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SOLFRIZZO M., PASCALE M., VISCONTI A., AVANTAGGIATO G. TOXICITY AND ANALYSIS OF MYCOTOXINS AND THEIR OCCURRENCE IN SOME ORGANIC PRODUCTS Consiglio Nazionale.

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Presentation on theme: "SOLFRIZZO M., PASCALE M., VISCONTI A., AVANTAGGIATO G. TOXICITY AND ANALYSIS OF MYCOTOXINS AND THEIR OCCURRENCE IN SOME ORGANIC PRODUCTS Consiglio Nazionale."— Presentation transcript:

1 SOLFRIZZO M., PASCALE M., VISCONTI A., AVANTAGGIATO G. TOXICITY AND ANALYSIS OF MYCOTOXINS AND THEIR OCCURRENCE IN SOME ORGANIC PRODUCTS Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

2 PRINCIPAL MYCOTOXINS PRESENT IN CEREALS AND RELEVANT FUNGAL PRODUCERS FUNGAL PRODUCERS F. graminearum, F. culmorum, F. crookwellense Aspergillus flavus, A. parasiticus Penicillium verrucosum, A. ochraceus F. graminearum, F. culmorum F. verticillioides (F. moniliforme), F. proliferatum Aflatoxins (B 1, B 2, G 1, G 2) MYCOTOXIN Ochratoxin A Fumonisins Zearalenone Deoxynivalenol CEREAL corn, wheat wheat, barley, corn, rye, oats, buckwheat wheat, corn, barley, oats, rye, spelt corn corn Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

3 SUMMARY OF IARC EVALUATIONS CONCERNING SOME MYCOTOXINS Global evaluation Mycotoxins Group 1: Carcinogenic to humans Aflatoxin B 1, B 2, G 1, G 2 Group2B: Group 2B: Possibly carcinogenic to humans Aflatoxin M 1 Ochratoxin A Fumonisins Group 3: Not classifiable as to its carcinogenicity to humansDeoxynivalenolNivalenolZearalenone Fusarenone X T2 toxin Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

4  It is slowly absorbed from the gastrointestinal tract and once reaches the blood it binds to serum albumin  It is distributed via the blood, to kidneys, liver, muscle and fat  It is transferred to milk in rats, rabbits and humans, minimal in ruminants  Its major metabolite is the less toxic ochratoxin α  It is excreted in the urine and faeces  Its serum half-life varies widely among species, e.g h in mice, h in rats, h in pigs, 510h in one macaque monkey, 840h in a human volunteer OCHRATOXIN A ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

5 Nephrotoxic in all mammalian species tested Cytotoxic and carcinogenic effects (mainly at the renal proximal tubule) Sensitivity to nephrotoxicity: pig > rat > mice The biological basis and significance of the renal tumours are unclear (National Toxicology Program, USA 1989)Genotoxic Genotoxicity (induce DNA damage and chromosomal aberrations) both in vitro and in vivo The mechanism of genotoxicity is unclear, and there is no evidence that it is mediated by direct interaction with DNA Embryotoxic and teratogenic in rats and mice Immunosuppressive in a number of species O CHRATOXIN A Toxicity Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

6 O CHRATOXIN A OBSERVATIONS IN HUMANS BIOMARKERS OF EXPOSURE Blood and urine concentrations Blood and urine concentrations of OTA are considered a convenient biomarker of exposure during recent weeks EPIDEMIOLOGICAL STUDIES human blood samples human milk It has been found in human blood samples (mainly in cool temperate climatic areas of the northern hemisphere) and in human milk in Europe (up to 6.6 ng/ml) and Africa (up to 337 ng/ml) No cases of acute intoxication in humans urinary tract tumors Balkan endemic nephropathy (BEN) It is a possible determinant of urinary tract tumors and Balkan endemic nephropathy (BEN) Epidemiological and clinical data available do not provide a basis for calculating the carcinogenicity in humans and the etiology of BEN may involve other nephrotoxic agents

7 O CHRATOXIN A OCCURRENCE IN HUMAN BLOOD CountryYearPositive/analysedRange (ng/ml) Bulgaria1984 – 9082/5761 – 35 Canada1988 – 94207/ – 35 Czechoslovakia199035/ – 1.3 Czech Republic1994 – / – 14 Croatia / – 16 Denmark / – 13 France / – 160 Germany / – 14 Hungary / – 10 Italy199265/650.1 – 2 Japan / – 0.28 Poland / – 40 Sierra Leone199612/361.5 – 18 Spain /750.5 – 4 Switzerland / – 6 Sweden198938/ – 7 Tunisia / – 9 Former-Iugoslavia /

8 JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES O CHRATOXIN A Provisional Tolerable Weekly Intake PTWI = 0.1 µg/kg body weight NOEL = 21 µg/kg of body weight per day (rats) Safety factor = 1500 Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

9  Poor absorption from the digestive tract (≤ 4% of the dose) and rapid distribution and elimination  Accumulation (as unmetabolized fumonisins) in liver and kidney  Little or no evidence of residues in food products derived from animals  Little or no evidence of in vitro or in vivo metabolism F UMONISINS ABSORPTION, DISTRIBUTION AND METABOLISM Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

10 FUMONISINS TOXICITY High acute and chronic toxicity towards animals Target organs: liver, kidney, heart or homologous organs Leukoencephalomalacia in equids and rabbits; pulmonary edema and hydrothorax in pigs; nephrotoxicity in rabbits and rats; cardiovascular effects in several species; liver and kidney cancer in rodents Biochemical modes of action Disruption of lipid metabolism (sphingolipid metabolism through inhibition of ceramide synthase and metabolism of fatty acids and glycero-phospholipids) both in vitro and in vivo Not mutagenic and not genotoxic both in vitro and in vivo Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

11 JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES FUMONISINS Provisional Tolerable Daily Intake PTDI = 2 µg/kg body weight NOEL = 200 µg/kg of body weight per day (rodents) Safety factor = 100 Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

12  rapid appearance and low bioavailability (≤7%) in sheep and cows; higher bioavailability (55%) in pigs  main distribution to plasma, kidneys, and liver  biotransformation (de-epoxidation and glucuronidation) to less toxic compounds  elimination half-life at 3.9h in pigs DEOXYNIVALENOL ABSORPTION, DISTRIBUTION AND METABOLISM Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

13 Deoxynivalenol Toxicity Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY Animal Toxicity reduced growth; decreased feed consumption (anorexia) and emesis (vomiting) are related to increased central serotoninergic activity Inhibition of protein synthesis primary toxic effect Genotoxic Genotoxicity (chromosomal aberrations) both in vitro and in vivo The mechanism of genotoxicity is unclear, and the results are considered equivocal Immunosuppressive in a number of species Embryotoxic and teratogenic in mice

14 International Agency for Research on Cancer (1993)  not classifiable as to its carcinogenicity to humans (Group 3). Clinical observations  acute toxic effects including nausea, vomiting, abdominal pain, headache, dizziness have been attributed to consumption of contaminated grains (3-93 mg/kg) in Asia  no deaths in humans. Deoxynivalenol OBSERVATIONS IN HUMANS Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

15 JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES Deoxynivalenol Provisional Tolerable Daily Intake PTDI = 1 µg/kg body weight NOEL = 100 µg/kg of body weight per day (mice) Safety factor = 100 Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

16 The use of validated analytical methods is essential to ensure that results of surveys provide a reliable assessment of intake. Analytical methods of mycotoxins Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

17 The working group CEN/TC 275/WG 5 – ‘Biotoxins’ selects and elaborates methods of analysis for mycotoxins that are to become European Standards. The Standards can be used for mycotoxins which are subject to legal limits. CEN Report CR Criteria for analytical methods of mycotoxins Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

18 PERFORMANCE CHARACTERISTICS OF REPEATABILITY (RSD r ), REPRODUCIBILITY (RSD R ) AND RECOVERY FOR FUMONISNS LEVEL(µg/g) FB 1 or FB 2 < – 5.0  30  20  60  RSD r % RSD R % Recovery % (CEN Report CR 13505) Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

19 CEN standard methods Ochratoxin A in corn, barley, wheat bran, rye Ochratoxin A in wheat whole meal Aflatoxins in cereals, shell fruits and derived products Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

20 Draft CEN standard methods Fumonisins in maize Fumonisins in maize based foods Ochratoxin A in wine and beer Ochratoxin A in barley and roasted cofee Aflatoxins in fig paste, pistachios, peanut butter and paprika powder Aflatoxin M 1 in milk Patulin in clear and cloudy apple juice and puree Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

21 Develop and validate an analytical method to determine FUMONISINS (FB 1 and FB 2 ) in maize and maize based foods at levels of interest for future EU legislation with good recoveries, repeatability and reproducibility. OBJECTIVE Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

22 The project was designed in two phases: PRELIMINARY STUDY (Ruggedness test) Maize flour, corn flakes, extruded corn, maize-based infant formula, and muffin COLLABORATIVE STUDY Maize flour, corn flakes Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

23 RUGGEDNESS TEST (involving 4 laboratories) Identify critical factors in the procedure of fumonisin analysis by testing different: Extraction solvent mixture compositions Extraction solvent mixture compositions Ratios of test portion size/extraction solvent volume Ratios of test portion size/extraction solvent volume Extraction modes Extraction modes Types of clean-up Types of clean-up COLLABORATIVE STUDY (involving 24 laboratories) Validation of the optimized method for maize flour and corn flakes Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

24 RESULTS OF THE RUGGEDNESS-TEST  Extraction solvent composition and clean-up were critical factors in the analysis of fumonisins  Test portion size, extraction solvent volume and extraction mode had minor or no effect  Immunoaffinity column was essential for the purification of corn flakes, muffins and infant formula  CH 3 CN-water (1:1, v/v) gave higher fumonisin recovery than CH 3 OH-water (3:1, v/v), but gave rise to separation of two phases in several cases Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

25 Fluorescence response (mV) FumoniTest TM Time (min) FB 1 FB Fluorescence response (mV) Time (min) SAX FB 1 FB 2 EFFECT OF TWO DIFFERENT CLEAN-UP METHODS ON HPLC CHROMATOGRAM OF MUFFINS (SPIKED WITH 1.5 µg/g FB 1 +FB 2 ) EFFECT OF TWO DIFFERENT CLEAN-UP METHODS ON HPLC CHROMATOGRAM OF MUFFINS (SPIKED WITH 1.5 µg/g FB 1 +FB 2 ) 20µL = 20 mg injected20µL = 8 mg injected Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

26 CORN FLAKES (spiked with 1.5 µg/g FB 1 + FB 2 ) EFFECTS OF DIFFERENT PARAMETERS ON FUMONISINS RECOVERIES * * * * 50 ml 10 g Shaking Blending CH 3 OH 100 ml 25 g SAX IMA CH 3 CN FB 1 + FB 2 recovery (%) *p < 0.05 Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

27 ANALYTICAL METHOD FOR THE DETERMINATION OF FUMONISINS IN FIVE MAIZE-BASED MATRICES SAMPLE PREPARATION EXTRACT 20g corn material with 50mL acetonitrile:methanol:water (25:25:50, v/v/v) EXTRACT 20g corn material with 50mL acetonitrile:methanol:water (25:25:50, v/v/v) SHAKE for 20 min SHAKE for 20 min CENTRIFUGE for 10 min at 4000 rpm CENTRIFUGE for 10 min at 4000 rpm FILTER the supernatant through filter paper FILTER the supernatant through filter paper EXTRACT again the remaining solid material, SHAKE, CENTRIFUGE and FILTER EXTRACT again the remaining solid material, SHAKE, CENTRIFUGE and FILTER COLLECT the extracts COLLECT the extracts DILUTE extract with PBS solution (10 mL extract + 40 mL PBS) DILUTE extract with PBS solution (10 mL extract + 40 mL PBS) FILTER through microfibre filter FILTER through microfibre filter Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

28 IMMUNOAFFINITY CLEAN-UP ELUTE 10 mL of diluted extract through the FumoniTest TM column at 1-2 drop/second WASH with 10 mL PBS at 1-2 drops/second ELUTE fumonisins with 1.5 mL CH 3 OH ANALYTICAL METHOD FOR THE DETERMINATION OF FUMONISINS IN FIVE MAIZE-BASED MATRICES Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

29 HPLC ANALYSIS EVAPORATE to dryness under nitrogen stream at ca 60°C and reconstitute with 200 µl of HPLC grade acetonitrile:water (1:1, v/v) EVAPORATE to dryness under nitrogen stream at ca 60°C and reconstitute with 200 µl of HPLC grade acetonitrile:water (1:1, v/v) DERIVATIZE 50 µL extract with 50 µL OPA reagent DERIVATIZE 50 µL extract with 50 µL OPA reagent MIX and INJECT at exactly 3 min of adding OPA reagent MIX and INJECT at exactly 3 min of adding OPA reagent Column: RP C18 Column: RP C18 Mobile phase: methanol:0.1M NaH 2 PO 4 (75:25, v/v) adjusted to pH 3.35 with H 3 PO 4 Mobile phase: methanol:0.1M NaH 2 PO 4 (75:25, v/v) adjusted to pH 3.35 with H 3 PO 4 Flow rate: 1.0 mL/min Flow rate: 1.0 mL/min Detector: fluorescence (λ ex. = 335 nm, λ em. = 440 nm) Detector: fluorescence (λ ex. = 335 nm, λ em. = 440 nm) Injected amount: 20 µL (equivalent to 20 mg of matrix) Injected amount: 20 µL (equivalent to 20 mg of matrix) ANALYTICAL METHOD FOR THE DETERMINATION OF FUMONISINS IN FIVE MAIZE-BASED MATRICES Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

30 RECOVERY AND REPEATABILITY RESULTS OBTAINED IN DIFFERENT FUMONISINS SPIKED CORN MATRICES # RSD r = Relative Standard Deviation (n= 6) * Spiking level 2 µg/g Spiking level CORN FLOUR CORN FLAKES EXTRUDED CORN Mean (%) RSD r # (%) Mean (%) RSD r # (%) Mean (%) RSD # (%) MUFFINS INFANT FORMULA 0.5 µg/g 1.5 µg/g4.2 µg/g Recovery * Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

31 EFFECT OF EXTRACTION SOLVENT COMPOSITION AND REPEATED EXTRACTIONS ON FUMONISIN RECOVERY FB 1 + FB 2 content (µg/kg) Corn flour Corn flakes Extruded corn Muffins Infant formula MeOH:water (80:20) 1 extraction (n = 3) ACN:MeOH:water (25:25:50) 1 extraction (n = 3) ACN:MeOH:water (25:25:50) 2 extractions (n = 3)

32 Laboratorycode Laboratory code M ± 1SD FB 1 mass fraction (µg/kg) FB 1 1 mass fraction (µg/kg) Mean recovery =76%;RSD r = 21% RSD R = 26% (n = 21) Mean recovery = 76 %; RSD r r = 21% RSD R R = 26% (n = 21) FB Results± 1SD Results ± 1SD Meanofmeans± 1SD Mean of means ± 1SD Laboratory code M ± 1SD Collaborative study results for corn flour spiked with FB 1 and FB 2 Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

33 STATISTICAL ANALYSIS OF COLLABORATIVE STUDY RESULTS FOR FB 1 AND FB 2 DETERMINATION IN CORN FLAKES (data from 21 laboratories) STATISTICAL ANALYSIS OF COLLABORATIVE STUDY RESULTS FOR FB 1 AND FB 2 DETERMINATION IN CORN FLAKES (data from 21 laboratories) CORNFLAKESCORNFLAKES FB 1 FB 2 SamplesSamples Blank (<50 µg/kg) Blank Spiked (800 µg/kg) Spiked naturallycontaminatednaturallycontaminated Mean (µg/kg) RSD r (%) RSD R (%) Recovery(%)Recovery(%) HORRAT ratio *85* *86* *93* Blank (<50 µg/kg) Blank Spiked (400 µg/kg) Spiked naturallycontaminatednaturallycontaminated *87* *86* *98* Data from 20 laboratories * Referred to the level estimated by the homogeneity study measurements (n = 20) 1 Data from 20 laboratories * Referred to the level estimated by the homogeneity study measurements (n = 20) Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

34  Good performances in terms of precision, accuracy and sensitivity  Clean extracts from complex matrices due to the specificity of the antibody  Well resolved and clean chromatograms  Rapid sample preparation and clean-up procedure  Limited use of dangerous organic solvents ADVANTAGES OF IMMUNOAFFINITY CHROMATOGRAPHY CLEAN-UP Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

35 Deoxynivalenol is produced by Fusarium species in cereals in the field before harvest. Occurrence of deoxynivalenol in organic and conventional cereals in Italy and conventional cereals in Italy Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY Appropriate agricultural practices is the main approach for preharvest prevention of mycotoxin formation.

36 Soft wheat Organic soft wheat Durum wheat Spelt Organic spelt Samples CEREAL SAMPLES COLLECTED IN ITALY FOR DEOXYNIVALENOL ANALYSIS Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

37 SAMPLE PREPARATION Extraction by blending with Extraction by blending with water + PEG (polyethylene glycol) CAHILL et al., J. Chromatogr. A, 1999, 859, IMMUNOAFFINITY CLEAN-UP HPLC ANALYSIS Reversed-phase C18 / UV detection (220 nm) DONTest TM column ANALYTICAL METHOD FOR THE DETERMINATION OF OF DEOXYNIVALENOL IN CEREALS Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

38 Detection limit (signal/noise = 3:1)50 ng/g IMA column capacity 3,300 ng Range of application 50-10,000 ng/g Mean recovery (range ,000 ng/g) 80% Repeatability (RSD r )* 8% PERFORMANCES OF THE ANALYTICAL METHOD FOR THE DETERMINATION OF DON IN CEREALS *RSD r = Relative Standard Deviation Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

39 Soft wheat (a) Organic soft wheat (a) Durum wheat (a) Spelt (b) Organic spelt (a) Samples Incidence of contamination Range (ng/g) Mean of positives (ng/g) 5/42 (12%) 18/35 (51%) 24/26 (92%) 7/122 (6%) 18/20 (90%) – 1, (a) Northern Italy (b) Central and Southern Italy OCCURRENCE OF DON IN FRESHLY HARVESTED KERNELS OF SMALL CEREALS (1998) Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

40 Soft wheat Organic soft wheat (a) Durum wheat Organic spelt (a) 68/112 (61%) 45/45 (100%) 92/111 (83%) 30/30 (100%) – 1, (a) Northern Italy OCCURRENCE OF DON IN FRESHLY HARVESTED KERNELS OF SMALL CEREALS (1999) Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY Samples Incidence of contamination Range (ng/g) Mean of positives (ng/g)

41 Soft wheat Organic soft wheat (a) Durum wheat 10/26 (38%) 16/36 (44%) 16/26 (61%) – 6, ,100 (a) Northern Italy OCCURRENCE OF DON IN FRESHLY HARVESTED KERNELS OF WHEAT (2000) Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY Samples Incidence of contamination Range (ng/g) Mean of positives (ng/g)

42 OCCURRENCE OF DON IN CONVENTIONAL WHEAT FROM VARIOUS ITALIAN LOCATIONS (1999) DON mean level (ng/g) DURUMSOFT North46/64(72%) Central South 14/24(58%) 8/24(33%) INCIDENCE OF CONTAMINATION 52/55(95%) 28/30(93%) 9/26(35%) Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

43 OCCURRENCE OF DON IN CULTIVARS OF CONVENTIONAL WHEAT FROM VARIOUS ITALIAN LOCATIONS (2000) SOFT WHEAT DURUM WHEAT SIMETO ZENIT ERIDANO CENTAURO DON mean level (ng/g) 6,465 ng/g 3,010 ng/g SIMETO ERIDANO Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY DON mean level (ng/g)

44 ( * ) Number of samples ( * ) Range ( * ) Samples from Emilia Romagna (Northern Italy) ANNUAL VARIATION OF DON IN ORGANIC SOFT WHEAT Mean Crop year Positives (ng/g) Median %100%44% Incidence of contamination Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

45 ( * ) Samples from Emilia Romagna (Northern Italy) %100% ANNUAL VARIATION OF DON IN ORGANIC SPELT Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY ( * ) Number of samples ( * ) RangeMean Crop year Positives (ng/g) Median Incidence of contamination

46 CORRELATION BETWEEN FUSARIUM GRAMINEARUM AND DON CONTAMINATION IN DURUM WHEAT Kernels infected by Fusarium graminearum (%) r = 0.83 DON (ng/g) Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

47 DON occurrence CONCLUSIONS  Durum wheat samples were more contaminated than soft wheat samples.  An increasing DON contamination gradient was observed from South to North.  The higest DON levels were found in durum wheat samples (up to 6,400 ng/g) collected in Lombardy (Northern Italy ).  Low levels of DON contamination were found in organically grown cereals. Consiglio Nazionale delle Ricerche, ISPA-Bari-ITALY

48 European Mycotoxin Awareness Network (EC Project QLK1 – CT – 2000 – 01248) (EC Project QLK1 – CT – 2000 – 01248)

49 The European Mycotoxin Awareness Network (EMAN) is a European Commission (EC) funded project, which is co-ordinated by Leatherhead Food International (UK). Fourteen leading mycotoxin institutions in Europe are the partners of the project, providing the most up-to-date information on all areas of mycotoxins.

50 EMAN aims in bringing the research community closer to the food industry by making data and information available through the web

51 The dissemination is through:  Newsletters  Useful links  Interactive online training courses  Fact/information sheets

52  Evaluation of Test Kits & Rapid methods of analysis  Analytical Methodology  HACCP - Prevention & Control  Detoxification - Processing & Risk Assessment  Quality Assurance - Method Validation & Confirmatory Techniques  Sampling & Legislative Means of Control  Surveillance & Occurence Fact/information sheets on:


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