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Food Additives & Contaminants: Part A ISSN: 1944-0049 (Print) 1944-0057 (Online) Journal homepage:
Food Additives & Contaminants: Part A ISSN: 1944-0049 (Print) 1944-0057 (Online) Journal homepage:

Food Additives & Contaminants: Part A

ISSN: 1944-0049 (Print) 1944-0057 (Online) Journal homepage: http://www.tandfonline.com/loi/tfac20

Screening of veterinary drug residues in food by LC-MS/MS. Background and challenges

Thierry Delatour, Lucie Racault, Thomas Bessaire & Aurélien Desmarchelier

To cite this article: Thierry Delatour, Lucie Racault, Thomas Bessaire & Aurélien Desmarchelier (2018): Screening of veterinary drug residues in food by LC-MS/MS. Background and challenges, Food Additives & Contaminants: Part A, DOI: 10.1080/19440049.2018.1426890

Accepted author version posted online: 11 Jan 2018. Published online: 22 Jan 2018.

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FOOD ADDITIVES & CONTAMINANTS: PART A, 2018

https://doi.org/10.1080/19440049.2018.1426890

FOOD ADDITIVES & CONTAMINANTS: PART A, 2018 https://doi.org/10.1080/19440049.2018.1426890
FOOD ADDITIVES & CONTAMINANTS: PART A, 2018 https://doi.org/10.1080/19440049.2018.1426890
PART A, 2018 https://doi.org/10.1080/19440049.2018.1426890 Screening of veterinary drug residues in food by LC-MS/MS.

Screening of veterinary drug residues in food by LC-MS/MS. Background and challenges

Thierry Delatour, Lucie Racault, Thomas Bessaire and Aurélien Desmarchelier

Nestlé Research Center, Institute of Food Safety and Analytical Science, Lausanne, Switzerland

ABSTRACT

Regulatory agencies and government authorities have established maximum residue limits (MRL) in various food matrices of animal origin for supporting governments and food operators in the monitoring of veterinary drug residues in the food chain, and ultimately in the consumer s plate. Today, about 200 veterinary drug residues from several families, mainly with antibiotic, antipar- asitic or antiinflammatory activities, are regulated in a variety of food matrices such as milk, meat or egg. This article provides a review of the regulatory framework in milk and muscle including data from Codex Alimentarius, Europe, the U.S.A., Canada and China for about 220 veterinary drugs. The article also provides a comprehensive overview of the challenge for food control, and emphasizes the pivotal role of liquid chromatography-mass spectrometry (LC-MS), either in tandem with quadrupoles (LC-MS/MS) or high resolution MS (LC-HRMS), for ensuring an adequate consumer protection combined with an affordable cost. The capability of a streamlined LC-MS/ MS platform for screening 152 veterinary drug residues in a broad range of raw materials and finished products is highlighted in a production line perspective. The rationale for a suite of four methods intended to achieve appropriate performance in terms of scope and sensitivity is presented. Overall, the platform encompasses one stream for the determination of 105 com- pounds in a run (based on acidic QuEChERS-like), plus two streams for 23 β -lactams (alkaline QuEChERS-like) and 10 tetracyclines (low-temperature partitioning), respectively, and a dedicated stream for 14 aminoglycosides (molecularly-imprinted polymer).

ARTICLE HISTORY

Received 22 November 2017 Accepted 4 January 2018

KEYWORDS

Veterinary drugs; food; regulation; trade; global market; LC-MS/MS

Introduction

Today, in a global marketplace, food quality and safety have gained increasing attention from consu- mers, governments and food producers. A broad range of chemical contaminants are monitored or controlled in food commodities and products due to their possible adverse effects on human health. Contaminants are either natural compounds, such as mycotoxins (Alshannaq and Yu 2017 ), plant tox- ins (Koleva et al. 2012 ; de Nijs et al. 2017 ) or marine toxins (Ralston et al. 2011 ; Lopes et al. 2013), or chemical structures developed and manufactured at industrial scale for various applications. For instance, some are used as pesticides (González- Rodríguez et al. 2011 ; Jeong et al. 2014), flame retar- dants (Li et al. 2015; Fernandes et al. 2016 ) or veterinary drugs. The presence of veterinary drug residues in food products constitutes a potential health risk for

consumers as they might induce various effects such as allergic reactions, carcinogenic or teratogenic mechanisms, or induce antimicrobial resistance (Baynes et al. 2016 ). In particular, antimicrobial resistance is considered as a quickly increasing threat to global public that now requires appropriate actions across governments and society. Briefly, anti- microbial resistance happens when microorganisms exposed to antimicrobial drugs change and ulti- mately impair treatment with antibiotics in human medicine (Hao et al. 2014 ; Lekshmi et al. 2017). Then, infections persist in the body, with increasing risks of spread to others. Both the World Health Organisation (WHO) and the World Organisation for Animal Health (OIE) have addressed the threat specifically. In 2009, the WHO has created the Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) as a response to a worldwide solicitation of experts from human

CONTACT Thierry Delatour

Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/tfac

© 2018 Nestlé Research Center

at www.tandfonline.com/tfac © 2018 Nestlé Research Center thierry.delatour@rdls.nestle.com Nestlé Research Center,

thierry.delatour@rdls.nestle.com

© 2018 Nestlé Research Center thierry.delatour@rdls.nestle.com Nestlé Research Center, Lausanne, Switzerland

Nestlé Research Center, Lausanne, Switzerland

2

2 T. DELATOUR ET AL. health and veterinary medicine areas. The AGISAR has revised the list

T. DELATOUR ET AL.

health and veterinary medicine areas. The AGISAR has revised the list of critically important antimicro- bials initially published in 2005 with the addition of new substances (WHO 2011 ). The OIE has also issued a list of veterinary drugs of particular concern (OIE 2015 ). Incidentally, veterinary drugs may be used in an incorrect manner with production ani- mals including sometimes disrespect of withdrawal time after treatment; this leads to residues in milk, eggs and edible tissues that can be detected either as the parent compound or metabolites/conjugates. This applies beyond antibiotics as antiparasitics, antiinflammatories, growth promoters or tranquili- zers can also be found in food by misuse or incorrect practice at the farm. For food industry and authority bodies, the chal- lenge related to the control of veterinary drug resi- dues lies in the management of three factors together. They are: the number of chemical com- pounds, the range of food matrices and the regula- tion. Today, there are about 200 veterinary drug residues that need to be taken into account for con- trol in foodstuffs such as meat, fat, milk, egg, fish, seafood and honey (Robert et al. 2013; Staub Spörri et al. 2014 ; Turnipseed et al. 2014; Munaretto et al. 2016 ). On a chemical analysis standpoint, the scope further extents when matrix derivatives (fresh vs.

powder), species (chicken, beef

ished products require attention. The regulation, often different from one region to the other, drives the requirements in terms of limit of detection, usually in the µg/kg levels or even lower in the case of banned compounds. Obviously, the complexity associated with the control of veterinary drugs sig- nificantly increases when the impact of the business is global and the portfolio of products broad. The analytical setup required for such monitoring from the farm (raw materials) to the fork (finished pro- ducts) has to be optimized carefully for ensuring an effective control with regard to the coverage (num- ber of analytes), the throughput (analysis turn- around time) and the analytical cost (cost-effective quality control). In that respect, multiresidue screen- ing tests/methods are attractive tools for a reliable consumer protection with regard to the possible presence of veterinary drug residues in food. In the food operations, screening is commonly executed with rapid tests for a quick decision-mak- ing process with regard to the acceptance of the

.) and related fin-

batch at the factory. Tests are usually based on immunochemical techniques such as enzyme-linked immuno-sorbent assay (ELISA), lateral-flow assay or based on other devices (Abouzied et al. 2012 ; Sheu

et al. 2013; Bion et al. 2015 ). Such tests are easy to

use; however, their scope is usually limited in terms of analytes and matrices, and the specificity of the detection is sometimes questionable. Liquid chroma- tography-mass spectrometry (LC-MS) is an alterna- tive technical approach that is now popular for the screening of more than a 100 veterinary drugs in a single run. By the end of the 20 th century, LC-MS had evolved dramatically as a major analytical tool, providing both sufficient sensitivity to reach the regulatory limits and adequate certainty in the iden- tification of the compounds detected (EC 2002; Delatour et al. 2007 ; Hird et al. 2014 ). Furthermore, LC-MS is versatile enough to be used either as a screening tool or a quantitative method (or both), depending on the application. The present series of six articles is intended to present the approach chosen by a worldwide food company for the control of 152 veterinary drug residues in a broad range of raw materials and fin- ished products based on liquid chromatography-tan- dem mass spectrometry (LC-MS/MS). With the constant increase in the demand for high-through- put analysis together with better consumer protec- tion, particular attention was paid to the scope of the method in terms of analytes, matrices as well as detection levels. Compounds of interest were grouped according to their physico-chemical proper- ties and adequate analytical setups were developed and validated in order to reach the appropriate screening performance (Bessaire et al. 2018; Delatour et al. 2018 ; Desmarchelier et al. 2018a, 2018b , 2018c ; Savoy et al. 2018). We also studied the stability of the analytes for providing useful data aimed at facilitating the management of samples in routine testing laboratories (Desmarchelier et al. 2018c ).

Regulatory framework

Codex Alimentarius (Codex 2017 ) established max- imum residue levels (MRL) for veterinary drugs through the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) based upon

a risk assessment of the joint FAO/WHO Expert

Committee on Food Additives (JECFA). National legislations are, however, varying significantly from Codex Alimentarius recommendations, thus, implying the generation of a complex regulatory environment for international food trade. This might be related to the differences found in risk assessment. In Europe, the European Medicines Agency (EMA) is the regulatory organization in charge of proposing MRLs set by the Committee for Medicinal Products for Veterinary Use (CVMP). The European regulation No 470/2009 lays down rules and procedures to establish the MRL for a pharmacologically active substance which may be permitted in food of animal origin (EC 2009). Substances with MRLs (or not applicable) and a list of prohibited substances are available in a European document (EC 2010 ). Europe has further introduced the principle of minimum required per- formance limit (MRPL) for certain residues in food of animal origin such as chloramphenicol, nitrofur- ans and medroxyprogesterone acetate (EC 2003 ), thus ensuring public protection against drugs which are not authorized in the European Union. In the U.S.A., the Food and Drug Administration (FDA) establishes tolerances for veterinary drugs under the Federal Food, Drug, and Cosmetic Act (FFDCA), and limits are published in the Code of Federal Regulation (CFR 2016 ). The FDA also pro- hibits the usage of some drugs under the 21 Code of Federal Regulation for extra label animal and human uses in food-producing animals (e.g. chlorampheni- col, unless used for topical use). Specifically, as a response to the threat on antimicrobial resistance, the prohibition is also applicable to the extra-label use of some classes of antibiotics (e.g. sulfonamide antibiotics and potentiated sulfonamides are prohib- ited in adult lactating dairy cattle or dairy cattle aged above 20 months). In Canada, the Health Canadas Veterinary Drugs Directorate (VDD) sets standards (MRLs) for veterinary drugs in foods; it also pro- duced a list of banned drugs, and both the docu- ments are available at the Health Canadas website (HC 2017a , 2017b ). In China, the Ministry of Agriculture (MOA) issued the National Standard No. 235 for maximum residue level of veterinary drugs in food of animal origin and the National Standard No. 193 for prohibited veterinary drugs and other chemicals in food animals (MOA 2002 ; USDA 2011 ).

FOOD ADDITIVES & CONTAMINANTS: PART A

; USDA 2011 ). FOOD ADDITIVES & CONTAMINANTS: PART A 3 In this article, a non-exhaustive

3

In this article, a non-exhaustive review of the regulatory framework that encompasses data from Codex Alimentarius, Europe, the U.S.A., Canada and China is presented for a total of 220 veterinary drugs (MRLs and banned) in milk and muscle (Table 1).

Methods available

In the early stage of LC-MS devoted to the analysis of veterinary drug residues in food, the applications were restricted to a few compounds, usually less than 20 (Oka et al. 1997 ; Bogialli et al. 2003), as evidenced by the graph depicted in Figure 1 . At that time, the sensitivity of mass spectrometry platforms was not as it is now and the electrospray sources were more prone to matrix effects, consequently to ion suppres- sion or enhancement. Therefore, sample prepara- tions often required cartridge-based solid-phase extraction (SPE) to both concentrate the analytes of interest prior to analysis and concomitantly discard undesirable compounds from the matrix. Obviously, such an approach is not appropriate for handling several tens of compounds in a single run because it is too labor-intensive and expensive in a high- throughput and economically demanding environ- ment. Nonetheless, some groups succeeded to deter- mine about a 100 or more veterinary drug residues in a single run by LC-MS using acetonitrile extrac- tion followed by either ultracentrifugation (Ortelli et al. 2009), polymeric SPE (Kaufmann et al. 2008 ; Stolker et al. 2008 ; Peters et al. 2009), or in combi- nation with methanol (Yamada et al. 2006 ). The introduction of extraction procedures like QuEChERS (Anastassiades et al. 2003 ; Rejczak and Tuzimski 2015) or salting-out-supported liquid extraction (Kaufmann et al. 2014 ; Wang et al. 2015 ) together with the significant advances in the performance of mass spectrometry platforms over the years (in terms of sensitivity and ionization stability) were pivotal in the development of multi- residue LC-MS methods for a broad range of com- pounds. During the period 1997 2010, eight LC-MS methods covering from 51 to 100 analytes were described in the literature, while 20 have been devel- oped during the years 2011 2016. The increase is even more obvious with methods that include more than a 100 compounds; two methods were published during the period 19972010, while 18 are from the years 2011 2016 ( Figure 1). Interestingly, most of

4

4 T. DELATOUR ET AL. Table 1. Maximum residue limits (MRLs) established in milk and muscle

T. DELATOUR ET AL.

Table 1. Maximum residue limits (MRLs) established in milk and muscle by Europe (EU) ([EC] European Commission 2010 ), Canada (Ca) ([HC] List of maximum residue limits (MRLs) for veterinary drugs in foods 2017a), China (Ch) ([MOA] National Standard No. 235, 2002 ), the U.S.A. ([HC] List of maximum residue limits (MRLs) for veterinary drugs in foods 2017a ) and the Codex Alimentarius (Co) ([Codex] Codex Alimentarius Maximum residue limits (MRLs) and risk management recommendations (RMRs) for residues of veterinary drugs in food CAC/MRL 2-2017, 2017).

 

Milk (µg/kg)

 

Muscle (µg/kg)

 

Compounds

Regulated marker

EU

 

Co

Ca

Ch

USA

EU

 

Co

Ca

Ch

 

USA

Abamectin (B1a) Albendazole Albendazole Albendazole Albendazole Oxide Albendazole Oxide Albendazole Oxide Altrenogest Amitraz Amoxicillin Ampicillin Amprolium Apramycin Avilamycin Azaperone Azaperone Bacitracin (A, B, C) Baquiloprim Betamethasone Bromhexine Buquinolate Cabergoline Carazolol Carbasalate Carbomycin Carprofen Carprofen Cefacetril Cefalexin Cefalonium Cefapirin Cefapirin Cefazolin Cefoperazone Cefquinome Ceftiofur Ceftiofur Chlorhexidine Chlormadinone Chlortetracycline Chlortetracycline Clavulanic acid Clenbuterol Clodronic acid Clopidol Clorsulon Closantel Cloxacillin Colistin Cyfluthrin Cyhalothrin Cypermethrin Cypermethrin Cyromazine Danofloxacin Decoquinate Deltamethrin Derquantel Destomycin A Dexamethasone Diazinon Dichlorvos Diclazuril Diclofenac Dicloxacillin

 

#

#

20

10

25

Albendazole sulfone Albendazole sulfoxide Albendazole 2-aminosulfone Albendazole oxide Albendazole sulfone Albendazole 2-aminosulfone

100

A

100

A

100

A

100

A

100

A

100

A

100

A

100

A

100

A

100

A

100

A

100

50

100

A

50

100

A

100

A

100

A

100

A

100

A

100

A

 

1

1

sum of metabolites containing 2,4-DMA moiety 10

 

10

10

 

4

4

10

10

50

50

10

50

10

4

10

10

10

50

10

50

10

 

500

500

 

500

 

#

1000

 

Dichloroisoeverninic acid

50

200

200

Azaperone

100

B

60

B

60

B

Azaperol

100

B

60

B

60

B

 

100

 

500

500

150

 

500

500

 

500

30

0.3

 

0

0.75

 

1

#

 

100

 

0.10

 

0.15

 

1

5

5

#

 

0

Carprofen

500

C

Carprofen glucuronide

500

C

 

125

 

100

 

100

200

 

200

 

20

Cefapirin

60

D

20

20

50

D

100

100

Deacetylcefapirin

60

D

50

D

50

50

20

20

50

50

Ceftiofur

100

E

1000

E

Desfuroylceftiofur

100 E 100

 

100

100

100

1000 E 1000

1000

1000

1000

 

0

 

2.5

 

Chlortetracycline

100 F 100 G 100

100

300 G 100 F

 

200 G 200

 

2000 G

4-epi-chlrotetracycline

100

F

100

F

200

 

200

100

 

100

 

0.05

0.05

 

0.10

 

0.20

 

#

 

20

20

5000

200

 

200

 

16

35

100

45

1000

 

1000 1500

1000

30

30

10

300

 

10

300

 

10

50

50

50

150

 

150

150

 

20

40

10

20

50

30

20

Cypermethrin

20

H

100

H

20

H

50

H

Alpha-Cypermethrin

20

H

100

H

20

H

50

H

#

300

 

50

30

30

100

 

100

70

100

 

200

#

1000

1000

1000

20

30

30

10

30

30

 

0.3

 

2000

 
 

0.3

 

0.3

0

0.75

 

1

1

20

20

20

20

 

50

20

100

 

150

 

500

500

500

 

500

 

0.1

5

30

300

 

Table 1. (Continued).

FOOD ADDITIVES & CONTAMINANTS: PART A

1. (Continued). FOOD ADDITIVES & CONTAMINANTS: PART A 5   Milk (µg/kg)   Muscle (µg/kg)  

5

 

Milk (µg/kg)

 

Muscle (µg/kg)

 

Compounds

Regulated marker

EU

 

Co

Ca

Ch

USA

EU

 

Co

Ca

Ch

USA

Dicyclanil

Dicyclanil

#

200

S

150

Dicyclanil

2,4,6-triamino-pyrimidine-5-carbonitrile #

 

200

S

Difloxacin

#

300

 

300

 

Dihydrostreptomycin

200

 

200

I

125

200

I

125

500

 

600

I

500

600

I

500

Diminazene

150

150

500

500

Doramectin (B1a)

#

15

#

40

5

10

10

30

Doxycycline

Doxycycline

#

#

100

 

100

Enrofloxacin

Ciprofloxacin

100

J

100

J

100

J

20

100

J

Enrofloxacin

Enrofloxacin

100

J

100

J

100

J

100

100

J

Eprinomectin

Eprinomectin (B1a)

20

20

20

12

50

100

100

100

Erythromycin

40

50

40

0

200

 

100

100

200

100

Ethopabate

500

500

Famphur

100

Febantel

Oxfendazole sulphone Fenbendazole Oxfendazole sulphone Fenbendazole Sulfoxide Fenthion and metabolites

10

K

100

K

100

K

50

K

100

K

100

K

Fenbendazole

 

100

K

100

K

100

K

100

100

K

400

Fenbendazole

10

K

100

K

100

K

50

K

100

K

100

K

Fenbendazole

 

600

600

Fenthion

 

100

 

Fenvalerate

40

100

25

20

Florfenicol

Florfenicol

#

100

L

200

Florfenicol

Florfenicol-amine

#

#

100

L

100

100

300

Fluazuron

#

200

 

200

Flubendazole

Flubendazole 2-amino 1H-benzimidazol-5-yl-(4-fluorophenyl) methanone

50

M

10

10

M

Flubendazole

50

M

10

M

Flugestone acetate

1

1

0.5

 

Flumequine

50

50

200

 

500

500

 

Flumethrin

30

30

10

10

Flunixin

Flunixin

20

20

25

Flunixin

5-hydroxyflunixin

40

6

2

Fluralaner

65

Fluvalinate

10

Gamithromycin

#

50

20

150

Gentamicin(s)

Sum of C1, C1a, C2, C2a

100

 

200

100

200

50

100

100

100

100

Halofuginone

#

10

10

10

Haloxon

100

Hydrocortisone

10

Hygromycin B

0

Imidocarb

50

50

300

 

300

Isometamidium

100

100

100

100

 

Ivermectin

Ivermectin B1a

#

10

10

30

30

10

10

20

Kanamycin A

150

 

100

 

Ketoprofen

50

100

Kitasamycin

200

 

Lasalocid A

#

10

400

50

Levamisole

#

10

10

100

10

100

Lincomycin

150

 

150

150

100

 

200

100

100

100

Maduramicin

100

240

Malathion

4000

Marbofloxacin

75

150

 

Mebendazole

#

60

60

Meloxicam

15

35

20

20

Metamizol

4-Methylaminoantipyrin

50

100

 

200

 

Methylprednisolone

2

10

Metoserpate

20

Monensin

2

2

10

2

10

50

50

50

Monepantel

Monepantel sulfone

#

300

 

500

Morentel

N-methyl-1,3-propanediamine

50

100

100

 

150

Moxidectin

40

40

50

20

50

50

Nafcillin

30

300

 

Narasin

15

50

600

 

Neomycin

Neomycin B

1500 1500 1500

500

150

500

 

500

500

500

1200

Nequinate

100

Netobimin

Albendazole oxide Albendazole sulfone Albendazole 2-aminosulfone

100

A

100

A

Netobimin

100

A

100

A

Netobimin

100

A

100

A

Nicarbazin

200

4000

200

4000

Nitroxinil

#

400

 

400

Norgestonet

0.12

 

0.2

 

Novobiocin

50

100

100

1000

1000

6

6 T. DELATOUR ET AL. Table 1. (Continued).   Milk (µg/kg)   Muscle (µg/kg)   Compounds

T. DELATOUR ET AL.

Table 1. (Continued).

 

Milk (µg/kg)

 

Muscle (µg/kg)

 

Compounds

Regulated marker

EU

Co

Ca

Ch

USA

EU

 

Co

Ca

Ch

USA

Nystatin

0

Olaquindox

Methylphenylquinolin-carboxylic acid

4

Ormetoprim

100

Oxacillin

30

 

30

300

 

300

Oxfendazole

Oxfendazole Sulphone

10 K

 

100

K

100

K

50 K

 

100

K

Oxfendazole

Fenbendazol

840

Oxibendazole

100

 

100

Oxolinic acid

#

100

100

Oxyclozanide

10

 

20

Oxytetracycline

Oxytetracycline

100 N 100

 

100

100

300 G 100 N

200

200

100

2000 G

Oxytetracycline

4-epi-oxytetracycline

100

N

100

N

Paromomycin

#

500

Penethamate

Penicillin G

4

O

50

O

Penicillin G (Benzylpenicillin) Penicillin G

4

O

4

10

4

0

50

O

50

10

50

0

Penicillin V (Phenoxymethylpenicillin) Permethrin Phoxim Piperazine Pirlimicyn Polymyxin B

 

25

 

50

 

50

#

10

25

50

50

 

400

 

400

100

 

100

 

200

400

 

400

100

 

100

300

300

 

4 u/

 
 

mL

Prednisolone Progesterone Pyrantel Pyrantel Ractopamine Rafoxanide Rifaximin Robenidine Roxarsone (Arsanilic acid) Salicylate Aluminium Salicylate Sodium Salicylic Acid Salinomycin Sarafloxacin Semduramicin Sisapronil Sodium acetylsalicylate Spectinomycin Spiramycin Spiramycin Streptomycin SULFONAMIDE

 

6

4

 

5

Pyrantel

1

N-methyl-1,3-propanediamine

150

 

10

10

30

 

10

 

30

30

60

 
 

100

100

100

Arsenic

500

Salicylic Acid

8

200

 

Salicylic Acid

#

400

Salicylic Acid

#

 

200

600

 

10

10

 

130

130

130

 

#

100

 

#

200

 

200

200

300

 

500

100

500

100

Spiramycin

200 P 200 P 200 P 200 P

 

200

P

200

P

Neo-Spiramycin

200

P

200

P

200

 

200

I

125

200

I

500

600

I

500

600

I

500

Sum of all substances belonging to the sulfonamide

100

Q

100

Q

100

Q

100

Q

Sulfabenzamide

10

Q

100

Q

Sulfabromethazine

10

100

Sulfacetamide

10

Q

100

Q

Sulfachloropyrazine

0

Sulfachlorpyridazine

100

Q

100

Sulfadiazine

100

Q

Sulfadimethoxine

10

Q

10

100

Q

100

Sulfadoxine

10

Q

100

Q

Sulfaethoxypyridazine

10

Q

0

100

Q

0

Sulfaguanidine

10

Q

100

Q

Sulfamerazine

100

Q

Sulfamethazine

25

10

Q

25

100

100

Q

100

(Sulfadimidine)

Sulfanilamide

10

Q

100

Q

Sulfanitran

100

Q

Sulfapyridine

10

Q

100

Q

Sulfaquinoxaline

10

Q

100

Q

100

Sulfathiazole

10

Q

100

Q

Sulfomyxin

0

Tetracycline

Tetracycline

100 R 100

 

100

100

300 G 100 R

200

200

100

2000 G

Tetracycline

4-epi-tetracycline

100

R

100

R

Thiabendazole

Thiabendazole

100 S 100 S 50 S 100 S 100 S 50 S

100 S 50

 

100

S

100

S

100

S

100

S

100

Thiabendazole

5-hydroxy-thiabendazole

100

S

100

S

100

S

100

S

100

S

Thiamphenicol

50

 

50

50

50

Tiamulin

Tiamulin

100 T

 

Table 1. (Continued).

FOOD ADDITIVES & CONTAMINANTS: PART A

1. (Continued). FOOD ADDITIVES & CONTAMINANTS: PART A 7 Milk (µg/kg) Muscle (µg/kg) Compounds Regulated

7

Milk (µg/kg)

Muscle (µg/kg)

Compounds

Regulated marker

EU

Co

Ca

Ch

USA

EU

Co

Ca

Ch

USA

Tiamulin

8-alpha-hydroxymutilin

100

 

100

100 T

 

Tildipirosine

#

400

400

Tilmicosin

50

50

50

100

100

75

100

Tolfenamic acid

50

50

Toltrazuril

Toltrazuril sulfone

100

 

100

100

 

Trenbolone

Beta-trenbolone

2

2

Trichlorfon

50

50

50

Triclabendazole

Ketotriclabendazole

10

225

200

100

 

Trimethoprim

50

50

50

50

Tripelennamine

20

200

Tulathromycin A

#

300

 

1000

Tylosin

50

100

50

50

100

100

200

200

200

Tylvalosin

Tylvalosin

50

U

50

50

U

Tylvalosin

3-O-acetyltylosin

50

U

50

U

Valnemulin

50

Virginiamycin (M1)

10

100

100

100

Zeranol

2

2

20

Zilpaterol

2

10

Zoalene (Dinitolmide)

Zoalene

3000 V 3000 V 3000 V

Zoalene (Dinitolmide)

3-amino-5-nitro-o-toluamide

3000 V 3000 V 3000 V

Superscripted capitals flag residues regulated as a sum; # stands for analytes which are not for use in animals for which milk are produced for human consumption .

for which milk are produced for human consumption ’ . Figure 1. Methods from the literature

Figure 1. Methods from the literature (years 19972016) devoted to the analysis of veterinary drug residues by LC-MS techniques, including both triple-quadrupole and high-resolution platforms.

these methods (years 2011 2016) have been devel- oped for a single food matrix (11 methods), showing the challenge related to the development of an analy- tical approach applicable to a broad range of food matrices, from raw materials and processed ingredi- ents to finished products. Five LC-MS-based methods have been single-laboratory validated for the determi- nation of veterinary drug residues in more than two raw materials. The LC-MS/MS technology has been used to screen about 130 compounds in egg, honey, milk and tissue (Robert et al. 2013), 120 residues in tissue, milk and egg (Chen et al. 2016) or quantify 115 compounds in milk powder, fish and egg (Dasenaki and Thomaidis 2015). High-resolution mass spectro- metry has been applied for the quantification of veter- inary drugs in tissue, fish, honey, kidney and liver (Kaufmann et al. 2011) and the screening 105 com- pounds in meat, milk and egg (Deng et al. 2001).

Despite significant recent progress in sample pre- paration and instrument performance, the analysis of a comprehensive list of veterinary drug residues (>120) in a broad range of food materials (raw materials, processed ingredients and finished products) remains a challenge for a single multiresi- due LC-MS method. Such a method is expected to be designed for high-throughput, cost-effective and business-oriented with the ultimate goal to protect consumers and facilitate trade in a global market. Today, this method does not exist and only a com- bination of methods can fit best with the needs, in terms of throughput, cost and consumer protection.

Screening versus quantification

LC-MS is a versatile technology, now broadly accepted and recognized as the gold standard for

8

8 T. DELATOUR ET AL. both quantification and screening of chemical con- taminants in food, and

T. DELATOUR ET AL.

both quantification and screening of chemical con- taminants in food, and specifically veterinary drug residues (Hird et al. 2014). Several multiresidue methods based on LC-MS/MS or LC-HRMS have been described in the literature for the quantitative determination of veterinary drugs in food. Interestingly, over 18 methods designed for more than a 100 compounds were published in the years 2011 2016; 10 of them have been established for quantification purposes. The other eight methods are intended to offer a screening capability. Although isotope dilution-based quantification remains the most reliable approach for LC-MS (Delatour 2004 ), it is unfortunately not applicable to multiresidue analysis because most of the isoto- pomers are commercially not available and, if they would, the impact on the cost would render the analysis not sustainable in a challenging economic environment. Technically, matrix-matched calibration is often applied for quantification because it appears as a convenient manner to mimic the response of the analytes in the matrix of interest. However, food composition is complex and subjected to natural variation triggering significant variability in the response factors, at least in the some sections of the chromatographic profile (Figure 2). Therefore, it is a challenge to select a mixture of blank matrix samples used for the calibration that accounts for the possible variations within the matrix of interest. In a routine testing laboratory, such an approach requires the usage of several calibrations (one per matrix category) which may impair both the cost-effective- ness and the throughput of the laboratory when a

broad range of food samples needs to be processed daily. It should be emphasized that validation pro- vides performance data only in a certain range based on performance assessment at some levels defined in the validation plan (recovery, precision and accu- racy). Some groups have assessed performance at four (Schneider et al. 2012 ; Wang et al. 2015 ) or three levels (Gómez-Pérez et al. 2012 , 2014 , 2015 ) and sometimes at a single one (Dasenaki and Thomaidis 2015 ). Piatowska and coworkers ( 2016 ) have single-laboratory validated at the MRL accord- ing to the criteria defined by the European Commission (EU 2002). It has also been proposed to build two calibration curves with concentrations that differ by one order of magnitude and assign appropriate compounds to the curve with a range that fits the best to the MRL (Kaufmann et al. 2011 , 2014 ). In practice, the validation of a quantitative LC-MS method for the simultaneous determination of more than a 100 compounds is a labor-demand- ing task which does not guarantee adequate preci- sion due to unpredictable matrix effects from the sample. Furthermore, such a work does not spare additional tests for samples that contain analyte(s) at levels outside the validated range. Interestingly, recent surveys conducted in the U.S. A. and Europe have identified only low rates of non- compliant samples with regard to veterinary drug residues in live animals and animal products. In the U.S.A., the rate of non-compliance was found at 1.15% (11 positive samples out of 953 targeted samples) in milk (FDA 2015 ). In Europe, rates of non-compliance were found at 0.04% for the β -ago- nists, at 0.72% for antibacterials, at 0.03% for

β -ago- nists, at 0.72% for antibacterials, at 0.03% for Figure 2. Comparison of penicillin G

Figure 2. Comparison of penicillin G responses in various food matrices.

FOOD ADDITIVES & CONTAMINANTS: PART A

FOOD ADDITIVES & CONTAMINANTS: PART A 9 Figure 3. Distribution of the RASFF notifications (%) for

9

FOOD ADDITIVES & CONTAMINANTS: PART A 9 Figure 3. Distribution of the RASFF notifications (%) for

Figure 3. Distribution of the RASFF notifications (%) for the major safety-related food hazards (years 20132016, n: total number of notifications). Source: RASFF Annual Reports 20132016.

sedatives in pig, and at 0.03 0.54% for anthelmintics and 0.190.51% for the non-steroidal antiinflamma- tory drugs depending on the species (EFSA 2016 ). These data show that screening methods would operationally be more appropriate for clearing com- pliant raw materials to be accepted in the production line. Any positive sample that requires quantitative determination can anyway be tested by an adequate quantitative approach such as isotope dilution or standard addition. With regard to risk management and business efficiency, it appears more effective to obtain a quick response of the compliant samples/ parameters while keeping enough attention to the four major risks of public health concern that are pathogenic microorganisms, mycotoxins, pesticides and heavy metals (Figure 3 ).

A streamlined LC-MS/MS platform

Due to the large portfolio of products to be con- t rolled for the possible presence of veterinary drug residues, our primary intention was to establish a LC-MS/MS analytical platform applicable to regu- lated raw materials, namely milk, meat/muscle, fish/seafood, egg and fat. In a global food business, most of these stuffs are traded after being pro- cessed as powdered materials for being incorpo- rated in recipes. We therefore included these powdered materials (e.g. beef meat powder, white and yolk egg powders) in the scope of the

analytical platform in order to obtain a tool that fits with the current business practices. Specifically, the following dairy powdered ingredients were included in the scope: full-cream, fat-filled and skimmed milk, whey proteins, lactose and case- inate. Some baby/infant-related finished products (infant formulae and cereals, baby food) were also part of the scope for an effective control of these product categories. Particular emphasis was put on hydrolyzed infant formulae as free amino acids and low molecular mass peptides can interfere with some sample preparation conditions, leading to impaired method performance for this category of product. The list of veterinary drugs (152 in total) was estab- lished based on inputs from different sources such as regulations from various countries and Codex Alimentarius, field information from corporate agri- culture services, specific market needs and constraints, positive findings or assessment of likelihood of occur- rence. In essence, aminoglycosides, amphenicols, aver- mectins, benzimidazoles, β-lactams, coccidiostats, lincosamides, macrolides, non-steroidal antiinflamma- tories, quinolones, sulfonamides, tetracyclines and others were selected in the scope (Figure 4). From an analytical standpoint, the goal was to first develop a method based on a generic sample preparation intended to include as many compounds as possible. Then, specific methods were developed additionally for drug classes that required dedicated conditions, in

10

10 T. DELATOUR ET AL. Figure 4. Categories of veterinary drug compounds included in the scope

T. DELATOUR ET AL.

10 T. DELATOUR ET AL. Figure 4. Categories of veterinary drug compounds included in the scope

Figure 4. Categories of veterinary drug compounds included in the scope of the current study.

terms of both sample preparation and LC-MS/MS conditions (β-lactams, aminoglycosides, tetracyclines). In the end, a suite of four methods was necessary to screen the entire set of 152 veterinary drug residues in a broad range of raw materials, processed powdered ingredients and some finished products at levels that fit with the regulatory requirements. Some groups have concluded earlier the need for a suite of methods (instead of a single one) for an appropriate screening that matches the established scope (Martos et al. 2010; Staub Spörri et al. 2014). Our analytical platform, as a suite of four methods, was defined as follows. Streams are depicted in Figure 5, and full technical details are available elsewhere

(Bessaire et al. 2018; Desmarchelier et al., 2018a, 2018b; Savoy et al. 2018).

a. Multiclass (105 compounds): The QuEChERS procedure was adapted in order to cover the broadest drug/matrix combination as possible. Specific reconstitution conditions with a higher amount of methanol and dedicated LC-MS/MS conditions with a lower source temperature were required for a suitable analysis of aver- mectins (6 compounds).

b. β -Lactams (23 compounds): Another variation of the QuEChERS method was optimized due to the insufficient sensitivity of amoxicillin and

due to the insufficient sensitivity of amoxicillin and Figure 5. Flowchart for the analysis of 152

Figure 5. Flowchart for the analysis of 152 veterinary drug residues in food raw materials, processed ingredients and some finished products by LC-MS/MS.

ampicillin with the Multiclassprocedure (stringent regulatory limits at 4 µg/kg in milk). Despite the significant relevance for monitoring these two compounds, they are often not included in large-scope multiresidue methods or, if so, validated at levels higher than regulatory limits. Briefly, the modifica- tions from the Multiclass protocol are the use of an alkaline aqueous extraction buffer, the absence of primary secondary amines for dispersive SPE, and extract volume reduction without evaporation to dryness.

c. Tetracyclines (10 compounds): Poor absolute recovery and sensitivity were observed for these analytes using the extraction protocol and LC- MS/MS conditions of the Multiclassprocedure. This was rationalized in terms of chelation of these compounds with metal ions available in the matrix, the LC column or the stainless steel parts of the LC system. To circumvent this phenomenon, ethylenediaminetetraacetic acid (EDTA) was supplemented in the sample pre- paration media, and oxalic acid was added in both the dilution solvent and the mobile phase. Furthermore, a 10-min extended gradient was developed for the separation of the epimers regulated in Europe.

d. Aminoglycosides (14 compounds): This important class of antibiotics cannot be extracted with organic solvents due to a strong hydrophilic behavior. For the same reason, they also require LC conditions that do not make use of conventional reversed phase chro- matographic conditions. Therefore, a dedicated procedure was optimized with an extraction under acidic aqueous conditions followed by a selective clean-up with molecularly imprinted polymer-solid phase extraction (MIP-SPE). Analytes were subsequently detected by ion- pair reversed phase LC-MS/MS.

The monitoring of chemical contaminants, particu- larly with veterinary drugs, is a dynamic field that requires constant assessments and adaptations, lead- ing to scope extensions and possibly method mod- ifications in order to fit with an evolving context. In that regard, the complementarity of the two QuEChERS-based extraction conditions developed in the current work, either acidic for the

FOOD ADDITIVES & CONTAMINANTS: PART A

acidic for the FOOD ADDITIVES & CONTAMINANTS: PART A 11 ‘ Multifamily ’ stream or alkaline

11

Multifamily stream or alkaline for the β-lactams, offers interesting perspectives in terms of analyte scope extension. The four methods developed in the current work have been validated as screening tools and, in that regard, the concept of screening target concentration (STC) has been used. Due to the occurrence of matrix effects that sometimes induce unpredictable variations in the response factor we have chosen to apply a double extraction for each sample; the first test portion is extracted as such, while the second one is spiked at the STC. Both extracts are processed, analyzed, and corresponding signals compared against a cutoff value determined during the valida- tion. This approach is very reliable as it takes into account the intrinsic matrix effect of each sample to be analyzed. We did not retain the common approach that compares absolute signal abundances because it does not guarantee sufficient reliability, and ultimately does not prevent false negative responses, which is not acceptable in a food safety perspective.

Acknowledgment

We would like to thank Weijia Gan and Longfei Wang, Nestlé Food Safety Institute (China), for their invaluable help in accessing an English version of the National Standard No. 235 (Ministry of Agriculture of the People s Republic of China).

Disclosure statement

No potential conflict of interest was reported by the authors.

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