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Estimação do período de carência de medicamento veterinário em produtos comestíveis (tecidos) de origem animal por modelos de regressão / Estimation of the withdrawal period for veterinary drugs in edible tissues of animal origin by regression modelsRosa, Simone Cristina 12 August 2016 (has links)
Resíduos de medicamento veterinário podem estar presentes em produtos comestíveis de origem animal, tais como carne, leite, ovos e mel. Para assegurar que a concentração de tais resíduos não excede um limite considerado seguro (Limite Máximo de Resíduo - LMR) deve ser estabelecido o período de carência, que é o tempo que deve ser respeitado para que um animal possa ser enviado para o abate após ter recebido um dado medicamento veterinário. A estimação do período de carência usualmente é feita pelo ajuste de um modelo de regressão linear simples, seguido pelo cálculo de um limite de tolerância. Para isso, os pressupostos de homocedasticidade e de normalidade dos erros do modelo devem ser atendidos. No entanto, violações desses pressupostos são frequentes nos estudos de depleção residual. No presente trabalho foram utilizados dois bancos de dados da quantificação de resíduo de medicamento veterinário em tecidos de bovinos e o período de carência foi estimado para fígado, gordura, músculo e rins. Os modelos de regressão foram ajustados para a média dos resultados de cada animal, para a média dos resultados de cada extração analítica e para os resultados obtidos para cada réplica, sendo que para esta última situação foi ajustado um modelo de regressão linear com efeitos mistos. O modelo linear ajustado para as médias obtidas para cada extração analítica apresentou maior precisão nas estimativas dos parâmetros do modelo e também menor período de carência. No entanto, para esse modelo também foram detectados mais pontos potencialmente influentes comparado aos demais modelos ajustados. Não foi possível calcular o limite de tolerância e, consequentemente, predizer o período de carência quando utilizado o modelo com efeitos mistos. Conclui-se que a o ajuste de outros modelos estatísticos mais robustos e flexíveis deve ser considerado para a estimação do período de carência de medicamento veterinário. / Veterinary drugs residues can be found in foodstuffs of animal origin such as meat, milk, eggs and honey. In order to ensure that the concentration of these residues does not exceed a safe limit (Maximum Residue Limit - MRL) it is necessary to establish a withdrawal period, which is the waiting time necessary for an animal to be sent for slaughtering after having received a veterinary drug. The estimation of the withdrawal period is normally obtained by the fitting of a simple linear regression model, followed by the calculation of a tolerance limit. For this, the assumptions of homoscedasticity and the normality of the errors must be met. However, violations of these assumptions are frequent in the residual depletion studies. In the present study two database of the quantification of veterinary drug residue in bovine tissues were used and the withdrawal period was estimated for liver, fat, muscle and kidneys. The regression models were fitted to the mean value of the results obtained for each animal, to the mean value of the results obtained for each analytical extraction and to the results obtained for the repeated sample measurements, and a linear mixed model was fitted for this later situation. The linear model fitted to the mean value of the results obtained for each analytical extraction showed greater precision in the parameters estimates of the model as well as shorter withdrawal period. However, for this model, more potentially influential points were detected compared to other models fitted. It was not possible to calculate the tolerance limit, and, consequently, to predict the withdrawal period using the mixed effects model. In conclusion, the fitting of the other more robust and flexible statistical models should be considered for the estimation of the withdrawal period of veterinary drug.
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Estimação do período de carência de medicamento veterinário em produtos comestíveis (tecidos) de origem animal por modelos de regressão / Estimation of the withdrawal period for veterinary drugs in edible tissues of animal origin by regression modelsSimone Cristina Rosa 12 August 2016 (has links)
Resíduos de medicamento veterinário podem estar presentes em produtos comestíveis de origem animal, tais como carne, leite, ovos e mel. Para assegurar que a concentração de tais resíduos não excede um limite considerado seguro (Limite Máximo de Resíduo - LMR) deve ser estabelecido o período de carência, que é o tempo que deve ser respeitado para que um animal possa ser enviado para o abate após ter recebido um dado medicamento veterinário. A estimação do período de carência usualmente é feita pelo ajuste de um modelo de regressão linear simples, seguido pelo cálculo de um limite de tolerância. Para isso, os pressupostos de homocedasticidade e de normalidade dos erros do modelo devem ser atendidos. No entanto, violações desses pressupostos são frequentes nos estudos de depleção residual. No presente trabalho foram utilizados dois bancos de dados da quantificação de resíduo de medicamento veterinário em tecidos de bovinos e o período de carência foi estimado para fígado, gordura, músculo e rins. Os modelos de regressão foram ajustados para a média dos resultados de cada animal, para a média dos resultados de cada extração analítica e para os resultados obtidos para cada réplica, sendo que para esta última situação foi ajustado um modelo de regressão linear com efeitos mistos. O modelo linear ajustado para as médias obtidas para cada extração analítica apresentou maior precisão nas estimativas dos parâmetros do modelo e também menor período de carência. No entanto, para esse modelo também foram detectados mais pontos potencialmente influentes comparado aos demais modelos ajustados. Não foi possível calcular o limite de tolerância e, consequentemente, predizer o período de carência quando utilizado o modelo com efeitos mistos. Conclui-se que a o ajuste de outros modelos estatísticos mais robustos e flexíveis deve ser considerado para a estimação do período de carência de medicamento veterinário. / Veterinary drugs residues can be found in foodstuffs of animal origin such as meat, milk, eggs and honey. In order to ensure that the concentration of these residues does not exceed a safe limit (Maximum Residue Limit - MRL) it is necessary to establish a withdrawal period, which is the waiting time necessary for an animal to be sent for slaughtering after having received a veterinary drug. The estimation of the withdrawal period is normally obtained by the fitting of a simple linear regression model, followed by the calculation of a tolerance limit. For this, the assumptions of homoscedasticity and the normality of the errors must be met. However, violations of these assumptions are frequent in the residual depletion studies. In the present study two database of the quantification of veterinary drug residue in bovine tissues were used and the withdrawal period was estimated for liver, fat, muscle and kidneys. The regression models were fitted to the mean value of the results obtained for each animal, to the mean value of the results obtained for each analytical extraction and to the results obtained for the repeated sample measurements, and a linear mixed model was fitted for this later situation. The linear model fitted to the mean value of the results obtained for each analytical extraction showed greater precision in the parameters estimates of the model as well as shorter withdrawal period. However, for this model, more potentially influential points were detected compared to other models fitted. It was not possible to calculate the tolerance limit, and, consequently, to predict the withdrawal period using the mixed effects model. In conclusion, the fitting of the other more robust and flexible statistical models should be considered for the estimation of the withdrawal period of veterinary drug.
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Predicting drug residue depletion to establish a withdrawal period with data below the limit of quantitation (LOQ)McGowan, Yan January 1900 (has links)
Doctor of Philosophy / Department of Statistics / Christopher Vahl / Veterinary drugs are used extensively for disease prevention and treatment in food producing animals. The residues of these drugs and their metabolites can pose risks for human health. Therefore, a withdrawal time is established to ensure consumer safety so that tissue, milk or eggs from treated animals cannot be harvested for human consumption until enough time has elapsed for the residue levels to decrease to safe concentrations. Part of the process to establish a withdrawal time involves a linear regression to model drug residue depletion over time. This regression model is used to calculate a one-sided, upper tolerance limit for the amount of drug residue remaining in target tissue as a function of time. The withdrawal period is then determined by finding the smallest time so that the upper tolerance limit falls below the maximum residue limit. Observations with measured residue levels at or below the limit of quantitation (LOQ) of the analytical method present a special challenge in the estimation of the tolerance limit. Because values observed below the LOQ are thought to be unreliable, they add in an additional source of uncertainty and, if dealt with improperly or ignored, can introduce bias in the estimation of the withdrawal time. The U.S. Food and Drug Administration (FDA) suggests excluding such data while the European Medicine Agency (EMA) recommends replacing observations below the LOQ with a fixed number, specifically half the value of the LOQ. However, observations below LOQ are technically left censored and these methods are do not effectively address this fact. As an alternative, a regression method accounting for left-censoring is proposed and implemented in order to adequately model residue depletion over time. Furthermore, a method based on generalized (or fiducial) inference is developed to compute a tolerance limit with results from the proposed regression method. A simulation study is then conducted to compare the proposed withdrawal time calculation procedure to the current FDA and EMA approaches. Finally, the proposed procedures are applied to real experimental data.
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Διερεύνηση των επιπέδων κτηνιατρικών ανθελμιθικών ουσιών στο γάλα και εκτίμηση της πρόσληψης από τον άνθρωπο / Investigation on the concentration levels of veterinary anthelminthics residues in milk and assessment of human intakeΤσιμπούκης, Δημήτριος 04 September 2013 (has links)
Σκοπός: Ο προσδιορισμός των επιπέδων συγκέντρωσης καταλοίπων κτηνιατρικών παρασιτοκτόνων ουσιών (ανθελμινθικών), σε νωπό γάλα μηρυκαστικών από περιοχές της Νοτίου Ελλάδος και η εκτίμηση της πρόσληψής τους από τον άνθρωπο. Συγκεκριμένα εξετάσθηκαν οι ουσίες, Albendazole, Febantel, Fenbendazole, Mebendazole και κάποιοι μεταβολίτες τους (Albendazole sulfoxide, Albendazole sulfone, Fenbendazole sulfone) στο νωπό γάλα προβάτων, αιγών και βοοειδών.
Μέθοδοι: Χημική ανάλυση δειγμάτων γάλακτος, με τη βοήθεια Υγρής Χρωματογραφίας Υψηλής Απόδοσης και ανιχνευτή Συστοιχίας Διόδων, Υπεριώδους (UV). Χρήση βάσης δεδομένων σχετικά με την εκτίμηση της ημερήσιας κατανάλωσης γάλακτος και Φέτας (λήψη προσωπικών συνεντεύξεων, συμπλήρωση ερωτηματολογίων, συχνοτήτων κατανάλωσης τροφίμων, από δείγμα 723 μαθητών ηλικίας 10-12 ετών, από τη Νότια Ελλάδα).
Αποτελέσματα: 34 από τα 123 δείγματα γάλακτος βρέθηκαν να περιέχουν κατάλοιπα των διερευνώμενων ουσιών, εκ των οποίων τα 11 υπερέβαιναν τα θεσπισμένα από την Ε.Ε. ανώτατα επιτρεπτά όρια καταλοίπων. Η Εκτιμώμενη Ημερήσια Πρόσληψη των ουσιών αυτών, από το εξετασθέν δείγμα πληθυσμού, κυμαίνεται από 0,4-15,9% της Αποδεκτής Ημερήσιας Πρόσληψης, ανάλογα με την ουσία και το τρόφιμο (νωπό αγελαδινό γάλα ή τυρί Φέτα). Υπάρχει γεωγραφική διακύμανση στη συχνότητα εμφάνισης των καταλοίπων η οποία είναι ιδιαίτερα αυξημένη σε περιοχές οι οποίες στερούνται επαρκών υπηρεσιών ελέγχου τροφίμων.
Συμπεράσματα: Από την παρούσα εργασία προκύπτει ότι 11.4% των δειγμάτων γάλακτος, περιέχει κατάλοιπα ανθελμινθικών ουσιών, σε επίπεδα συγκεντρώσεων που υπερβαίνουν το ανώτατο επιτρεπτό όριο (έως και 7 φορές για τη Febantel). Το εύρημα αυτό, εγείρει ερωτήματα για την πλήρη εφαρμογή της Ο.Κ.Π.. Ωστόσο η κατανάλωση νωπού γάλακτος το οποίο περιέχει κατάλοιπα των υπό διερεύνηση ενώσεων, στα προαναφερθέντα επίπεδα συγκεντρώσεων, δεν οδηγεί σε υπέρβαση της Ανώτερης Ημερήσιας Πρόσληψης. Από την άλλη πλευρά, είναι απαραίτητο να τονιστεί ότι οι ουσίες αυτές είναι δυνατό να ανιχνευθούν και σε άλλα τρόφιμα ζωικής προέλευσης για τα οποία δεν έχουν θεσπιστεί MRLs και συνεπώς δε διεξάγονται οι αντίστοιχοι έλεγχοι. Κατά συνέπεια, είναι απαραίτητη η εκπαίδευση των κτηνοτρόφων σε θέματα Ο.Κ.Π., η εντατικοποίηση των ελέγχων και η στελέχωση των κρατικών υπηρεσιών, έτσι ώστε να αντισταθμίζονται οι ελλείψεις των νόμων και να αποφευγονται πιθανές δυσμενείς συνέπειες για τη δημόσια υγεία. / Aim: The determination of the concentration levels, of veterinary parasiticide drug (anthelmintics) residues, in ruminants’ raw milk, from regions of Southern Greece, and the residues’ intake estimation for humans. In particular, the investigated, residues were Albendazole, Febantel, Fenbendazole, Mebendazole and some of their metabolites (Albendazole sulfoxide, Albendazole sulfone, Fenbendazole sulfone), in sheep, goat and bovine raw milk.
Methods: Chemical analysis of raw milk samples with High Performance Liquid Chromatography and UV Diode Array Detector. A databank concerning the daily consumption of milk and feta cheese was utilized (personal interviews and filling in of food frequency questionnaires, from a population sample of 723 pupils aged from 10-12 years old, in Southern Greece).
Results: 34 out of the 123 milk samples, were found to contain residues of the investigated compounds and 11 of the contaminated samples, contained residues, exceeding the EU established MRLs. The Estimated Daily Intake for these residues resulting from the interviewed population sample, was ranging from 0,4 to 15,9% of the Acceptable Daily Intake, depending on the substance and the kind of food (raw bovine milk or feta cheese). There is a geographical variation concerning the residue occurrence, which is high in regions where food control agencies are poorly staffed.
Conclusions: The present study indicates that 11.4% of milk samples analysed, contains concentration levels of anthelmintic residues above the maximum residue limit (up to 7 times for Febantel). This finding raises questions about the full implementation of Good Veterinary Practice. However, consumption of raw milk containing the aforementioned concentration levels of the compounds under investigation, does not result to exceedance of the Acceptable Daily Intake. On the other hand, it is necessary to emphasize that these substances are possible to be detected in other foods of animal origin for which no MRLs have been established and therefore the respective controls are not carried out. Consequently, training of stock-farmers on GVP, intensification of controls and staffing of government agencies, are needed to counterbalance deficiencies of laws and avoid potential adverse effects on public health.
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Estudo de depleção residual de benzoato de emamectina em filés de peixe e estimativa de período de carência / Depletion study of emamectin benzoate in fish fillet and determination of withdrawal periodFraccarolli Neto, Pedro 11 June 2018 (has links)
O benzoato de emamectina, um antiparasitário da classe das avermectinas, é amplamente utilizado em diversos países para o tratamento de infecções causadas por helmintos intestinais e ectoparasitas, os quais estão relacionados a grandes prejuízos na produção aquícola. Apesar de sua eficácia ser conhecida na aquicultura, seu uso não está regulamentado no Brasil. Diante da demanda nacional por uma maior variedade de medicamentos veterinários regulamentados para uso em espécies aquícolas, o presente projeto visou estimar um período de carência para o antiparasitário benzoato de emamectina, a partir de um estudo experimental de depleção residual desse fármaco em tilápia (filé com pele em proporção natural), a espécie de maior importância comercial para a produção aquícola no Brasil. Para tanto, fez-se necessárias as seguintes etapas: (i) incorporar o benzoato de emamectina na ração através da técnica de revestimento polimérico em equipamento de leito fluidizado; (ii) desenvolver e validar métodos analíticos para a determinação do benzoato de emamectina na ração e em filé de tilápia empregando cromatografia líquida de alta eficiência acoplada à espectrometria de massas (LC- MS/MS); e (iii) realizar um ensaio com tilápias para avaliar a depleção residual de emamectina B1a no filé. O revestimento da ração com 1,5% de etilcelulose permitiu incorporar o benzoato de emaectina na ração sem alterar a estrutura física da mesma, o que torna o processo vantajoso, visto que a ração mantém suas características nutricionais e de flutuabilidade. Além disso, o processo foi homogêneo (CV de 2,1%) e não apresentou taxa de lixiviação quantificável do fármaco para a água, contribuindo para uma maior segurança em relação à dose de tratamento a ser administrada e em relação ao risco potencial ao meio ambiente. A emamectina B1a foi extraída da ração por processo sólido-líquido e do filé de tilápia pelo método QuEChERS modificado. Os métodos foram avaliados mediante os seguintes parâmetros: seletividade, curva analítica, linearidade, precisão, exatidão, limite de detecção (LD) e de quantificação (LQ). Todos os parâmetros avaliados se encontraram conformes às recomendações dos guias de validação tomados como referências, qualificando os métodos como adequados para os objetivos propostos no presente trabalho. Para avaliar a depleção de emamectina B1a no filé de tilápia, os peixes receberam o fármaco via ração em dose de 50 ?g/kgPV/dia durante sete dias consecutivos. As curvas de depleção residual de emamectina B1a se ajustaram ao modelo exponencial de primeira ordem. Tomando como referência o limite máximo de resíduo de 100 ?g/kg recomendado pelo Codex Alimentarius, não houve a necessidade de se propor um período de carência mínimo para o abate dos peixes, considerando as condições experimentais empregadas. / Emamectin benzoate, an antiparasitic of the class of avermectins, it is widely used in several countries for the treatment of infections caused by intestinal helminths and ectoparasites, which are related to great losses in aquaculture production. Although its known effectiveness for aquaculture, its use is not regulated in Brazil. The national demand for a greater variety of regulated veterinary drugs for use in aquaculture species,the current project that aimed to evaluate a withdrawal period for the antiparasitic emamectin benzoate, based on an experimental study of residual depletion of this drug in tilapia ( fillet with skin in natural proportion) the species of major commercial importance for aquaculture production in Brazil. To do so, it was necessary to: (i) incorporate emamectin benzoate into the feed through the polymer coating technique in fluidized bed equipment; (ii) to develop and validate the analytical methods for the determination of emamectin benzoate in the feed and in tilapia fillet using high-performance liquid chromatography coupled to mass spectrometry (LC-MS / MS) and (iii) perform a tilapia test to evaluate the depletion of emamectin B1a in fillet. The feed coating with 1.5% ethylcellulose allowed to incorporate the emaectin benzoate into the feed without altering the physical structure, which makes the process advantageous, since the feed retains its nutritional and buoyancy characteristics. In addition, the process was homogeneous (CV 2,1%) and did not present quantifiable leaching rate of the drug into the water, contributing to a greater safety in relation to the dose of treatment to be administered and in relation to potential risk to the environment. Emamectin B1a was extracted from the feed by solid-liquid process and from tilapia fillet by the modified QuEChERS method. The methods were evaluated using the following parameters: selectivity, analytical curve, linearity, precision, accuracy, limit of detection (LD) and quantification (LQ). All the evaluated parameters were in accordance with the recommendations of the validation guides taken as references, qualifying the methods as adequate for the objectives proposed in the present work. To evaluate the depletion of emamectin B1a tilapia fillet, the fish received the drug via feed at a dose of 50 ?g / kgPV / day for seven consecutive days. The residual depletion curves of emamectin B1a were fitted to the first order exponential model. Taking into account the maximum residue limit of 100 ?g / kg recommended by the Codex Alimentarius, there was no need to propose a minimum withdrawal period for the slaughtering of fish, considering the experimental conditions used.
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