydrocarbons

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Ecotoxicology and Human Environmental Health

Phthalate Metabolites, Hydroxy-Polycyclic Aromatic Hydrocarbons, and Bisphenol Analogues in Bovine Urine Collected from China, India, and the United States Hongkai Zhu, Lei Wang, Chunguang Liu, Zachary Stryker, Bommanna G. Loganathan, and Kurunthachalam Kannan Environ. Sci. Technol., Just Accepted Manuscript • Publication Date (Web): 03 Sep 2019 Downloaded from pubs.acs.org on September 3, 2019

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Environmental Science & Technology

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Phthalate Metabolites, Hydroxy-Polycyclic Aromatic Hydrocarbons, and

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Bisphenol Analogues in Bovine Urine Collected from China, India, and the

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United States

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Hongkai Zhu,† Lei Wang,‡ Chunguang Liu,‡ Zachary Stryker,†

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Bommanna G. Loganathan,§ and Kurunthachalam Kannan*,†,#

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†Wadsworth

Center, New York State Department of Health, and Department of Environmental

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Health Sciences, School of Public Health, State University of New York at Albany, Empire State

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Plaza, P.O. Box 509, Albany, New York 12201-0509, United States

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‡MOE

Key Laboratory of Pollution Processes and Environmental Criteria, College of

Environmental Science and Engineering, Nankai University, Tianjin 300350, China §Department

of Chemistry and Watershed Studies Institute, Murray State University, 1201 Jesse

D. Jones Hall, Murray, Kentucky 42071-3300, United States #Biochemistry

Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd

Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia

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*Corresponding author at: Wadsworth Center, Empire State Plaza, P.O. Box 509, Albany, New

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York 12201-0509, United States

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Fax: +1 518 473 2895

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E-mail: [email protected] (K. Kannan)

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Submitted to: Environmental Science & Technology

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ACS Paragon Plus Environment


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Graphical Abstract

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ABSTRACT

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Human exposure to endocrine-disrupting chemicals (EDCs) has aroused considerable public

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concern over the last three decades. Nevertheless, little is known with regard to the exposure of

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EDCs in farm animals. In this study, concentrations of 22 phthalate metabolites (PhMs), 15

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hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs), and 8 bisphenols (BPs) were

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determined in 183 bovine urine samples collected from China, India, and the United States. The

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median concentrations of urinary PhMs, OH-PAHs, and BPs in bovines, collectively, were 66, 4.6,

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and 16 ng/mL, respectively. Mono-n-butyl phthalate (mBP; median: 14 ng/mL) and ∑4DEHP (four

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secondary metabolites of di(2-ethylhexyl) phthalate; 13 ng/mL) were the dominant PhMs;

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hydroxy-fluorene (OH-Fluo; 1.2 ng/mL) and -phenanthrene (OH-Phen; 1 ng/mL) were the

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dominant OH-PAHs; 4,4′-di-hydroxydiphenylmethane (BPF; 10) and 2,2-bis(4-hydroxyphenyl)

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propane (BPA; 6.7) were the dominant BPs. Bovine urine samples from India and China contained

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the highest concentrations of PhMs and OH-PAHs, whereas those from India and the United States

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contained the highest concentrations of BPs. PhM and OH-PAH concentrations were significantly

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higher in the urine of bulls than cows; no such difference was found for BPs. Our ﬁndings establish

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baseline exposure information for three classes of EDCs in domestic farm animals.

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INTRODUCTION

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Endocrine-disrupting chemicals (EDCs) have received considerable attention due to their links

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with human diseases.1,

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significance.3 Phthalates, bisphenol analogues (BPs), and polycyclic aromatic hydrocarbons

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(PAHs) are three frequently studied classes of EDCs.4 Phthalates and BPs are typically used as

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plasticizers and solvents in industrial, medical, and consumer products.5,

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phthalate (DEHP) and bisphenol A (BPA) are prototype phthalates and BPs, respectively, with

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corresponding annual production quantities of over 2 and 5 million tons.7 Due to their widespread

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exposure and adverse effects on human health, DEHP and BPA have been listed as the top 20

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EDCs found in the U.S. aquatic environment.8 PAHs originate mainly from the incomplete

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combustion of coal, petroleum, and biomass. Human exposure to phthalates, BPs, and PAHs has

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been linked to endocrine disruption, cytotoxicity, genotoxicity, reproductive toxicity, and

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neurotoxicity.5, 9, 10

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EDCs are a complex mixture of over 800 chemicals of toxicological

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Di(2-ethylhexyl)

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Phthalates, BPs, and PAHs have been reported to occur in air, water, sediment, soil, wastewater,

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and indoor dust.5, 9, 10,11 Because phthalates and PAHs have short half-lives (on the order of a few

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hours) in human bodies and are excreted quickly via urine,12 their metabolites (including primary

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and secondary metabolites) have been identified as biomarkers of exposure.13, 14 BPs are excreted

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as glucuronidated or sulfated conjugates15 and are measured in urine as total BPs, following

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deconjugation.16, 17

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Measurements of exposure to EDCs in farm animals provide information not only on the health

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effects on the animal itself but also on the potential contamination in food products derived from

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these animals. Nevertheless, very little is known about the body burdens of EDCs in farm animals.

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A few studies have raised concern over potential exposure of farm animals to EDCs.18 Certain

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species of farm animals, however, have been used as models in toxicological studies. For example, 4


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a low-dose intramuscular pre-pubertal exposure of pigs to DEHP affected reproductive

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endocrinology in adulthood,19 and exposure of sheep to BPA affected fetal programming.20 Farm

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animals have multiple pathways of exposure to EDCs (soil/surface water) and possess different

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metabolic potentials (e.g., rumen fermentation, microbiome) in comparison to humans.21-23 Thus,

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studies on the sources and magnitude of exposure to EDCs in domestic animals merit investigation.

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A better understanding of the magnitude of exposure to EDCs in bovines would help in the

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development of strategies to mitigate exposure, which will ensure the safety of animal-origin foods.

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In this study, bovine urine samples collected from China, India, and the United States were

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analyzed to (1) determine the occurrence and profiles of PhMs, OH-PAHs, and BPs; (2) identify

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country-specific and gender-related differences in exposure; and (3) estimate daily exposure doses

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and cumulative risks of target chemicals.

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MATERIALS AND METHODS

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Sample Collection. Bovine urine samples (n = 183) were collected from three countries: China

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(Tianjin; n = 100), India (Mettupalayam, Tamil Nadu; n = 45), and the United States (Murray,

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Kentucky; n = 38) between March and November of 2018. The three sites selected for urine sample

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collection were rural and agricultural areas with no point sources in the vicinity. The bovines from

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the farm in China were zero-grazed; in other words, they were housed permanently in shelters and

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fed commercial feed. In contrast, the cattle from India and the United States were allowed to graze

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in open pastures/grasslands and fed with a combination of grain and grass. The urine samples were

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collected from various breeds, i.e., Simmental, Holstein, Jersey, Indian buffalo, Angus, Corriente,

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Shorthorn, and an indigenous breed (Table S1 in the Supporting Information; SI). Cattle were

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further classified as beef cattle (n = 58; 32%), dairy cows (n = 110; 60%), and working cattle (i.e.,

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buffalos from India; n = 15; 8%). Spot urine samples were collected directly into a clean container

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and stored at -20º C until analysis.

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Analytical Methods. Urine samples were analyzed for 22 PhMs (including phthalic acid [PA],

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mono-methyl phthalate [mMP], mono-ethyl phthalate [mEP], mono-2-iso-butyl phthalate [mIBP],

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mono-n-butyl phthalate [mBP], mono-benzyl phthalate [mBzP], mono-cyclohexyl phthalate

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[mCHP], mono-(2-ethylhexyl) phthalate [mEHP], mono-(2-ethyl-5-hydroxyhexyl) phthalate

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[mEHHP], mono-(2-ethyl-5-oxohexyl) phthalate [mEOHP], mono-(2-ethyl-5-carboxypentyl)

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phthalate

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carboxypropyl) phthalate [mCPP], mono-isononyl phthalate [mINP], mono-octyl phthalate [mOP],

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mono-hexyl phthalate [mHxP], mono-2-heptyl phthalate [mHpP], mono-carboxy-iso-octyl

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phthalate [mCIOP], mono-carboxy-iso-nonyl phthalate [mCINP], mono-n-pentyl phthalate

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[mPeP], mono-isopropyl phthalate [mIPrP], and mono-(7-carboxy-n-heptyl) phthalate [mCHpP]),

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8 BPs (including 2,2-bis(4-hydroxyphenyl)propane [BPA], 4,4′-(hexafluoroisopropylidene)

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diphenol [BPAF], 4,4′-(1-phenylethylidene)bisphenol [BPAP], 4,4′-sulfonyldiphenol [BPS], 4,4′-

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di-hydroxydiphenylmethane [BPF], 4,4′-(1,4-phenylenediisopropylidene)bisphenol [BPP], 4,4′-

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cyclo-hexylidenebisphenol [BPZ], and 2,2-bis(4-hydroxyphenyl)butane [BPB]), and 15 OH-PAHs

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(including

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hydroxyfluorene [2-OHFluo], 3-hydroxyfluorene [3-OHFluo], 9-hydroxyfluorene [9-OHFluo], 1-

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hydroxyphenanthrene [1-OHPhen], 2-hydroxyphenanthrene [2-OHPhen], 3-hydroxyphenanthrene

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[3-OHPhen], 4-hydroxyphenanthrene [4-OHPhen], 9-hydroxyphenanthrene [9-OHPhen], 1-

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hydroxypyrene [1-OHPyr], 1-hydroxychrysene [1-OHChry], 6-hydroxychrysene [6-OHChry], 3-

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hydroxybenzo[c]-phenanthrene [3-OHBcP], and 1-hydroxybenz[a]-anthracene [1-OHBaA]).

[mECPP],

mono-[(2-carboxymethyl)

1-hydroxynaphthalene

[1-OHNap],

hexyl]

phthalate

[mCMHP],

2-hydroxynaphthalene

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mono-(3-

[2-OHNap],

2-

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The methods for the analysis of these three classes of chemicals in urine samples have been

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described previously.13,

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glucuronidase from E. coli K12; Roche Diagnostics GmbH, Mannheim, Germany), followed by

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solid-phase extraction (for PhMs; ABS Elut-NEXUS SPE cartridges; 60 mg, 3 mL, Agilent, Santa

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Clara, CA) or liquid-liquid extraction (for BPs and OH-PAHs: with a mixture of ethyl

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acetate/pentane/toluene, 5:4:1, v/v). Identification and quantification of target analytes were

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performed on a Shimadzu high-performance liquid chromatography (HPLC) system (Shimadzu

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Corporation, Kyoto, Japan), interfaced with API 5500 triple-quadrupole mass spectrometry

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(MS/MS), under the negative ion multiple-reaction monitoring mode. The chromatographic

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separations of 22 PhMs, 8 BPs, and 15 OH-PAHs were achieved using Ultra AQ C18 (100 mm ×

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2.1 mm, 3 µm; Restek, Bellefonte, PA), Betasil C18 (100 mm × 2.1 mm, 5 µm; Thermo Electron

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Corp., Waltham, MA), and Eclipse Plus C18 RRHD chromatographic columns (150 mm × 2.1

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mm, 1.8 µm; Phenomenex, Torrance, CA), respectively. The limits of quantification (LOQs)

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ranged from 0.05 to 1.0 ng/mL for PhMs, from 0.12 to 1.2 ng/mL for BPs, and from 0.01 to 0.16

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ng/mL for OH-PAHs, which were calculated from the lowest acceptable calibration standard that

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displayed a signal-to-noise ratio ≥ 10.

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Briefly, sample preparation entailed enzymatic deconjugation (β-

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Additional details regarding chemicals and reagents used (Tables S2–S4) and analytical

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methods for the determination of target compounds (Texts S1–S3) are provided in the SI. Typical

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HPLC-MS/MS chromatograms of standard and sample are shown in Figure S1. Urinary creatinine

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(CR) concentrations were determined by following the method described previously.25

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Quality Assurance (QA)/Quality Control (QC). For each batch of 20 samples analyzed, a

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procedural blank (HPLC-grade water in place of urine), a matrix spiked sample (10 ng/mL for

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each compound), and two Standard Reference Materials (SRMs 3672 and 3673; purchased from

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the National Institute of Standards and Technology, Gaithersburg, MD) were processed (Tables

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S5–S7). Procedural blanks contained, on average (in ng/mL), 0.17 mCPP, 0.54 mBzP, 1.1 PA, and

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2.3 mEHP. The blank values for these four metabolites were subtracted from reported sample

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concentrations. The relative recoveries of target analytes spiked into urine samples ranged from

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85% to 103% for PhMs, 100% to 102% for BPs, and 80% to 108% for OH-PAHs. The relative

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recoveries of target compounds certified in the two SRMs ranged from 80% to 118%. A calibration

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standard (i.e., 10 ng/mL for each compound) was injected after every 20 samples to monitor for

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the instrumental drift in sensitivity over time, and a pure solvent (methanol) was injected after

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every 10 samples to monitor for carryover of target chemicals between samples. Duplicate analysis

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of randomly selected samples (n = 20) showed a relative standard deviation of 50% were considered for further discussion.

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PhMs. Eleven of the 22 PhMs were found in > 70% of the samples collected from China and

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India. Only PA (df: 68%), mIBP (87%), mBzP (74%), mEHHP (92%), and mINP (100%) were

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frequently found in samples from the United States, whereas other PhMs were less frequently

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detected (< 50%). These results suggest widespread exposure of bovines to phthalates in China

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and India; the frequency and magnitude of exposure are smaller in the United States. There has

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been an evidence of decline in DEP, DBP, and DEHP exposure concomitant with an increase in

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DINP exposure in the U.S. population since 2000.26, 27 The increasing exposure to DINP in the

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U.S. population suggests increasing usage of this compound in recent years, which is reflected in

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frequent detection in bovine urine from the United States.

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PA was found at the highest concentration in bovine urine from China (median: 22 ng/mL; 32%

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of the total PhM concentrations), followed by mBP (18 ng/mL; 29%), mEHP (9.7 ng/mL; 15%),

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and mIBP (4.3 ng/mL; 7.8%). The median urinary concentrations of PhMs in Indian bovine were

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as follows: mEP (15 ng/mL; 33%) > PA (8.8 ng/mL; 22%) > mEHP (7.9 ng/mL; 21%) > mIBP

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(2.8 ng/mL; 6.3%). PA was the major metabolite in bovine urine from the United States but at

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concentrations 20 times lower than those from China. Overall, the metabolites of six frequently

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used phthalates, DEP, DBP, DIBP, DEHP, DINP, and BzBP, were the most commonly detected

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ones in bovine urine from the three countries,28 which were similar to those found in humans

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(Table S8).29-32

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The distribution of five DEHP metabolites in bovine urine was different from those observed

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for humans. The major DEHP metabolites found in human urine were mECPP, mEHHP, mEOHP,

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and mCMHP, with trace levels of mEHP (< 10% of total DEHP metabolites).33, 34 In bovine urine,

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however, mEHP accounted for 70% of the total DEHP metabolite concentrations. This pattern may

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be related to the ruminant metabolism or anaerobic environment that occurs in the rumen of

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bovines.

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OH-PAHs. Among the 15 OH-PAHs analyzed, 2-OHNap, 2-OHPhe, 3-OHPhe, and 2/3/9-

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OHFluo were found in all bovine urine samples. 1-OHNap, 1/9-OHPhen, 4-OHPhen, and 1-OHPyr

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also were found in > 50% of the samples. This pattern was consistent with what was found in

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human urine13, 35, 36 and suggested ubiquitous exposure to Nap, Fluo, Phen, and Pyr. 1/6-OH-Chry,

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1-OHBaA, and 3-OHBcP were rarely detected in urine. This may be due to the fact that high

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molecular weight (HMW) PAHs, such as Chry, BaA, and BcP, which are excreted mainly through

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feces.35

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The median concentrations of 2/3/9-OHFluo in all three countries were 1.2 ng/mL, followed,

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in decreasing order, by 1-OHPyr (0.74 ng/mL), 2-OHNap (0.46 ng/mL), 2-OHPhen (0.39 ng/mL),

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1/9-OHPhen (0.31 ng/mL), 1-OHNap (0.25 ng/mL), 3-OHPhen (0.19 ng/mL), and 4-OHPhen

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(0.09 ng/mL). Two bovine urine samples from the United States contained elevated 2-OHNap

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concentrations (2,430 and 1,010 ng/mL). Replicate analysis of these two samples yielded similar

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values, which indicates sporadic exposure to contaminated feed or environment. Geometric mean

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concentrations of OH-PAHs in bovine urine collected from Ghana were in the ranges of 0.61 to

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22 ng/mL for 2-OHNap, 2.6 to 15 ng/mL for ∑5OHPhen, 0.31 to 6.7 ng/mL for ∑3OHFluo, and

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from 0.99 to 2.3 ng/mL for 1-OHPyr,36 which were slightly higher than those found in our study.

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One study reported that 1-OHPyr concentrations in bovine urine were highest in cattle farms

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located near a highway (median: 5.93 ng/mL), followed by those from farms in rural (1.4 ng/mL)

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and urban (0.71 ng/mL) areas.37

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No significant differences were found in OH-PAH composition among samples from China,

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India, and the United States. ∑3OHFluo accounted for 27–35% of the total Σ11OH-PAH

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concentrations, followed by ∑5OHPhen (25–30%), ∑2OHNap (19–25%), and 1-OHPyr (11–22%).

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In contrast, ∑2OHNap was the predominant OH-PAH in human urine (> 60% of total

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concentrations).13, 38, 39 The difference is explained by the exposure sources (e.g., cigarette smoke

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and grilled foods for humans) and metabolism between cattle and humans. Cigarette smoke and

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grilled food have been reported as the sources of Nap exposure in humans.40, 41 Phenanthrene and

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fluoranthene in bovines were thought to originate from biomass burning (as described below).

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BPs. Of the 8 BPs measured, BPF, BPA, and BPS were found in >70% of the urine samples

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analyzed, whereas BPAF, BPAP, BPP, BPZ, and BPB were found sporadically and at low

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concentrations. The distribution of urinary BPs among the three countries was similar. BPF was

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found at the highest median concentrations (6.3, 64, and 40 ng/mL for the samples from China,

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India, and United States, respectively; 64–78% of the total concentrations), followed by BPA (3.1,

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8.8, and 7.8 ng/mL; 21–31%) and BPS ( 1.0

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were extracted for each class of compounds, which collectively accounted for 70–83% of the

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variances (Figure 3 and Table S9).

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For PhMs, PC1 and PC2 explained 47% and 23%, respectively, of the total variance. The

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metabolites of HMW phthalates (mEHP, mECPP, mEOHP, mEHHP, mINP, and mBzP) clustered

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in PC1 (0.74–0.95), whereas the metabolites of low molecular weight (LMW) phthalates (PA,

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mEP, mBP, and mIBP) clustered in PC2 (0.43–0.91) (Figure 3A). This corresponds to the usage

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pattern of phthalates, namely, HMW phthalates (DEHP, DINP, and BzBP) that are used in

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polyvinyl chloride (PVC) polymers and plastisol applications, whereas LMW phthalates (DEP,

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DBP, and DIBP) are used in personal care products, paints, adhesives, enteric-coated tablets, and

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food packaging/plastic film. For OH-PAHs (Figure 3B), PC1 accounted for 56% of the total

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variance, with greater loadings of ∑OHPhen (0.86) and ∑OHFluo (0.94), indicating sources that

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originate from the incomplete combustion of biomass at low temperatures. Biomass burning in

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farms can be a source of such a pattern. PC2 explained 19% of the total variance with greater

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loadings of ∑OHNap (0.80) and ∑OHPyr (0.73), which is explained by emissions from vehicular

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traffic. PC plots of BPF, BPA, and BPS showed distinctive clustering (Figure 3C), which suggests

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different sources for these compounds. BPA is used in polycarbonate plastics and epoxy resins.

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BPF has a broad range of applications in lacquers, varnishes, liners, plastic adhesives, and water

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pipes.65 BPS is used in epoxy glues, can coatings, and thermal receipt papers as well as in

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sulfonated poly(ether ketone ether sulfone) and as an additive in dyes and tanning agents.66

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Cumulative Daily Intake. Based on the measured urinary concentrations of PhMs, OH-PAHs,

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and BPs, we estimated the daily intakes of four phthalates (i.e., DEP, DIBP, DBP, and DEHP),

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four PAHs (i.e., Nap, Fluo, Phen, and Pyr), and ∑BPs (sum of BPF, BPA, and BPS) by bovines

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(see SI for details; Table S10). The median EDIs of phthalates, PAHs, and ∑BPs by bovine are

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presented in Tables S11–S12. A rough estimate of intakes based on the measured urinary

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concentrations suggested that these cows are exposed at several µg/kg bw doses of phthalates,

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PAHs, and ∑BPs on a daily basis, which are at least 20-fold below their respective threshold doses.

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These results suggest that the current exposure doses of these three classes of EDCs do not pose a

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risk to the health of bovines. It should be noted, however, that several uncertainties exist in our

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exposure assessment. The pharmacokinetics of target compounds in bovines are not well

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understood, and we followed values reported for humans. Furthermore, the reference doses used

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in this study were suggested for humans, as no reference doses values are available for bovines. In

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addition, the discussion of concentrations of target chemicals between the countries is tempered

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by the small sample size from each country. Thus, the data should be interpreted within these

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limitations in mind.

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Nevertheless, our data establish baseline concentrations for three classes of EDCs in bovine for

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the first time. Our results indicate that bovines in China and India are exposed to large

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concentrations of phthalates and PAHs, whereas those in India and the United States are exposed

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to large concentrations of BPs. These results also provide evidence for the sources of EDCs in

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food products of animal origin. Further studies are needed to describe the sources, pathways, and

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health effects of EDCs in domestic animals.

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ASSOCIATED CONTENT

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Supporting Information

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Details of reagents used in analysis, sample extraction, and instrumental methods; Tables

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containing bovine sample information (Table S1) and details of analytical standards (Tables S2–

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S4) and quality control data (Tables S5–S7); compilation of data on the occurrence and profiles of

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major PhMs in human urine (Table S8); principal component analysis results (Table S9),

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parameters used in the calculation of intakes of phthalates, PAH, and BPs (Table S10), and EDI

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values of phthalates, PAHs, and BPs for bovines (Table S11) and compilation of data on their EDIs

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in human urine (Table S12). Figure showing typical chromatograms of standard and sample

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(Figure S1).

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AUTHOR INFORMATION

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Corresponding Author

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*Tel.: +1 518 474 0015. Fax: +1 518 473 2895.

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E-mail: [email protected].

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Notes

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The authors declare no competing financial interest.

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Acknowledgements

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This study was partly supported (sampling in China) by the 111 Program of the Ministry of

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Education of China (T2017002). Authors are thankful to Mr. Jason Robertson, Ms. Cassandra

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Peterson and Mr. Adam Martin, Murray State University, for their help in collecting cow urine

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samples from Murray, KY.

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Table 1. Concentrations (ng/mL) of Phthalate Metabolites (PhMs), Hydroxy-Polycyclic Aromatic Hydrocarbons (OH-PAHs) and Bisphenol Analogues (BPs) in Bovine Urine Collected from China, India, and the United States China (n = 100) India (n = 45) the United States (n = 38) a df/% range median df/% range median df/% range median Phthalate Metabolites (PhMs) PA 100 2.5–133 22 91 nd–68 8.8 68 nd–47 1.3 mEP 94 nd–9.8 2.7 100 1.6–212 15 0 mBP 100 1.8–542 18 100 0.15–38 1.9 42 mIBP 100 0.44–280 4.3 100 0.61–39 2.8 87 nd–0.79 0.21 mBzP 99 nd–6.9 1.8 89 nd–2.0 0.62 74 nd–1.4 0.19 mEHP 100

Phthalate Metabolites, Hydroxy-Polycyclic Aromatic Hydrocarbons

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