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Risk-based approach to develop a national residue program: prioritizing the residue control of veterinary drugs in fishery products

Risk-based approach to develop a national residue program: prioritizing the residue control of... Veterinary drugs are widely used to protect production-related diseases and promote the growth of farmed fish. The use of large amounts of veterinary drugs may have potential risk and cause adverse effects on both humans and the environment. In this study, we developed risk-based ranking based on a scoring system to be applied in the national residue program. In this approach, the following three factors of veterinary drugs that may occur as residues in fishery products were considered: potency (acceptable daily intake), usage (number of dose and withdrawal period), and residue occurrence. The overall ranking score was calculated using the following equation: potency × usage (sum of the number of sales and withdrawal period) × residue occurrence. The veterinary drugs that were assigned high score by applying this approach were enrofloxacin, amoxicillin, oxolinic acid, erythromycin, and trimethoprim. The risk-based approach for monitoring veterinary drugs can provide a reliable inspection priority in fishery products. The developed ranking system can be applied in web-based systems and residue- monitoring programs and to ensure safe management of fishery products in Korea. Keywords: Risk, Priority, Veterinary medicine, Inspection, Fishery products Background farm (Kim et al. 2019). However, overuse or noncompli- Aquatic products are a major food resource with a low- ance of withdrawal period of veterinary drugs has been cost and high-efficiency productivity, and farmed fish increasing due to the shift in farming environment such production have been continuously increasing (Kim as changes in climate and incidence of antibiotic resist- et al. 2010; Kim et al. 2014). In Korea, seafood consump- ant bacteria (Kang et al. 2018). tion per capita was approximately 60 kg in 2014–2016, An analysis of the sales of antimicrobials in animal maintaining the highest level of fishery product husbandry and fish farm by the Korea Animal Health consumption in the world (FAO 2016). To meet the Products Association (KAHPA) revealed that approxi- demand for fish and crustaceans, most of them are pro- mately 1000 tons of antimicrobials was sold each year duced under dense farming conditions, which can be a during 2011–2015. The highest volume of antimicrobials stress factor and increase the possibility of disease preva- was sold for use in pigs farms (53%, 481 tons) followed lence (Uchida et al. 2016). Thus, the authorized veterin- by fishery (22%, 201 tons), poultry (17%, 157 tons), and ary drugs such as antibiotics and anthelmintics have cattle industries (8%, 71 tons) (KAHPA 2019; Lee et al. been continuously used to prevent diseases in fishery 2018). As a large amount and several kinds of veterinary drugs are used yearly, useful tools are needed to develop * Correspondence: hskang1235@korea.kr; adstar@cheminet.kr more effective risk management strategies under limited Pesticide and Veterinary Drugs Residue Division, National Institute of Food budget of governmental authorities (Kang et al. 2019). and Drug Safety Evaluation, Osong, Cheongju, Chungcheongbuk-do 361-709, The Irish government has developed a national residue Republic of Korea CHEM.I.NET Ltd., Room 302, 773-3, Mok-dong, Yangcheon-gu, Seoul, South program for effective prioritization residue evaluation Korea and sampling plan such as veterinary drugs and Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 2 of 7 pesticides in livestock products. The risk-based approach residue occurrence (detection rate + noncompliant sam- is applied in the national residue program to determine ple number). the prioritization of veterinary drugs through ranking system based on risk factors such as potency, usage, and Sample selection and data collection residue occurrence (Danaher et al. 2016). The ranking Taking into consideration the detection characteristics, system reflects the factors considering the risk through a the substances were selected (Table 1). In terms of the simplified model for prioritization of compounds to save selected veterinary drugs, data on ADI, number of veter- cost and time. Thus, similar ecological models have been inary drug sales (usage), withdrawal period of veterinary proposed in other countries for the management of vet- drugs in fishery products, and veterinary drug residue erinary drugs. Indeed, Italy has developed the priority occurrence in fishery products (detection rate, noncom- model “RANKVET” considering 48 veterinary drug resi- pliant history) were collected. due occurrences in environment compartments to assess the potential risks (Di Nica et al. 2015). Portugal applies Compilation of data for risk analysis prioritization based on antibiotic usage, ecosystem ex- To select the priority of test samples, the classification posure, and antibiotic metabolism in livestock and criteria were divided into three categories as follows and humans (Almeida et al. 2014). coded, and the priority was determined by scoring. Global regulatory authorities have established the 1) Potency (P ): ADI was used as a basic data for asses- maximum residue limits (MRLs) for veterinary drugs in sing the safety of veterinary drugs for risk-based animal products to protect potential human health ef- prioritization. The data provided by the European Medi- fect. The Korean Ministry of Food and Drug Safety sets cine Agency (EMA) and FAO/WHO Joint Expert Com- the MRLs for 55 veterinary drugs in fishery products, mittee of Food Additives (JECFA) were utilized as the and 18 substances are managed as prohibited substances ADI used in this study. in consideration of their carcinogenicity and genotoxicity 2) Usage (U ): The number of sales was calculated (MFDS 2019). However, risk-based priority study to sup- based on the Korea Animal Health Product Association’s port national residue inspection remains still limited in 2013 statistics (KAHPA 2019). The withdrawal period Korea. In this study, we classified three factors that can was used in the veterinary drug guidebook for fishery evaluate the risk for effective management of veterinary products presented by National Institute of Fisheries and drugs used in fishery products: (1) potency, (2) usage, Science (NIFS 2016). and (3) residue occurrence. We then collected data and 3) Residue occurrence (R ): It was calculated based r, f assigned scores according to each indicator. Our results on the research data conducted by the National Institute of risk-based prioritization can be applied to the safety of Food and Drug Safety Evaluation in 2014–2016 (Kang management of veterinary drugs and the establishment et al. 2018; Shin et al. 2018). In addition, the number of of domestic inspection sampling plans in aquatic animal noncompliant sample and detection rate were utilized products. for the residue occurrence. Methods Prioritization model Ranking for prioritization In previous studies, most of the priority models and sys- The collected data were scored by dividing the data on tems have been applied in eco-surveillance. Thus, to the potency, usage, and residual level into four classes to prioritize veterinary drugs used in fishery products, a prioritize the veterinary drugs used in fishery products. priority equation based on risk-based approach in do- For easy substitution in the calculated equation, the mestic animal production by the Food Safety Authority scores were assigned up to 4 points. Ireland (FSAI) was used. The collected data, the coded data, and the score were applied in the following equa- 1) The potency was calculated based on the ADI. The tion. Based on the calculated scores, the substances were ADI was scored as 0.1<, 0.01–0.1, 0.001–0.01, and < classified into four groups according to the quartiles. 0.001 mg/kg bw/day. When there was no ADI, it was calculated based on the maximum score. 2) The usage was calculated by dividing the number of Priority ¼ P  U  R r r r; f sales and withdrawal period of the veterinary drugs, scoring them, and adding the scores. The unit of where Priority is the risk-based predicted priority of dose was kg, and it was assigned scores as follows: veterinary drugs in fishery products, high (10,000 kg or more), middle (1000–10,000 kg), P is the ADI of veterinary drugs, U is the usage low (1–1000 kg), and very low (< 1 kg). The r r (number of sales + withdrawal period), and R is the withdrawal period was assigned scores as follows: r, f Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 3 of 7 Table 1 Target veterinary drugs and their MRL in fishery not set, 50–100 days, 10–50 days, and 10 days or products by the Food Code less. Class Compound MRL (mg/kg) 3) The residue occurrence was calculated based on the Amphenicols Florfenicol 0.2 number of noncompliant samples and detection Florfenicol amine 0.2 rate. The frequency of noncompliant samples with Thiamphenicol 0.05 respective Korean MRL values was assigned scores Cephalosporins Cefalexin 0.2 as follows: 5 times or more, 3–5 times, 1–2 times, Ceftiofur n.a. and zero. The detection rate of each veterinary drug in aquatic animals was assigned scores as follows: Desfuroyl Ceftiofur n.a. 1% or higher, 0.1–1%, 0.01–0.1%, and < 0. Quinolones Ciprofloxacin 0.1 Difloxacin 0.3 Results and discussion Enrofloxacin 0.1 Data collection of veterinary drugs Flumequine 0.5 The target veterinary drugs with set MRLs were selected Nalidixic acid 0.03 as study substances (Table 1). To determine risk-based Norfloxacin n.a. priorities for the target drugs, five indicators (viz., ADI, Ofloxacin n.a. number of sales, withdrawal period, number of noncom- Oxolinic acid 0.1 pliant samples, and detection rate) were selected, and Pefloxacin n.a. the scores of 1–4 were assigned to each indicator Macrolides Clindamycin 0.1 (Tables 2 and 3). Priority is described in the Methods. Erythromycin 0.2 Priority was calculated based on the calculated scores Josamycin 0.05 and classified into four groups based on the quartiles of Kitasamycin 0.2 th the scores. Ten substances were assigned the 75 or Lincomycin 0.1 Spiramycin 0.2 Table 2 Scoring categories for risk-ranking of veterinary drugs Penicillins Amoxicillin 0.05 in fishery products Ampicillin 0.05 Parameter Score Description Pleuromutilins Tiamulin 0.1 Potency (P ) Sulfonamides Sulfachlorpyrazine 0.1 Acceptable daily intake 1 > 0.1 mg kg-1 bw day-1 Sulfachlorpyridazine 0.1 2 0.01–0.1 mg kg-1 bw day-1 Sulfadiazine 0.1 3 0.001–0.01 mg kg-1 bw day-1 Sulfadimethoxine 0.1 4 < 0.001 mg kg-1 bw day-1 Sulfadoxine 0.1 Usage (U ) Sulfaguanidine 0.1 Number of sales 1 < 0 (very low) Sulfamerazine 0.1 21–1000 (low) Sulfamethazine 0.1 Sulfamethoxazole 0.1 3 1000–10,000 (medium) Sulfamethoxypyridazine 0.1 4 > 10,000 (high) Sulfamonomethoxine 0.1 Withdrawal Period 1 < 10 days Sulfaphenazole 0.1 210–50 days Sulfaquinoxaline 0.1 350–100 days Sulfathiazole 0.1 4- Sulfisoxazole 0.1 Residue occurrence (R ) r, f Trimethoprim 0.05 Noncompliant samples 1 Zero Tetracyclines Chlortetracycline 0.2 Doxycycline 0.05 2 One or two Oxytetracycline 0.2 3 Three to five Tetracycline 0.2 4 Greater than five Others Ormethoprim 0.1 Detection rate 1 < 0% Praziquantel 0.02 20–0.1% Non-applicable MRL is given for the sum of the parent drug and its metabolite or epimer 3 0.1–1% MRL is given for the sum of sulfonamides 4>1% Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 4 of 7 Table 3 Overall-rank coding and scoring of veterinary drugs in aquatic products Substance ADI ADI Number Number Withdrawal Withdrawal Number of Number of Detection Detection (mg/ Rank of Sales of sales period period (days) noncompliant noncompliant rate rate rank kg) (kg) rank (days) rank samples samples rank Amoxicillin 0.002 3 112,021 4 20 2 4 3 0.88 3 Ampicillin 0.003 3 37,359 4 20 2 0 1 0 1 Cefalexin 0.5 1 656 2 5 1 0 1 0 1 Ceftiofur 0.02 2 7308 3 - 4 0 1 0.07 2 Chlortetracycline 0.03 2 75,454 4 - 4 0 1 0.07 2 Ciprofloxacin 0.002 3 0 1 - 4 0 1 3.82 4 Clindamycin 0.03 2 600 2 15 2 0 1 1 Difloxacin 0.01 3 - 1 - 4 0 1 1 Doxycycline 0.003 3 1553 3 - 4 0 1 1 Enrofloxacin 0.002 3 40,668 4 - 4 7 4 11.61 4 Erythromycin 0.0007 4 6671 3 30 3 0 1 0.22 3 Florfenicol 0.01 3 63,815 4 14 2 0 1 0.44 3 Flumequine 0.03 2 2704 3 8 1 0 1 0.44 3 Josamycin 0.002 3 0 1 - 4 0 1 1 Kitasamycin 0.5 1 572 2 - 4 0 1 1 Lincomycin 0.03 2 7300 3 10 2 0 1 0.07 2 Nalidixic acid 0.002 3 0 1 - 4 0 1 0.51 3 Norfloxacin - 4 0 1 - 4 0 1 1 Ofloxacin - 4 0 1 - 4 0 1 1 Ormethoprim 0.1 2 - 1 - 4 0 1 0.29 3 Oxolinic acid 0.0025 3 6349 3 28 3 1 2 2.79 4 Oxytetracycline 0.03 2 191,780 4 30 3 0 1 7.71 4 Pefloxacin - 4 0 1 - 4 0 1 1 Praziquantel 0.17 1 - 1 - 4 0 1 0.07 2 Spiramycin 0.05 2 1322 3 - 4 0 1 0.29 3 Sulfachlorpyrazine 0.05 2 - 1 30 3 0 1 1 Sulfachlorpyridazine 0.05 2 873 2 30 3 0 1 0.07 2 Sulfadiazine 0.05 2 8487 3 30 3 1 2 0.51 3 Sulfadimethoxine 0.05 2 1606 3 30 3 0 1 0.15 3 Sulfadoxine 0.05 2 332 2 30 3 0 1 1 Sulfaguanidine 0.05 2 38 2 30 3 0 1 1 Sulfamerazine 0.05 2 219 2 30 3 0 1 1 Sulfamethazine 0.05 2 10,269 4 30 3 0 1 0.37 3 Sulfamethoxazole 0.05 2 21,816 4 30 3 0 1 0.07 2 Sulfamethoxypyridazine 0.05 2 219 2 30 3 0 1 0.15 3 Sulfamonomethoxine 0.05 2 198 2 30 3 0 1 1 Sulfaphenazole 0.05 2 - 1 30 3 0 1 1 Sulfaquinoxaline 0.05 2 780 2 30 3 0 1 1 Sulfasoxazole 0.05 2 - 1 30 3 0 1 1 Sulfathiazole 0.05 2 22,902 4 30 3 0 1 1 Tetracycline 0.03 2 0 1 - 4 0 1 0.07 2 Thiamphenicol 0.045 2 82 2 15 2 0 1 1 Tiamulin 0.03 2 13,598 4 - 4 0 1 0.07 2 Trimethoprim 0.02 2 6614 3 - 4 1 2 2.2 4 Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 5 of 7 higher scores and, therefore, were selected as priority Table 4 Risk-based ranking of veterinary drugs in aquatic products substances (Table 4). Substance Score Priority Quartile The ADI value can be an indicator of safety of veterin- ary drugs. Among the veterinary drugs collected, four Enrofloxacin 192 1 Q4 veterinary drugs including erythromycin had no ADI or Amoxicillin 108 2 had low values (< 0.001 mg/kg bw/day), and therefore, Oxolinic acid 108 2 they were assigned 4 points. The usage of drugs was as Erythromycin 96 4 follows: oxytetracycline > amoxicillin > chlortetracycline Trimethoprim 84 5 > florfenicol> enrofloxacin. There were 17 veterinary Ciprofloxacin 75 6 drugs, including ceftiofur, which did not have a with- Florfenicol 72 7 drawal period or had no set withdrawal period and, Oxytetracycline 70 8 therefore, were assigned 4 points. When the usage was ranked by adding the scores of the number of sales and Nalidixic acid 60 9 withdrawal period, enrofloxacin and tiamulin showed Sulfadiazine 60 9 high values. Thus, frequently used veterinary drugs oc- Spiramycin 56 11 Q3 cupied a high proportion of those with high scores. In Sulfamethazine 56 11 terms of residue occurrence, 4 points were assigned to a Chlortetracycline 48 13 high number of noncompliant samples, and enrofloxacin Sulfadimethoxine 48 13 showed the highest number of noncompliant samples (7 Tiamulin 48 13 cases); thus, 4 points were assigned. Moreover, sub- Ceftiofur 42 16 stances with the detection rate of 1% or more were assigned 4 points, and they included chlortetracycline Doxycycline 42 16 and enrofloxacin (Table 3). Sulfamethoxazole 42 16 Norfloxacin 40 19 Q2 Determination of risk-based priority Ofloxacin 40 19 Enrofloxacin (fluoroquinolone) had the highest score of Pefloxacin 40 19 192. Enrofloxacin had 3 ADI points (0.002 mg/kg bw/ Sulfamethoxypyridazine 40 19 day), a high value of usage (40,668 kg), and withdrawal Ormethoprim 40 19 period, and the highest number of noncompliant sam- Ampicillin 36 24 ples (7 cases). Enrofloxacin is used for the prevention and treatment of infection by pathogenic bacteria such Flumequine 32 25 as Vibriosis, and the amount of active ingredients is 100 Difloxacin 30 26 g/kg or L (NIFS 2016). In this study, enrofloxacin had Josamycin 30 26 high scores in potency, usage, and residue occurrence, Lincomycin 30 26 and therefore, it was ranked high among the prioritized Sulfachlorpyridazine 30 26 substances, but it was ranked low in the risk-based na- Tetracycline 30 26 tional residue program in Ireland. In the corresponding Sulfathiazole 28 31 study, the use of enrofloxacin, in livestock products, was Sulfadoxine 20 32 Q1 analyzed, and therefore, it was difficult to compare the results of the corresponding study with those of this Sulfaguanidine 20 32 study because of lack of sufficient information when Sulfamerazine 20 32 used in fishery products (FSAI 2014). Next, the total Sulfamonomethoxine 20 32 score of amoxicillin was 108, indicating a high score Sulfaquinoxaline 20 32 among the investigated substances. In fact, amoxicillin, Clindamycin 16 37 trimethoprim, and sulfadiazine among quartile (Q4) sub- Sulfachlorpyrazine 16 37 stances among the substances investigated in this study Sulfaphenazole 16 37 were shown to have high priority for management in Sulfasoxazole 16 37 consideration of frequency of use in the UK and toxico- logical results based on ADI (Capleton et al. 2006). Thiamphenicol 16 37 Moreover, amoxicillin was shown to be a high-priority Praziquantel 15 42 substance as a result of Ireland’s national residue pro- Kitasamycin 12 43 gram monitoring, which was derived using the same for- Cefalexin 6 44 mula as in this study. Oxolinic acid, trimethoprim, ciprofloxacin, florfenicol, and oxytetracycline were Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 6 of 7 mostly detected in fishery products in Korea, and the oc- Thus, newly generated data need constant updating currence pattern was similar to the results of this study through a web-based system. Lastly, carryover from feed (Kang et al. 2018). Nalidixic acid had no number of sales to food of unavoidable and unintended residues of veter- but had higher priority than that of other compounds inary drugs and pesticides should be added in risk-based due to the detection rate and ADI. Our findings suggest priority for the national residue program. that nalidixic acid can be used continuously in fishery products according to veterinarian prescription. On the Conclusions contrary, cephalosporin-based cephalexin had the lowest This study can be applied to the prioritization of moni- score (total 6 points) because of a high ADI value and toring and safety management of veterinary drugs in short withdrawal period. Cefalexin was also found to fishery products, and it can be actively utilized in the have a very low priority in the results. establishment of future national residue programs and domestic food re-inspection system in fishery products. Applications of the study In the future, dataset and equation for all factors of the In this study, a risk-based approach was used to risk-based approach should be updated in newly devel- prioritize veterinary drugs used in fishery products for oped web-based system. the development of new governmental risk management. Abbreviations The risk of veterinary drugs was ranked based on the ADI: Acceptable daily intakeEMAEuropean Medicine AgencyFSAIFood Safety risk-based approach by using the following three risk Authority IrelandJECFAJoint Expert Committee of Food AdditivesKAHPAKorea Animal Health Products AssociationMRLMaximum residue limits factors: (1) potency, (2) usage, and (3) residue occur- rence. These factors were investigated based on the risk Acknowledgments of the substances, priority was set up based on scientific Hui-Seung Kang and Songyi Han contributed equally to this work. grounds, and monitoring test was conducted, thereby in- Authors’ contributions creasing the efficiency of the national inspection priority. The authors contributed to this manuscript as follows: H-S K. studied the de- Ireland not only applies the priority of the substances to sign, data analysis, and writing of the manuscript; SY H. contributed the writ- ing of the manuscript and drafting of the manuscript; B-H C. reviewed the be tested to the actual national residue program using manuscript; and HJ L. studied the design and data analysis. All authors the risk-based priority in the calculation program but reviewed, edited, and approved the manuscript for submission. also uses it to estimate the minimum number of samples Funding required for the monitored livestock products. To effect- This work was supported by the Ministry of Food and Drug Safety, republic ively accomplish the safety management of national resi- of Korea (Grant Number 18162MFDS521) in 2018–2019 and 19161MFDS581 due substances, a risk-based prioritization program is in 2019. necessary. As of May 2018, the Korea Food Code Availability of data and materials suggested simultaneous multi-residue method (50 sub- The datasets used and/or analyzed during the current study are available stances) as a qualification method (MFDS 2019). How- from the corresponding author on reasonable request. ever, it is difficult for an individual food safety lab to Consent for publication analyze all veterinary drugs including illegal use in terms Not applicable of time and cost. Analyzing substances according to the Competing interests priority presented in this study is expected to increase The authors declare that they have no competing interests. the efficiency of analysis in the food safety lab. Author details Pesticide and Veterinary Drugs Residue Division, National Institute of Food Limitation of this study and Drug Safety Evaluation, Osong, Cheongju, Chungcheongbuk-do 361-709, Risk-based priority has an uncertainty for each factor in 2 Republic of Korea. Food Contaminants Division, National Institute of Food the calculated model. Although the usage is calculated and Drug Safety Evaluation, Osong, Cheongju, Chungcheongbuk-do 361-709, Republic of Korea. CHEM.I.NET Ltd., Room 302, 773-3, Mok-dong, based on the data of veterinary drug sales, priority Yangcheon-gu, Seoul, South Korea. should be calculated by analyzing the actual dose of vet- erinary drugs used in aquatic products. In this study, we Received: 30 July 2019 Accepted: 12 November 2019 used the withdrawal period data according to veterinary drug guidebook for fishery products presented by the References National Institute of Fisheries and Science. However, a Almeida A, Duarte S, Nunes R, Rocha H, Pena A, Meisel L. Human and veterinary antibiotics used in Portugal—a ranking for ecosurveillance. Toxics. 2014;2(2): low-cost intraperitoneal or intramuscular injection has 188–225. recently been developed. Thus, the withdrawal period Capleton AC, Courage C, Rumsby P, Holmes P, Stutt E, Boxall AB, Levy LS. might differ with the administration route (injection and Prioritising veterinary medicines according to their potential indirect human exposure and toxicity profile. Toxicol Lett. 2006;163(3):213–23. oral). Additionally, in 2016–2018, the MRLs were up- Danaher M, Shanahan C, Butler F, Evans R, O’Sullivan D, Glynn D, Camon T, dated by the Korean regulation. Ceftiofur, trichlorfone, Lawlor P, O’Keeffe M. Risk-based approach to developing a national residue and ethoxyquin were updated by the Korean Food Code. sampling plan for testing under European Union regulation for veterinary Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 7 of 7 medicinal products and coccidiostat feed additives in domestic animal production. Food Addit Contam Part A. 2016;33(7):1155–65. Di Nica V, Menaballi L, Azimonti G, Finizio A. RANKVET: a new ranking method for comparing and prioritizing the environmental risk of veterinary pharmaceuticals. Ecol Indicators. 2015;52:270–6. FAO. The State of World Fisheries and Aquaculture 2016. Food and Agriculture Organization of the United Nations. Retrieved from https://www.fao.org/ publications. Accessed 1 July 2019. FSAI. Risk-based approach to developing the national residue sampling plan, Food safety Authority of Ireland. 2014, Retrieved from https://www.fsai.ie/ publications_riskbased_residue_sampling. Accessed 1 July 2019. KAHPA. Korea animal health product association statistics. Retrieved from http:// www.kahpa.or.kr/ENG/ Accessed 1 July 2019. (2019) Kang H-S, Kwon NJ, Jeong J, Lee K, Lee H. Web-based Korean maximum residue limit evaluation tools: an applied example of maximum residue limit evaluation for trichlorfon in fishery products. Environ Sci Pollut Res. 2019; 26(7):7284–99. Kang H-S, Lee S-B, Shin D, Jeong J, Hong J-H, Rhee G-S. Occurrence of veterinary drug residues in farmed fishery products in South Korea. Food Control. 2018; 85:57–65. Kim H-Y, Chung S-Y, Choi S-H, Lee J-S, Choi I-S, Cho M-J, Shin M-S, Song J-S, Choi J-C, Park H-O. Monitoring of veterinary drug residues in foods produced in Korea. Kor J Food Sci Technol. 2010;42(6):653–63. Kim J, Shin D, Kang H-S, Lee E, Choi SY, Lee H-S, Cho BH, Lee KB, Jeong J. Determination of ceftiofur residues by simple solid phase extraction coupled with liquid chromatography-tandem mass spectrometry in eel, flatfish, and shrimp. Mass Spectrometry Lett. 2019;10(2):43–9. Kim JW, Cho MY, Jee B-Y, Park M, Kim NY. Administration and use of aquaculture drugs in Korea. J Fish Pathol. 2014;27(1):67–75. Lee HJ, Cho SH, Shin D, Kang HS. Prevalence of antibiotic residues and antibiotic resistance in isolates of chicken meat in Korea. Korean J Food Sci Anim Resour. 2018;38(5):1055–63. MFDS. Korean food standard code. 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Risk-based approach to develop a national residue program: prioritizing the residue control of veterinary drugs in fishery products

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Life Sciences; Fish & Wildlife Biology & Management; Marine & Freshwater Sciences; Zoology; Animal Ecology
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Abstract

Veterinary drugs are widely used to protect production-related diseases and promote the growth of farmed fish. The use of large amounts of veterinary drugs may have potential risk and cause adverse effects on both humans and the environment. In this study, we developed risk-based ranking based on a scoring system to be applied in the national residue program. In this approach, the following three factors of veterinary drugs that may occur as residues in fishery products were considered: potency (acceptable daily intake), usage (number of dose and withdrawal period), and residue occurrence. The overall ranking score was calculated using the following equation: potency × usage (sum of the number of sales and withdrawal period) × residue occurrence. The veterinary drugs that were assigned high score by applying this approach were enrofloxacin, amoxicillin, oxolinic acid, erythromycin, and trimethoprim. The risk-based approach for monitoring veterinary drugs can provide a reliable inspection priority in fishery products. The developed ranking system can be applied in web-based systems and residue- monitoring programs and to ensure safe management of fishery products in Korea. Keywords: Risk, Priority, Veterinary medicine, Inspection, Fishery products Background farm (Kim et al. 2019). However, overuse or noncompli- Aquatic products are a major food resource with a low- ance of withdrawal period of veterinary drugs has been cost and high-efficiency productivity, and farmed fish increasing due to the shift in farming environment such production have been continuously increasing (Kim as changes in climate and incidence of antibiotic resist- et al. 2010; Kim et al. 2014). In Korea, seafood consump- ant bacteria (Kang et al. 2018). tion per capita was approximately 60 kg in 2014–2016, An analysis of the sales of antimicrobials in animal maintaining the highest level of fishery product husbandry and fish farm by the Korea Animal Health consumption in the world (FAO 2016). To meet the Products Association (KAHPA) revealed that approxi- demand for fish and crustaceans, most of them are pro- mately 1000 tons of antimicrobials was sold each year duced under dense farming conditions, which can be a during 2011–2015. The highest volume of antimicrobials stress factor and increase the possibility of disease preva- was sold for use in pigs farms (53%, 481 tons) followed lence (Uchida et al. 2016). Thus, the authorized veterin- by fishery (22%, 201 tons), poultry (17%, 157 tons), and ary drugs such as antibiotics and anthelmintics have cattle industries (8%, 71 tons) (KAHPA 2019; Lee et al. been continuously used to prevent diseases in fishery 2018). As a large amount and several kinds of veterinary drugs are used yearly, useful tools are needed to develop * Correspondence: hskang1235@korea.kr; adstar@cheminet.kr more effective risk management strategies under limited Pesticide and Veterinary Drugs Residue Division, National Institute of Food budget of governmental authorities (Kang et al. 2019). and Drug Safety Evaluation, Osong, Cheongju, Chungcheongbuk-do 361-709, The Irish government has developed a national residue Republic of Korea CHEM.I.NET Ltd., Room 302, 773-3, Mok-dong, Yangcheon-gu, Seoul, South program for effective prioritization residue evaluation Korea and sampling plan such as veterinary drugs and Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 2 of 7 pesticides in livestock products. The risk-based approach residue occurrence (detection rate + noncompliant sam- is applied in the national residue program to determine ple number). the prioritization of veterinary drugs through ranking system based on risk factors such as potency, usage, and Sample selection and data collection residue occurrence (Danaher et al. 2016). The ranking Taking into consideration the detection characteristics, system reflects the factors considering the risk through a the substances were selected (Table 1). In terms of the simplified model for prioritization of compounds to save selected veterinary drugs, data on ADI, number of veter- cost and time. Thus, similar ecological models have been inary drug sales (usage), withdrawal period of veterinary proposed in other countries for the management of vet- drugs in fishery products, and veterinary drug residue erinary drugs. Indeed, Italy has developed the priority occurrence in fishery products (detection rate, noncom- model “RANKVET” considering 48 veterinary drug resi- pliant history) were collected. due occurrences in environment compartments to assess the potential risks (Di Nica et al. 2015). Portugal applies Compilation of data for risk analysis prioritization based on antibiotic usage, ecosystem ex- To select the priority of test samples, the classification posure, and antibiotic metabolism in livestock and criteria were divided into three categories as follows and humans (Almeida et al. 2014). coded, and the priority was determined by scoring. Global regulatory authorities have established the 1) Potency (P ): ADI was used as a basic data for asses- maximum residue limits (MRLs) for veterinary drugs in sing the safety of veterinary drugs for risk-based animal products to protect potential human health ef- prioritization. The data provided by the European Medi- fect. The Korean Ministry of Food and Drug Safety sets cine Agency (EMA) and FAO/WHO Joint Expert Com- the MRLs for 55 veterinary drugs in fishery products, mittee of Food Additives (JECFA) were utilized as the and 18 substances are managed as prohibited substances ADI used in this study. in consideration of their carcinogenicity and genotoxicity 2) Usage (U ): The number of sales was calculated (MFDS 2019). However, risk-based priority study to sup- based on the Korea Animal Health Product Association’s port national residue inspection remains still limited in 2013 statistics (KAHPA 2019). The withdrawal period Korea. In this study, we classified three factors that can was used in the veterinary drug guidebook for fishery evaluate the risk for effective management of veterinary products presented by National Institute of Fisheries and drugs used in fishery products: (1) potency, (2) usage, Science (NIFS 2016). and (3) residue occurrence. We then collected data and 3) Residue occurrence (R ): It was calculated based r, f assigned scores according to each indicator. Our results on the research data conducted by the National Institute of risk-based prioritization can be applied to the safety of Food and Drug Safety Evaluation in 2014–2016 (Kang management of veterinary drugs and the establishment et al. 2018; Shin et al. 2018). In addition, the number of of domestic inspection sampling plans in aquatic animal noncompliant sample and detection rate were utilized products. for the residue occurrence. Methods Prioritization model Ranking for prioritization In previous studies, most of the priority models and sys- The collected data were scored by dividing the data on tems have been applied in eco-surveillance. Thus, to the potency, usage, and residual level into four classes to prioritize veterinary drugs used in fishery products, a prioritize the veterinary drugs used in fishery products. priority equation based on risk-based approach in do- For easy substitution in the calculated equation, the mestic animal production by the Food Safety Authority scores were assigned up to 4 points. Ireland (FSAI) was used. The collected data, the coded data, and the score were applied in the following equa- 1) The potency was calculated based on the ADI. The tion. Based on the calculated scores, the substances were ADI was scored as 0.1<, 0.01–0.1, 0.001–0.01, and < classified into four groups according to the quartiles. 0.001 mg/kg bw/day. When there was no ADI, it was calculated based on the maximum score. 2) The usage was calculated by dividing the number of Priority ¼ P  U  R r r r; f sales and withdrawal period of the veterinary drugs, scoring them, and adding the scores. The unit of where Priority is the risk-based predicted priority of dose was kg, and it was assigned scores as follows: veterinary drugs in fishery products, high (10,000 kg or more), middle (1000–10,000 kg), P is the ADI of veterinary drugs, U is the usage low (1–1000 kg), and very low (< 1 kg). The r r (number of sales + withdrawal period), and R is the withdrawal period was assigned scores as follows: r, f Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 3 of 7 Table 1 Target veterinary drugs and their MRL in fishery not set, 50–100 days, 10–50 days, and 10 days or products by the Food Code less. Class Compound MRL (mg/kg) 3) The residue occurrence was calculated based on the Amphenicols Florfenicol 0.2 number of noncompliant samples and detection Florfenicol amine 0.2 rate. The frequency of noncompliant samples with Thiamphenicol 0.05 respective Korean MRL values was assigned scores Cephalosporins Cefalexin 0.2 as follows: 5 times or more, 3–5 times, 1–2 times, Ceftiofur n.a. and zero. The detection rate of each veterinary drug in aquatic animals was assigned scores as follows: Desfuroyl Ceftiofur n.a. 1% or higher, 0.1–1%, 0.01–0.1%, and < 0. Quinolones Ciprofloxacin 0.1 Difloxacin 0.3 Results and discussion Enrofloxacin 0.1 Data collection of veterinary drugs Flumequine 0.5 The target veterinary drugs with set MRLs were selected Nalidixic acid 0.03 as study substances (Table 1). To determine risk-based Norfloxacin n.a. priorities for the target drugs, five indicators (viz., ADI, Ofloxacin n.a. number of sales, withdrawal period, number of noncom- Oxolinic acid 0.1 pliant samples, and detection rate) were selected, and Pefloxacin n.a. the scores of 1–4 were assigned to each indicator Macrolides Clindamycin 0.1 (Tables 2 and 3). Priority is described in the Methods. Erythromycin 0.2 Priority was calculated based on the calculated scores Josamycin 0.05 and classified into four groups based on the quartiles of Kitasamycin 0.2 th the scores. Ten substances were assigned the 75 or Lincomycin 0.1 Spiramycin 0.2 Table 2 Scoring categories for risk-ranking of veterinary drugs Penicillins Amoxicillin 0.05 in fishery products Ampicillin 0.05 Parameter Score Description Pleuromutilins Tiamulin 0.1 Potency (P ) Sulfonamides Sulfachlorpyrazine 0.1 Acceptable daily intake 1 > 0.1 mg kg-1 bw day-1 Sulfachlorpyridazine 0.1 2 0.01–0.1 mg kg-1 bw day-1 Sulfadiazine 0.1 3 0.001–0.01 mg kg-1 bw day-1 Sulfadimethoxine 0.1 4 < 0.001 mg kg-1 bw day-1 Sulfadoxine 0.1 Usage (U ) Sulfaguanidine 0.1 Number of sales 1 < 0 (very low) Sulfamerazine 0.1 21–1000 (low) Sulfamethazine 0.1 Sulfamethoxazole 0.1 3 1000–10,000 (medium) Sulfamethoxypyridazine 0.1 4 > 10,000 (high) Sulfamonomethoxine 0.1 Withdrawal Period 1 < 10 days Sulfaphenazole 0.1 210–50 days Sulfaquinoxaline 0.1 350–100 days Sulfathiazole 0.1 4- Sulfisoxazole 0.1 Residue occurrence (R ) r, f Trimethoprim 0.05 Noncompliant samples 1 Zero Tetracyclines Chlortetracycline 0.2 Doxycycline 0.05 2 One or two Oxytetracycline 0.2 3 Three to five Tetracycline 0.2 4 Greater than five Others Ormethoprim 0.1 Detection rate 1 < 0% Praziquantel 0.02 20–0.1% Non-applicable MRL is given for the sum of the parent drug and its metabolite or epimer 3 0.1–1% MRL is given for the sum of sulfonamides 4>1% Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 4 of 7 Table 3 Overall-rank coding and scoring of veterinary drugs in aquatic products Substance ADI ADI Number Number Withdrawal Withdrawal Number of Number of Detection Detection (mg/ Rank of Sales of sales period period (days) noncompliant noncompliant rate rate rank kg) (kg) rank (days) rank samples samples rank Amoxicillin 0.002 3 112,021 4 20 2 4 3 0.88 3 Ampicillin 0.003 3 37,359 4 20 2 0 1 0 1 Cefalexin 0.5 1 656 2 5 1 0 1 0 1 Ceftiofur 0.02 2 7308 3 - 4 0 1 0.07 2 Chlortetracycline 0.03 2 75,454 4 - 4 0 1 0.07 2 Ciprofloxacin 0.002 3 0 1 - 4 0 1 3.82 4 Clindamycin 0.03 2 600 2 15 2 0 1 1 Difloxacin 0.01 3 - 1 - 4 0 1 1 Doxycycline 0.003 3 1553 3 - 4 0 1 1 Enrofloxacin 0.002 3 40,668 4 - 4 7 4 11.61 4 Erythromycin 0.0007 4 6671 3 30 3 0 1 0.22 3 Florfenicol 0.01 3 63,815 4 14 2 0 1 0.44 3 Flumequine 0.03 2 2704 3 8 1 0 1 0.44 3 Josamycin 0.002 3 0 1 - 4 0 1 1 Kitasamycin 0.5 1 572 2 - 4 0 1 1 Lincomycin 0.03 2 7300 3 10 2 0 1 0.07 2 Nalidixic acid 0.002 3 0 1 - 4 0 1 0.51 3 Norfloxacin - 4 0 1 - 4 0 1 1 Ofloxacin - 4 0 1 - 4 0 1 1 Ormethoprim 0.1 2 - 1 - 4 0 1 0.29 3 Oxolinic acid 0.0025 3 6349 3 28 3 1 2 2.79 4 Oxytetracycline 0.03 2 191,780 4 30 3 0 1 7.71 4 Pefloxacin - 4 0 1 - 4 0 1 1 Praziquantel 0.17 1 - 1 - 4 0 1 0.07 2 Spiramycin 0.05 2 1322 3 - 4 0 1 0.29 3 Sulfachlorpyrazine 0.05 2 - 1 30 3 0 1 1 Sulfachlorpyridazine 0.05 2 873 2 30 3 0 1 0.07 2 Sulfadiazine 0.05 2 8487 3 30 3 1 2 0.51 3 Sulfadimethoxine 0.05 2 1606 3 30 3 0 1 0.15 3 Sulfadoxine 0.05 2 332 2 30 3 0 1 1 Sulfaguanidine 0.05 2 38 2 30 3 0 1 1 Sulfamerazine 0.05 2 219 2 30 3 0 1 1 Sulfamethazine 0.05 2 10,269 4 30 3 0 1 0.37 3 Sulfamethoxazole 0.05 2 21,816 4 30 3 0 1 0.07 2 Sulfamethoxypyridazine 0.05 2 219 2 30 3 0 1 0.15 3 Sulfamonomethoxine 0.05 2 198 2 30 3 0 1 1 Sulfaphenazole 0.05 2 - 1 30 3 0 1 1 Sulfaquinoxaline 0.05 2 780 2 30 3 0 1 1 Sulfasoxazole 0.05 2 - 1 30 3 0 1 1 Sulfathiazole 0.05 2 22,902 4 30 3 0 1 1 Tetracycline 0.03 2 0 1 - 4 0 1 0.07 2 Thiamphenicol 0.045 2 82 2 15 2 0 1 1 Tiamulin 0.03 2 13,598 4 - 4 0 1 0.07 2 Trimethoprim 0.02 2 6614 3 - 4 1 2 2.2 4 Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 5 of 7 higher scores and, therefore, were selected as priority Table 4 Risk-based ranking of veterinary drugs in aquatic products substances (Table 4). Substance Score Priority Quartile The ADI value can be an indicator of safety of veterin- ary drugs. Among the veterinary drugs collected, four Enrofloxacin 192 1 Q4 veterinary drugs including erythromycin had no ADI or Amoxicillin 108 2 had low values (< 0.001 mg/kg bw/day), and therefore, Oxolinic acid 108 2 they were assigned 4 points. The usage of drugs was as Erythromycin 96 4 follows: oxytetracycline > amoxicillin > chlortetracycline Trimethoprim 84 5 > florfenicol> enrofloxacin. There were 17 veterinary Ciprofloxacin 75 6 drugs, including ceftiofur, which did not have a with- Florfenicol 72 7 drawal period or had no set withdrawal period and, Oxytetracycline 70 8 therefore, were assigned 4 points. When the usage was ranked by adding the scores of the number of sales and Nalidixic acid 60 9 withdrawal period, enrofloxacin and tiamulin showed Sulfadiazine 60 9 high values. Thus, frequently used veterinary drugs oc- Spiramycin 56 11 Q3 cupied a high proportion of those with high scores. In Sulfamethazine 56 11 terms of residue occurrence, 4 points were assigned to a Chlortetracycline 48 13 high number of noncompliant samples, and enrofloxacin Sulfadimethoxine 48 13 showed the highest number of noncompliant samples (7 Tiamulin 48 13 cases); thus, 4 points were assigned. Moreover, sub- Ceftiofur 42 16 stances with the detection rate of 1% or more were assigned 4 points, and they included chlortetracycline Doxycycline 42 16 and enrofloxacin (Table 3). Sulfamethoxazole 42 16 Norfloxacin 40 19 Q2 Determination of risk-based priority Ofloxacin 40 19 Enrofloxacin (fluoroquinolone) had the highest score of Pefloxacin 40 19 192. Enrofloxacin had 3 ADI points (0.002 mg/kg bw/ Sulfamethoxypyridazine 40 19 day), a high value of usage (40,668 kg), and withdrawal Ormethoprim 40 19 period, and the highest number of noncompliant sam- Ampicillin 36 24 ples (7 cases). Enrofloxacin is used for the prevention and treatment of infection by pathogenic bacteria such Flumequine 32 25 as Vibriosis, and the amount of active ingredients is 100 Difloxacin 30 26 g/kg or L (NIFS 2016). In this study, enrofloxacin had Josamycin 30 26 high scores in potency, usage, and residue occurrence, Lincomycin 30 26 and therefore, it was ranked high among the prioritized Sulfachlorpyridazine 30 26 substances, but it was ranked low in the risk-based na- Tetracycline 30 26 tional residue program in Ireland. In the corresponding Sulfathiazole 28 31 study, the use of enrofloxacin, in livestock products, was Sulfadoxine 20 32 Q1 analyzed, and therefore, it was difficult to compare the results of the corresponding study with those of this Sulfaguanidine 20 32 study because of lack of sufficient information when Sulfamerazine 20 32 used in fishery products (FSAI 2014). Next, the total Sulfamonomethoxine 20 32 score of amoxicillin was 108, indicating a high score Sulfaquinoxaline 20 32 among the investigated substances. In fact, amoxicillin, Clindamycin 16 37 trimethoprim, and sulfadiazine among quartile (Q4) sub- Sulfachlorpyrazine 16 37 stances among the substances investigated in this study Sulfaphenazole 16 37 were shown to have high priority for management in Sulfasoxazole 16 37 consideration of frequency of use in the UK and toxico- logical results based on ADI (Capleton et al. 2006). Thiamphenicol 16 37 Moreover, amoxicillin was shown to be a high-priority Praziquantel 15 42 substance as a result of Ireland’s national residue pro- Kitasamycin 12 43 gram monitoring, which was derived using the same for- Cefalexin 6 44 mula as in this study. Oxolinic acid, trimethoprim, ciprofloxacin, florfenicol, and oxytetracycline were Kang et al. Fisheries and Aquatic Sciences (2019) 22:29 Page 6 of 7 mostly detected in fishery products in Korea, and the oc- Thus, newly generated data need constant updating currence pattern was similar to the results of this study through a web-based system. Lastly, carryover from feed (Kang et al. 2018). Nalidixic acid had no number of sales to food of unavoidable and unintended residues of veter- but had higher priority than that of other compounds inary drugs and pesticides should be added in risk-based due to the detection rate and ADI. Our findings suggest priority for the national residue program. that nalidixic acid can be used continuously in fishery products according to veterinarian prescription. On the Conclusions contrary, cephalosporin-based cephalexin had the lowest This study can be applied to the prioritization of moni- score (total 6 points) because of a high ADI value and toring and safety management of veterinary drugs in short withdrawal period. Cefalexin was also found to fishery products, and it can be actively utilized in the have a very low priority in the results. establishment of future national residue programs and domestic food re-inspection system in fishery products. Applications of the study In the future, dataset and equation for all factors of the In this study, a risk-based approach was used to risk-based approach should be updated in newly devel- prioritize veterinary drugs used in fishery products for oped web-based system. the development of new governmental risk management. Abbreviations The risk of veterinary drugs was ranked based on the ADI: Acceptable daily intakeEMAEuropean Medicine AgencyFSAIFood Safety risk-based approach by using the following three risk Authority IrelandJECFAJoint Expert Committee of Food AdditivesKAHPAKorea Animal Health Products AssociationMRLMaximum residue limits factors: (1) potency, (2) usage, and (3) residue occur- rence. These factors were investigated based on the risk Acknowledgments of the substances, priority was set up based on scientific Hui-Seung Kang and Songyi Han contributed equally to this work. grounds, and monitoring test was conducted, thereby in- Authors’ contributions creasing the efficiency of the national inspection priority. The authors contributed to this manuscript as follows: H-S K. studied the de- Ireland not only applies the priority of the substances to sign, data analysis, and writing of the manuscript; SY H. contributed the writ- ing of the manuscript and drafting of the manuscript; B-H C. reviewed the be tested to the actual national residue program using manuscript; and HJ L. studied the design and data analysis. All authors the risk-based priority in the calculation program but reviewed, edited, and approved the manuscript for submission. also uses it to estimate the minimum number of samples Funding required for the monitored livestock products. To effect- This work was supported by the Ministry of Food and Drug Safety, republic ively accomplish the safety management of national resi- of Korea (Grant Number 18162MFDS521) in 2018–2019 and 19161MFDS581 due substances, a risk-based prioritization program is in 2019. necessary. As of May 2018, the Korea Food Code Availability of data and materials suggested simultaneous multi-residue method (50 sub- The datasets used and/or analyzed during the current study are available stances) as a qualification method (MFDS 2019). How- from the corresponding author on reasonable request. ever, it is difficult for an individual food safety lab to Consent for publication analyze all veterinary drugs including illegal use in terms Not applicable of time and cost. Analyzing substances according to the Competing interests priority presented in this study is expected to increase The authors declare that they have no competing interests. the efficiency of analysis in the food safety lab. Author details Pesticide and Veterinary Drugs Residue Division, National Institute of Food Limitation of this study and Drug Safety Evaluation, Osong, Cheongju, Chungcheongbuk-do 361-709, Risk-based priority has an uncertainty for each factor in 2 Republic of Korea. Food Contaminants Division, National Institute of Food the calculated model. Although the usage is calculated and Drug Safety Evaluation, Osong, Cheongju, Chungcheongbuk-do 361-709, Republic of Korea. CHEM.I.NET Ltd., Room 302, 773-3, Mok-dong, based on the data of veterinary drug sales, priority Yangcheon-gu, Seoul, South Korea. should be calculated by analyzing the actual dose of vet- erinary drugs used in aquatic products. In this study, we Received: 30 July 2019 Accepted: 12 November 2019 used the withdrawal period data according to veterinary drug guidebook for fishery products presented by the References National Institute of Fisheries and Science. However, a Almeida A, Duarte S, Nunes R, Rocha H, Pena A, Meisel L. Human and veterinary antibiotics used in Portugal—a ranking for ecosurveillance. Toxics. 2014;2(2): low-cost intraperitoneal or intramuscular injection has 188–225. recently been developed. 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