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The development of nontargeted screening strategy for veterinary drugs and their metabolites is very important for food safety. In this study, a nontargeted screening strategy was developed to find the potentially hazardous substances based on mass defect filtering (MDF) using liquid chromatography-high-resolution mass spectrometry. First, the drug metabolites of 112 veterinary drugs from seven classes of antimicrobials were predicted. Second, three MDF models were established, including the traditional rectangular MDF, the enhanced parallelogram MDF, and the polygonal MDF. Finally, the strategy was applied to nontargeted screening of veterinary drugs in 36 milk samples. The polygonal MDF model based on the distribution area of parent drugs and their metabolites showed a better filtering effect. After removing food components and performing MDF, about 10% of the substances remained, and four veterinary drugs and six drug metabolites were discovered and identified, showing the effectiveness of this strategy. The nontargeted screening strategy can rapidly remove interfering substances and find the suspected compounds. It can also be used for nontargeted screening of veterinary drugs and their metabolites in other food matrices.

As analytical capabilities in the early 2000s began to enable the detection of chemicals in environmental media at increasingly small concentrations, chemicals with the potential to cause adverse human and ecosystem health effects began to be found nearly ubiquitously worldwide. The types of chemicals that were targeted for analysis included natural and synthetic hormones, human and veterinary pharmaceuticals, chemicals in personal care products, novel pesticides, nanoparticles, microplastics, and other chemicals of natural and synthetic origin. The impacts of these chemicals on environmental and human health in many cases remain unknown. Collectively, these chemicals became known as "emerging contaminants" or "contaminants of emerging concern". Much progress has been made toward understanding the sources of these contaminants in the environment, the processes that control their fate and transport once they are released into the environment, and the ability of technology and/or best management practices to mitigate their occurrence. As the Journal of Environmental Quality (JEQ) celebrates its 50th anniversary, we sought to understand how publications in the journal have made impactful contributions in the research area of emerging contaminants. Here, we present the trajectory of publications in JEQ that have shaped knowledge in this field, highlight the importance of these contributions, and conclude with opportunities for JEQ to continue attracting high-quality emerging contaminants research. This article is protected by copyright. All rights reserved.

Physiologically based pharmacokinetic (PBPK) models have become important tools for the development of novel human drugs. Food-producing animals and pets comprise an important part of human life, and the development of veterinary drugs (VDs) has greatly impacted human health. Owing to increased affordability of and demand for drug development, VD manufacturing companies should have more PBPK models required to reduce drug production costs. So far, little attention has been paid on applying PBPK models for the development of VDs. This review begins with the development processes of VDs; then summarizes case studies of PBPK models in human or VD development; and analyzes the application, potential, and advantages of PBPK in VD development, including candidate screening, formulation optimization, food effects, target-species safety, and dosing optimization. Then, the challenges of applying the PBPK model to VD development are discussed. Finally, future opportunities of PBPK models in designing dosing regimens for intracellular pathogenic infections and for efficient oral absorption of VDs are further forecasted. This review will be relevant to readers who are interested in using a PBPK model to develop new VDs.

Pesticides and veterinary drugs are generally employed to control pests and insects in crop and livestock farming. However, remaining residues are considered potentially hazardous to human health and the environment. Therefore, regular monitoring is required for assessing and legislation of pesticides and veterinary drugs. Various approaches to determining residues in various agricultural and animal food products have been reported. Most analytical methods involve sample extraction, purification (cleanup), and detection. Traditional sample preparation is time-consuming labor-intensive, expensive, and requires a large amount of toxic organic solvent, along with high probability for the decomposition of a compound before the analysis. Thus, modern sample preparation techniques, such as the quick, easy, cheap, effective, rugged, and safe method, have been widely accepted in the scientific community for its versatile application; however, it still requires a laboratory setup for the extraction and purification processes, which also involves the utilization of a toxic solvent. Therefore, it is crucial to elucidate recent technologies that are simple, portable, green, quick, and cost-effective for onsite and infield residue detections. Several technologies, such as surface-enhanced Raman spectroscopy, quantum dots, biosensing, and miniaturized gas chromatography, are now available. Further, several onsite techniques, such as ion mobility-mass spectrometry, are now being upgraded; some of them, although unable to analyze field sample directly, can analyze a large number of compounds within very short time (such as time-of-flight and Orbitrap mass spectrometry). Thus, to stay updated with scientific advances and analyze organic contaminants effectively and safely, it is necessary to study all of the state-of-art technology.

Veterinary biocides used in animal husbandry have the potential to cause human health concerns. Biocidal products for veterinary use, which contain pesticides approved in Korea, comprise 49 active ingredients within 234 products. Within 17 of these products there are 3 ingredients which are highly hazardous pesticides: coumaphos, dichlorvos and methomyl. In this study, the content of the active ingredients of 160 products sold domestically was investigated. Samples were collected for 119 biocidal products for veterinary use. These were analysed by high‐performance liquid chromatography (HPLC) and gas chromatography (GC). Seventeen products were noncompliant (insufficient or excess quantity of active ingredients). The ingredients that were below the stated concentrations were amitraz, chlorpyrifos‐methyl, cypermethrin, cyromazine, dichlorvos, fipronil, muscamone and trichlorfon. The ingredients that exceeded the stated concentrations were abamectin, fluvalinate and pyriproxyfen. The noncompliance rate in biocidal products for veterinary use was 9.19%. The results of this study show that three highly hazardous pesticides (coumaphos, dichlorvos and methomyl) and 10 active ingredients (abamectin, amitraz, chlorpyrifos‐methyl, cypermethrin, cyromazine, fipronil, fluvalinate, muscamone, pyriproxyfen and trichlorfon) deviated from the stated concentrations. Thus, management plans should be established to ensure compliant veterinary drugs by post‐distribution quality control, such as planning for regular inspection., Three highly hazardous pesticides (coumaphos, dichlorvos and methomyl) and 10 active ingredients (abamectin, amitraz, chlorpyrifos‐methyl, cypermethrin, cyromazine, fipronil, fluvalinate, muscamone, pyriproxyfen and trichlorfon) deviated from the stated concentrations. Thus, management plans should be established to distribute compliant veterinary drugs by post‐distribution quality control, such as planning inspection.

Residues of veterinary drugs in poultry meat have serious health effects on humans (e.g., antimicrobial resistance, carcinogenicity, and hypersensitivity), which make the control of veterinary drug residues an important parameter in ensuring consumer protection. This work was performed to quantitatively determine two co-formulated anti-infective veterinary agents, tylosin tartrate (TYT) and doxycycline hydrochloride (DOX) in different tissues of broiler chickens (liver, muscles, and fat) using high performance liquid chromatography. The chicken was treated with the recommended dose of a binary mixture of the drugs (Tydovet). Moreover, the study aimed to estimate the withdrawal time of both drugs in chicken tissues. The analysis was done by solvent extraction and solid-phase extraction for clean-up of samples from the tissue matrix, followed by liquid chromatographic determination of the cited drugs with UV-detection. Residue decline with time was tracked, and both antibiotics were found to be more persistent in liver tissues than other tissues (muscle and fat). The effect of freezing and cooking was investigated on tissue residue levels. While freezing had little effect on the concentration of both antibiotics; cooking, as anticipated, led to a marked decline. Therefore, it is recommended to pay attention to the proper withdrawal periods before marketing to ensure the hygienic suitability of broilers edibles for safe human consumption. PRACTICAL APPLICATION: This novel study measures tylosin and doxycycline residues simultaneously in different tissues (muscle, fat, and liver) after administration of Tydovet powder to the broiler chicken. Residues in fat persisted for a longer time than in muscle in case of TYT, whereas the reverse was noticed in DOX.

Alternatives to the use of conventional veterinary drugs in food-producing animals have gained attention, such as the use of natural products (NPs), mainly to soften the risks to the animal, the environment, and consumer's health. Although NPs have consistent advantages over conventional drugs, they cannot be considered risk free under food safety matters. In this way, this document presents a comprehensive overview of the importance of considering both the pharmacological and toxicological properties of the constituents of a NP from plants intending the standardization and regulation of its use in food-producing animals. Terpenes are the most diverse class of natural substances present in NP of vegetal origin with a broad range of biological activities that can be explored in veterinary science; however, certain plants and terpenes also have significant toxic effects, a fact that can harm the health of animals and consequently generate economic losses and risks for humans. In this context, this review gathered scientific data of vegetal species of importance to ethnoveterinary for food-producing animals, which produce terpenes, its biological effects, and their implications on food safety issues for consumers. For this, more than 300 documents were selected from different online scientific databases. The present data and discussion may contribute to the rational commercial exploration of this class of NPs in veterinary medicine.

Background Proton pump inhibitors (PPIs) are among the most commonly prescribed medications for esophagitis and upper gastrointestinal erosion and ulceration in cats. Newer PPIs such as lansoprazole and esomeprazole are believed to be effective in cats, but the effect of many of these PPIs on gastric pH in cats has not been explored. Hypothesis/objectives To evaluate the efficacy of PO esomeprazole, dexlansoprazole, and lansoprazole on intragastric pH in healthy cats. We hypothesized that esomeprazole and lansoprazole would provide superior acid suppression compared to dexlansoprazole and reach pH goals extrapolated from people for the treatment of esophagitis and duodenal ulceration. Animals Twelve healthy research cats. Methods Randomized, 3-way crossover study. Cats were given esomeprazole and lansoprazole at a dosage of 1 mg/kg PO q12h or dexlansoprazole at 6 mg/kg PO q12h. Intragastric pH was recorded at baseline and for 4 days of treatment. Mean pH and the mean percentage time (MPT) intragastric pH was ≥3 or ≥4 were compared among and within treatment groups. Results Cats treated with lansoprazole had a lower MPT ± SD of intragastric pH ≥3 (8.8 ± 6.8%) and mean ± SD pH (1.6 ± 0.5) than did cats treated with dexlansoprazole (41.2 ± 34.6% and 3.11 ± 1.6, respectively) or esomeprazole (54 ± 33.8% and 4.1 ± 3.9, respectively;P ≤ .04). Esomeprazole was the only treatment that achieved the goals defined for people for the treatment of duodenal ulceration by Day 4 of treatment (MPT ± SD of intragastric pH ≥4 of 77.1 ± 29.2%). Conclusions and clinical importance Orally administered esomeprazole might be a superior acid suppressant in cats compared to PO lansoprazole or dexlansoprazole.

A review of 79 papers published in 2019 is presented. The topics ranged from detailed descriptions of analytical methods, to fate and occurrence studies, to ecological effects and sampling techniques for a wide variety of emerging contaminants likely to occur in agricultural environments. New methods and studies on veterinary pharmaceuticals, antibiotics, anthelmintics, and engineered nanomaterials in agricultural environments continue to expand our knowledge base on the occurrence and potential impacts of these compounds. This review is divided into the following sections: Introduction, Analytical Methods, Antibiotics in Agroecosystems, Pharmaceutical Fate and Occurrence, Anthelmintics and Engineered Nanomaterials. PRACTITIONER POINTS: New research describes innovative new techniques for emerging contaminant detection in agricultural settings Newer classes of contaminants include human and veterinary pharmaceuticals Research in nanomaterials show that these also occur in agricultural environments and will likely be topics of future work.

BACKGROUND Sulfamethazine (SMZ), a veterinary drug widely used in animal husbandry, is harmful to human health when excess residues are present in food. In this study, a fast, reliable, and sensitive immunochromatographic assay (ICA) was developed on the basis of the competitive format by using time-resolved fluorescent nanobeads (TRFN) as label for the detection of SMZ in egg, honey, and pork samples. RESULTS Under optimized working conditions, this method had limits of detection of 0.016, 0.049, and 0.029 ng mL-1 and corresponding linear ranges of 0.05 to 1.00, 0.05 to 5.00, and 0.05 to 1.00 ng mL-1 in egg, honey, and pork samples, respectively. The recovery experiments showed that the average recoveries ranged from 90.5% to 113.9%, 82.4% to 112.0%, and 79.8% to 93.4% with corresponding coefficients of variation of 4.1% to 11.7%, 7.5% to 11.5%, and 4.8% to 8.7% for egg, honey, and pork samples, respectively. The developed TRFN-ICA was also systematically compared with high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) by analyzing 45 actual samples from egg, honey, and pork. CONCLUSION Overall, the developed TRFN-ICA had high reliability and excellent potential for the ultrasensitive detection of SMZ for food safety monitoring, also providing a universal platform for the on-site detection of other targets. © 2020 Society of Chemical Industry.

The use of veterinary drugs in food-producing animals may result in the presence of low levels of drug residues in these edible, animal-derived foods, with potential dietary exposure to humans. Since therapeutic doses of antibiotics have been shown to affect bacterial populations in the gastrointestinal tract microbiome and can also promote the emergence of antibiotic-resistant bacteria, there is concern that animal drugs at residue level concentrations could also perturb the intestinal microbiome composition and modify the antimicrobial resistance profile of the human intestinal microbiota. This review provides updated information on the VICH GL#36(R2), on evaluating the safety of veterinary drug residues in animal-derived foods and their effects on the human intestinal microbiome; discusses critical research knowledge gaps and challenges in evaluating the impact of drug residues in animal-derived foods on the human intestinal microbiome; and analyzes integrated basic and applied research approaches, currently being conducted at FDA, on studies that specifically address key regulatory science questions. Moreover, this review aims to emphasize future research needs on scientific methodology and provides general recommendations on drug inactivation, bioavailability, and antimicrobial resistance, to improve the safety evaluation and risk assessment of antimicrobial residues and their impact on the gastrointestinal microbiota, with the goal of ensuring food safety.

Infant formulas are manufactured products to meet specific nutritional requirements for infants. However, infant formulas can contain harmful substances, such as chemical contaminants and residues, normally due to possible contamination of the raw material or from the production chain. Some studies have demonstrated that veterinary drugs, pesticides, mycotoxins, heavy metals, packaging materials, within other chemicals are found in infant formulas from different sources of contamination. It is known that some of these substances can be hepatotoxic, carcinogenic, teratogenic, mutagenic, immunotoxic, contributing to antibiotic resistance, among other detrimental consequences for consumers' health. The purpose of this review is to assess the scientific evidence concerning the occurrence, sources, and pathways of contamination, as well as the detrimental impacts on infant health due to the possible presence of chemical contaminants and residues in infant formulas. Moreover, strategies to reduce the risk of contamination of infant formulas are presented to ensure the highest standards of quality of infant formulas. The entire infant formula manufacturing process should be monitored and controlled to minimize the risk of contamination during processing, storage, and distribution, besides ensuring the use of raw materials with as low as acceptable levels of harmful substances in order to assure that the final product shall comply with the maximum levels and maximum residue limits, when established, for residues and contaminants in the final product.

The humankind is pretty dependent on food to control several biological processes into the organism. As the world population increases, the demand for foodstuffs follows the same trend claiming for a high food production situation. For this reason, a substantial amount of chemicals is used in agriculture and livestock husbandries every year, enhancing the likelihood of contaminated foodstuffs being commercialized. This outlook becomes a public health concern; thus, the governmental regulatory agencies impose laws to control the residues and contaminants in food matrices. Currently, one of the most important analytical techniques to perform it is LC. Despite its already recognized effectiveness, it is often time consuming and requires significant volumes of reagents, which are transformed into toxic waste. In this context, miniaturized LC modes emerge as a greener and more effective analytical technique. They have remarkable advantages, including higher sensitivity, lower sample amount, solvent and stationary phase requirements, and more natural coupling to MS. In this review, most of the critical characteristics of them are discussed, focusing on the benchtop instruments and their related analytical columns. Additionally, a discussion regarding the last 10 years of publications reporting miniaturized LC application for the analysis of natural and industrial food samples is categorized. The main chemical classes as applied in the crops are highlighted, including pesticides, veterinary drugs, and mycotoxins.

It is often difficult to compare studies examining the effects of endectocides on dung fauna because of different experimental approaches, for example, active ingredients (eprinomectin, doramectin, ivermectin, moxidectin) and formulations (injectable, pour-on, spiked). To gain a better understanding, we performed a quantitative meta-analysis using 22 studies to assess the overall effect of endectocide residues on the occurrence (presence or absence) and abundance of aphodiine dung beetles. Our results document a positive effect on the occurrence of adult beetles, indicating that adults tend to be attracted to dung with residues. Conversely, larvae are less likely to occur in the presence of residues. Thus, either adults that colonize dung with residues do not lay eggs or, more likely, the larvae that hatch from these eggs die early in development. Abundance of adult and larval stages was shown to be significantly reduced in dung containing residues. When individual endectocides were compared, only ivermectin demonstrated a significantly negative effect on the abundance of both adults and larvae, possibly owing to a small sample size for other agents. In laboratory studies, only dung "spiked" with endectocides reduced the abundance of larvae, whereas during field research, only pour-on applications were shown to reduce the abundance of larvae. The present study further documents the nontarget effects of endectocide residues on dung-dwelling organisms, provides robust evidence on the consequences of different application methods, and emphasizes the need for standardized methodological techniques in future studies. Environ Toxicol Chem 2020;39:863-872. © 2020 SETAC.

MALDI-TOF MS approach for determination of six quinolones residues in fillets of pangasius (Pangasionodon hypophthalmus) was studied, considering that is a very sensitive analytical technique with simple and high-throughput operation, contributing to knowledge regarding application of this technique to the determination of small-molecular-weight organic compound residues in foods. LIFT-MS/MS showed to be a successful approach to identify the presence of all quinolone residues in the fish fillet, at their respective MRL level. This study opens an important field of research for the development of simple and high-throughput bioanalytical screening methods for the determination of veterinary drug residues in foods.

In the Southern High Plains of the United States, beef cattle feed yards and row crop agriculture are predominant sources of agrochemical usage. Beef cattle feed yards use large quantities of veterinary pharmaceuticals to promote cattle growth and health, along with insecticides to control insect pests, whereas row crop-based agriculture relies on herbicides, fungicides, and insecticides to increase yields. Previous studies have documented the occurrence of agrochemicals beyond feed yard and row crop agriculture boundaries in uncultivated, marginal areas, raising concern that migratory pollinators and pollinators indigenous to the Southern High Plains frequenting these remaining habitat corridors may become exposed to toxic agrochemicals. Larvae of the painted lady butterfly (Vanessa cardui) were used to investigate the potential toxicity of agrochemicals used on feed yards and in row crop agriculture among pollinators. Moxidectin, an antiparasiticide used on beef cattle feed yards, was determined to be extremely toxic to V. cardui larvae, with a lethal dose at which 50% of larvae died of 2.1 ± 0.1 ng/g. Pyraclostrobin, clothianidin, and permethrin all delayed V. cardui development. However, moxidectin was the only chemical that produced significant toxic effects at environmentally relevant concentrations. These results indicate that agrochemicals originating from feed yards have the potential to adversely impact the development of pollinator larvae occurring in the Southern High Plains. Environ Toxicol Chem 2019;38:2629-2636. © 2019 SETAC.

Rationale Electrospray ionization mass spectrometry (ESI-MS) in conjunction with liquid chromatography (LC) can provide accurate quantitative data, but it is not well-suited for the rapid screening (RS) of analytes incurred into complex matrices. This study was designed to determine the usefulness of ESI for rapid detection and quantitation of veterinary drugs from complex biological matrices under near real-time conditions. Methods Nine veterinary drugs or metabolites, clenbuterol, erythromycin, flunixin, 5-hydroxyflunixin, meloxicam, ractopamine, salbutamol, tylosin and zilpaterol, present in cow urine, sheep urine, sheep tissues (kidney, muscle, liver and lung) or pig kidney, were simultaneously analyzed. A simple sample clean-up procedure, which included dilution with 10% sodium carbonate followed by extraction with ethyl acetate, was used. For tissues, an additional pre-extraction with hexane was performed to remove fat prior to MS analysis. Samples were introduced into the mass spectrometer through the LC autosampler, but no chromatographic separation was employed. A Sciex 5600+ triple time-of-flight mass spectrometer with a dual-spray source interfaced with a Shimadzu Nexera LC system was used. Samples were analyzed in positive ion mode. Results Sample extraction times were typically 10-30 min or less and instrumental analysis time was 1 min/sample. Regression coefficients of matrix-matched standard curves across all compounds ranged from 0.9701-0.9999 in urine (cow and sheep) and tissues (sheep kidney, liver, lung, muscle and pig kidney). Limits of detection ranged from 0.11 to 2.03 ng/mL across analytes in urine and 0.11 to 8.86 ng/g across tissues. Correlations between RS-ESI-MS and LC/MS/MS results were 0.956 to 0.998 for incurred residues of flunixin in cow urine, ractopamine in pig kidney and zilpaterol in sheep urine. Conclusions RS-ESI-MS provided rapid, sensitive, and accurate analyses of nine veterinary drugs from complex matrices with very little sample preparation and produced quantitative data akin to LC/MS/MS.

Rationale A current trend in monitoring chemical contaminants in animal products is to use high-resolution mass spectrometry (HRMS). In this study, several HRMS data acquistion modes using Orbitrap MS for simultaneous full-scan MS in combination with MS2 analysis were evaulated for their effectiveness in detecting and identifying both targeted and non-targeted veterinary drug residues in aquacultured eel samples. Methods Sample preparation consisted of an acidic acetonitrile extraction with solid-phase extraction cleanup for analysis using LC/HRMS. Different data acquisition methods, including full-scan MS with non-targeted all ion fragmentation (AIF), multiplexed or variable data-independent analysis (mDIA or vDIA), targeted data-dependent MS2 (DDMS2), and parallel reaction monitoring (PRM) acquisition, were explored. The methods were evaluated with fortified eel tissue and imported eel samples to determine how many analytes could be detected and identified. Results For non-targeted data acquisition, the number of analytes detected using DIA methods matched the results obtained by AIF, but the resulting product ion scans were more diagnostic because characteristic ions were predominant in the DIA MS2 spectra. In targeted analysis for a limited list of 68 compounds, full-scan MS followed by PRM was advantageous compared with DDMS2 because high-quality MS2 spectra were generated for almost all the analytes at target testing levels. Conclusions For residue screening, AIF has fast MS1 scan speed with adequate detection of product ions but may lead to false positive findings. DIA methods are better suited to monitor for both targeted and non-targeted compounds because they generate more characteristic MS2 spectra for retrospective library searching. For follow-up targeted analysis, PRM is prefered over DDMS2 when searching for a limited set of compounds.

Rationale Carry-over is an undesirable contamination from medicated to non-medicated during the production of feedingstuffs. In 2014 the European Parliament and the Council started working to produce a new regulatory act that will fix tolerable levels of drugs by carry-over in non-target feed to have a harmonized practice to evaluate this contamination by veterinary drugs. Methods We developed a rapid and effective multi-analyte method coupling ultraperformance liquid chromatography to tandem mass spectrometry (UPLC/MS/MS) for the detection of 37 drugs belonging to different classes of antimicrobials (sulfonamides, tetracyclines, macrolides, quinolones, pleuromutilins and streptogramins) in feeds at carry-over levels. The method was in-house validated in the concentration range 0.25-2.0 mg kg-1 , according to the Regulation (UE) 2017/625 requirements and the guideline included in the Commission Decision 2002/657/EC for official methods. Results The UPLC/MS/MS method allows the determination of the antimicrobials in 15 min, by providing results compliant to the criteria established by the European Commission legislation. All the analytes showed a limit of detection (LOD) in the range 2.0-5.0 μg kg-1 and a limit of quantification (LOQ) at 10.0 μg kg-1 ; oxytetracycline, doxycycline, spiramycin and virginiamycin have a higher LOD and LOQ (15.0 μg kg-1 ; 30.0 μg kg-1 , respectively). Recoveries were satisfactory ranging from 90.4% to 103.1%. Conclusions The method is characterized by an effective clean-up of all drugs without the use of large sample size and organic solvent extraction.

Edible insects are expected to become an important nutrient source for animals and humans in the Western world in the near future. However, before insects can be put on the market, the safety of their use for feed and food is warranted. This literature study was prepared to provide an overview of the actual knowledge of possible food safety hazards, including chemical, microbiological, and allergenic agents and prions, to human and animal health upon the use of insects for food and feed, and to highlight data gaps and suggest the way forward. From the data available, heavy metals of concern are cadmium in black soldier fly and arsenic in yellow mealworm larvae. Investigated mycotoxins do not seem to accumulate. Residues of pesticides, veterinary drugs, and hormones, as well as dioxins and PCBs, are sometimes found in insects. Contamination of insects with pathogens to human health is a consequence of a combination of the substrates used and the farming and processing steps applied. Insects harbor a wide variety of microorganisms, and some human pathogenic bacteria may be present. In addition, insects may harbor and transmit parasites. There is no evidence so far insects may harbor pathogenic viruses or prions, but they may act as vectors. Insects and insect-derived products may have allergenic potential. In this review, evidence on some safety aspects is displayed, and data gaps are identified. Recommendations are given for future research to fill the most relevant data gaps.

The much anticipated review of ‘under our care’ by the RCVS, alongside its evolving stance on remote prescribing, prompts us to write on behalf of the Arwain Vet Cymru project. We at Arwain Vet Cymru are in the process of rolling out training support for a national network of veterinary prescribing champions across Wales, with every practice providing farm animal services in Wales given the opportunity to have a representative in the network. We have over 80 per cent of practices actively engaged in the training, which culminates in the implementation of a bespoke antimicrobial stewardship intervention in each participating practice. An early outcome of the project shows that there is deep concern among many …

A gradient elution high-performance liquid chromatographic method with a diode array detector is introduced for the first time for the simultaneous estimation of three drugs, namely, oxytetracycline hydrochloride (OXT), lidocaine (LDC), and bromhexine hydrochloride (BRH), in a veterinary formulation (OxyClear® solution) that contains many interfering additives. The method used a C-8 column. The chromatographic eluting solution included acidified water (0.1% trifluoroacetic acid in water) and acetonitrile at a 1-ml/min flow rate and 254 nm as a nominated detection wavelength. The chromatographic process was assessed in terms of linearity, precision, accuracy, LOD, and LOQ. OXT, LDC, and BRH were linear in the range of 1-60, 5-100, and 1-60 μg/ml, respectively. The three drugs were determined successfully without the interference of three excipients having UV absorbances. Furthermore, the purities of the peaks of the three drugs were confirmed by comparing the UV spectra of investigated peaks to the UV reference spectra in Clarke's Analysis of Drugs and Poisons. The greenness value of the method was 0.69 with a faint green-colored pictogram using the AGREE tool. These merits recommend the application of the planned method in QC laboratories for purity testing and concentration assays for the pure drugs and commercial formulations.

Monitoring of dairy products should preferably focus on the most relevant food safety hazards in the dairy supply chain. For this purpose, the possible presence of microbiological, chemical, and physical hazards as well as trends in the dairy supply chain that may affect their presence were assessed. A literature review was combined with available data from EFSA, RASFF, and the Dutch monitoring program on chemical hazards as well as expert information. This study revealed that microbiological hazards are encountered more frequently in dairy products than chemical and physical hazards. Listeria monocytogenes, Staphylococcus aureus, Salmonella, and human pathogenic Escherichia coli were identified as the most important microbiological hazards in dairy products. Soft and semisoft cheeses are most frequently associated with L. monocytogenes and S. aureus enterotoxins, whereas raw milk is most frequently associated with human pathogenic E. coli and Campylobacter spp., Cronobacter spp., and Salmonella spp. are the microbiological hazards of most concern in powdered infant formula. Based on literature, monitoring, and RASFF data, the most relevant chemical hazards in dairy products are aflatoxin M1, dioxins, and dioxin-like compounds and residues of veterinary drugs. Chemical hazards primarily occur at the dairy farm and may accumulate during further processing. The most relevant physical hazards are metal, glass, and plastic particles introduced during processing. Analysis of trends in the near future revealed that increased milk production is seen as most relevant in relation to food safety. Other trends affecting food safety are climate change and changes at the farm level, which aim to improve animal welfare and environmental sustainability.

A simple multiresidue method was developed for detecting and quantifying 92 veterinary antimicrobial drugs from eight classes (β-lactams, quinolones, sulfonamides, tetracyclines, lincomycins, macrolides, chloramphenicols, and pleuromutilin) in livestock excreta and water by liquid chromatography with tandem mass spectrometry. The feces samples were extracted by ultrasound-assisted extraction with a mixture of acetonitrile/water (80:20, v/v) and edetate disodium, followed by a cleanup using solid-phase extraction with an amino cartridge. Water samples were purified with hydrophilic-lipophilic balance solid-phase extraction column. Urine samples were extracted with acetonitrile and edetate disodium. Detection of veterinary antimicrobial drugs was achieved by liquid chromatography with tandem mass spectrometry using both positive and negative electrospray ionization mode. The recovery values of veterinary antimicrobial drugs in feces, urine, and water samples were 75-99, 85-110, and 85-101% and associated relative standard deviations were less than 15, 10, and 8%, respectively. The limits of quantification in feces, urine, and water samples were 0.5-1, 0.5-1, and 0.01-0.05 μg/L, respectively. This method was applied to determine real samples obtained from local farms and provides reliable quantification and identification results of 92 veterinary antimicrobial drugs in livestock excreta and water.

Veterinary drugs administered to food animals primarily enter ecosystems through the application of livestock waste to agricultural land. Although veterinary drugs are essential for protecting animal health, their entry into the environment may pose a risk for nontarget organisms. A means to predict environmental concentrations of new veterinary drug ingredients in soil is required to assess their environmental fate, distribution, and potential effects. The Canadian predicted environmental concentrations in soil (PECsoil) for new veterinary drug ingredients for use in intensively reared animals is based on the approach currently used by the European Medicines Agency for VICH Phase I environmental assessments. The calculation for the European Medicines Agency PECsoil can be adapted to account for regional animal husbandry and land use practices. Canadian agricultural practices for intensively reared cattle, pigs, and poultry differ substantially from those in the European Union. The development of PECsoil default values and livestock categories representative of typical Canadian animal production methods and nutrient management practices culminates several years of research and an extensive survey and analysis of the scientific literature, Canadian agricultural statistics, national and provincial management recommendations, veterinary product databases, and producers. A PECsoil can be used to rapidly identify new veterinary drugs intended for intensive livestock production that should undergo targeted ecotoxicity and fate testing. The Canadian PECsoil model is readily available, transparent, and requires minimal inputs to generate a screening level environmental assessment for veterinary drugs that can be refined if additional data are available. PECsoil values for a hypothetical veterinary drug dosage regimen are presented and discussed in an international context. Integr Environ Assess Manag 2017;13:331-341. © 2016 Her Majesty the Queen in Right of Canada. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of SETAC. Reproduced with the permission of the Minister of Health.

The human gastrointestinal tract ecosystem consists of complex and diverse microbial communities that have now been collectively termed the intestinal microbiome. Recent scientific breakthroughs and research endeavours have increased our understanding of the important role the intestinal microbiome plays in human health and disease. The use of antimicrobial new animal drugs in food-producing animals may result in the presence of low levels of drug residues in edible foodstuffs. There is 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), which was issued by a trilateral organization of the European Union, the USA, and Japan called the International Cooperation on Harmonization of Technical Requirements for Veterinary Medicinal Products (VICH). The guidance describes a general approach currently used by national regulatory agencies and international committees to assess the effects of antimicrobial new animal drug residues in animal-derived food on human intestinal bacteria. The purpose of this review is to provide an overview of this current approach as part of the antimicrobial new animal drug approval process in participating countries, give insights on the microbiological endpoints used in this safety evaluation, and discuss the availability of new information. Copyright © 2016 John Wiley & Sons, Ltd.

The Joint Food and Agriculture Organization and World Health Organization (FAO/WHO) Expert Committee on Food Additives (JECFA) is one of three Codex committees tasked with applying risk analysis and relying on independent scientific advice provided by expert bodies organized by FAO/WHO when developing standards. While not officially part of the Codex Alimentarius Commission structure, JECFA provides independent scientific advice to the Commission and its specialist committees such as the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) in setting maximum residue limits (MRLs) for veterinary drugs. Codex methods of analysis (Types I, II, III, and IV) are defined in the Codex Procedural Manual as are criteria to be used for selecting methods of analysis. However, if a method is to be used under a single laboratory condition to support regulatory work, it must be validated according to an internationally recognized protocol and the use of the method must be embedded in a quality assurance system in compliance with ISO/IEC 17025:2005. This paper examines the attributes of the methods used to generate residue depletion data for drug registration and/or licensing and for supporting regulatory enforcement initiatives that experts consider to be useful and appropriate in their assessment of methods of analysis. Copyright © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd.

Maximum residue limits (MRLs) for residues of veterinary drugs are the maximum concentrations of residues permitted in or on a food by national or regional legislation. In the process of MRLs recommendations by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), analysis of pharmacokinetic data describing the ADME process (absorption, distribution, metabolism and excretion) is a crucial step and requires the use of different pharmacokinetic tools. The results of animal metabolism studies are the prime determinants of the residue definition in food commodities. Substances labelled with radioactive isotopes are used so that the disposition of the residue can be followed as total residue and main metabolites concentrations. Residue depletion studies with radiolabelled parent drug will lead to the estimate of the time course of the total residue and to determine a marker residue. Depletion studies with an unlabelled drug provide more information on the time course of the marker residue in raw commodities after administration under approved practical conditions of use. By use of this information and after conversion with the total/residue marker ratio, MRLs are derived by comparison of the acceptable daily intake with the daily intakes calculated with different scenarios of dietary exposure. Progress in pharmacokinetic model such as physiologically based pharmacokinetics and population pharmacokinetics will drive the future research in this field to improved veterinary drug development. Copyright © 2016 John Wiley & Sons, Ltd.

The degradation of veterinary drugs approved for use in aquaculture is very important in the evaluation of the impact of these drugs on the environment and to ensure safe food production. The purpose of this study is to provide guidance on how the interpretation of environmental fate data can be used by applicants to aid in protecting the environment and for the basis for food production, by suggesting the correct interpretation of data as part of an effective registration process. Tests were performed using a modification of the Organisation for Economic Co-operation and Development (OECD) 308 guideline using erythromycin and oxolinic acid under combinations of aerobic and anaerobic conditions, with and without sediment, in sea water and fresh water. Estimated DT50 s of erythromycin in fresh and sea water ranged from 6.8 to 37.9 days and estimated DT90 s were from 22.6 to 125.9 days. Degradation was more rapid in fresh water than in sea water with the formation of three degradation products: anhydroerythomycin A, erythromycin A enol ether, and pseudoerythomycin A enol ether. Estimated DT50 s of oxolinic acid in fresh and sea water were from 10.3 to 63.0 days and estimated DT90 s were from 34.3 to 209.4 days which suggests that oxolinic acid is more persistent in the environment than erythromycin. Copyright © 2016 John Wiley & Sons, Ltd.

Advanced analytical technologies like ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry can be used for veterinary drug screening of animal urine. The technique is sufficiently robust and reliable to detect veterinary drugs in urine samples of animals where the maximum residue limit of these compounds in organs like muscle, kidney, or liver has been exceeded. The limitations and possibilities of the technique are discussed. The most critical point is the variability of the drug concentration ratio between the tissue and urine. Ways to manage the false positive and false negatives are discussed. The capability to confirm findings and the possibility of semi-targeted analysis are also addressed. Copyright © 2016 John Wiley & Sons, Ltd.

Spain holds > 95% of the European breeding population of the Eurasian griffon vulture Gyps fulvus. Vultures provide important ecosystem services in carcass removal and influence emissions of greenhouse gases. Despite the known toxicity of the non-steroidal anti-inflammatory drug diclofenac to this species and other Gyps vultures, in March 2013 the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) approved the use of two medicines containing diclofenac for veterinary use in horses, pigs and cattle in Spain. To assess the potential impact of medicated ungulate carcasses on Eurasian griffon vulture populations in Spain, we first used information on the metabolism and elimination of diclofenac from medicated cattle and pigs to calculate residue levels in relation to time elapsed between dosing and death. Secondly, probabilities of the death of a vulture per meal were calculated based upon experimental studies of diclofenac toxicity. Finally, annual numbers of vulture deaths expected to be caused by diclofenac were obtained by multiplying the death rates per meal by the estimated numbers of vulture meals taken from expected numbers of medicated carcasses suggested by AEMPS. Assuming that vultures feed on carcasses that were treated with diclofenac 8 h before the animal's death, the annual number of vulture deaths caused by diclofenac was estimated at 715–6389, depending upon the estimate of numbers of medicated carcasses assumed and the version of the dose–response model used. Using a density-independent simulation model of a vulture population, the expected rate of decline of the Spanish population of Eurasian griffon vultures caused by these deaths is 0·9–7·7% per year. A density-dependent simulation model also indicated substantial population-level effects. Formal estimates of precision and sensitivity analyses of effects of unmeasured variables highlight the uncertainty of estimates using currently available data. Synthesis and applications. Due to the possibility of causing an important impact on vulture populations, our findings justify a precautionary ban on the veterinary use of diclofenac in Spain and encourage the use of meloxicam, a vulture-safe alternative drug. A programme of monitoring of non-steroidal anti-inflammatory drug contamination of ungulate carcasses available to vultures and of moribund and dead obligate and facultative avian scavengers would be needed to be confident that a damaging level of contamination is not present., A. Margalida was upported by a Ramón y Cajal research contract from the Ministry of Economy and Competitiveness (RYC-2012-11867). J.A. Sanchez-Zapata, J. A. Donázar and A. Margalida were funded by project CGL2012-40013-CO2-01-02 and CGL2015-66966-C2-1-2-R.

This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

The use of antibiotics in agriculture, particularly in food-producing animals, is pervasive and represents the overwhelming majority of antibiotic use worldwide. The link between antibiotic use in animals and antibiotic resistance in humans is unequivocal. Transmission can occur by ingesting undercooked meats harboring resistant bacteria, by direct contact of animals by animal handlers, and by various other means. Antibiotics used in aquaculture and antifungals used in horticulture are also an evolving threat to human health. Regulations aimed at decreasing the amount of antibiotics used in food production to limit the development of antibiotic resistance have recently been implemented. However, further action is needed to minimize antibiotic use in agriculture. This article describes the extent of this current problem and serves as the official position of the Society of Infectious Diseases Pharmacists on this urgent threat to human health.

Rationale Previously, we have reported a liquid chromatography/tandem mass spectrometry method for the identification and quantification of regulated veterinary drugs in food animals. The method uses three selected transition ions per analyte but structural characterization is also needed. This work is a continuation of two previous publications in which we propose structures of the selected transition ions of 130 veterinary drugs altogether. Methods In this work, 24 additional veterinary drugs were analyzed by infusion into a high-resolution quadrupole time-of-flight (QTOF) mass spectrometer using electrospray ionization (ESI) in positive or negative mode. The TOF analyzer was calibrated to achieve low error mass accuracy in the MS and MS/MS modes. Also, the MS2 and MS3 spectra were obtained by using a Q-Trap mass spectrometer to further determine the possible pathways of ion formation. Results The low error mass spectrometry analysis allowed the elucidation of the ion formulae of selected transition ions for qualitative identification. The rational interpretation of data including a review of the published literature led to the proposed structures of the MS/MS product ions of 24 compounds covering two classes of regulated veterinary drugs (anthelmintics and thyreostats). In addition, the use of MS2 and MS3 experiments led to the establishment of fragmentation patterns. Conclusions The identification and quantification of veterinary drug residues is helpful information for regulatory monitoring programs in defense of regulatory enforcement actions. Published in 2016. This article is a U.S. Government work and is in the public domain in the USA.

A multi-group screening method to detect residues of veterinary drugs in meat and environmental contaminants in wheat flour has been developed using liquid chromatography coupled to quadrupole-Orbitrap high-resolution mass spectrometry (LC-HRMS). The procedure was tested for over 300 representative compounds (173 veterinary drugs, 122 pesticides and 9 mycotoxins) analysing in parallel negative and positive (spiked) samples according to European validation rules. The Screening Target Concentrations (STCs) were chosen conservatively with respect to the method purposes. Interpretation of results was based on retention time, mass accuracy of precursor and MS2 spectral library. Evaluating the percentage of false negative results, 280 out of the 304 analytes were detectable at the STCs (false compliant rate ≤ 5%). In wheat flours, incurred levels of mycotoxins, deoxynivalenol and 3-acetyldeoxynivalenol, higher than STCs, were frequently found, whereas in meat, the most detected veterinary drugs were antibiotics generally at negligible concentrations (