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Antibiotic Pollution in Marine Food Webs in Laizhou Bay, North China: Trophodynamics and Human Exposure Implication Sisi Liu, Hongxia Zhao, Hans-Joachim Lehmler, Xiyun Cai, and Jingwen Chen Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.6b04556 • Publication Date (Web): 20 Jan 2017 Downloaded from http://pubs.acs.org on January 21, 2017
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Antibiotic Pollution in Marine Food Webs in Laizhou Bay, North
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China: Trophodynamics and Human Exposure Implication
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Sisi Liu,† Hongxia Zhao,*† Hans-Joachim Lehmler,§ Xiyun Cai,† Jingwen Chen*†
4 5 6
†
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Education), School of Environmental Science and Technology, Dalian University of
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Technology, Linggong Road 2, Dalian 116024, China
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§
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Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of
Department of Occupational and Environmental Health, College of Public Health,
The University of Iowa, IA 52242, USA
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ABSTRACT
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Little information is available about the bioaccumulation and biomagnification of
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antibiotics in marine food webs. Here we investigate the levels and trophic transfer of
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9 sulfonamide (SA), 5 fluoroquinolone (FQ), and 4 macrolide (ML) antibiotics, as
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well as trimethoprim in nine invertebrate and ten fish species collected from a marine
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food web in Laizhou Bay, North China in 2014 and 2015. All the antibiotics were
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detected in the marine organisms, with SAs and FQs being the most abundant
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antibiotics. Benthic fish accumulated more SAs than invertebrates and pelagic fish,
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while invertebrates exhibited higher FQ levels than fish. Generally, SAs and
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trimethoprim biomagnified in the food web, while the FQs and MLs were biodiluted.
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Trophic magnification factors (TMF) were 1.2 - 3.9 for SAs and trimethoprim, 0.3 -
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1.0 for FQs and MLs. Limited biotransformation and relatively high assimilation
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efficiencies are the likely reasons for the biomagnification of SAs. The pH dependent
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distribution coefficients (logD) but not the lipophilicity (logKOW) of SAs and FQs had
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a significant correlation (r = 0.73; p < 0.05) with their TMFs. Although the calculated
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estimated daily intakes (EDI) for antibiotics suggest that consumption of seafood from
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Laizhou Bay is not associated with significant human health risks, this study provides
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important insights into the guidance of risk management of antibiotics.
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Keywords: Antibiotics, Biomagnification, Health risk, Trophic dilution
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INTRODUCTION
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Antibiotics are largely used in human medicine, animal husbandry, agriculture and
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aquaculture. In 2013 alone, China, the largest producer and user of antibiotics in the
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world, used about 162,000 tons of antibiotics.1,2 Most antibiotics are only partially
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metabolized in humans or animals.3 Approximately 60% of antibiotics are ultimately
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released as the parent compounds into the environment.2 As a consequence, over 30
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antibiotics, including sulfonamide (SA), fluoroquinolone (FQ), and macrolide (ML)
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antibiotics, have been detected with concentrations up to µg/L levels in surface waters
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and ng/g levels in sediments.4-7 For example, eleven antibiotics were found in
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seawater of Bohai Bay, North China with the total concentrations ranging from 2.3 to
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6,800 ng/L.4 Seventeen antibiotics were detected in sediments from East Sea of China
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at concentrations ranging from not detected to 537.4 ng/g dry weight (dw).5
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Continuous inputs from numerous pollution sources have led to antibiotics with the
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characteristic of “pseudo-persistence” (i.e., the inputs of antibiotics exceed the ability
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of the ecosystem to remove them completely from the natural environment8) in
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natural water environment, which increases the possibility of bioaccumulation and
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biomagnification of antibiotics in aquatic organisms. Furthermore, antibiotics can give
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rise to an increase in the antibiotic resistance of pathogenic bacteria, which is a
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particular concern.1 As a result, there is a need to investigate and assess the negative
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effects of antibiotic contamination on ecosystem and, ultimately, human health.
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Antibiotics have been reported to have the potential to accumulate in aquatic biota
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by several field-monitoring data in aquatic organisms at various trophic levels, such as
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aquatic plants, mussels, and fish.7,9-11 For example, the concentrations of ΣSAs, ΣFQs
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and ΣMLs were as high as 15 ng/g dw, 6,500 ng/g dw, and 6 ng/g dw, respectively, in
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hydrophytes from Baiyangdian Lake, North China,7 and 77 ng/g dw, 1,600 ng/g dw, 4
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and 36 ng/g dw, respectively, in mollusks from Bohai Sea, China.9 Higher
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concentrations of ΣSAs and ΣMLs were found in wild fish from the Haihe River,
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North China and reached to 996 ng/g dw and 45 ng/g dw, respectively.10 Consistent
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with the occurrence of antibiotics in wild aquatic species, our earlier laboratory study
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revealed significant bioconcentration of sulfadiazine and sulfamethoxazole (BCF
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values: 1.7 - 170 L/kg) in common carp (Cyprinus carpio) at environmentally relevant
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concentrations.12 Hence, these antibiotics (i.e., SAs, FQs and MLs) may have a
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comparable trophic magnification potential and, thus, pose a risk for aquatic
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organisms, and even humans. Trophodynamics of these chemicals in aquatic food
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webs are an important criterion for assessing their ecological and health risks.13
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However, there are only limited works about the trophic transfer of antibiotics in
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aquatic food webs.14,15 Boonsaner et al. found that oxytetracycline can transfer into
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seven-striped carp (Probarbus jullieni) from watermeal (Wolffia globosa).14
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Roxithromycin was reported to have significant bioaccumulation through dietary
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uptake but no biomagnification potential in an artificial food chain including algae,
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water flea and fish.15 These studies only included one antibiotic, and the artificial food
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chains investigated consisted of two or three species. Overall, little comprehensive
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data are available about the trophodynamics of antibiotics to aquatic organisms, in
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particular with respect to marine food webs.
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To explore the trophodynamics of antibiotics in aquatic ecosystems, this study
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analyzed 19 widely-used antibiotics (Table S1), including 9 SA, 5 FQ, and 4 ML
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antibiotics, as well as trimethoprim, in a marine food web (9 invertebrate and 10 fish
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species) from the coastal area of Laizhou Bay, North China. The trophic levels of all
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organisms were determined by using the stable carbon and nitrogen isotope method.
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The influence of physicochemical factors including octanol/water partition coefficient 5
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(KOW), fraction of neutral molecules (fn) and pH dependent distribution coefficient
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(logD) on trophodynamics of antibiotics was also investigated. In addition, antibiotic
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concentrations were used to assess human health risks associated with the
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consumption of seafood from Laizhou Bay. This study presents the first
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characterization of trophic transfer of antibiotics in the marine food web of Laizhou
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Bay, and provides important insights that can guide the risk assessment of antibiotics.
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EXPERIMENTAL SECTION
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Sampling. Samples of marine organism, including 9 invertebrate species (3
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shellfish, 5 crustaceans, and 1 cephalopod) and 10 fish species (Table S2), were
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collected from Laizhou Bay with a bottom trawl from March 2014 to April 2015. The
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sampling months and sites for each species are described in detail in Table S2. The
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location of sampling sites is shown in Figure S1.
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All the samples were sealed in polytetrafluoroethylene plastic bags and transported
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immediately on ice to the laboratory. The invertebrates and fish species were cleaned
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with deionized water, and their lengths and weights were measured. Because the
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reproducible homogenization of whole marine organisms is challenging, the following
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tissues were dissected: soft abdomen for crabs; soft body for other invertebrates; and
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muscle from the backbone for fish. The tissue samples from one to six similarly sized
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individuals for the same species were homogenized, lyophilized, wrapped in
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aluminum foil and stored at -20°C until analysis. Three different homogenized
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samples were analyzed for each species.
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Sample Preparation and Instrumental Analysis. Sample extraction and clean-up
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were performed following a reported method with minor modifications.7 Briefly,
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target antibiotics were extracted from the biota samples with an accelerated solvent 6
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extraction system (ASE 350; Dionex, Sunnyvale, CA, USA) and purified using Oasis
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HLB cartridges (6 mL, 500 mg; Waters, Milford, MA, USA) as detailed in the
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Supporting Information (SI).
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Chemical analysis was performed on an Agilent 1100 high performance liquid
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chromatograph-tandem 6410B quadrupole mass spectrometer (LC-MS/MS) equipped
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with an electrospray ionization (ESI) source using multiple reaction monitoring
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(MRM) positive mode. Ten µL of the final extract were injected into an XTerra® MS
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C18 column (2.1 mm × 100 mm, 3.5 µm; Waters, Milford, MA, USA) maintained at
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40 °C. A gradient elution program was initiated with 95% A (0.1% v/v formic acid
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with 15.9 mM ammonium formate in water, pH = 2.4) and 5% B
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(methanol/acetonitrile, 1/1 in v/v), followed by a linear gradient from 5% to 88% B (0
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- 30 min) at a flow rate of 0.3 mL/min. The MRM transitions and fragment voltage,
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collision energy, and retention times are listed in Table S3.
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The carbon stable-isotope ratio (δ13C) and nitrogen stable-isotope ratio (δ15N) of
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the samples were determined using an Isoprime 100 isotope ratio mass spectrometer
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interfaced to a vario PYRO cube elemental analyzer (Elementar, Hanau, Germany) as
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described in the SI.
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Quality Assurance and Quality Control. All the analytical standards had purities
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exceeding 98% and their sources are described in the SI. The method detection limits
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(MLOD) and the method quantification limits (MLOQ) are defined as three and ten
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times the standard deviation (SD) of the mean procedural blanks (n = 6), respectively.
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The MLODs and MLOQs ranged from 0.02 to 1.5 ng/g wet weight (ww) and 0.08 to
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5.0 ng/g ww, respectively (Table S4). The recoveries (n = 6) of SAs, FQs, MLs and
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trimethoprim from spiked samples (i.e., farm raised fish) were 67% to 117%, 49% to
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128%, 64% to 111% and 90%, respectively, and the relative standard deviations (RSD) 7
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were less than 19% (Table S4). All samples were spiked with surrogate standards
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prior to extraction to assess recoveries of target compounds in biotic samples (Table
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S4). The recoveries of the surrogate standards varied from 32% to 121%. The reported
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final concentrations of antibiotics were corrected for the recoveries of their respective
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surrogates.
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The levels of all the target antibiotics in solvent blanks were below or near to their
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respective MLODs. Enrofloxacin, ofloxacin, ciprofloxacin, norfloxacin and enoxacin
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were detected in 58% to 71% of the procedural blanks. Concentrations of these five
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antibiotics in procedural blanks were subtracted from those in the corresponding
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samples for batches with blank contamination.
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Data Analysis. To account for lipid effects on δ13C, all δ13C values were adjusted for the C/N ratios as follows:16 δ 13 C adjusted = δ 13 C - 3.32 + 0.99 × C/N
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(1)
Trophic level of a consumer (TLconsumer) was calculated using the following equation: TLconsumer = (δ 15 N consumer - δ 15 N baseline ) / ∆N + TLbaseline
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(2)
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where ∆N is the enrichment factor of 3.8‰ representing the increase in δ15N from one
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TL to the next;17,18 TLbaseline is the trophic level of the baseline indicator. In the present
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study, northern maoxia shrimp (Acetes chinensis) was selected as the baseline
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indicator and assigned to TL = 2 according to previous studies.19,20
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The relative contribution of benthic vs. pelagic carbon sources in the diets of biota
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(i.e., relative carbon sources) was calculated using δ15N and δ13C values as detailed in
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the SI. 21
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The antibiotic concentration below the MLOQ was assigned a randomly-generated
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value between zero and the compound-specific MLOQ for statistical analysis. The 8
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random values obtained followed normal distribution. The data were log-transformed
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prior to analysis to obtain a greater homogeneity of variance. The differences in
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antibiotic concentrations between invertebrates and fish species and between benthic
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and pelagic fish were analyzed using the Student's t-test. The Mann-Whitney U test
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was used if the data were not normally distributed. All the data are presented as the
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arithmetic mean ± one standard deviation if they follow normal distribution otherwise
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the geometric mean (GM) values and 95% confidence intervals (CI) are given. A
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p-value of < 0.05 was considered statistically significant.
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RESULTS AND DISCUSSION
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Antibiotic Concentrations and Profiles in the Biotas. The detection frequencies
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of the 19 target antibiotics in all the samples are listed in Table S5. Sulfamethoxazole
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had the highest detection frequency (95%), followed by trimethoprim (91%).
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Ofloxacin (67%) and anhydroerythromycin (58%) occurred with the highest detection
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frequency among FQs and MLs, respectively. Among the marine species investigated,
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the swimming crab (Portunus trituberculatus) was the organism with the highest
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detection frequency (90%), while the fat greenling (Hexagrammos otakii) had the
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lowest detection frequency (21%) (Table S6). Overall, the high detection frequencies
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indicate widespread antibiotic contamination in marine organisms from Laizhou Bay.
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The total concentrations of all the antibiotics ranged from 57 to 1,370 ng/g ww
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(GM (95% CI): 300 (250, 360) ng/g ww) in all the biota samples. The total antibiotic
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concentrations in invertebrates (range: 57 to 1,230 ng/g ww; 370 (270, 500) ng/g ww)
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were significantly higher (p < 0.05) than those in fish (98 to 610 ng/g ww; 240 (200,
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300) ng/g ww). Benthic fish (i.e., flathead, eelgoby, javeline goby, fat greenling and
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tongue sole; 170 to 610 ng/g ww, mean ± SD: 360 ± 130 ng/g ww) tended to 9
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accumulate more antibiotics (p < 0.05) than pelagic fish (i.e., halfbeak, dotted gizzard
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shad, silvery pomfret, Chinese sea perch and mullet; 98 to 440 ng/g ww, 190 (150,
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240) ng/g ww). The highest antibiotic residues were detected in mactra quadrangularis
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(Mactra veneriformis; 1,300 ± 90 ng/g ww), with FQs accounting for 90% of the total
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antibiotic concentrations. Similar observations have been reported for mollusks
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(Meretrix merehjgntrix; 0.7 to 1,580 ng/g dw) from the Bohai Sea, China.9 The lowest
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antibiotic concentrations were detected in northern maoxia shrimp (64 ± 10 ng/g ww),
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most likely due to their variable exposure to antibiotics associated with their strong
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floating habit.17
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Concentrations of Σ SAs, ΣFQs, ΣMLs and trimethoprim in all the biota samples
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ranged from 19 to 451 ng/g ww, not detected (nd) to 1,200 ng/g ww, nd to 15 ng/g
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ww and nd to 50 ng/g ww, respectively. SAs and FQs were the most abundant
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antibiotic classes detected in most biota samples, accounting for 52% and 45% of total
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antibiotic concentrations, respectively (Figure 1). Trimethoprim (2%) and MLs (1%)
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made only minor contributions to the total antibiotic concentrations. The levels of
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ΣFQs in invertebrates (175 (92, 330) ng/g ww) were significantly higher (p < 0.05)
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than those in fish (56 (38, 81) ng/g ww). The opposite trend was found for ΣSAs
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(invertebrates: 100 (68, 140) ng/g ww; fish: 160 (120, 210) ng/g ww; p < 0.05). The
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average concentrations of ΣSAs in benthic fish (260 ± 130 ng/g ww) was significantly
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higher (p < 0.05) than those in pelagic fish (120 (86, 160) ng/g ww). No statistically
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significant difference in ΣFQ levels was observed for benthic vs. pelagic fish (benthic
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fish: 89 ± 33 ng/g ww; pelagic fish: 43 (24, 77) ng/g ww; p > 0.05). Overall, benthic
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fish accumulates more SAs than invertebrates and pelagic fish, whereas invertebrates
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exhibit higher FQ levels than fish. Several factors, including different habits and/or 10
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antibiotic partition between water and sediments, likely explain differences in levels
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of the antibiotic classes investigated. For example, the higher concentrations of
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antibiotics in invertebrates and benthic fish are likely a result of their intimate contact
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with antibiotic-contaminated sediments. It is well established that antibiotics,
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especially FQs, can be adsorbed to organic matter in sediments.22 As a consequence,
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some FQs (e.g., ofloxacin, ciprofloxacin, norfloxacin and enrofloxacin) accumulate in
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sediments in many polluted environments.7,23
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Relative abundance (%)
100
SAs TMP FQs Invertebrates Benthic fish
MLs Pelagic fish
80 60 40 20
M M ac Sw an tra i tis qu mm shr Ja adr ing imp N Vpan R ang cra or e es az ul b th in e or ar er ed sto c is n r n la m ap e m ao a cr xi w ab a s he hr lk Pr imp Fa Oct awn Ja t gr opu ve ee s lin nl e in Fl go g at by Ch To Eel head n in gu go es e by e s so D Si ea p le ot lv ted er Merc gi y po ull h zz m et ar fr Had sh et lfb ad ea k
0
214 215
Figure 1. Abundance profiles of different antibiotic classes (percentage of the total measured
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concentrations) reveal significant differences among invertebrates, benthic fish and pelagic fish.
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SAs, TMP, FQs and MLs represent sulfonamides, trimethoprim, fluoroquinolones and macrolides,
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respectively.
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Antibiotic concentrations normalized for dry weight (Table S6) exhibited the same
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trends observed for wet weight adjusted concentrations. Briefly, normalized ΣSA
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concentrations (dw) were significantly higher (p < 0.05) in fish than those in 11
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invertebrates, whereas no statistically significant difference was observed between
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benthic and pelagic fish (p > 0.05). Moreover, there were no significant differences (p >
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0.05) in total antibiotic or ΣFQ concentrations (dw) between fish and invertebrates or
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between benthic and pelagic fish. The moisture content of all organisms ranged from
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41% for fat greenling to 83% for octopus and significantly correlated (p < 0.05) with
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dry weight normalized concentrations of ΣMLs. No significant correlations (p > 0.05)
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were observed between moisture content and wet weight normalized antibiotic
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concentrations. Significant positive relationships (p < 0.05) were identified between
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sizes (lengths and weights) and wet weight concentrations of ΣSAs.
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A comparison of antibiotic levels in the organisms collected from the Laizhou Bay
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with levels reported in earlier studies from China reveals several distinct differences
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(Table S7). The levels of ΣSAs in all the species from Laizhou Bay were much higher
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than those reported for aquatic organisms from coastal areas of Dalian6 and Hailing
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Island.24 Levels of ΣFQs in organisms from Laizhou Bay were also higher than those
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reported for Haihe River10 and coastal areas of Hailing Island.24 Levels of these three
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antibiotic classes in fish from Laizhou Bay were higher than those detected in fish
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from rivers of the Pearl River Delta.25 In contrast, levels of ΣMLs in this study were
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much lower than those reported in organisms from Baiyangdian Lake,7 Bohai Sea,9
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Haihe River,10 and coastal areas of Hailing Island.24 Levels of Σ SAs and ΣFQs in
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biota samples from Laizhou Bay were similar to those from Baiyangdian Lake.7 The
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different levels for antibiotics in different parts of China are most likely related to
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regional differences in the use of antibiotics.2
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Only limited information regarding levels of antibiotics in global biotas is currently
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available (Table S7). The levels of Σ FQs (nd to 0.73 ng/g ww) in shrimps and fish 12
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collected from Canada fish markets were much lower than those reported from
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China.26 In mussels from the coastal areas of Ireland, the concentrations of
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trimethoprim were up to 9.22 ng/g dw, which is similar to those observed in shellfish
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(2.0 to 9.7 ng/g dw) in the present study.29 Sulfamethoxazole and trimethoprim, the
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only two antibiotics analyzed, were not detected in any sample in national monitoring
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studies conducted in Germany and the United States.27,28
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Food Web Structure. To characterize food web relationships of the aquatic
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organisms collected from Laizhou Bay and assess the trophodynamics of antibiotics,
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TLs and relative carbon sources were calculated using adjusted δ13C and δ15N values
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(Figure S2). Adjusted δ13C values ranged from -22.8 ± 0.1 for eelgoby to -13.2 ± 2.3
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for mullet. The δ15N values ranged from 6.6 ± 0.4 for northern maoxia shrimp to 14.6
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± 0.1 for silvery pomfret. Estimated TLs ranged from 2.00 ± 0.10 for northern maoxia
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shrimp to 4.10 ± 0.02 for silvery pomfret (Figure 2). Apparent intra-species
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variability in TL values was observed in this study and, as has been suggested by
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previous studies, may be attributed to the variation in the body sizes of the collected
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aquatic organisms.18,30,31 No significant seasonal variation was found in the TL values
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of consumers (Table S8, p > 0.05).
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Relative carbon sources of these species were used to assess if different species
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belong to the same food web.21 Relative carbon source values close to 1 are thought to
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indicate more pelagic feeding, whereas values close to 0 indicate more benthic
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feeding.21 Values of relative carbon sources ranged from -0.40 ± 0.30 for dotted
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gizzard shad to 1.40 ± 0.01 for fat greenling (Figure 2). All species investigated were
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distributed close to the mean value of the relative carbon sources of 0.4 (vertical line
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in Figure 2). Eelgoby (Odontamblyopus rubicundus; 2.70 ± 0.05) and mullet (Liza 13
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haematocheilus; -2.40 ± 0.03) were an exception, which indicates that their diets
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might include sources which do not belong to the food web under investigation.
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Therefore, both species were not included in the calculation of trophic magnification
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factors (TMF) in this study.
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5.0
Invertebrates Benthic fish Pelagic fish
4.5
Trophic level (TL)
Chinese sea perch
Javeline goby
Silvery pomfret
4.0
Flathead Mantis shrimp Swimming crab
3.5 Mullet 3.0
Prawn Dotted gizzard shad
2.5 Halfbeak 2.0
Fat greenling
Eelgoby
Octopus Japanese stone crab Tongue sole
Mactra quadrangularis Razor clam Veined rapa whelk
Northern maoxia shrimp -2
-1
0 1 Relative carbon source
2
3
277 278
Figure 2. Relative carbon sources and trophic levels (TL) characterize the food web relationships
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of the species collected from Laizhou Bay. Green circles (), blue diamonds () and black
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triangles () represent invertebrates, benthic fish and pelagic fish, respectively. Data are
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presented as mean ± one standard deviation of relative carbon sources (n = 3) and TL values (n =
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3). The red vertical solid line and dotted lines represent the mean value of relative carbon sources
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for all species and the boundaries of relative carbon sources for species in the same food web.32
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Trophic Transfer of Antibiotics in the Marine Food Web. TMFs of individual
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antibiotics and the three antibiotic classes (i.e, SAs, FQs, and MLs) in the food web
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were determined from the slope of the regression between log-transformed antibiotic 14
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concentrations (ww) in biota and the TLs of the corresponding species (Figure 3;
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Table S9). Overall, the TMF values followed the order SAs ≥ trimethoprim > MLs >
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FQs.
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sulfamonomethoxine, sulfachlorpyridazine, sulfadimidine, and ∑SAs increased
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significantly with increasing TLs (p < 0.05). Similarly, a significant positive
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correlation (p < 0.05) was observed between the TL values and trimethoprim
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concentrations (ww). The TMF values were 1.2 - 3.9 for SAs and 2.4 for trimethoprim.
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These TMF values are greater than those reported previously for other
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pharmaceuticals, such as diphenhydramine (TMF = 0.38) and carbamazepine (TMF =
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1.17) in an effluent stream from the North Bosque River, USA and propranolol (TMF
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= 0.31) and diclofenac (TMF = 1.06) in a freshwater food web from Taihu Lake,
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China.18,31 A similar trophic transfer for SAs was also observed in Baiyangdian Lake,
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North China, where fish (nd - 98.3 ng/g dw, mean: 20.8 ng/g dw) had the highest
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concentrations of SAs, followed by crustaceans (nd - 30.6 ng/g dw, 11.7 ng/g dw) and
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then aquatic plants (nd -15 ng/g dw, 1.67 ng/g dw).7 These results demonstrate that
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SAs and trimethoprim, like other pharmaceuticals, have the potential to biomagnify in
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a marine food web. Previous studies have shown that SAs such as sulfamethoxazole
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and trimethoprim are well absorbed in the intestinal tracts33-35 but not efficiently
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metabolized in aquatic organisms, such as crustaceans, mollusks, fish.35-38 Therefore,
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trophic magnification of SAs and trimethoprim in this marine food web is likely due
308
to their low metabolic transformation and efficient assimilation in animals at higher
309
trophic levels.
For
SAs,
concentrations
(ww)
of
sulfadiazine,
15
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sulfamethoxazole,
Environmental Science & Technology
log concentration (ng/g ww)
3.0 (a) Sulfamethoxazole
y = 0.34x + 0.60 r = 0.85, p < 0.05 TMF = 2.19
2.5
1.2
1.5
0.0
3
log concentration (ng/g ww)
3.5 (c) Enrofloxacin
4
2
y = -0.40x + 3.44 r = 0.76, p < 0.05 TMF = 0.40
3.0
3
3.0 (d) Ofloxacin
2.5
2.0
2.0
1.5
4 y = -0.42x + 2.91 r = 0.77, p < 0.05 TMF = 0.38
2.5
1.0
1.5 2
log concentration (ng/g ww)
y = 0.38x - 0.85 r = 0.54, p < 0.05 TMF = 2.40
-1.2 2
0.8
(b) Trimethoprim
2.4
2.0
1.0
3
(e) Azithromycin
4
2
y = -0.16x + 0.73 r = 0.88, p < 0.05 TMF = 0.70
0.6
0.2
0.0
0.0
-0.5 4
4
(f) Anhydroerythromycin y = -0.20x + 0.97 r = 0.66, p < 0.05 TMF = 0.64 1.0
0.5
3
3
1.5
0.4
2
310
3.6
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2
Trophic level (TL)
3 Trophic level (TL)
4
311
Figure 3. Relationships between trophic levels (TL) and log-transformed wet weight normalized
312
concentrations (ww) describe trophic magnification for (a) sulfamethoxazole, (b) trimethoprim
313
and trophic dilution for (c) enrofloxacin, (d) ofloxacin, (e) azithromycin and (f)
314
anhydroerythromycin in the marine food web from Laizhou Bay. Slopes, correlation coefficients
315
(r), p-values and trophic magnification factors (TMF) from the regression analyses are shown
316
(Table S9 for additional details). Data are presented as mean ± one standard deviation of TL
16
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317
values (n = 3) and log-transformed antibiotic concentrations which were detected in at least two
318
out of three homogenized samples.
319 320
The TMF values ranged from 0.3 to 0.8 for FQs and from 0.5 to 1.0 for MLs,
321
respectively. Significant negative relationships (p < 0.05) were observed for
322
correlations between TL values and concentrations of ΣFQs and ΣMLs. Moreover,
323
there were significant negative correlations (p < 0.05) between the TL values and
324
concentrations of three FQs (i.e., enoxacin, enrofloxacin, and ofloxacin) and two MLs
325
(i.e., azithromycin and anhydroerythromycin) in the species under investigation.
326
These findings demonstrate that both antibiotic classes undergo trophic dilution in the
327
marine food web of Laizhou Bay. Literature TMF values for both classes of
328
antibiotics are limited and only TMF values for roxithromycin have been reported.15,18
329
In this study, the TMF values for azithromycin (0.7, 95% CI: 0.5 - 0.9) and
330
anhydroerythromycin (0.6, 95% CI: 0.5 - 0.9) were higher than values reported for
331
roxithromycin (0.21 - 0.29) in an artificial aquatic food chain but slight lower than
332
values for roxithromycin (1.11) in a freshwater food web from Taihu Lake, China.15,18
333
Unfortunately, the detection frequency of roxithromycin (23%) was too low to
334
calculate a TMF value in this study (Table S5). For the other seven antibiotics, no
335
significant correlations (p > 0.05) were observed between TL values and their wet
336
weight concentrations.
337 338
Influence of Physicochemical Factors on Trophic Magnification of Antibiotics.
339
Octanol-water partition coefficients (Kow) are excellent predictors of the
340
biomagnification of hydrophobic organic compounds in aquatic food webs.39 The
341
TMF values of the antibiotics investigated in this study decreased with increasing 17
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342
logKOW; however, this correlation was not statistically significant (p > 0.05, Figure
343
4a). Negative relationships or no relationships between TMF and logKOW values are
344
also observed for phthalate esters,40 and some hydrophobic compounds (e.g., dioxins,
345
polychlorinated biphenyls).41-43 No significant correlation between TMFs of these
346
antibiotics and their logKOW values is not entirely surprising because the antibiotics
347
investigated are polar molecules and contain ionizable functional groups. Like other
348
ionic compounds, an ionic form of an antibiotic cannot diffuse across cell membranes
349
and is not readily absorbed in the intestinal tracts of marine organisms.29,44 Therefore,
350
logKOW is not a good biomagnification predictor for these antibiotics. We also
351
investigated if measures of the fraction of the non-ionic form of an antibiotic, such as
352
the fraction of neutral molecules (fn) and the pH dependent distribution coefficient
353
(logD),45 are better predictors of its biomagnification in a marine food web. Indeed,
354
we found that the SAs and trimethoprim with higher TMF values displayed higher fn
355
values (Table S1, p < 0.05) than the FQs and MLs (Figure S3). Furthermore, a
356
significant positive correlation (r = 0.73; p < 0.05) was observed between TMFs of the
357
antibiotics and their logD (pH = 7.5, Table S1) values, with the exception of the three
358
ML antibiotics (Figure 4b). A similar correlation between BCF values of other
359
pharmaceuticals and their pH-corrected liposome-water partition coefficients was
360
observed in some invertebrates.46 The correlation suggests that logD of ionizable
361
organic chemicals, such as antibiotics, is a better predictor of their biomagnification
362
potential in marine food webs than logKOW.
363
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Trophic magnification factor (TMF)
Trophic magnification factor (TMF)
Page 19 of 33
SAs FQs TMP MLs
(a) y = -0.16x + 1.72 p > 0.05
4 2 0
0
1
2
3
4
8 6 4 2 0
-1.00 -0.75 -0.50 -0.25
logKOW
364
SAs FQs TMP
(b) y = 2.21x + 2.52 r = 0.73, p < 0.05
0.00
0.25
logD
365
Figure 4. Relationships between TMFs of detected antibiotics and physicochemical factors
366
(logKOW (a) and logD values (b)). The TMF values for SAs, trimethoprim, FQs and MLs are
367
indicated by blue triangles (), red circles (), green inverted triangles () and orange diamonds
368
(), respectively. Equations, correlation coefficients (r) and p-values of the regression analyses
369
are shown. LogKOW and logD values of antibiotics (Table S1) were collected from elsewhere.
370 371
Biotransformation processes within the food web are one possible explanation for
372
the lack of a correlation between TMFs and logD values for the ML antibiotics.
373
Although biotransformation was not directly assessed in this study, there is some
374
literature evidence demonstrating that aquatic organisms have the capacity to
375
metabolize ML antibiotics.47-49 For example, Liu et al. reported that erythromycin and
376
roxithromycin are readily metabolized by crucian carp (Carassius auratus) and
377
eliminated via the bile, most likely due to the induction of cytochrome P450 enzymes
378
(measured
379
exposure.47,48 Chen et al. observed faster hepatic clearance rates for tertiary amines
380
(e.g., MLs) than other amines (e.g., SAs) in liver S9 fractions of rainbow trout
381
(Oncorhynchus mykiss).49 Unfortunately, the biotransformation of antibiotics by
382
aquatic organisms at different TLs is not fully understood and future studies are
383
needed.
as
ethoxyresorufin-O-deethylase
activity)
19
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following
antibiotic
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384
Assessment of Human Health Risks. All species investigated in this study are
385
caught for human consumption.50-52 Estimated daily intakes (EDI, Table S10) for each
386
antibiotic following consumption of seafood were calculated assuming a worst-case
387
scenario for rural and urban residents in China.53 For urban residents, EDIs of
388
antibiotics ranged from 0.5 ng/kg bw/d for roxithromycin to 144 ng/kg bw/d for
389
enrofloxacin. EDIs for rural residents ranged from 0.3 ng/kg bw/d for roxithromycin
390
to 78 ng/kg bw/d for enrofloxacin. The EDIs for urban residents were two times
391
higher than those for rural residents due to the higher fish consumption of urban
392
residents.54 All EDI values were two to five orders of magnitude lower than the
393
respective acceptable daily intakes (ADI, Table S10). Based on the EDI values and
394
the respective ADIs, hazard quotients of individual antibiotics (HQ; Table S10,
395
Figure S4) were calculated for urban and rural residents and used to assess potential
396
human health risks from dietary exposure to antibiotics.53 Vragovic et al. suggested
397
that a HQ < 0.01 indicates a negligible risk whereas a HQ ≥ 0.01 indicates a
398
considerable risk.55 A HQ > 0.05 is considered a distinct risk.55 The HQ of
399
enrofloxacin for urban residents (HQ = 0.07, i.e., 7% of ADI) exceeded 0.05 (Figure
400
S4). The HQs of ciprofloxacin (HQ = 0.01, i.e., 1% of ADI) and clarithromycin (HQ =
401
0.01, i.e., 1% of ADI) for urban residents and enrofloxacin for rural residents (HQ =
402
0.04, i.e., 4% of ADI) were ≥ 0.01. These results suggest that there is an appreciable
403
human health risk associated with the exposure to antibiotics due to consumption of
404
seafood from Laizhou Bay.
405
We also calculated hazard index values (HI = ΣHQi) assuming a similar
406
toxicological mode of action (MOA) for substances belong to the same class to assess
407
if consumption of seafood from Laizhou Bay represents a human health risk.53 The HI
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408
values of ΣMLs for urban residents (HI = 0.014) exceeded 0.01. The HI values of
409
ΣFQs were 0.094 and 0.050 for urban and rural residents, respectively (Table S10).
410
The high risk of FQs in seafood represents a potential concern because of the
411
relatively low ADIs (1,600 to 11,400 ng/kg bw/d) and high EDIs (8.6 to 144 ng/kg
412
bw/d). Compared to FQs and MLs, SAs exhibited relatively high biomagnification
413
potential but represented a small ingestion risk (i.e., the HI values of SAs are < 0.01).
414
Exposure Implications. Due to intensive local aquaculture activities, ambient
415
wastewater discharge and runoff from farming, large amounts of antibiotic residues
416
have been discharged into the water bodies of Laizhou Bay,4,56,57 which increases the
417
possibility of bioaccumulation and biomagnification of antibiotics in aquatic
418
organisms. Our comprehensive investigation of the trophodynamics of antibiotics in a
419
marine food web from this region demonstrates that several antibiotics undergo
420
trophic transfer to top predators or low-trophic level invertebrates and accumulate in
421
certain tissues, such as the liver and blood.25 In order to reduce the potential exposure
422
risks, more strict maximal residue limits (MRL) of antibiotics in seafood need to be
423
set for Chinese residents. While consumption of seafood alone is unlikely to represent
424
a major human health risk in China, humans are exposed to antibiotics by a variety of
425
other exposure pathways, such as other food intakes,58,59 drug abuse,60 tap water,61 and
426
inhalation of contaminated dust.62 Moreover, this study did not investigate levels of
427
antibiotic metabolites in the food web from Laizhou Bay. Emerging evidence suggests
428
that the biotransformation products of antibiotics may be more toxic (e.g.,
429
protein-reactive) and/or bioaccumulative than the parent compounds.63-65 For example,
430
sulfamethoxazole can be hydroxylated and further oxidized in humans and rats to
431
nitroso-sulfamethoxazole, which can bind covalently to cysteine residues of cellular
432
proteins and cause toxicity.63,64 Furthermore, decarboxylation of antibiotics, such as 21
ACS Paragon Plus Environment
Environmental Science & Technology
433
FQs and cephalosporins, may generate more fat-soluble metabolites that are more
434
bioaccumulative than the parent antibiotics.65 In addition, ecotoxicological studies
435
suggest that some antibiotics investigated (e.g., ciprofloxacin, erythromycin,
436
sulfamethoxazole and trimethoprim) can induce phototoxicity to Daphnia magna,
437
disrupt the immune system in mollusks, or impair the development of fish in their
438
early life stages.66-68 Therefore, the environmental behavior of antibiotics in aquatic
439
food webs and potential ecological and human health risks associated with exposure
440
to antibiotics and their metabolites warrant further attention.
441 442
ASSOCIATED CONTENT
443
Supporting Information. Text, figures, and tables addressing (1) physicochemical
444
properties of selected antibiotics in this study; (2) chemicals used in the analysis; (3)
445
details about sample extraction and cleanup, and stable isotope analysis; (4)
446
calculations of TMFs, relative carbon sources, estimated daily intakes (EDI) and
447
hazard quotients (HQ); (5) sampling figure and tables about sample information; (6)
448
table about MLODs, MLOQs, spiked recoveries and RSD of target antibiotics; (7)
449
table about LC-MS/MS parameters and retention times of antibiotics; (8) tables about
450
detection frequencies and concentrations in biota samples; (9) table about slopes, r
451
and p-values of regression analyses between logarithm concentrations and TLs, and
452
TMF values of antibiotics; (10) table about the comparison of antibiotic levels in
453
aquatic organisms from Laizhou Bay with those reported in other locations; (11) table
454
and figure about EDIs and HQs of antibiotics for rural and urban residents; (12) figure
455
about relationship between TMFs and logKOW values. This material is available free of
456
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
458
Corresponding Authors
459
* Hongxia Zhao, phone/fax: +86-411-8470 7965, e-mail:
[email protected],
460
address: Linggong Road 2, Ganjingzi District, Dalian 116024, China; Jingwen Chen,
461
phone/fax: +86-411-8470 6269, e-mail:
[email protected], address: Linggong Road
462
2, Ganjingzi District, Dalian 116024, China.
463 464
ACKNOWLEDGEMENT
465
This study was supported by the National Basic Research Program of China
466
(2013CB430403), the National Natural Science Foundation of China (21325729,
467
21277017) and the Basic Research Project of Key Laboratory of Liaoning Provincial
468
Education Department (LZ2015023).
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REFERENCES
470
(1) Zhu, Y. G.; Johnson, T. A.; Su, J. Q.; Qiao, M.; Guo, G. X.; Stedtfeld, R. D.; Hashsham, S. A.;
471
Tiedje, J. M. Diverse and abundant antibiotic resistance genes in Chinese swine farms. P. Natl. Acad.
472
Sci. USA. 2013, 110 (9), 3435-3440; DOI 10.1073/pnas.1222743110.
473
(2) Zhang, Q. Q.; Ying, G. G.; Pan, C. G.; Liu, Y. S.; Zhao, J. L. Comprehensive evaluation of
474
antibiotics emission and fate in the river basins of China: Source analysis, multimedia modelling, and
475
linkage to bacterial resistance. Environ. Sci. Technol. 2015, 49 (11), 6772-6782; DOI
476
10.1021/acs.est.5b00729.
477
(3) Bound, J. P.; Voulvoulis, N. Pharmaceuticals in the aquatic environment - a comparison of risk
478
assessment
479
10.1016/j.chemosphere.2004.05.010.
480
(4) Zou, S. C.; Xu, W. H.; Zhang, R. J.; Tang, J. H.; Chen, Y. J.; Zhang, G. Occurrence and
481
distribution of antibiotics in coastal water of the Bohai Bay, China: Impacts of river discharge and
482
aquaculture activities. Environ. Pollut. 2011, 159 (10), 2913-2920; DOI 10.1016/j.envpol.2011.04.037.
483
(5) Shi, H.; Yang, Y.; Liu, M.; Yan, C. X.; Yue, H. Y.; Zhou, J. L. Occurrence and distribution of
484
antibiotics in the surface sediments of the Yangtze Estuary and nearby coastal areas. Mar. Pollut. Bull.
485
2014, 83 (1), 317-323; DOI 10.1016/j.marpolbul.2014.04.034.
486
(6) Na, G. S.; Fang, X. D.; Cai, Y. Q.; Ge, L. K.; Zong, H. M.; Yuan, X. T.; Yao, Z. W.; Zhang, Z. F.
487
Occurrence, distribution, and bioaccumulation of antibiotics in coastal environment of Dalian, China.
488
Mar. Pollut. Bull. 2013, 69 (1-2), 233-237; DOI 10.1016/j.marpolbul.2012.12.028.
489
(7) Li, W. H.; Shi, Y. L.; Gao, L. H.; Liu, J. M.; Cai, Y. Q. Occurrence of antibiotics in water,
490
sediments, aquatic plants, and animals from Baiyangdian Lake in North China. Chemosphere 2012, 89
strategies.
Chemosphere
2004,
56
(11),
24
ACS Paragon Plus Environment
1143-1155;
DOI
Page 25 of 33
Environmental Science & Technology
491
(11), 1307-1315; DOI 10.1016/j.chemosphere.2012.05.079.
492
(8) Mackay, D.; Hughes, D. M.; Romano, M. L.; Bonnell, M. The role of persistence in chemical
493
evaluations. Integr. Environ. Assess. Manag. 2014, 10 (4), 588-594; DOI 10.1002/ieam.1545.
494
(9) Li, W. H.; Shi, Y. L.; Gao, L. H.; Liu, J. M.; Cai, Y. Q. Investigation of antibiotics in mollusks
495
from coastal waters in the Bohai Sea of China. Environ. Pollut. 2012, 162, 56-62; DOI
496
10.1016/j.envpol.2011.10.022.
497
(10) Gao, L. H.; Shi, Y. L.; Li, W. H.; Liu, J. M.; Cai, Y. Q. Occurrence, distribution and
498
bioaccumulation of antibiotics in the Haihe River in China. J. Environ. Monitor. 2012, 14 (4),
499
1248-1255; DOI 10.1039/C2em10916f.
500
(11) He, X. T.; Wang, Z. H.; Nie, X. P.; Yang, Y. F.; Pan, D. B.; Leung, A. O. W.; Cheng, Z.; Yang, Y. T.;
501
Li, K. B.; Chen, K. C. Residues of fluoroquinolones in marine aquaculture environment of the Pearl
502
River
503
10.1007/s10653-011-9420-4.
504
(12) Zhao, H. X.; Liu, S. S.; Chen, J. W.; Jiang, J. Q.; Xie, Q.; Quan, X. Biological uptake and
505
depuration of sulfadiazine and sulfamethoxazole in common carp (Cyprinus carpio). Chemosphere
506
2015, 120, 592-597; DOI 10.1016/j.chemosphere.2014.09.075.
507
(13) Zhang, K.; Wan, Y.; Jones, P. D.; Wisemans, S.; Giesy, J. P.; Hu, J. Y. Occurrences and fates of
508
hydroxylated polybrominated diphenyl ethers in marine sediments in relation to trophodynamics.
509
Environ. Sci. Technol. 2012, 46 (4), 2148-2155; DOI 10.1021/es203195s.
510
(14) Boonsaner, M.; Hawker, D. W., Evaluation of food chain transfer of the antibiotic oxytetracycline
511
and
512
10.1016/j.chemosphere.2013.05.070.
Delta,
human
South
risk
China.
Environ.
assessment.
Geochem.
Chemosphere
Health
2013,
2012,
93
25
ACS Paragon Plus Environment
34
(6),
(3),
323-335;
1009-1014;
DOI
DOI
Environmental Science & Technology
513
(15) Ding, J. N.; Lu, G. H.; Liu, J. C.; Zhang, Z. H. Evaluation of the potential for trophic transfer of
514
roxithromycin along an experimental food chain. Environ. Sci. Pollut. Res. 2015, 22 (14), 10592-10600;
515
DOI 10.1007/s11356-015-4265-5.
516
(16) Post, D. M.; Layman, C. A.; Arrington, D. A.; Takimoto, G.; Quattrochi, J.; Montana, C. G.
517
Getting to the fat of the matter: Models, methods and assumptions for dealing with lipids in stable
518
isotope analyses. Oecologia. 2007, 152 (1), 179-189; DOI 10.1007/s00442-006-0630-x.
519
(17) Ma, X. D.; Zhang, H. J.; Wang, Z.; Yao, Z. W.; Chen, J. W.; Chen, J. P. Bioaccumulation and
520
trophic transfer of short chain chlorinated paraffins in a marine food web from Liaodong Bay, North
521
China. Environ. Sci. Technol. 2014, 48 (10), 5964-5971; DOI 10.1021/Es500940p.
522
(18) Xie, Z. X.; Lu, G. H.; Liu, J. C.; Yan, Z. H.; Ma, B. N.; Zhang, Z. H.; Chen, W. Occurrence,
523
bioaccumulation, and trophic magnification of pharmaceutically active compounds in Taihu Lake,
524
China. Chemosphere 2015, 138, 140-147; DOI 10.1016/j.chemosphere.2015.05.086.
525
(19) Cui, Y.; Wu, Y.; Xu, Z. L.; Zhang, J. Potential dietary influence on the stable isotopes and fatty
526
acid composition of migratory anchovy (Coilia mystus) around the Changjiang Estuary. J. Mar. Biol.
527
Assoc. UK. 2015, 95 (1), 193-205; DOI 10.1017/S0025315414000873.
528
(20) Cabana, G.; Rasmussen, J. B. Comparison of aquatic food chains using nitrogen isotopes. P. Natl.
529
Acad. Sci. USA. 1996, 93 (20), 10844-10847; DOI 10.1073/pnas.93.20.10844.
530
(21) McKinney, M. A.; McMeans, B. C.; Tomy, G. T.; Rosenberg, B.; Ferguson, S. H.; Morris, A.;
531
Muir, D. C. G.; Fisk, A. T. Trophic transfer of contaminants in a changing arctic marine food web:
532
Cumberland Sound, Nunavut, Canada. Environ. Sci. Technol. 2012, 46 (18), 9914-9922; DOI
533
10.1021/es302761p.
534
(22) Tolls, J. Sorption of veterinary pharmaceuticals in soils: A review. Environ. Sci. Technol. 2001, 35
26
ACS Paragon Plus Environment
Page 26 of 33
Page 27 of 33
Environmental Science & Technology
535
(17), 3397-3406; DOI 10.1021/es0003021.
536
(23) Kim, S. C.; Carlson, K. Temporal and spatial trends in the occurrence of human and veterinary
537
antibiotics in aqueous and river sediment matrices. Environ. Sci. Technol. 2007, 41 (1), 50-57; DOI
538
10.1021/es060737+.
539
(24) Chen, H.; Liu, S.; Xu, X. R.; Liu, S. S.; Zhou, G. J.; Sun, K. Y.; Zhao, J. L.; Ying, G. G.
540
Antibiotics in typical marine aquaculture farms surrounding Hailing Island, South China: Occurrence,
541
bioaccumulation and human dietary exposure. Mar. Pollut. Bull. 2015, 90 (1-2), 181-187; DOI
542
10.1016/j.marpolbul.2014.10.053.
543
(25) Zhao, J. L.; Liu, Y. S.; Liu, W. R.; Jiang, Y. X.; Su, H. C.; Zhang, Q. Q.; Chen, X. W.; Yang, Y. Y.;
544
Chen, J.; Liu, S. S.; Pan, C. G.; Huang, G. Y.; Ying, G. G. Tissue-specific bioaccumulation of human
545
and veterinary antibiotics in bile, plasma, liver and muscle tissues of wild fish from a highly urbanized
546
region. Environ. Pollut. 2015, 198, 15-24; DOI 10.1016/j.envpol.2014.12.026.
547
(26) Tittlemier, S. A.; Van de Riet, J.; Burns, G.; Potter, R.; Murphy, C.; Rourke, W.; Pearce, H.;
548
Dufresne, G. Analysis of veterinary drug residues in fish and shrimp composites collected during the
549
Canadian Total Diet Study, 1993-2004. Food Addit. Contam. 2007, 24 (1), 14-20; DOI
550
10.1080/02652030600932937.
551
(27) Subedi, B.; Du, B. W.; Chambliss, C. K.; Koschorreck, J.; Rudel, H.; Quack, M.; Brooks, B. W.;
552
Usenko, S. Occurrence of pharmaceuticals and personal care products in German fish tissue: A national
553
study. Environ. Sci. Technol. 2012, 46 (16), 9047-9054; DOI 10.1021/es301359t.
554
(28) Ramirez, A. J.; Brain, R. A.; Usenko, S.; Mottaleb, M. A.; O'Donnell, J. G.; Stahl, L. L.; Wathen, J.
555
B.; Snyder, B. D.; Pitt, J. L.; Perez-Hurtado, P.; Dobbins, L. L.; Brooks, B. W.; Chambliss, C. K.
556
Occurrence of pharmaceuticals and personal care products in fish: Results of a national pilot study in
27
ACS Paragon Plus Environment
Environmental Science & Technology
Page 28 of 33
557
the United States. Environ. Toxicol. Chem. 2009, 28 (12), 2587-2597; DOI 10.1897/08-561.1.
558
(29) McEneff, G.; Barron, L.; Kelleher, B.; Paull, B.; Quinn, B. A year-long study of the spatial
559
occurrence and relative distribution of pharmaceutical residues in sewage effluent, receiving marine
560
waters
561
10.1016/j.scitotenv.2013.12.123.
562
(30) Borga, K.; Fjeld, E.; Kierkegaard, A.; McLachlan, M. S. Consistency in trophic magnification
563
factors of cyclic methyl siloxanes in pelagic freshwater food webs leading to brown trout. Environ. Sci.
564
Technol. 2013, 47 (24), 14394-14402; DOI 10.1021/es404374j.
565
(31) Du, B.; Haddad, S. P.; Luek, A.; Scott, W. C.; Saari, G. N.; Kristofco, L. A.; Connors, K. A.; Rash,
566
C.; Rasmussen, J. B.; Chambliss, C. K.; Brooks, B. W. Bioaccumulation and trophic dilution of human
567
pharmaceuticals across trophic positions of an effluent-dependent wadeable stream. Philos. Trans. R.
568
Soc. London, Ser. B. 2014, 369 (1656), 1-10; DOI Artn 2014005810.1098/Rstb.2014.0058.
569
(32) Jia, H. L.; Zhang, Z. F.; Wang, C. Q.; Hong, W. J; Sun, Y. Q.; Li, Y. F. Trophic transfer of methyl
570
siloxanes in the marine food web from coastal area of Northern China. Environ. Sci. Technol. 2015, 49
571
(5), 2833-2840; DOI 10.1021/es505445e.
572
(33) Klopman, G.; Stefan, L. P.; Saiakhov, R. D. ADME evaluation: 2. A computer model for the
573
prediction of intestinal absorption in humans. Eur. J. Pharm. Sci. 2002, 17 (4-5), 253-263; DOI
574
10.1016/S0928-0987(02)00219-1.
575
(34) Meshi, T.; Sato, Y. Studies on sulfamethoxazole/trimethoprim: absorption, distribution, excretion
576
and metabolism of trimethoprim in rat. Chem. Pharm. Bullet. 1972, 20 (10), 2079-2090; DOI
577
10.1248/cpb.20.2079.
578
(35) Touraki, M.; Niopas, I.; Kastritsis, C. Bioaccumulation of trimethoprim, sulfamethoxazole and
and
marine
bivalves.
Sci.
Total
Environ.
2014,
28
ACS Paragon Plus Environment
476,
317-326;
DOI
Page 29 of 33
Environmental Science & Technology
579
N-acetyl-sulfamethoxazole in Artemia nauplii and residual kinetics in seabass larvae after repeated oral
580
dosing
581
10.1016/S0044-8486(99)00036-8.
582
(36) Connors, K. A.; Du, B. W.; Fitzsimmons, P. N.; Hoffman, A. D.; Chambliss, C. K.; Nichols, J. W.;
583
Brooks, B. W. Comparative pharmaceutical metabolism by rainbow trout (Oncorhynchus mykiss) liver
584
S9 fractions. Environ. Toxicol. Chem. 2013, 32 (8), 1810-1818; DOI 10.1002/etc.2240.
585
(37) Nouws, J. F. M.; et al. Pharmacokinetics, hydroxylation and acetylation of sulphadimidine in
586
mammals, birds, fish, reptiles and molluscs. In Comparative Veterinary Pharmacology, Toxicology
587
and Therapy; Van Miert, A. S. J. P. A. M., Bogaert, M. G., Debackere M., Eds.; MTP Press:
588
Lancaster, England 1985; pp 301-318.
589
(38) Chair, M.; Nelis, H. J.; Leger, P.; Sorgeloos, P.; de Leenheer, A. P. Accumulation of trimethoprim,
590
sulfamethoxazole, and N-acetylsulfamethoxazole in fish and shrimp fed medicated Artemia franciscana.
591
Antimicrob. Agents Chemother. 1996, 40 (7), 1649-1652.
592
(39) Kelly, B. C.; Ikonomou, M. G.; Blair, J. D.; Morin, A. E.; Gobas, F. A. P. C. Food web-specific
593
biomagnification of persistent organic pollutants. Science 2007, 317 (5835), 236-239; DOI
594
10.1126/science.1138275.
595
(40) Mackintosh, C. E.; Maldonado, J.; Jing, H. W.; Hoover, N.; Chong, A.; Ikonomou, M. G.; Gobas,
596
F. A. P. C. Distribution of phthalate esters in a marine aquatic food web: Comparison to polychlorinated
597
biphenyls. Environ. Sci. Technol. 2004, 38 (7), 2011-2020; DOI 10.1021/es034745r.
598
(41) Kobayashi, J.; Imuta, Y.; Komorita, T.; Yamada, K.; Ishibashi, H.; Ishihara, F.; Nakashima, N.;
599
Sakai, J.; Arizono, K.; Koga, M. Trophic magnification of polychlorinated biphenyls and
600
polybrominated diphenyl ethers in an estuarine food web of the Ariake Sea, Japan. Chemosphere 2015,
of
medicated
nauplii.
Aquaculture.
1999,
175
29
ACS Paragon Plus Environment
(1-2),
15-30;
DOI
Environmental Science & Technology
601
118, 201-206; DOI 10.1016/j.chemosphere.2014.08.066.
602
(42) Khairy, M. A.; Weinstein, M. P.; Lohmann, R. Trophodynamic behavior of hydrophobic organic
603
contaminants in the aquatic food web of a tidal river. Environ. Sci. Technol. 2014, 48 (21),
604
12533-12542; DOI 10.1021/es502886n.
605
(43) Zheng, G. M. W., Y.; Hu, J. Y. Intrinsic clearance of xenobiotic chemicals by liver microsomes:
606
Assessment of trophic magnification potentials. Environ. Sci. Technol. 2016, 50 (12), 6343-6353; DOI
607
10.1021/acs.est.6b01178.
608
(44) Erickson, R. J.; McKim, J. M.; Lien, G. J.; Hoffman, A. D.; Batterman, S. L. Uptake and
609
elimination of ionizable organic chemicals at fish gills: II. Observed and predicted effects of pH,
610
alkalinity, and chemical properties. Environ. Toxicol. Chem. 2006, 25 (6), 1522-1532; DOI
611
10.1897/05-359R.1.
612
(45) Fu, W. J.; Franco, A.; Trapp, S. Methods for estimating the bioconcentration factor of ionizable
613
organic chemicals. Environ. Toxicol. Chem. 2009, 28 (7), 1372-1379; DOI 10.1897/08-233.1.
614
(46) Meredith-Williams, M.; Carter, L. J.; Fussell, R.; Raffaelli, D.; Ashauer, R.; Boxall, A. B. A.
615
Uptake and depuration of pharmaceuticals in aquatic invertebrates. Environ. Pollut. 2012, 165, 250-258;
616
DOI 10.1016/j.envpol.2011.11.029.
617
(47) Liu, J. C.; Lu, G. H.; Ding, J. N.; Zhang, Z. H.; Wang, Y. H. Tissue distribution, bioconcentration,
618
metabolism, and effects of erythromycin in crucian carp (Carassius auratus). Sci. Total Environ. 2014,
619
490, 914-920; DOI 10.1016/j.scitotenv.2014.05.055.
620
(48) Liu, J. C.; Lu, G. H.; Wang, Y. H.; Yan, Z. H.; Yang, X. F.; Ding, J. N.; Jiang, Z. Bioconcentration,
621
metabolism, and biomarker responses in freshwater fish Carassius auratus exposed to roxithromycin.
622
Chemosphere 2014, 99, 102-108; DOI 10.1016/j.chemosphere.2013.10.036.
30
ACS Paragon Plus Environment
Page 30 of 33
Page 31 of 33
Environmental Science & Technology
623
(49) Chen, Y.; Hermens, J. L. M.; Jonker, M. T. O.; Arnot, J. A.; Armitage, J. M.; Brown, T.; Nichols, J.
624
W.; Fay, K. A.; Droge, S. T. J. Which molecular features affect the intrinsic hepatic clearance rate of
625
ionizable organic chemicals in fish? Environ. Sci. Technol. 2016, ASAP; DOI 10.1021/acs.est.6b03504.
626
(50) Search fishbase; http://www.Fishbase.Se/search.php. Access date: Jun 2016.
627
(51) Tian, S. Y.; Zhu, L. Y.; Liu, M. Bioaccumulation and distribution of polybrominated diphenyl
628
ethers in marine species from Bohai Bay, China. Environ. Toxicol. Chem. 2010, 29 (10), 2278-2285;
629
DOI 10.1002/etc.275.
630
(52) Jin, J.; Liu, W. Z.; Wang, Y.; Tang, X. Y. Levels and distribution of polybrominated diphenyl
631
ethers in plant, shellfish and sediment samples from Laizhou Bay in China. Chemosphere 2008, 71 (6),
632
1043-1050; DOI 10.1016/j.chemosphere.2007.11.041.
633
(53) U.S. Environmental Protection Agency. Guidance for assessing chemical contaminant data for
634
use in fish advisories-Risk assessment and fish consumption limits, 3rd, ed.; Office of Water:
635
Washington, DC, 2000.
636
(54) National Burean of Statistics of China; http://data.stats.gov.cn. Access date: July 2016.
637
(55) Vragovic, N.; Bazulic, D.; Njari, B. Risk assessment of streptomycin and tetracycline residues in
638
meat and milk on Croatian market. Food Chem. Toxicol. 2011, 49 (2), 352-355; DOI
639
10.1016/j.fct.2010.11.006.
640
(56) Zhang, R. J.; Zhang, G.; Zheng, Q.; Tang, J. H.; Chen, Y. J.; Xu, W. H.; Zou, Y. D.; Chen, X. X.
641
Occurrence and risks of antibiotics in the Laizhou Bay, China: Impacts of river discharge. Ecotox.
642
Environ. Safe. 2012, 80, 208-215; DOI 10.1016/j.ecoenv.2012.03.002.
643
(57) Zhang, R. J.; Tang, J, H.; Li, J.; Zheng, Q.; Liu, D.; Chen, Y. J.; Zou, Y. D.; Chen, X. X.; Luo, C.
644
L.; Zhang, G. Antibiotics in the offshore waters of the Bohai Sea and the Yellow Sea in China:
31
ACS Paragon Plus Environment
Environmental Science & Technology
Page 32 of 33
645
Occurrence,
646
10.1016/j.envpol.2012.11.008.
647
(58) Hu, X. G.; Zhou, Q. X.; Luo, Y. Occurrence and source analysis of typical veterinary antibiotics in
648
manure, soil, vegetables and groundwater from organic vegetable bases, Northern China. Environ.
649
Pollut. 2010, 158 (9), 2992-2998; DOI 10.1016/j.envpol.2010.05.023.
650
(59) Yamaguchi, T.; Okihashi, M.; Harada, K.; Konishi, Y.; Uchida, K.; Do, M. H. N.; Bui, H. D. T.;
651
Nguyen, T. D.; Nguyen, P. D.; Chau, V. V.; Dao, K. T. V.; Nguyen, H. T. N.; Kajimura, K.; Kumeda, Y.;
652
Bui, C. T.; Vien, M. Q.; Le, N. H.; Hirata, K.; Yamamoto, Y. Antibiotic residue monitoring results for
653
pork, chicken, and beef samples in Vietnam in 2012-2013. J. Agric. Food Chem. 2015, 63 (21),
654
5141-5145; DOI 10.1021/jf505254y.
655
(60) Li, Y. B.; Xu, J.; Wang, F.; Wang, B.; Liu, L. Q.; Hou, W. L.; Fan, H.; Tong, Y. Q.; Zhang, J.; Lu,
656
Z. X. Overprescribing in China, driven by financial incentives, results in very high use of antibiotics,
657
injections, and corticosteroids. Health Affair. 2012, 31 (5), 1075-1082; DOI 10.1377/hlthaff.2010.0965.
658
(61) Leung, H. W.; Jin, L.; Wei, S.; Tsui, M. M. P.; Zhou, B. S.; Jiao, L. P.; Cheung, P. C.; Chun, Y. K.;
659
Murphy, M. B.; Lam, P. K. S. Pharmaceuticals in tap water: Human health risk assessment and
660
proposed monitoring framework in China. Environ. Health Persp. 2013, 121 (7), 839-846; DOI
661
10.1289/ehp.1206244.
662
(62) Hamscher, G.; Pawelzick, H. T.; Sczesny, S.; Nau, H.; Hartung, J. Antibiotics in dust originating
663
from a pig-fattening farm: A new source of health hazard for farmers? Environ. Health Persp. 2003, 111
664
(13), 1590-1594; DOI 10.1289/ehp.6288.
665
(63) Callan, H. E.; Jenkins, R. E.; Maggs, J. L.; Lavergne, S. N.; Clarke, S. E.; Naisbitt, D. J.; Park, B.
666
K. Multiple adduction reactions of nitroso sulfamethoxazole with cysteinyl residues of peptides and
distribution
and
ecological risks.
Environ. Pollut.
32
ACS Paragon Plus Environment
2013,
174,
71-77;
DOI
Page 33 of 33
Environmental Science & Technology
667
proteins: Implications for hapten formation. Chem. Res. Toxicol. 2009, 22 (5), 937-948; DOI
668
10.1021/tx900034r.
669
(64) Gill, H. J.; Hough, S. J.; Naisbitt, D. J.; Maggs, J. L.; Kitteringham, N. R.; Pirmohamed, M.; Park,
670
B. K. The relationship between the disposition and immunogenicity of sulfamethoxazole in the rat. J.
671
Pharmacol. Exp. Ther. 1997, 282 (2), 795-801.
672
(65) Komuro, M.; Higuchi, T.; Hirobe, M. Application of chemical cytochrome P-450 model systems
673
to studies on drug metabolism: VIII. Novel metabolism of carboxylic acids via oxidative
674
decarboxylation. Bioorg. Med. Chem. 1995, 3 (1), 55-65; DOI 10.1016/0968-0896(94)00141-O.
675
(66) Jung, J. Y.; Kim, Y.; Kim, J.; Jeong, D. H.; Choi, K. Environmental levels of ultraviolet light
676
potentiate the toxicity of sulfonamide antibiotics in Daphnia magna. Ecotoxicol. 2008, 17 (1), 37-45;
677
DOI 10.1007/s10646-007-0174-9.
678
(67) Gust, M.; Fortier, M.; Garric, J.; Fournier, M.; Gagné, F. Effects of short-term exposure to
679
environmentally relevant concentrations of different pharmaceutical mixtures on the immune response
680
of the pond snail Lymnaea stagnalis. Sci. Total Environ. 2013, 445-446, 210-218; DOI
681
10.1016/j.scitotenv.2012.12.057.
682
(68) Wang, H. L.; Che, B. G.; Duan, A. L.; Mao, J. W.; Dahlgren, R. A.; Zhang, M. H.; Zhang, H. Q.;
683
Zeng, A. B.; Wang, X. D. Toxicity evaluation of β-diketone antibiotics on the development of
684
embryo-larval zebrafish (Danio rerio). Environ. Toxicol, 2014, 29 (10), 1134-1146; DOI
685
10.1002/tox.21843.
33
ACS Paragon Plus Environment