Antimicrobial drug residues in milk and meat: causes, concerns, prevalence, regulations, tests, and test performance

This paper presents a historical review of antimicrobial use in food animals, the causes of residues in meat and milk, the types of residues found, their regulation in Canada, tests used for their detection, and test performance parameters, with an emphasis on immunoassay techniques. The development of residue detection methods began shortly after the introduction of antimicrobials to food animal production in the late 1940s. From initial technical concerns expressed by the dairy industry to the present public health and international trade implications, there has been an ongoing need for reliable, sensitive, and economical methods for the detection of antimicrobial residues in food animal products such as milk and meat. Initially there were microbial growth inhibition tests, followed by more sensitive and specific methods based on receptor binding, immunochemical, and chromatographic principle. An understanding of basic test performance parameters and their implications is essential when choosing an analytical strategy for residue testing. While each test format has its own attributes, none test will meet all the required analytical needs. Therefore the use of a tiered or integrated system employing assays designated for screening and confirmation is necessary to ensure that foods containing violative residues are not introduced into the food chain.     

A bioeconomic model for comparing beef cattle genotypes at their optimal economic slaughter end point

A bioeconomic model of a feedlot was developed for the comparison of beef cattle genotypes under specified management and marketing conditions. The optimization behavior of commercial feedlot managers is incorporated into the model using optimum economic rotation theory. The days spent in the feedlot (rotation) by a group of animals are derived using this theory so as to maximize an objective function. Differences among breeds in the present value of profits from a single rotation, expressed per animal, represent the expected price premium paid for a feeder animal of a particular breed. Feed requirements and growth rates for a genotype are predicted over time for a specified diet from estimated mature size. Estimates of carcass fatness over time as a function of the energy content of the diet and estimates of dressing percentage over time are used for each genotype. A base model is described that incorporates biological parameters estimated for 11 breeds from a major breed comparison experiment and uses prices of inputs and outputs for Ontario feedlots. Sensitivity of the model to these biological and economic assumptions is shown. When breeds are compared at constant days fed, weight, or fat depth slaughter points, rankings are inconsistent, relative to those when each breed is slaughtered at its optimal economic point. The model can be used to establish appropriate slaughter end points for comparing beef cattle breeds and crosses and to evaluate breeding objectives for feedlot traits in genetic improvement programs.     

Intensive (pasture) beef cattle operations: the perspective of New Zealand

Beef production in New Zealand has characteristics typical of a temperate climate and pasture-based animal husbandry. The specific pathogens which may contaminate fresh beef and which are empirically considered to be of public health importance are similar to those in other countries with temperate climates, i.e. Salmonella, Campylobacter, Escherichia coli O157:H7, Listeria monocytogenes and Toxoplasma gondii. With the exception of T. gondii, it is likely that almost all transmission of these hazards through consumption of beef results from unseen microbial cross-contamination from gastrointestinal sources during slaughter, dressing and further processing. Gaining comprehensive information on carcass contamination levels is an essential first step in establishing food safety objectives for a particular beef production system, and in designing risk-based hazard analysis and critical control point (HACCP) plans. It is likely that the lower mean and maximum numbers of indicator micro-organisms on New Zealand carcasses (when compared with other countries) are in part due to the pre-slaughter cleanliness status of cattle reared under temperate, pasture conditions. Similarly, the failure to detect specific pathogens of gastrointestinal origin in a comprehensive baseline survey most probably reflects the limited pathway for faecal contamination during slaughter and dressing under processing conditions in New Zealand. The New Zealand example provides strong evidence for the need to design HACCP plans according to the specific national (or regional) situation. Reducing all pathways for faecal contamination of products to the maximum extent practicable will be the most important factor in achieving desired food safety objectives for fresh beef. Variable densities of microbial pathogens in gastrointestinal contents are also likely to have a significant effect on subsequent contamination levels of beef carcasses: however, effective controls for limiting the presence of most pathogens of concern in the live animal have yet to be identified.     

Food safety issues affecting the dairy beef industry

The ability of dairy farmers to market cull cows and veal calves may be affected by the final rule on Pathogen Reduction and HACCP (Hazard Analysis Critical Control Points) Systems, a sweeping reform of USDA food safety regulations that was published on July 25, 1996. Although the regulations apply only to slaughter and processing plants handling meat and poultry, the rule will have an impact on food animal producers, including dairy farmers. Under this regulation, plant operators are required to evaluate potential hazards and to devise and implement controls that are appropriate for each product and plant to prevent or reduce those hazards. Processing plants may need to consider the potential hazards associated with incoming animals, such as illegal drug residues, which may result in marked changes in the relationships among some producers, livestock markets, and slaughter plants. Such information may actually improve the marketability of some animal classes because documentation will help the packer ensure the safety of products for sale to domestic and foreign markets. Dairy scientists are in an excellent position to explain the food safety issues to dairy farmers and to help develop the appropriate strategies that are necessary to guide the changes needed. These scientists can be conduits for information, the research leaders for practical solutions to reduce public health risks, and valuable resources to help farmers adjust to the impact of these new in-plant regulatory systems.     

Patterns of chemical residues detected in US beef carcasses between 1991 and 1993

A study of data from 12 states in the Food Safety Inspection Service's Residue Violation Information System was conducted to describe patterns of violative chemical residues in US beef during 1991, 1992, and 1993. In 1991, 3,249 violative residues were found in 2,734 carcasses in the 12 states included in the study. In 1992, 3,132 violative residues were found in 2,813 carcasses, and in 1993, 2,317 violative residues were found in 2,051 carcasses. During each of the 3 years, the Calf Antibiotic and Sulfonamide Test and Swab Test On Premises projects detected most of the violative residues, and producers/independent growers and dairy farms were recorded as the responsible sources for most of the violations. Also, most of the animals found to have violative residues were bob calves and culled cows. In bob calves, neomycin was the most frequently identified violative chemical, followed by tetracycline, gentamicin, oxytetracycline, and penicillin. In culled cows, penicillin was the most frequently identified violative chemical and was the chemical most frequently found in combination with other chemicals in cows with multiple violative residues. Distribution patterns of violative chemical residues by slaughter class and residue type varied among the 5 Food Safety Inspection Service regions. These specific regional characteristics support the need for customized intervention, education, assessment, and prevention programs.     

Modifying the formulation or delivery mechanism to increase the activity of anthelmintic compounds

The development of resistance to current chemical classes of broad-spectrum anthelmintics poses an undeniable threat to the long-term viability of the animal health industry. Alternative treatment strategies including vaccines, biological control and breeding of parasite-resistant animals are unlikely to be widely available in the near future and even then, they will be integrated with chemotherapy. To compound the severity of the situation there appears to be no new chemical class of anthelmintics, with unique mode of action, on the horizon. The significant cost of drug research and the development costs of a drug that is to be used in food-producing animals, together with the small market share of animal health products compared to human pharmaceutical/medical and cosmetic products, provide little incentive for anthelmintic development. The chemical actives that are currently available, are all that we are likely to have for the foreseeable future. If effective parasite treatment is to continue, existing actives must be used more efficiently. Recognising the potential for the animal's physiological behaviour to assist drug action is of significant value. Reduction of feed intake before oral anthelmintic treatment slows ruminant digesta flow, prolongs and extends the availability and therefore increases efficacy, of the benzimidazole and ivermectin compounds. This is a cost effective option that can be employed which not only increases efficacy of 'older' compounds, but will be instrumental in prolonging the useful life of the 'newer' drugs. In a related approach the co-administration of metabolic inhibitors can prolong drug clearance and extend availability and increase the action of existing anthelmintics. However, given the large costs which would be associated with this development (host toxicity, residue safety) it is probable that the value of such combinations would be more appropriate for use in the treatment of non-food producing animals. The most promising approach for improved formulation lies in innovative delivery systems using chemical or physical carriers. Solubility-defining salts, oils, solid/drug matrices, liposomes and related microparticles that reduce drug absorption/metabolism and can specifically direct large quantities of active, over an extended or pre-determined period, to the site(s) of parasitic infection. The use of lipophilic actives/vehicles which deposit in and are released from body fat is of particular value in extending drug availability. The prophylactic action of extended drug residence time, when used with effective grazing/treatment management programmes, provides opportunities for sustainable antiparasitic action. Clearly, with the paucity of new chemical classes of anthelmintics, the use of 'intelligent' but still relatively inexpensive carriers/delivery systems for existing actives will form the basis of future parasite control.     

Illegal use of beta-adrenergic agonists in the United States

Clenbuterol (CBL) is a member of the class of drugs called beta-agonists, which have powerful desirable and undesirable effects. Clenbuterol has the ability to increase muscle mass and residues in tissue of treated animals but can cause symptoms of acute poisoning in people. Symptoms, but no deaths, from CBL residue-induced food poisoning have been reported from investigations of separate events in Spain and France. In 1991, FDA sent letters to all states and USDA/FSIS advising them of the possibility of illegal CBL use in domestic animals and of our concern about adverse effects on public health if residue was present in food. The FDA asked U.S. Customs to be alert to attempts at illegal importation and to advise that we were prepared to investigate distribution, sale, or use of the drug. Analytical methods are available to assay for CBL residue in edible tissues and in the retinal tissues of the eye. Methods are being developed for assay of noninvasive samples such as hair. Residues of CBL have been found in one sample of edible tissue and several samples of retinal tissues from show animals and in some classes of commercial meat-producing animals. Several individuals have been found guilty of distributing CBL, cases are pending, and investigations are continuing. It is possible that CBL will be approved for safe conditions of use. The scenario of ultimately one or more beta-agonist drugs approved for legal use in food-producing animals and the probable continued availability of several illegal analogs will be a challenging containment task for regulators and the leaders of the meat-producing livestock industries.     

The seasonal variation of thermophilic campylobacters in beef cattle, dairy cattle and calves

The epidemiology of clinical cases of campylobacter in temperate climates shows a striking seasonality. In the search for a seasonal environmental reservoir changes in the carriage rate and population size of campylobacters in bovine hosts with time have been measured. Most probable number (MPN) methodology was used to enumerate thermophilic campylobacters in samples taken from the small intestines of beef cattle at slaughter and the fresh faeces of four dairy herds and new-born calves. Statistical analyses revealed significant evidence for seasonal periodicity in the data from dairy herds (P = 0.044). Not only was there a departure from constancy within a 12-month interval but these data revealed a true seasonality, that is, the same periodicity in numbers from one year to the next. Each herd had two peaks per year, in approximately spring and autumn. Peaks coincided in herds on neighbouring farms but those on farms in the north preceded those on farms in the south by 2 and 1 months, respectively (P = 0.0057). Intestinal carriage by beef cattle at slaughter was 89.4% (n = 360) with an average MPN campylobacters per gram fresh weight (MPN gfw-1) of 6.1 x 10(2). Average MPN gfw-1 in faeces from the dairy herds and calves were 69.9 (S.D. 3) and 3.3 x 10(4) (S.D. 1.7 x 10(2)). There was no evidence of seasonal periodicity in the size of the campylobacter population in beef cattle at slaughter. Calves were campylobacter free at birth but became colonized with a few days.     

Economics of gastrointestinal parasitism of cattle

Understandably, cattle are raised for profit, as beef and/or dairy. Anything that negates that equation results in a loss to the producer and to the livestock economy. Thus, parasites negatively affect the economy of the industry. Worldwide, gastrointestinal nematode parasites, especially Ostertagia ostertagi, and those of the respiratory tract (Dictyocaulus viviparus) have a potentially major impact on herd health. In the past 10-15 years, anthelmintic (AH) drug development and the strategic use of AH have positively balanced the economic equation, so that overall, parasitism in cattle is often observed or determined to be subclinical or economical. Other control measures, such as better pasture management, are also being developed to enhance herd health and the cattle economy. The determination of the economic impact of parasitism has thus become less apparent, to the extent that measures, such as performance parameters, must be used to measure differences between treated and untreated animals or herds. These include weight gain, reproduction, lactation and forage use. To determine the effectiveness of control measures, field trials are designed to measure these parameters by the demonstration of improved performance. Because these trials are conducted in a competitive mode, results are often debated by competitors and by the scientific community because of study design. Variables must then be taken into consideration in the interpretation of results. It is now well known that, with the generation of new AH and appropriately-timed administration, parasitism of well-managed herds has been reduced to subclinical levels. Thus, we are now in the process of fine-tuning the positive effect of these control measures for enhanced production. Understandably, beef and dairy producers have 'production of high quality commodities' at a cost-effective level as a common goal. Successful cattlemen calculate expenditures and income by line item including veterinary expenses and cost and labor in administration of AH. Return is based on performance. Again, nematode parasites can disturb the equation enough to make production less profitable or even unprofitable. Most USA beef cattle producers believe that worm parasites do have an effect on cattle health and production so that 77% use AH and the market impact is that AH have become integrated into cattle herd health programs. However, to be most cost-effective, programs must be strategic but flexible with scheduling tailored for the region and the cattle operation. Other technologies should eventually provide rapid identification of worm populations by species and numbers and recognition of individual animal response to parasites and inheritance of that trait by their progeny. Computerized programs for analysis of seasonality of the epidemiology of gastrointestinal parasites and of herd performance could predict appropriate timing and cost benefit for control measures. Modes of AH administration are being developed which are more reliable and convenient in terms of delivery and labor. Control measures must also include better pasture management with less impact on the environment and to justify investment in land. In addition, successful producers are better educated, more cost-conscious, consumer-oriented, sensitive to the environment and attuned to the economics of parasitism.     

Animal models and ethological strategies for early drug-testing in humans

The preclinical evaluation of psychotropic drugs relies on the use of animal tests which are thought to generate clinically relevant information concerning the psychiatric condition for which the drug can be used. Despite their importance, views on the usefulness of animal "models" vary widely, ranging from outright negation on the grounds that human minds are unique, to the more biological view that because of a partially common phylogenetic history, animals share many behavioural features with humans, e.g. learning, attention, aggression or sociality, which are altered in psychiatric disorders. The widespread use of ethology with its emphasis upon the function and origin of behaviour, particularly social behaviour, is based upon this evolutionary view. Many ethopharmacological tests in animals use situations which bias the animal's behaviour towards flight or sociality but their validation requires clinical feedback from humans. Unfortunately, information relating to human social mechanisms is rarely obtainable from conventional clinical-assessment schemes. To help overcome this problem, we have applied ethological principles to a new Challenge Interview Situation which is designed to bias the behaviour of healthy subjects towards flight. Analysis shows that by staring, moving closer or asking the subjects to relate emotional experiences, shifts in non-verbal behaviour towards avoidance and mild social withdrawal are achieved which resemble behavioural strategies recorded ethologically in depressed patients as well as animals in an arrested flight situation. The Challenge Interview is intended for early drug studies in humans where sociality is a target and can be adapted for concomitant endocrine and biochemical studies if required.     

Antagonist properties of a phosphono isoxazole amino acid at glutamate R1-4 (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid receptor subtypes

All three subtypes of beta-adrenoceptors are coupled to stimulation of adenylyl cyclase activity via the stimulatory guanine-nucleotide-binding protein. Nevertheless, the beta3 adrenoceptor (beta3-AR) differs significantly from the other subtypes in terms of pharmacology. Most strikingly, it recognizes as agonists several compounds acting as potent beta1-AR and beta2-AR antagonists. Furthermore, the human beta3-AR is quite different from the animal beta3-AR. Molecular modelling studies followed by site-directed mutagenesis was used here to identify some of the amino acid residues which may be implicated in ligand binding and signal transduction of the beta3-AR. Three contiguous residues, valine-leucine-alanine, which are present in the first transmembrane domain at positions 48-50 of the human receptor but are absent in all known rodent sequences, were thought to be important for species specificity. When these three residues were deleted from the human receptor, no 'rodent-like' pharmacological profile was obtained in terms of either binding or adenylyl cyclase activation. Glycine at position 53, also in the first transmembrane domain in the human beta3-AR, has been suggested to participate in beta2-/beta3-AR subtype selectivity. Replacement of this glycine residue by phenylalanine, which is the residue present at the homologous position in the human beta2-AR, left the beta3-AR pharmacological profile unaltered in terms of specificity and selectivity. Aspartate residue 117, in the third transmembrane domain, has been found to be essential for ligand binding and consequently adenylyl cyclase activation in several bioamine receptors. When this residue was replaced by a leucine residue in the beta3-AR, ligand binding and signal transduction were suppressed. Finally, replacement of asparagine at position 312 in the sixth transmembrane domain by an alanine residue, led to alterations in the signal-transduction pathway.     

含砷废渣危害及资源化技术研究进展

在冶金和化工过程中有大量的含砷废渣产生,特别是在云南和广西,大量的含砷废渣没有得到合适的处置,给企业和环境保护带来了巨大压力。含砷废渣一般属于HW24或HW48类危险废物,长时间堆放会污染大气以及地下水,从而对人体造成伤害。而今部分含砷废渣被进行焚烧或者固化填埋处置,没有得到很好的资源化利用。详细阐述了将黑铜泥、次氧化锌、硫酸铜滤渣和砷碱渣等资源化提取有价值产品的方法,为砷渣工业化和研究提供借鉴依据。     

National and international veterinary reference laboratories for infectious diseases

Reference laboratories play an increasingly important role in the harmonisation of laboratory diagnostic tests and the standardisation of veterinary vaccines. This is particularly important in building confidence between international trading partners. The authors review aspects of the organisation, designation and support of reference laboratories for infectious diseases of animals and discuss the principal activities which such laboratories would normally perform. These activities include advice and consultancy, publications and communication, training, research, disease surveillance, maintenance of culture collections, evaluation of reference methods, preparation of reference materials and organisation of inter-laboratory comparisons.     

Amino acid sequence environment modulates the disruption by osteogenesis imperfecta glycine substitutions in collagen-like peptides

Ostoegenesis imperfecta (OI) or "brittle bone" disease is associated with mutations in the genes for type I collagen chains and produces variable phenotypes, ranging from lethal cases at birth to mild cases with increased bone fractures. The most common OI mutations are single base substitutions leading to replacement of Gly by another residue, breaking the typical (Gly-X-Y)n repeating sequence pattern of the collagen triple-helix. Triple-helical peptides were designed to focus on residues 892-921 of the alpha1 chain of type I collagen, where two OI Gly-->Ser mutations are found in close proximity, a mild mutation at site 901 and a lethal mutation at site 913. Peptides were designed to include amino acid sequences around these mutation sites, and were synthesized with the normal sequence or with the Gly-->Ser mutated sequence. The peptide including the normal sequence residues 892-909 with four Gly-Pro-Hyp triplets at the C-terminus formed a stable triple-helix, and introduction of a Ser residue for Gly at the 901 mutation site led to a 50% loss of triple-helix content and a decrease in thermal stability, with little effect on folding. A peptide including residues 904-921 again formed a stable triple-helix, but the introduction of the Gly-->Ser substitution at site 913 led to a much greater decrease in thermal stability. These studies demonstrate the impact of local sequences flanking the Gly substitution on structural consequences and support the concept of variability and regional effects along the collagen molecule.     

Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney

This experiment was an attempt to use the soybean residue derived from the production of "soy milk". The residue contains about 18% protein, 70% carbohydrates and 7.5% lipid as fish feed for rearing common carp, Cyprinus carpio. There were 4 types of diets: (1) soybean residue, (2) soybean residue digested with Papain, (3) soybean residue (64%) mixed with beef liver (34%) and (4) same mixture as (3) but digested with Papain. The results indicate that the percentage increase in weight and length of fish feeding with beef liver supplemented diets was higher than those feeding with soybean residue alone. This was possibly due to the fact that beef liver was able to supplement the nutrient deficiency in soybean. The two types of feeds (2 and 4) digested with Papain also yielded significantly better fish growth in terms of weight and length gains, than their counterparts without digestion. Furthermore, the water turbidity of the tanks added with digested feeds was significantly less, as Papain was able to hyrolyse the protein substrates suspended in the water, and thus lowered the turbidity.     

Novelty seeking and drug use: Contribution of an animal model.

Although sensation seeking or novelty seeking is a reliable predictor of drug use in humans, individual differences in free-choice novelty seeking in animal models have generally failed to predict drug use. In the current article, hierarchical multiple regression analyses were used on data collected from a large sample of rats. Rats were screened on measures of inescapable and free-choice novelty tests and then were trained to lever press for sucrose or intravenous amphetamine. Although scores from the inescapable novelty test weakly predicted responding for amphetamine, the addition of free-choice novelty preference scores into the regression analyses significantly improved the predictive models. These results indicate that, similar to evidence in humans, individual differences in novelty seeking may be able to predict drug use in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Multiresidue liquid chromatographic method for determining residues of mono- and dibasic penicillins in bovine muscle tissues

A liquid chromatographic method with UV detection at 325 nm was developed for simultaneous determination of amoxicillin, ampicillin, penicillin G, and cloxacillin residues in bovine muscle tissue as their mercaptide derivatives. The penicillins are extracted from bovine tissues with 0.1 M phosphate buffer (pH 8.5), cleaned up on a t-C18 Sep-Pak cartridge, and eluted with 2 mL acetonitrile. After the acetonitrile in the eluate is evaporated to dryness, the residue is dissolved in 200 microL (40 + 60, v/v) acetonitrile-phosphate buffer (pH 6.5) and derivatized with acetic anhydride and mercuric chloride in the presence of 1,2,4-triazole at 65 degrees C for 30 min. Gradient analysis on a Spherisorb 5 microns ODS(2) (octadecyl silane) analytical column using a binary mobile phase consisting of acetonitrile and 0.10 M phosphate buffer (pH 6.5) in the presence of 0.0157 M sodium thiosulfate at 1 mL/min permits determination of each intact penicillin in bovine muscle tissue at > or = 10 ppb with recoveries > or = 72%. This laboratory method provides detection sensitivities equivalent to those of rapid tests used for screening beta-lactam drug residues in bovine tissue samples for regulatory enforcement.     

Presence of intestinal, liver and heart/adipocyte fatty-acid-binding protein types in the liver of a chimaera fish

Exact tests of equivalence and efficacy with a non-zero lower bound based on two independent binomial proportions for comparative trials are proposed. These exact tests are desirable for studies with small sample sizes. They generalize classical methods to include testing of null hypotheses of prespecified differences and can be used to demonstrate a new treatment's efficacy or its equivalence to a standard treatment. The proposed exact tests use unconditional distributions of the test statistics. Variances of test statistics are estimated via a constrained maximum likelihood method (Farrington and Manning). Data from oncology and vaccine clinical trials are used to illustrate the exact tests.     

Drug residues in untreated swine

The concentration of sulfadimidine was measured in the urine of pigs which were housed (over five days) in boxes where other pigs have been treated orally with sulfadimidine before. Sulfadimidine was measured in the urine of the unmedicated pigs in a concentration of up to 4 micrograms/ml. Considering these urine concentrations, violative sulfadimidine tissue residues would be expectable in the carcass after slaughter. The practice of fixing withdrawal times must be considered again to ensure that drug residues in tissues are below the MRL before slaughter also in unmedicated animals.