Preface to the proceedings of the SASKVAL III international workshop on validation and regulatory analysis

A total of 76 participants attended the Workshop held in Calgary, Alberta, Canada. They came from Canada (39), the USA (14), Belgium (4), Qatar (3), France (3), 2 each from the Netherlands, Portugal, the UK, Ireland, and one each from the Kingdom of Saudi Arabia, Republic of Korea, Switzerland, Israel, and Hong Kong, Of these, 33 were from government, 15 were from academia, 17 were instrument and equipment manufacturers and primary producers, 10 represented industry and one was a retired government official. While the majority of participants were involved in generating the database for risk analysis and risk assessment for the veterinary drugs of interest to this community, a sizeable number of participants were risk managers directly involved in making risk policy and risk management decisions. This Proceedings captures some of the relevant contributions presented at the SASKVAL III Workshop which was organized to assemble experts from the research community and those in the non-scientific policy-forming sector involved in the primary production of agri-food and aquaculture products for which veterinary drugs are used. The goal was to provide a forum for the two groups to gain a better understanding of the underlying issues related to the practice of using these drugs in food animal production and how they impact both human health safety issues and global trade with the expectation that this would enable the development of a firm knowledge base for making sound risk assessment and risk management decisions. In addition, it was expected that the workshop would provide the required forum to assist and inform public debate on current and emerging challenges facing the agri-food industry to help increase face-to-face public debate/discussion between the scientists in the analytical community and experts involved in policy decision-making. In that regard, the workshop was designed to centre on seven themes. One of the papers submitted for publication consideration in this section Effective management tools for moving standards through the Codex Standard Setting Process at the CCRVDF, authored by Jack Kay, described how the CCRVDF develops codes of practice related to veterinary drugs and their associated residues in food of animal origin, agreeing priorities for the assessment of the safety of veterinary drugs by the Joint World Health Organization/Food and Agriculture Organization (WHO/FAO) of the United Nations Expert Committee on Food Additives (JECFA), recommending maximum residue limits (MRLs) for veterinary drugs used in food animal production and considering sampling protocols and methods of analysis for veterinary drugs.1 The next two papers were submitted under Theme 2 – Chemical Residue and Contaminant Testing: Emerging and Alternate Technologies. In today's market economy, many nutritional and health studies recommend a higher consumption of fat composed of polyunsaturated fatty acids (PUFA), mainly n-3 polyunsaturated fatty acids which are abundant in fatty fish the major natural dietary source of long chain n-3 fatty acids. Processors and producers are finding ways to increase the amount of n-3 fatty acids in animal feed by addition of linseed oil or fish oil as a way to increase human intake of those compounds through the consumption of food from animal origin other than fatty fish. Consequently, many products including meat, milk, eggs, and dairy products enriched with n-3 fatty acids can now be found in the market. Unfortunately, this practice can result in the rapid oxidation of these high polyunsaturated fatty acids to potentially cytotoxic and genotoxic aldehydes, including malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), 4-hydroxy-2-hexenal (4-HHE), crotonaldehyde (CRT), benzaldehyde (BNZ), hexanal (HXL), 2,4-nonadienal and 2,4-decadienal. A 2011 safety assessment of MDA, crotonaldehyde and 4-HNE by the Belgian Superior Health Council concluded that these compounds were of major concern for human health. To protect consumers from ingesting potentially toxic compounds, a method authored by Douny et al.2 using the latest liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform technology was validated and used to characterize and measure these aldehydes in food or animal feed to establish their residue profile in consumer products whose labels claim to contain enriched fatty acids. In the second paper submitted under this theme, Akre and Mizuno3 demonstrated how difficult it is to develop a single method for the analysis and detection of natural and synthetic steroids, stilbenes, and resorcylic acid lactones in bovine urine despite recent advances made in the detection capabilities of current platform technologies such as gas chromatography-tandem mass spectrometry (GC-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Most laboratories conducting residue testing for monitoring drug use in the food animal population in support of regulatory requirements use multi-residue methods to increase laboratory efficiencies in sample analysis and to reduce the cost of operating those laboratories. Under Theme 3 – High Throughput Analysis in Labs and Food Production – Berendsen et al.4 presented results of a recent international collaborative laboratory study to revise and update the acceptance criteria for the characteristic operational parameters including retention times, ion ratios, etc., which were previously based on single analyte methods using vintage equipment, none of which is currently available in our regulatory laboratories. In this study, the authors assessed existing criteria in the light of currently applied methodologies and developed new evidence-based criteria applicable to modern and emerging analytical methods applied in the field of veterinary drug residue testing. Datasets were constructed from the analysis of in-house prepared homogeneous materials using relevant and state-of-the-art (front end) analytical instruments, combining chromatographic separation and mass spectrometric detection techniques. These datasets provided the basis for the proposed new/amended criteria. The amended criteria were then validated by a collaborative study employing in-house prepared homogeneous unknown test materials in collaboration with residue testing laboratories from all over the world, to ensure validity of the proposed criteria for confirmatory analysis. The results of this collaborative study will be presented to the next session of the CCRVDF which will meet in October 2016 in the USA to consider how it can incorporate the new acceptance criteria for mass spectrometric detection techniques into the Codex Criteria for the Performance of Analytical Methods Used in Regulatory Monitoring Programs. Urine samples obtained from food animals are used extensively in some regulatory programmes to screen for the presence/absence of veterinary drug residues and contaminants. In North America, regulatory decisions can only be made on analysis performed directly on the edible tissue (not urine) to demonstrate that the concentration of an approved veterinary drug detected in that particular food sample exceeds the MRL defined by the Competent Authority as safe for human consumption. Kaufmann5 reviewed the practice of using advanced analytical technologies like ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC-HRMS) for veterinary drug screening of animal urine where the MRLs of those compounds in organs like muscle, kidney, or liver have been exceeded. He discussed the limitations and possibilities of the technique drawing attention to the most critical point which is the variability of the drug concentration ratio between the tissue and urine and offered strategies to manage the potential for false positive and false negative results. Ramadan et al.6 described a validated LC-MS/MS method for the quantitative analysis and confirmation of 120 pesticide residues in apples and cucumbers based on the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, Safe) approach to sample extraction. The validated method has been used for over two years in the routine analysis of these matrices in Qatar's residue monitoring programme. Matus and Boison7 reported the development and validation of a liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF/MS) method for 17 anticoccidial drugs and ractopamine residues in animal tissues quail liver, bovine kidney, liver, muscle, chicken muscle, and horse muscle. The method which describes a short extraction time of 3 h and short chromatographic run times provides test results in 1 day for 24 samples and has been demonstrated to be suitable for the analysis of an additional 110 veterinary drugs including nitroimidazoles, NSAIDs, corticosteroids, hormones, steroids, β-agonists, tranquilizers, macrolides, desoxycarbadox, phenicols, endectocides, zeranols, estradiols, fluoroquinolones, and sulphonamides. Since food is extensively traded on the world market, it is imperative that all countries involved in global trade respect the basic tenet of the World Trade Organization (WTO) that countries engaged in global trade activities adopt the scientific, risk-based standards established by the Codex Alimentarius Commission that will facilitate trade rather than become barriers to trade. In that same vein, Codex has also recommended that all laboratories providing analytical support services to the residue control programme must be accredited to an international testing standard such the ISO/IEC 1705:2005 and that the methods used in support of that work must be validated in accordance with accepted criteria. Since the EU is a major trading partner in global trade, developments in food safety issues undertaken by the EU will usually have significant implications to the rest of the trading partners. So, under Theme 4 – International Harmonization of Analytical Methods and Processes – McEvoy8 reviewed past food and feed safety crises that have shaped the development of EU food law and showed that the current flexible regulatory framework and support mechanisms underpinning its operation means that the EU is now in a much stronger position to identify and address food and feed safety incidents and prevent their escalation into crises than was the case previously. On the basis of past experience, unexpected or unforeseen events are most likely to trigger food and feed safety crises. Consequently, preparedness for such events will require ongoing investment in active and passive surveillance systems allied with vigilance on the part of all of the players in the feed and food chains, effective communication, sharing of intelligence, and coordination of activities between the member states and the European institutions. Having all of these elements in place, whilst not guaranteeing that there will never be any further food/feed safety incidents in the EU, would nevertheless appear to offer the best hope of preventing the escalation of such incidents into crises. He concluded that in this respect the EU is well placed to face future challenges. Continuing on the theme of international harmonization, van Ginkel and Sterk9 reviewed the current laboratory network system in support of residue monitoring programmes within the EU which formally started in the early 1990s and noted with interest that since then it has evolved and incorporated new techniques and methods for quality assurance and is moving in parallel with the shift at the EU headquarters itself from production-based control to risk-based control. The paradigm shift from production-based to risk-based control now is foreseen in the EU laboratory operations which will have a significant impact on the type of methodologies to be used and subsequently also on the specific roles of EU reference laboratories. In this presentation, van Ginkel and Sterk project how the laboratory operations at the EU Reference Laboratories (EURLs) will look in years to come. With all the recent scandalous events in the UK on the detection of phenylbutazone residues in meat that had intentionally been contaminated with horse meat and not properly labelled, Decloedt et al.10 presented a paper in Theme 5 – “Sports Doping: First Past the Post before Veterinary Drug Abuse –Show Cows and Race Horses” to highlight a situation that might be construed to be cheating as a result of feeding the race horse with mouldy corn (poor feed quality) or a herbal phyto-supplement. In the race-horse industry, all substances that are not allowed to be used in treating a horse in competition including most anabolic-androgenic steroids are clearly listed and posted. As zero-tolerance regulation is enforced, a question arose if the consumption of mouldy corn feed could lead to the excretion of steroids, due to the biotransformation of plant phytosterols to steroids that would lead to the implication of cheating when these are detected in the race horse. The authors used a rapid UHPLC-MS/MS analytical method, previously validated according to the Association of Official Racing Chemists (AORC) and European Commission (EC) guidelines, to measure steroids in different sample types and found that mouldy corn can develop concentrations of up to 3.0 ± 0.4 µg/kg 4-androstenedione. An herbal phyto-supplement was also shown to contain α-testosterone. The authors strongly recommended caution against the consumption of any feed or (herbal) supplement of which the detailed ingredients and quantitative analysis are unknown. Boison et al.11 presented a study which showed that the recovery of phenylbutazone (PBZ) and oxyphenbutazone (OXPBZ) residues from equine tissues are improved with the addition of a β-glucuronidase enzyme hydrolysis step. In the absence of enzymatic hydrolysis, liver tissue obtained from the horse sacrificed 6 days post dose contained the highest concentration of PBZ followed by kidney and muscle. With the additional enzymatic hydrolysis step in the sample preparation procedure, the recovery of PBZ was elevated by about a factor of 1.3 in liver, 1.4 in kidney, and 4.7 times in muscle tissues. The concentration of OXPBZ residues was highest in the kidney followed by liver but it was below the limit of quantification (LOQ) of the method for muscle using their previously published method without enzymatic hydrolysis. The authors, therefore, strongly recommended that methods developed for the analysis of PBZ and its OXPBZ metabolite consider the inclusion of this enzyme hydrolysis step. Talking about the use and monitoring of antimicrobial use in food animals without the issue of antimicrobial resistance is almost impossible. All too often though, we as chemists think we are doing a very good job by being able to measure as low as possible of the residues in the food animal. The microbiologists also believe that they are doing a very good job identifying the end points for assessment of antimicrobial resistance and communicating that information that the development of antimicrobial resistance in bacteria and the human population is on the rise sometimes making claims that this could be contributed by the consumption of low levels of antimicrobials in the foods of animal origin that consumers are exposed to. What we haven't done well yet is for both teams to come together and develop strategies to look at the issue collectively. Also to be included in this exercise is the toxicologists and policy decision-makers. We were very fortunate at this Workshop to have all the relevant groups together. So, under Theme 6 – Antibiotics in the Environment, Food Chain, Aquatic and Food Animal Production: Is There a Link to Antibiotic Resistance? – Cerniglia et al.12 provided the workshop participants with the most current update of the concern that antimicrobial new animal drugs in or on animal-derived food products at residue-level concentrations could disrupt the colonization barrier and/or modify the antimicrobial resistance profile of human intestinal bacteria. Therapeutic doses of antimicrobial drugs have been shown to promote shifts in the intestinal microbiome, and these disruptions promote the emergence of antimicrobial-resistant bacteria. To assess the effects of antimicrobial new animal drug residues in food on human intestinal bacteria, many national regulatory agencies and international committees follow a harmonized process, VICH GL36(R). The authors provide an overview of this current approach as part of the antimicrobial new animal drug approval process in participating countries, insights on the microbiological endpoints used in this safety evaluation, and the availability of new information. Daeseleire et al.13 describe some general aspects of antibiotic resistance such as microbiological versus clinical resistance, intrinsic versus acquired resistance, resistance mechanisms and transfer of resistance are briefly introduced and follow that with a description of a Belgian mission founded in 2012 to collect and analyze all data related to antibiotic use and resistance in animals in Belgium and to communicate these findings in a neutral and objective manner. One of the 10 objectives of the mission was to develop strategies that will result in a 50% reduction in antibiotic consumption in veterinary medicine in Belgium by 2020. The authors report on the achievements of this national project and described in detail the project undertaken by the Belgian Government in order to accomplish this mission. Fish and other aquatic organisms have become an increasingly source of food for human and the practice of aquaculture is and as is the to develop safe and effective drugs for treating fish In order to control and to use including veterinary The of aquaculture is to to the national objectives for development and food the of and The industry has on the use of veterinary but in to the of and consumer for safe the sector has to the potential risk associated with the use of these veterinary drugs are used in both the aquaculture and as well as being available in suitable for human the issues of antimicrobial use in food animal production are of global concern is well In countries, it is to fish with animal and which could lead to residues of drugs or in foods to an increase in antimicrobial To by the effective use of drugs for aquatic it is to the aquaculture system which the of the aquatic and the The study of the of a drug in the can provide a of information which the of or products by hydrolysis, and and the related to or An understanding of the of veterinary drugs to fish in aquatic systems might in effective and of of aquatic for and for food describes a study that was to the of and acid in aquatic systems for the effective use of of fish and which the and aquaculture systems in All veterinary drugs used in food animal production have to be to clinical and studies in a number of laboratory animals and the food animal to their being and for use in food animal The studies that to be in the process are very well and in all the studies there is a to use methods for the studies being Under Theme – and – et reviewed the general and methods for risk assessment described in Health Criteria and methods for the risk assessment of in food which the Joint of the Expert Committee on Food Additives (JECFA), to risk a from the CCRVDF, will assess veterinary drugs which are currently used under national or compounds which are used as a veterinary The authors described the different analysis tools used by to assess all compounds used as drugs to is a quality system with the process and the under which health and safety studies are and et describe the applicable for veterinary drug and a general overview of the requirements is followed by a specific and of the analytical method validation parameters and acceptance criteria of different international applied in the of veterinary drug and residue the authors some with respect to method validation and some new developments in and residue described the validated analytical methods in the risk assessment by and points that the work of will never be without the availability of validated analytical In the Boison et describe a method that was validated and used for the study of residues in and as well as tissues of

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