Absorption, Distribution, Metabolism, and in Vitro Digestion of Beta

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Absorption, distribution, metabolism and in vitro digestion of beta-cypermethrin in laying hens Xueke Liu, Peng Wang, Chang Liu, Yiran Liang, Zhiqiang Zhou, and Donghui Liu J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b02581 • Publication Date (Web): 10 Aug 2017 Downloaded from http://pubs.acs.org on August 11, 2017

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Journal of Agricultural and Food Chemistry

Absorption, distribution, metabolism and in vitro digestion of beta-cypermethrin in laying hens Xueke Liu, Peng Wang, Chang Liu, Yiran Liang, Zhiqiang Zhou and Donghui Liu* Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing, 100193, P. R. China. *Corresponding author: Tel.: +86 010-62731294; Fax: +86 010-62732937; E-mail: [email protected]

1

ACS Paragon Plus Environment


1

Abstract

2

Beta-cypermethrin (beta-CP), an important pyrethroid insecticide, and its main

3

acid metabolites are frequently detected in human samples. Because beta-CP may

4

pose some risk to human health, we studied dynamics and residues of beta-CP and its

5

metabolites in hen egg, droppings, blood and 15 other tissues after continuous

6

exposure. A digestive model was then used to study beta-CP’s digestive fate. Beta-CP

7

and its metabolites significantly accumulated in tissues with high lipid contents, and

8

were readily transferred to eggs. Beta-CP was mainly metabolized into acid

9

metabolites that accumulated in egg and edible tissues of laying hens, suggesting that

10

human may be exposed to beta-CP acid metabolites through food.

11 12 13

Keywords

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Beta-cypermethrin, Metabolites, Laying hens, Residue, Digestion

15 16

2


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Introduction

18

Pyrethroid insecticides have a broad spectrum and are used widely for vegetable

19

and crop pest control, as well as human health pest control It has been regarded to

20

be low toxic to humans, because it can be quickly metabolized to nontoxic

21

metabolites1-3. However, recent studies suggest that it might not be as safe as

22

previously thought. For example, a correlation between sperm concentration/sperm

23

DNA fragmentation and urinary pyrethroid metabolites

24

correlation between heart disease risk and pyrethroid exposure2, and a possible

25

association between urinary pyrethroid metabolites and risk of childhood acute

26

lymphocytic leukemia7.

4-6

, a potential positive

27

The pyrethroid beta-cypermethrin (beta-CP) has been extensively used to control

28

various pests in agricultural and residential areas for more than thirty years, and China

29

is greatest consumer of this product8. Beta-CP’s major animal metabolites are

30

3-phenoxybenzoic

31

cis/trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic

32

(cis/trans-DCCA)9-11, and these have been identified in human urine12-14, breast milk15,

33

16

34

metabolites via direct contact or feed. Therefore, beta-CP and its metabolites in the

35

human food chain are worthy of study.

acid

(3-PBA)

and acid

and other human samples17. Also, animals may be contaminated by beta-CP or its

36

Studies show that human can derive pesticide residues from food consumption18,

37

and some CP and its metabolites have been reported in some animal products19, 20.

38

Because humans consume chickens and eggs, the residues of cypermethrin and its 3



39

metabolites are worthy of study in these foods. Thus, we investigated the metabolic

40

behavior, excretion ratio, tissue residues and characteristics of maternal transfer of

41

beta-CP and its metabolites in laying hens after continuous exposure. We also

42

established a digestive model to further study the trend of beta-CP in the hen digestive

43

system.

44 45

Materials and Methods

46

Chemicals and animals

47

Beta-CP and trans/cis-DCCA standards were obtained from Jiangsu Yangnong

48

Chemical Group Co., Ltd. Chlorpyrifos, 3-PBA, 1,1,1,3,3,3-hexafluoroisopropanol

49

(HFIP, 99.5%), N,N-diisopropylcarbodiimide (DIC, 98%), lipase (L3126), pancreatin

50

(P7545) and pepsin (P7125) were obtained from Sigma-Aldrich. Cholic acid and

51

chenodeoxycholic acid were purchased from Aladdin Industrial Inc. Water was from a

52

Milli-Q purification system. All other reagents were chromatography-grade. The

53

chemical structures of beta-CP, trans/cis-DCCA and 3-PBA are shown in Supporting

54

Information (Figure S1).

55

Laying hens, weighing 1.8 kg, were purchased from Fujia Poultry Center

56

(Beijing, China); they were 35 weeks-of-age and caged individually with drinking

57

water and fed ad libitum. Hens were acclimated to laboratory conditions for one week

58

prior to experiments. Laboratory conditions were 22±2 °C with a 16/8 (light/dark)

59

cycle. Animal experiments were carried out in accordance with the guidelines of

60

Institutional Animal Care and Use Committee of China Agricultural University. 4


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Exposure experiment and sample collection

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Treated feed contained 1 mg/kg of beta-CP. Based on daily feed intake of hens,

64

the daily intake of beta-CP was approximately 0.07 mg/kg body weight. In addition,

65

the LD50 for cypermethrin for chickens exceeds 2000 mg/kg

66

concentration was less than 0.01% of the LD50. Treated feed was prepared by

67

dissolving beta-CP in n-hexane, adding this solution to feed, then homogeneous

68

mixing and removing n-hexane. After seven days of adaptation, 13 laying hens were

69

randomly assigned to treatment group (N=9) or control group (N=4). All animals were

70

individually caged with monitoring feed intake as well as collecting egg and

71

droppings. The treated hens were fed the fortified feed for 10 days and then the

72

control feed for 5 days. Three hens of treatment group and three of control group were

73

sacrificed after 10 days, and then all other hens were sacrificed at 15th day.

21

, so daily exposure

74

The eggs and droppings were collected and weighed daily, and the egg yolks and

75

whites were separately weighed and stored. Hen blood was collected at days 1, 3, 5, 7,

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10, 11, 13, and 15. In addition, heart, liver, spleen, lung, kidney, brain, thigh muscle,

77

breast muscle, muscular stomach, glandular stomach, ovary, chest skin, intestine,

78

ovum and abdominal fat were collected and weighed. Prior to analysis, samples were

79

stored at -20 °C.

80 81 82

Digestive Model The digestive model was designed to simulate three digestion stages (crop, 5



83

stomach, and small intestine)22, 23. The digestion process included 5 min of crop

84

(pH=4.3), 70 min of stomach(pH=3.0), and 150 min of small intestinal

85

digestion(pH=6.3). In addition, digestion was maintained at 41 °C, and 120 rpm. Feed

86

(1 g, 1 mg/kg beta-CP) was mixed with 1.6 mL of 0.012 M HCl for 5 min in

87

incubation tube. Then, 0.5 mL of stomach fluid (1.25 mg/mL pepsin in 0.4 M HCl)

88

was added and incubated for 70 min. Then, 0.8 mL of 0.54 M NaHCO3 solution was

89

added to adjust the pH, and chyme was transferred to a dialysis bag (8000-10000 Da).

90

Finally, 5 mL of bile (5.48 mg/L chenodeoxycholic acid and 5.65 mg/L cholic acid in

91

0.2 M phosphate buffer at pH 6.3) and 0.5 mL intestinal fluid (2.60 mg/mL lipase and

92

17.34 mg/mL pancreatin in 0.2 M phosphate buffer at pH 6.3) was added, and the

93

dialysis bag was sealed and immersed in 100 mL of 0.2 M phosphate buffer at pH 6.3

94

for 150 min. After incubation, chyme was centrifuged and separated into digestive

95

fluid and digestion residue. Beta-CP and its metabolites in dialysate, digestive fluid

96

and digestion residue were extracted and analyzed.

97 98

Sample preparation and analysis

99

First, 1 g of homogenized sample (expected 0.5 g of fat) was extracted twice

100

with 9 mL ethyl acetate for 5 min each using a vortex mixer. Extracts were

101

concentrated to dryness under nitrogen at 30 °C. To remove lipids, the remaining

102

extracts were dissolved in 1mL acetonitrile (fat, intestine, ovum and egg yolk were

103

dissolved in 2mL acetonitrile) and purified twice with 2 mL of n-hexane (fat, intestine,

104

ovum and egg yolk were purified twice with 4 mL n-hexane). When n-hexane was 6


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105

removed, the acetonitrile was concentrated to dryness. Derivatization of metabolites

106

was based on previously published mehtods24, 25. Briefly, extracts were reconstituted

107

in 250 µL of acetonitrile, and added 30 µL HFIP and 10 µL DIC for reaction. After

108

reaction for 10 min, 0.5 mL water and 0.5 mL n-hexane were added followed by

109

vortexing. After centrifugation, 150 µL n-hexane was transferred and mixed with 50

110

µL of chlorpyrifos n-hexane solution (0.2 mg/kg, as an internal standard), and

111

analyzed by GC-MS/MS.

112

A Thermo Scientific TSQ Quantum XLS system was used to assess beta-CP and

113

three acid metabolites. A HP-5 MS column (30 m × 0.25 mm × 0.25 µm) was used for

114

chromatographic separation and helium (99.999%) was the carrier gas with a flow

115

rate of 1.0 mL/min. The splitless mode was used during the injection process and the

116

inlet temperature was 270 °C. The oven temperature program was: 60 °C (1 min hold),

117

5 °C/min to 110 °C (2 min hold), 20 °C/min to 270 °C (1 min hold), and 10 °C/min to

118

290 °C (10 min hold). Tandem mass spectrometry was used with an electron impact

119

(EI) ion source. The ionization voltage and ion source temperature were set at 70 eV

120

and 290 °C, respectively. The scan mode used the selected reaction monitoring (SRM).

121

Other parameters are listed in Supporting Information (Table S1).

122

To evaluate the sample analysis methods, recovery and precision were assessed

123

by spiking the samples with analytes at three concentrations (n=3). Table S2 shows

124

the recoveries of beta-CP and its three metabolites were in 70.0-120.6% with relative

125

standard deviations (RSDs) of 0.2–14.9%. LOQs of different samples, based on the

126

signal-to-noise ratio (S/N) of 10, range from 0.1 to 0.6 ng/g, which was listed in Table 7



127

S3. The linearity of beta-CP and its three metabolites were good with correction

128

coefficients (r) of 0.9950-0.9998. Sample results were not corrected for recoveries

129

less than 100%.

130 131

Determination of antioxidant enzymes activities and lipid peroxidation

132

Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT),

133

reduce reactive oxygen species (ROS), which results in the oxidative stress26.

134

Malondialdehyde (MDA), a product of lipid peroxidation, may be an indicator of

135

oxidative stress27. Thus, SOD, CAT and MDA were measured. First, 0.15 g of brain,

136

ovary, liver and kidney were homogenized in 1 mL phosphate buffer (0.05 M, pH 7.0,

137

4 °C) and then centrifuged at 12,000 g for 10 min (4 °C). The enzyme solution

138

(supernatant) was first used to measure enzyme activity. Then, the reasonable enzyme

139

concentrations were used to measure SOD, MDA and CAT. Methods of these

140

indicator were same with the previous method28.

141 142

Statistical analysis

143

A first-order kinetics model was used to evaluate the elimination of beta-CP in

144

blood, egg yolks and droppings. Charts were created using OriginPro 8.0 (OriginLab

145

Corporation).

146

(IBM SPSS Inc.). Significant differences between groups were analyzed using an

147

independent sample Student’s t test (p < 0.05).

Antioxidant data were statistically analyzed with SPSS Statistics 19.0

148 8


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Results and Discussion

150

Dynamics in blood

151

The dynamics of beta-CP in blood is presented in Figure 1A. During the 10 days

152

of exposure, the concentrations of beta-CP in blood slowly increased and the

153

increment was small. During depuration with untreated feed, it quickly decreased.

154

Metabolites (trans/cis-DCCA and 3-PBA) were lower than LOQ. The data of beta-CP

155

during depuration were adjusted to the first-order kinetics equation, and R2 and the

156

half-life (t1/2) were 0.9885 and 4.42 days, respectively. Beta-CP was metabolized more

157

slowly in our experiments than in previous investigations29, perhaps because more

158

beta-CP in other tissues was redistributed to the blood.

159 160

Dynamics in egg whites and egg yolks

161

Concentrations trend of beta-CP and its three metabolites (trans/cis-DCCA and

162

3-PBA) in egg whites and egg yolks are depicted in Figure 1B. Unlike persistent

163

organochlorine pesticide30 and other chemicals 31, 32, concentrations of beta-CP in egg

164

yolks rapidly achieved a balanced state at the 5th day. During depuration, t1/2 of

165

beta-CP

166

α-hexabromocyclododecane (17.4 days)32 and α-hexachlorocyclohexane (6.71 days)

167

30

168

slowly depurated after continuous exposure than after single exposure29. The

169

maximum concentration of beta-CP was 4.8 ng/g in egg yolks on the 10th day, below

170

the maximum residue limit (MRL, 50 ng/g) allowed in eggs for the European Union

in

egg

yolks

was

only

3.56

days

compared

with

t1/2

of

. This revealed that beta-CP was not persistent in egg yolks, while beta-CP was more

9



171

and the United States. Concentrations of trans/cis-DCCA increased over time during

172

the 10 days of exposure and declined during the 5 days of depuration. Concentrations

173

of trans/cis-DCCA were greater than concentrations of 3-PBA, because 3-PBA was

174

more easily metabolized21. Thus, trans/cis-DCCA were more likely to be transferred

175

to egg yolks, and this may have implications for food safety.

176

The concentrations of beta-CP and its three metabolites (trans/cis-DCCA and

177

3-PBA) in egg whites were plotted over time in Figure 1C, and trends of beta-CP and

178

trans/cis-DCCA were similar; they had not significant change throughout the

179

experiment. The concentration of 3-PBA was less than LOQ. The concentrations of

180

beta-CP and trans/cis-DCCA were not significantly different, but were significantly

181

greater than 3-PBA in egg whites.

182 183

Dynamics in droppings and excretion rate of beta-CP

184

Excretion is an important pathway in reducing xenobiotic. As shown in Figure

185

1D and Figure S2, the concentrations of beta-CP in droppings were in a relatively

186

steady state during exposure, and rapidly decreased during depuration. The depuration

187

t1/2of beta-CP in droppings was only 1.20 days, and this may be due to incomplete

188

absorption from the feed during exposure, or uptake into hen tissues of higher lipid

189

contents during depuration29, 33, such as fat and skin9, 10. After the exposure ended,

190

concentrations of 3-PBA rapidly decreased, and trans/cis-DCCA were continuously

191

excreted. 3-PBA was most readily metabolized and excreted, and this was also

192

observed in egg and tissues. 10


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193

For further insight into excretion characteristics by dropping, excretion rate was

194

introduced. Excretion rates were calculated by dividing the mass of beta-CP in

195

droppings by it in ingested feed, and the results were presented in Figure S3.

196

Excretion rates of beta-CP increased and then decreased, ranging from 6.9% to 9.3%.

197

Under the exposure , the average excretion rate was 8.0%. In previous investigation,

198

excretion rate of chlordane was only 1.1%34. In comparison, excretion is an important

199

pathway for beta-CP elimination in laying hens.

200 201

Residues in tissues and distribution characteristics

202

Residues of beta-CP and its three metabolites in tissues at days 10 and 15appear

203

in Table 1. The highest concentrations of beta-CP at 10th day was observed in fat,

204

followed by ovum, skin, intestine, brain, ovary and other tissues. Similar to

205

organochlorine pesticides35, beta-CP is lipophilic and concentrates in lipid tissues. .

206

The similar results have been reported for beta-CP in mice9 and bovines10. Compared

207

to concentrations of beta-CP in tissues at the10th day, beta-CP at 15th day decreased

208

except in fat. likely because fat is chiefly composed of triglycerides, which

209

accumulate lipophilic xenobiotics. However, the brain and ovum have more

210

phospholipids and cholesterol but fewer triglycerides. In addition, the concentrations

211

of beta-CP were less than MRLs (50 ng/g) in the United States for fat and muscle, and

212

MRL (50 ng/g) in the European Union for edible offal.

213

Trans/cis-DCCA and beta-CP were similarly distributed in most tissues, but

214

trans/cis-DCCA were significantly higher than beta-CP in thigh muscle. 11



215

Concentrations of 3-PBA in the main detoxification organs, such as liver and kidney,

216

were significantly lower than in other tissues. Meanwhile, three metabolites were

217

found in all tissues in the decreasing order trans-DCCA>cis-DCCA>3-PBA. This

218

indicated that trans-DCCA was more stable. Comparing three metabolites at 10th day

219

and 15th day indicated that trans/cis-DCCA greatly decreased except in fat, and 3-PBA

220

was reduced in all tissues. The concentrations of 3-PBA were lower than LOQ in all

221

tissues at 15th day, indicating that 3-PBA could be more readily further metabolized.

222

The mass of beta-CP and its three metabolites in tissues were calculated by

223

multiplying their concentrations in tissues by mass of tissues, and appear in Figure 2.

224

The majority of beta-CP and its three metabolites were distributed in fat, ovum,

225

intestine, thigh muscle and breast muscle at 10th day. The mass of beta-CP was in fat

226

the highest, while its three metabolites were most abundant in thigh muscle at 10th day.

227

Because beta-CP was more lipophilic than the metabolites, and mass of thigh muscle

228

had absolute advantage. Subsequently, fat and intestine became the main storage

229

tissues of trans/cis-DCCA. Thus, trans/cis-DCCA were partially lipophilic, and

230

3-PBA was no lipophilic.

231 232

Activity of antioxidant enzymes and content of MDA

233

Because xenobiotics may break the balance of antioxidant system. we measured

234

SOD activity and MDA in brain (nerve center), ovary (reproductive organ), liver and

235

kidney (main detoxification organ) at the 10th day. These data appear in Figure 3. The

236

SOD activity was significantly increased in ovary, but was not significantly changed 12


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237

in other tissues. Significant enhancement of the SOD activity with low-dose

238

xenobiotics were observed in previous investigation28. There were no s differences

239

between treatment group and control group for CAT in four tissues (Figure 3). MDA

240

was decreased in the kidney and ovary but unchanged in the liver and brain. Thus,

241

oxidative stress induced by beta-CP was not significant at this dose. In turn, there

242

might be only slight stimulation for antioxidant system.

243 244

Digestive model

245

To further insight into the fate of beta-CP in digestive system, a digestive model

246

was utilized to observe the possible degradation behavior. As shown in Figure 4.

247

\trans/cis-DCCA and 3-PBA appeared in the digestive process, and mainly existed in

248

dialysate. However, beta-CP was mainly retained in the digestion residue, and was

249

degraded about 20% after digestion, perhaps due to the greater water-solubility of

250

three metabolites, along with the passive diffusion of absorption23. Although the

251

digestive model did not explain all aspects of the digestive process and absorption, we

252

did note that the beta-CP was metabolized and that its metabolites were absorbed.

253

Beta-CP and its metabolites (cis/trans-DCCA and 3-PBA) were transferred to

254

egg yolk, and accumulated in tissues with high lipid contents. Meanwhile, beta-CP

255

was found as metabolites in the eggs and edible tissues of laying hens, which may be

256

transferred to humans via food consumptions.

257 258

ASSOCIATED CONTENT 13



259

Supporting Information

260

Chemical structure of analytes, parameters of mass spectrometry, recovery and LOQ

261

of analytes in samples, excretion rate of beta-CP, and chromatograms of analytes in

262

some samples

263

AUTHOR INFORMATION

264

Corresponding Author

265

*Phone: +86 010-62731294; E-mail: [email protected]

266

ORCID

267

Donghui Liu: 0000-0002-7121-2364

268

Funding

269

This work was supported by the National Natural Science Foundation of China

270

(Contract Grants 21307155, 21337005, 21677175).

271 272

Reference

273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288

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Figure Caption

Figure 1 Dynamics of beta-CP and its metabolites in blood (A), egg yolks (B), egg whites (C) and droppings (D).

Figure 2 Mass distribution of beta-CP and its three metabolites (trans/cis-DCCA and 3-PBA) in tissues at 10 d (A) and 15 d (B).

Figure 3 Influences of beta-CP on SOD (A), CAT (B) and MDA (C) of four tissues of laying hens after 10 d exposure; asterisks indicate significant differences (p < 0.05).

Figure 4 Mass distribution of beta-CP and its three metabolites (trans/cis-DCCA and 3-PBA) in three digestive samples (A) and the main form of beta-CP in three digestive samples (B)

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Table 1 The residues of beta-CP and its three metabolites in tissues at 10th day and 15th day Tissues Beta-CP (ng/g) Cis-DCCA (ng/g) Trans-DCCA (ng/g) 10d 15d 10d 15d 10d 15d Heart 1.12 ± 0.34 0.36 ± 0.10 1.46 ± 0.36 0.10 ± 0.03 4.08 ± 1.71 0.16 ± 0.06 Liver 0.80 ± 0.31 0.40 ± 0.01 2.59 ± 1.10 0.14 ± 0.05 3.85 ± 2.44 0.15 ± 0.05 Spleen 0.49 ± 0.09 0.35 ± 0.06 1.18 ± 0.68 0.15 ± 0.06 6.53 ± 4.37 0.28 ± 0.09 Lung 0.55 ± 0.03 0.31 ± 0.08 2.74 ± 1.61 0.23 ± 0.04 3.73 ± 1.94 0.39 ± 0.06 Kidney 0.64 ± 0.26 0.35 ± 0.04 1.66 ± 0.74 0.32 ± 0.07 13.66 ± 0.41 0.48 ± 0.13 Brain 1.67 ± 0.55 0.35 ± 0.10 2.27 ± 1.44 0.21 ± 0.01 14.86 ± 10.17 0.36 ± 0.04 Thigh muscle 0.45 ± 0.19 0.42 ± 0.03 7.36 ± 5.04 0.55 ± 0.25 36.00 ± 25.09 0.22 ± 0.12 Breast muscle 0.51 ± 0.20 0.38 ± 0.11 3.72 ± 0.13 1.17 ± 0.61 6.15 ± 1.87 0.21 ± 0.10 Muscular stomach 1.42 ± 0.29 0.61 ± 0.19 14.35 ± 6.43 1.75 ± 0.91 12.58 ± 8.43 3.25 ± 1.73 Glandular stomach 1.41 ± 0.46 0.47 ± 0.05 10.55 ± 7.25 1.11 ± 0.55 6.61 ± 3.70 2.57 ± 1.33 Ovary 1.45 ± 0.32 1.09 ± 0.24 2.19 ± 1.34 0.98 ± 0.46 37.11 ± 25.67 5.36 ± 2.93 Skin 2.49 ± 0.72 1.28 ± 0.51 16.75 ± 11.64 2.41 ± 1.22 26.15 ± 18.02 3.60 ± 1.83 Intestine 2.26 ± 0.23 0.69 ± 0.30 13.22 ± 9.11 2.25 ± 1.18 26.77 ± 14.37 20.74 ± 11.83 Ovum 3.88 ± 0.87 0.41 ± 0.14 16.01 ± 6.74 6.60 ± 3.72 7.90 ± 5.31 3.89 ± 2.13 Fat 5.07 ± 1.12 5.65 ± 1.97 24.08 ± 14.75 13.88 ± 2.98 82.41 ± 2.48 51.94 ± 2.22 ND < LOQ

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3-PBA (ng/g) 10d 15d 0.17 ± 0.01 ND 0.20 ± 0.05 ND ND ND 0.13 ± 0.01 ND 0.16 ± 0.03 ND 0.76 ± 0.30 ND 1.23 ± 0.03 ND 0.69 ± 0.16 ND 1.61 ± 0.89 ND 1.73 ± 0.03 ND 3.83 ± 2.16 ND 1.96 ± 0.15 ND 1.10 ± 0.52 ND 1.06 ± 0.26 ND 0.85 ± 0.56 ND

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Absorption, Distribution, Metabolism, and in Vitro Digestion of Beta

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