Veterinary Drugs and Growth Promoters Residues in Meat and Processed Meats

101 Toxic Food Ingredients

101 Toxic Food Ingredients

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Milagro Reig and Fidel Toldra

Introduction

Veterinary drugs, which comprise a large number of different types of substances, are generally intended for therapeutic (to control infectious diseases) and prophylactic (to prevent against infections) purposes in farm animals. Other substances with growth promoting effect may exert antimicrobial effect against the microbial flora in the gut to take maximum profit of nutrients in the feed or by affecting the animal's metabolism. Most of these substances are orally active and can be administered either in the feed or in the drinking water. Other active hormones are applied in the form of small implants into the subcutaneous tissue of the ears. These are slow release (several weeks or months) devices and the ears are discarded at the slaughter. Growth promoters allow a better efficiency in the feed conversion rate. The net effect is an increased protein deposition, partly due to muscle proteases inhibition (Fiems, Buts, Boucque, Demeyer, & Cottyn, 1990), usually linked to fat utilization (Brockman & Laarveld, 1986). The result is a leaner meat (Lone, 1997) with some toughness derived from the production of connective tissue and collagen crosslinking (Miller, Judge, Diekman, Hudgens, & Aberle, 1989; Miller, Judge, & Schanbacher, 1990). Some recent fraudulent practices, consisting of the use of a kind of ''cocktails'' or mixtures of several substances like b-agonists and corticosteroids at very low amounts (Monson et al., 2007), are difficult to detect with modern analytical instrumentation. They try to obtain a synergistic effect for a similar growth promotion with lower probability of detection by official control laboratories (Reig & Toldra, 2007).

Thus, the use of veterinary drug substances as well as other substances with growth-promoting effects may usually constitute a clear economic benefit for farm production. However, its residues in the meat and other animal-derived

Department of Food Science, Instituto de Agroquimicá y Tecnología de Alimentos (CSIC), Burjassot (Valencia), Spain e-mail: [email protected]

F. Toldra (ed.), Safety of Meat and Processed Meat,

Food Microbiology and Food Safety, DOI 10.1007/978-0-387-89026-5_14,

© Springer Science+Business Media, LLC 2009

Table 14.1 List of substances having anabolic effect (group A) and veterinary drugs (group B) in accordance to the Council Directive 96/23/EC (EC, 1996)

Group A: Substances having anabolic effect Group B: Veterinary drugs and contaminants

Table 14.1 List of substances having anabolic effect (group A) and veterinary drugs (group B) in accordance to the Council Directive 96/23/EC (EC, 1996)

Group A: Substances having anabolic effect Group B: Veterinary drugs and contaminants

1. Stilbenes

1. Antibacterial substances

2. Antithyroid agents

Sulfonamides and quinolones

3. Steroids

2. Other veterinary drugs

Androgens

(a) Antihelmintics

Gestagens

(b) Anticoccidials, including nitroimidazoles

Estrogens

(c) Carbamates and pyrethroids

4. Resorcyclic acid lactones

(d) Sedatives

5. Beta-agonists

(e) Nonsteroidal anti-inflammatory drugs

6. Other compounds

(f) Other pharmacologically active substances

foodstuffs may cause harmful effects to consumers when eating them, mainly depending on the type of substance and its content as residue in the foodstuff. Even though some studies with steroids have shown that when used properly, the amount of residues in the meat is minimal for any sensitive effect in comparison to natural steroid content (Lone, 1997), other substances may exert harmful effects on consumers.

This chapter is providing a summarized view of main veterinary drugs and growth-promoting substances that may be used legally or illegally in animal production. The main groups of these substances as listed in European Directive 96/23/EC (EC, 1996) are shown in Table 14.1. This will also briefly describe its properties, causes of concern, and measures for its control.

Main Groups of Substances with Anabolic Effect and Veterinary Drugs

Substances with Anabolic Effect

Steroid Hormones and Other Substances Having Hormonal Action

These substances exert estrogenic (except 17b-estradiol and ester-like derivatives), androgenic, or gestagenic action and may be used for growth-promoting purposes. These include steroid hormones and hormone-like substances and include testosterone, progesterone, trenbolone acetate, zeranol, and melenges-trol acetate (see Table 14.2). Steroid hormones are essential for normal development and physiological function of most tissues. Synthetic hormones appear to bind to steroid receptors with equal or higher affinity than the natural hormones (Wilson, Lambright, Ostby, & Gray, 2002; Perry, Welshons, Bott, & Smith, 2005). So, trenbolone mainly binds to the androgen receptor, zeranol to the estrogen receptor and melengestrol that resembles natural progestins (EFSA, 2007). Maximum residue levels (MRL) have been established by national authorities and by the Codex Alimentarius. An important challenge

Table 14.2 Main properties of relevant androgens, estrogens, and gestagens

Substance

IUPAC name

CAS number

Structure

Formula

Molecular Melting mass (g/ point Solubility mol) (CC) in water s=

"G

ANDROGENS: 17a-nortest-osterone

17a-trenbolone

17-methyltest-osterone

17-hydroxyestr-4-en-3-one

17a-hydroxyestra-4,9, ll-trien-3-one

(17/3 (-hydroxy-17-methylandrost-4-en-3-one

434-22-0

10161-33-8

58-18-4

C18H2602 274.39

C18H2202 270.38

C20H30O2 302.44

s Insoluble

Slightly soluble i Insoluble a c-

Table 14.2 (continued)

Substance

IUPAC name

CAS number

Structure

Molecular Melting mass (g/ point Solubility Formula mol) PC) in water

ESTROGENS: Diethylstilbestrol

Dimestrol

Dienestrol

4,4'-( 1,2-diethyl-l ,2- 56-53-1 ethene-diyl) bisphenol; a,a'~ diethylstilbenediol

(E)-l,r-fl,2-diethyl- 130-79-0 1,2-ethenediyl) bis[4-methoxy benzene]; a,a'-diethyl-4,4'-dimethoxystilbene

4,4'-(1,2-diethylidene-1, 2-ethanediyl) bisphenol;

4,4'-(diethylidene ethylene)diphenol

84-17-3

OCH,

Ci8H20O2 268.34

C20H24O2 296.39

C18H1802 266.32

i Insoluble i Insoluble i Insoluble era P P

a 71

Table 14.2 (continued)

"G

Substance

IUPAC name

CAS number

Structure

Molecular Melting mass (g/ point Solubility Formula mol) PC) in water

GESTAGENS: 17a -hydroxypro-gesterone

17-hydroxypregn- 68-96-2

4-ene-3, 20-dione

C21H30O3 330.45

s Insoluble a c-

when analyzing these residues in meat is the ability to discriminate between endogenous production and exogenous administration.

Stilbenes

These substances are synthetic non-esteroidal estrogens. They exert estrogenic activity (growth and development of female sexual organs) and produce an increase of somatotropin secretion. Diethylstilbestrol was related to cancer and is banned. This substance leads to several reactive metabolites after oxidation in the body (Lone, 1997). Other stilbenes belonging to this group and its main properties are shown in Table 14.2.

Antithyroid Agents

These agents are able to interfere directly or indirectly on the synthesis, release or effect of the thyroideal hormones. These agents cause hypothyroidism by decreasing the basal metabolism rate, with water retention and weight increase. Representative compounds and its main properties are shown in Table 14.3.

Glucocorticoids

Corticoids are hormones of the adrenal cortex. These substances have physiological roles like the control of mineral and water balance. Glucocorticoids also have many important physiological functions and are thus involved in carbohydrate metabolism. They can be used with other hormones for growth promotion effect. Good representatives are dexamethasone and corticosterone. Main properties are reflected in Table 14.4.

b-Agonists b-adrenergic agonists are used as therapeutic agents for respiratory disorders under prescription of veterinary inspectors. However, they have been extensively used as growth promoters because they bind to b receptors of various tissues and change the carcass composition. These substances reduce proteoly-sis and increase protein synthesis and lipolysis (Lone, 1997). This group includes numerous substances like clenbuterol, mabuterol, cimaterol, salbutamol, etc. Table 14.5 presents its main properties.

Antimicrobial and Antibiotic Drugs Sulfonamides

This family of drugs is derived from sulfanilamide. Representative compounds are compiled in Table 14.6. They are broad spectrum antibiotics active against

Table 14.3 Main properties of relevant antithyroidal agents

Substance

IUPAC name number

Structure

Molecular Solubility mass Melting in water

Methylthiouracil 2,3-dihydro-6- 56-04-2 methyl-2-thioxo-4(1H)-

pyrimidinone

H3C\

C5H6N2OS 142.18 326

Slightly soluble in warm water

Propylthiouracil 2,3-dihydro-6- 51-52-5 propyl-2-thioxo-4(1H)-

pyrimidinone

C7H10N,OS 170.23

Slightly soluble

Tapazole

1,3-dihydro-l-methyl-2H-imidazole-2-thione

60-56-0

C4H6N2S 114.17 146

Freely soluble

Table 14.3 (continued)

Substance

IUPAC name

CAS number

Structure

Formula

Molecular Solubility mass Melting in water

Thiouracil 2,3-dihydro-2- 141-90-2

pyrimidinone c c

C4H4N2OS 128.15

No definite

Very slightly soluble

Table 14.4 Main properties of relevant glucocorticoids

Substance

IUPAC name

CAS number

Structure

Formula

Molecular Melting mass point Solubility

Betamethasone 9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione

378-44-9

Dexamethasone

(ll/?,16a)-9-fluoro-11,17-21 -trihydroxy-16-methylpregna-1,4-diene-3,20-dione

50-02-2

Flumethasone 6,9-difluoro-l 1,17,21 -trihydroxy-16-methylpregna-1,4-diene-3,20-dione

2135-17-3

2135-17-3

Flumethasone Structure
C22H29F05 392.45

C22H29F05 392.45

C22H29F05 392.45

CH2OH C22H28F205 410.46

Slightly soluble

Insoluble

Table 14.4 (continued)

Substance

IUPAC name

CAS number

Structure

Formula

Molecular Melting mass point Solubility

Corticosteroid

Cortisone

dihydroxypregn-4-ene-3,20-dione

17a,21-dihydroxy-4-pregnene-3,11,20-trione

50-22-6

53-06-5

C-nHmOi

CIIHiqOS

346.45

360.46

Insoluble

Slightly soluble era P P

a 71

Table 14.5 Names and main properties of representative agonists

IUP AC name

Molecular mass (g/mol)

Melting point ("C)

Solubility in water

4-amino-a-[(tert-butilamino) methyl]-3,5-dichlorobenzyl alcohol

ethyl)amino]methyl]-5- trifluoromethy 1) benzenemethanol

hidroxi-2-(tert-butilamino)etil] fenol

C13H18N2F3C10 310.75

Ci2HI8N2C120

C13H18N2F3C10 310.75

Very

Fairly

Sparingly soluble

Table 14.5 (continued)

IUPAC name

Molecular mass (g/mol)

Solubility in water

2-amino- 5-[ 1 -hydroxy-2-[( 1 -methyl-ethyl) amino]ethyl] benzonitrile

buty lamino)methy 1]-3,5-dibromobenzy 1 alcohol

Ractopamine

4-hydroxy-alpha-[[[3-(4-hy droxyphenyl)-1 -methylpropyl] amino]methyl] benzenemethanol

Visual Difference

Fairly

C,2H,8Br2N20

Fairly soluble

Fairly soluble

Table 14.6 Main properties of relevant antibiotics

Substance

IUPAC name

number Formula

Molecular Melting Solubility in mass (g/mol) point (°C) water

Sulfonamides

Sulfacetamide Sulfadiazine

Sulfadoxine Sulfadimethoxine

Sulfachlorpyridazine

ß-lactam antibiotics

Amoxicillin

Penicillin G calcium salt

Penicillin V

Tetracyclines

Tetracycline

N-[(4-aminophenyl)sulfonyl]-acetamide 4-amino-N-2-pyrimidinylsulfanilamide

4-amino-N-(5,6-dimethoxy-

4-pyrimidinyl)benzenesulfonamide 4-amino-N-(2,6-dimethoxy-4-pyrimidinyl)benzenesulfonamide

pyridazinyl)benzenesulfonamide

[2S-[2a,5a,6/?(S*)]]-6-[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7' oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid

[2S-(2a,5a,6/?)]-3,3-dimethyl-7-oxo-6[(phenylacetyl)amino]-4-thia-1 -1 -azabicyclo-[3,2.0]heptane-2-carboxylic acid calcium salt

3,3-dimethyl-7-oxo-6-[(phenoxyacetyl)amino]-4- 87-08-1 thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid

4-(dimethylamino)-l,4,4a,5,5a,6,11,12a- 60-54-8 octahydro-3,6,10,12,12a-pentahydroxy-6-_

144-80-9 C8H10N2O3S 214.24

68-35-9 C10H10N4O2S 250.28

2447-57-6 C12H14N404S 310.34

122-11-2 C12H14N404S 310.33

80-32-0 C10H9ClN4O2S 284.74

26787-78-0 C16H19N305S 365.41

61-33-6 (C16H17N204S)2Ca 706.84

c16h18n2o5s

C^H^lSfiOg

350.38

444.43

182 252

190-191

Slightly soluble Sparingly soluble in warm water Very slightly soluble Soluble in slight basic warm water Soluble

Slightly soluble g a s=

Soluble

120-128 Very slightly soluble in acid water s=

Table 14.6 (continued)

CAS

Molecular Melting

Solubility in

Substance

IUPAC name

number

Formula

mass (g/mol) point (°C)

water

methyl-1,11 -dioxo-2-

naphthacenecarboxamide

Oxytetracycline

4-(dimethylamino)-l,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11 -dioxo-2-naphthacenecarboxamide

79-57-2

C22FF4N2O9

460.44

Chlortetracycline

7-chloro-4-dimethylamino-

1,4,4a,5,5a,6,11,12a-octahydro-

3,6,10,12,12a-pentahydroxy-6-methyl-1,11-

dioxo-2-naphthacenecarboxamide

57-62-5

c22h23cin2o8

478.88

Slightly soluble

Aminoglycosides

Dihydrostreptomycin

(Diaminomethylideneamino)-2-

4,5-dihydroxy-6-(hydroxymethyl)-3-

methylaminooxan-2-yl]oxy-4-hydroxy-4-

(hydroxymethyl)- 5-methyloxolan-2-yl]oxy-

3,4,6-trihydroxycyclohexyl]guanidine

128-46-1

C,iH41N7012

583.62

Soluble

Gentamycin

Various: gentamycin Q; gentamycin C2; gentamycin Cla or D; gentamycin A

1403-66-3

-

-

Soluble

Streptomycin

5-(2,4-diguanidino-3,5,6-trihydroxy-cyclohexoxy)- 4-[4,5-dihydroxy-6-(hydroxymethyl)-3-methylamino-tetrahydropyran-2-yl] oxy-3-hydroxy-2-methyl-tetrahydrofuran-3-carbaldehyde

57-92-1

C21H39N7022

581.58

Soluble

Streptomycin B

128-45-0

C27H49N7O 2 7

743.72

Soluble

gram-positive and gram-negative bacteria, acting on specific targets in bacterial DNA synthesis (Croubels, Daeselaire, De Baere, De Backer, & Courtheyn, 2004), and have been used in human medicine for the treatment of systemic bacterial diseases even though they have been replaced by modern antibiotics but some like sulfamethazine (also known as sulfamidicine) are still used in animals due to low cost, easy administration, and high efficiency (Dixon, 2001).

b-Lactams

The chemical structure is based on the b-lactam ring. This group includes penicillins, b-lactamase inhibitors, and cephalosporins but also other subfamilies like cephamycines and clavulanic acid (see Table 14.6). They act on the growth ofgram-positive bacteria by disrupting the development ofbacterial cell wall. The b-lactams can also increase the feed efficiency and thus promote growth.

Tetracyclines

These are broad spectrum antibiotics with high activity against gram-positive and gram-negative bacteria, derived from certain Streptomyces spp., that act on bacterial protein synthesis. They can be used to treat respiratory disease in farm animals. At low doses can exert growth promotion effects in animals. Tetracycline, oxytetracycline, and chlortetracycline are some of the most well-known compounds in this group used in veterinary medicine (see Table 14.6).

Aminoglycosides

These antibiotics, which have a broad spectrum of activity, act against the synthesis of bacterial cell proteins in gram-negative bacteria. They are based on aminosugars linked by glycoside bridges to a central aglycone moiety. Streptomycin and dihydrostreptomycin belong to the streptomycin subgroup, while gentamicin and neomycin belong to the deoxystreptamine subgroup. They have different subclasses depending on the substituents to the deoxystrep-tamine moiety (i.e., neomycin A, B, or C) as shown in Table 14.6.

Macrolides

They were used to treat respiratory diseases, especially erythromycin. The structure is based on a macrocyclic lactone ring having carbohydrates attached. They are produced from certain Streptomyces strains. Macrolides act against gram-positive bacteria. Erythromycin is a good representative of this group. Tylosin, spiramycin, and lincomycin are also typical compounds belonging to this group which have been used for growth promotion (see Table 14.7).

Table 14.7 Main properties of relevant macrolides and quinolones

CAS

Molecular mass

Melting

Solubility

Substance

IUPAC name

number

Formula

(g/mol)

point f C)

in water

Macrolides

Tylosin

2-[12-[5-(4,5-dihydroxy-4,6-dimethyl-oxan-2-yl)oxy-4-dimethylamino-3-hydroxy-6-methyl-oxan-2-yl]oxy-2-ethyl-14-hydroxy-3-[(5-hydroxy-3,4-dimethoxy-6-methyl-oxan-2-yl)oxymethyl]-5,9,13-trimethyl-8,16-dioxo-l -oxacyclohexadeca-4,6-dien-11 -yl]acetaldehyde

1401-69-0

c46h77no17

916.14

128-132

Slightly soluble

Erythromycin

6-(4-dimethylamino-3-hydroxy-6-methyl-oxan-2-yl)oxy- 14-ethyl-7,12,13-trihydroxy-4-(5-hydroxy-4-methoxy-4,6-dimethyl-oxan-2-yl)oxy-3,5,7,9,l 1,13-hexamethyl-1 -oxacyclotetradecane-2,10-dione

114-07-8

c37h67no13

733.92

135-140

Fairly soluble

Spiramycin

Complex: spiramycin I, II and III

8025-81-8

I: C43H74N2014 II: C45h76n2015 III: C46h78n2015

I: 843.08 II: 885.12 III: 899.15

134-137

Slightly soluble

Quinolones

Enrofloxacin

1 -cyclopropyl-7-(4-ethyl-1 -piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxilic acid

93106-60-6

c19h22fn3o3

359.40

219-223

Slightly soluble

Sarafloxacin

6-fluoro-l-(4-fluorophenyl)-4-oxo-7-piperazin-l-ylquinoline-3-carboxylic acid

98105-99-8

C2oHI7F2N303

385.36

256

Soluble

Danofloxacin

l-Cyclopropyl-6-fluoro-7-[(lS,4S)-3-methyl-3,6-diazabicyclo[2.2.1]heptan-6-yl]-4-oxoquinoline-3-carboxylic acid

112398-08-0

c19h20fn3o3

357.37

263

They act against the bacterial DNA-gyrase with a broad antibacterial activity. Oxolinic acid, flumequine, and nalidixic acid are compounds of the first generation. They are synthesized from 3-quinolone carboxylic acid. The second generation compounds, which are more potent, are fluoroquinolones like sara-floxacin, enrofloxacin, and danofloxacin, which display fluorescence (see Table 14.7). These substances are poorly soluble in water at neutral pH but increase their solubility at basic pH.

Peptides

These are large and complex molecules which are obtained from bacteria and molds. Some of them are nisin, bacitracin, colistin, avoparcin, polymirxin, and virginiamycin (see Table 14.8). They can interact with the bacterial cell wall, resulting in cell membrane damage (Croubels et al., 2004). These antibiotics often have a mixture of several molecules (i.e., bacitracin A or F). Avoparcin was banned in the EU in 1997, while bacitracin and virginiamycin were banned in 1999 due to the risk of transmission of antibiotic resistance to bacteria (Verdon, 2009).

Amphenicols

These are broad spectrum antibiotics. Chloramphenicol, thiamphenicol, and fluorfenicol are the main representatives of this group. Chloramphenicol was banned in late 1980 s due to its toxic effects

Carbadox and Olaquindox

These are antibacterial synthetic quinoxaline compounds which have been used as growth promoters. Carbadox has shown mutagenic and carcinogenic effects in animals while olaquindox is strongly mutagenic (Croubels et al., 2004). Both antibiotics, shown in Table 14.8, are rapidly converted into quinoxaline-2-carboxylic acid (QCA) and methyl-3-quinoxaline-2-carboxylic acid (MQCA), respectively. These metabolites are mutagenic and carcinogenic (Verdon, 2009).

Nitrofurans

These are synthetic compounds with a broad spectrum of activity against bacteria. They are furazolidone, furaltadone, nitrofurazone, and nitrofurantoin (see Table 14.9). These substances are used against gastrointestinal infections in farm animals but were banned due to its genotoxic and mutagenic properties. They are rapidly metabolized in the organism (i.e., semicarbazide from nitro-furazone) making its detection more difficult.

Table 14.8 Main properties of relevant peptides, carbadox, and olaquindox

CAS Molecular Melting Solubility in

Substance IUPAC name number Formula mass (g/mol) point (°C) water

Table 14.8 Main properties of relevant peptides, carbadox, and olaquindox

CAS Molecular Melting Solubility in

Substance IUPAC name number Formula mass (g/mol) point (°C) water

Bacitracin A

5-(l-(4-(14-((l#-imidazol-5-yl)methyl)- 20-(2-amino-2-oxoethyl)-l l-benzyl-8-«r- butyl-17-(carboxymethyl)-3,6,9,12,15,18,21-heptaoxo-1,4,7,10,13,16,19-heptaazacyclohenicosan- 2-yl)butylamino)-3-methyl-l-oxopentan-2-ylamino)- 4-(2-(2-(1 -amino-2-methylbutyl)-4,5-dihydrothiazole- 4-carboxamido)-4-methylpentanamido)-5-oxopentanoic acid

1405-87-4

c66h103n17o16s

1422.70

221-225

Soluble

Nisin A

1414-45-5

C143H230N42O37S7

3354.12

Soluble at slight acid pH

Colistin

Af-(4-amino-1-(1-(4-amino-1-oxo-l-(3,12,23-tris(2-aminoethyl)- 20-( 1 -hydroxyethyl)-6,9-diisobutyl-2,5,8,ll,14,19,22-heptaoxo-1,4,7,10,13,18-hexaazacyclotricosan-15-ylamino)butan-2-ylamino)- 3-hydroxybutan-2-ylamino)-1 -oxobutan-2-yl)-N, 5-dimethylheptanamide

1066-17-7

c52h98ni6oi3

2797.32

200-220

Carbadox

(2-quinoxalinylmethylene)hydrazine carboxylic acid methyl ester N,N'-dioxide; 3-(2-quinoxalinylmethylene)carbazic acid methyl ester N,N'-dioxide

6804-07-5

CnH10N4O4

262.22

239.5

Insoluble

Olaquindox

N-(2-hydroxyethyl)-3-methyl-2-

quinoxalinecarboxamide 1,4-di oxide

23696-28-8

c12h13n3o4

263.25

207-213

Slightly soluble

Table 14.9 Main properties of relevant nitrofurans s=

"G

Substance

IUPAC name

number Structure

Formula

Molecular mass (g/ Solubility mol) in water

Furaltadone

Furazolidone

furanyl)methylene]amino]-2-oxazolidinone

furanyl)methylene]-amino]-2-oxazolidinone

C13H16N406 324.29

O CANSOS 225.16

Slightly soluble

Very slightly soluble

Nitrofurantoin l-[[(5-nitro-2- 67-20-9

furanyl)methylene]amino]-2,4-imidazolidinedi one

CUV O

.O CsHfiN40, 238.16

Very slightly soluble a s=

Nitrofurazone 2-[(5-nitro-2-

furanyl)methylene]-hydrazinecarboxamide

59-87-0

0?ISL O

C6H6N404 198.14

Very slightly soluble uj

GO LO

Other Veterinary Drugs Antihelmintic Agents

The faeces of animals may contain eggs or larvae from worm parasites (helminths) that can be ingested by other animals, specially cattle and sheep, with pasture. These drugs act on the metabolism of the parasite. There are several groups like benzimidazoles (thiabendazole, albendazole) that had widespread use, imidazothiazoles (tetramisole, levamisole), avermectins (ivermectin, dora-mectin), and anilides (oxyclozanide, rafoxanide, and nitroxynil).

Anticoccidials, Including Nitroimidazoles

Coccidia parasites are transmitted by faecal infection, especially in farms. Anticoccidials are used in poultry to prevent and control coccidiosis, a contagious infection caused by parasites that causes serious effects such as bloody diarrhoea and loss of egg production. There are several groups of compounds against coccidiosis like nitrofurans, carbanilides, 4-hydroxyquinolones, pyri-midines, and the ionophores. Ionophores are polyether antibiotics used against coccidia parasites in poultry. They include monensin, salinomycin, narasin, and lasalocid.

Nitroimidazoles are obtained synthetically with a structure based on a 5-nitroimidazole ring. Main compounds are dimetridazole, metronidazole, ronidazole, and ipronidazole. They are toxic for the bacteria when the 5-nitro group is reduced to free radicals by nitro reductase of the anaerobic bacteria (Verdon, 2009). These compounds are mutagenic, carcinogenic, and toxic toward eukaryotic cells, and thus, have been banned in the EU in the 1990s for use in food-producing animals

Sedatives

These compounds are used to control the stress in farm animals but after several weeks they can also induce some growth promotion by redistribution of fat to muscle tissue. Some compounds are carazolol, chlorpromazine, azaperone, and xylazine.

Corticoids

Corticoids are hormones of the adrenal cortex. They are used as antiinflammatory agent for therapeutic purposes. Derivatives of prednisolone constitute the most important group of synthetic corticoids. Corticosteroids are involved in many physiological roles, specially in carbohydrate metabolism and in control of water balance. They may exert some growth promotion when used in combination with other hormones or b-agonists. Some used corticoids for such purposes are dexamethasone, betamethasone, flumethasone, cortisone, desoxymethasone, and hydrocortisone.

Causes of Concern Due to the Presence of Residues in Meat

The presence of residues of veterinary drugs, growth promoting agents, or its metabolites in meat and other animal-derived foodstuffs is causing concern during the last decades to the sanitary authorities in different countries, especially in the European Union. Main causes of concern for these residues are based on their potential adverse toxic effects to consumers or the promotion of antibiotic resistance to microorganisms. In the case of meat products, they may also contain different types of residues having its origin in the meat used as raw material (Reig and Toldra, 2007, 2008).

The European Food Safety Authority has recently issued an opinion about the contribution of residues in meat and meat products of substances with hormonal activity, specifically testosterone, trenbolone acetate, zeranol, and melengestrol acetate. A quantitative estimation of risk to consumers could not be established even though the individual epidemiological and toxicological data available and the reported evidence in the literature for an association between some forms of hormone-dependent cancers and red meat consumption (EFSA, 2007).

Diethylstilbestrol was already related to cancer in the 1940 s. It is genotoxic and mutagenic and has been related to the development of premature telarche and ovarian cysts in humans (Lone, 1997). Zeranol is a potent estrogen receptor agonist (Takemura et al., 2007), resembling its action to estradiol (Leffers, Naesby, Vendelbo, Skakkebaek, & Jorgensen, 2001). b-agonists are substances well known for its effects on consumers like gross tremors of the extremities, tachycardia, nausea, headaches, and dizziness. These effects were reported in Italy after consumption of lamb and bovine meat containing residues of clen-buterol (Barbosa et al., 2005).

Antibiotics have been extensively used in recent decades in order to improve feed conversion and reduce toxins formation, resulting in a promotion of animal growth productivity. But some of these antibiotics may have adverse effect on consumers. So, furazolidone, a major metabolite of nitrofuran, has shown mutagenic and carcinogenic properties (Guo, Chou, & Liau, 2003). Chloramphenicol may cause an irreversible type of bone marrow depression that might lead to aplastic anaemia (Mottier, Parisod, Gremaud, Guy, & Stadler, 2003). Allergy may be caused by enrofloxacin (Pecorelli, Bibi, Fioroni, & Galarini, 2004). Tumor production has been reported for sulfamethazine and also some toxic effect of sulphonamides on the thyroid gland (Pecorelli et al., 2004).

Anticoccidials, which are used in poultry to prevent and control coccidiosis, may lead to the presence of coccidiostat residues in poultry products (Hagren

Connolly, Elliott, Lovgren, & Tuomola, 2005). Its safety margin is narrow due to its toxic effects on humans like the specific dilatation of coronary artery (Peippo, Lovgren, & Tuomola, 2005).

However, at this moment the main concern on the use of antibiotics for growth promotion is the potential emergence of drug-resistant bacteria and disruption of the colonization barrier of the resident intestinal micro flora (Cerniglia & Kotarski, 2005). Intestinal flora is essential for human physiology, food digestion, and metabolism of nutrients (Chadwick, George, & Claxton, 1992; Vollard & Clasener, 1994), but the proportion of major bacterial species can experience large variations depending on the type of diet (Moore & Moore, 1995). Thus, the intestinal microflora may change in density and composition after continuous exposure to antibiotics residues present in foodstuffs like meat and meat products. Any species of the indigenous microflora may develop antimicrobial resistance as well as impair colonization resistance. For instance, concern emerged about the possible contribution of avoparcin use in farm animals to the emergence of glycopeptide resistance in enterococci. As a consequence of the use of such glycopeptide antibiotic as a growth promoter, vancomycin-resistant enterococci (VRE) were reported to be commonly found in the commensal flora of food animals, on meat from these animals and in the commensal flora of healthy humans (van den Bogaard, Bruinsma, & Stobberingh, 2000). Another potential indirect effect would be the increased susceptibility to infection by pathogens like Salmonella spp. and Escherichia coli (Cerniglia & Kotarski, 1998).

Control of Veterinary Drugs and Growth Promoters Residues in Meat

The presence of residues and its associated potential harmful effects on human health makes the control of veterinary drug residues an important issue for consumer protection.

The control of veterinary drug residues in the United States is under the National Residue Program (NRP) which is administered by the USDA Food Safety and Inspection Service (FSIS). There are two programmes, the domestic and the import residue sampling programmes. The FSIS domestic residue sampling programme is focused on preventing the occurrence of violative residues in food-producing animals. This programme provides several sampling plans to verify and ensure that slaughter establishments are fulfilling their responsibilities under the HACCP regulation, and according to the regulations of the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA). The import residue testing program is mainly determining the operativeness and effectiveness of the residue control programme of an exporting country (Ellis, 2004). For both programmes, the type of sampling consists of monitoring plans and surveillance plans. The Part Number 556 under title 21 Food and Drugs of the Code of Federal Regulations gives the tolerances for residues of new animal drugs in foods (CFR, 2008).

The tolerances are based upon residues of drugs in edible products of food-producing animals treated with such drugs (Byrnes, 2005).

Some of these substances like estradiol, progesterone, and testosterone are allowed in the United States under strict application measures and acceptable withdrawal periods. The use of certain growth promoters is allowed in other countries like Canada, Mexico, Australia, and New Zealand. However, the use of growth promoters is officially banned since 1988 in the European Union (EC, 1988).

The use of veterinary drugs in food animal species is strictly regulated in the European Union and, in fact, only some of them can be permitted for specific therapeutic purposes under strict control and administration by a veterinarian (Van Peteguem & Daeselaire, 2004). In the European Union, the monitoring of residues of substances having hormonal or thyreostatic action as well as b-agonists is regulated through the Council Directive 96/23/EC (EC, 1996). Member States have set up national monitoring programmes and sampling procedures following this Directive which establishes the measures to monitor certain substances and residues in live animals and animal products. Some residues may remain in the edible parts of an animal after administration of a veterinary drug. Table 14.1 lists the main veterinary drugs and substances with anabolic effect as defined in such Directive. Group A includes unauthorized substances with anabolic effect, while group B includes veterinary drugs some of them having established maximum residue limits (MRL). The MRL is based on the type and amount of residual substance in the foodstuff that cannot constitute any risk for the consumers. MRL may differ from one international authority to another. The residues to monitor involves not only the active substance and its degradation products but also its metabolites that may remain in the foodstuffs (Bergweff & Schloesser, 2003; Bergweff, 2005).

Commission Decisions 93/256/EC (EC, 1993a) and 93/257/EC (EC, 1993b) gave the criteria that the analytical methodology should follow for the adequate screening, identification, and confirmation of these residues. Commission Decision 2002/657/EC (EC, 2002) implemented the Council Directive 96/23/EC (EC, 1996) and is in force since 1 September 2004. This Decision provides rules for the analytical methods to be used in testing of official samples and specific common criteria for the interpretation of analytical results of official control laboratories for such samples. According to this Decision, a minimum number of identification points are required for the correct identification of the substance. These points are achieved depending on the analytical technique used (i.e., four identification points are achieved when using mass spectrometry for the detection of substances in group A but only three for those in group B). Other requirements are the relative retention of the analyte that must correspond to that of the calibration solution at a tolerance of ±0.5% for GC and ±2.5% for LC. New concepts were also given in this Decision that allows the determination of the level of confidence in the routine analytical result. These are the decision limit (CCa), defined as the limit at and above which it can be concluded with an error probability of a that a sample is non-compliant and the detection capability (CCb) which is defined as the smallest content of the substance that may be detected, identified, and/or quantified in a sample with an error probability of b. Thus, both limits are very useful even though its determination is rather complex.

In summary, there are numerous analytical techniques which are available for the control of the presence of veterinary drug residues, including growth promoting substances, in meats. New instrumentation provides an increased sensitivity. These methodologies have been recently reviewed and available elsewhere (Toldra & Reig, 2006; Reig & Toldra, 2009,a,b; Verdon, 2009).

Acknowledgments Project A-05/08 from Conselleria de Sanitat, Generalitat Valenciana (Valencia, Spain) is acknowledged.

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