The Food Animal Residue Avoidance Databank (FARAD). Past, present and future.

During the last one-and-one-half decades, FARAD has established an unparalleled compilation of residue and pharmacokinetic information for veterinary species. In order to fulfill its mission, FARAD has become as much a research project as an educational one. Pressing problems, such as disease-altered kinetics, minor-species drug use, and industrial contaminants in livestock, require the new methods of analysis FARAD is developing. The data upon which this work is based can be greatly augmented by participation by other nations. In the United States, it was the cooperation of both academic and regulatory organizations that made the success of FARAD possible. Similar international cooperation can facilitate use of the FARAD model in other countries for the economic benefit of all participants, enhancement of food safety, and promotion of animal welfare.

Food borne microbial pathogens of cultured aquatic species.

This article provides a broad overview of microbial pathogens associated with marine and fresh water aquatic animals, including Vibrio species, Escherichia coli, Streptococcus iniae, Salmonella species, and Edwardsiella tarda. Historically, cultured fish were not considered important vectors of human pathogens. This situation is changing, partly due to increasing animal densities as a consequence of a rapidly growing industry and partly due to increasing awareness by health care providers of pathogens in aquatic species that may result in human illness. Concerns facing the industry are also discussed along with possible solutions.

Mercury distribution in American alligators (Alligator mississippiensis) in Florida.

Thirty American alligators (Alligator mississippiensis), including 24 wild-caught and six control captive farm-raised alligators, were analyzed for whole body mercury contamination. Wild-caught animals were collected from Water Conservation Area 3 in the Everglades ecosystem (n = 12) and from Alachua, Brevard, and Collier counties outside the Everglades (n = 12). Using cold-vapor atomic absorption spectrophotometry, samples of brain, cervical spinal cord, liver, paired kidneys, paired testes, paired ovaries, paired oviducts, heart, lungs, spleen, bile, tail and leg muscle, and tail and leg scales were analyzed on a wet weight basis to determine mercury concentration. Mercury was consistently detected in all specimens except for bile. Farm-raised alligators, fed a commercially prepared diet, contained very low mercury concentrations in all tissues analyzed. In comparison with alligators from outside the Everglades, Everglades alligators had significantly elevated concentrations of mercury in all tissues analyzed except ovaries, oviduct, bile, tail scales, and leg scales (paired two-sample Student's tau-test, P < 0.05). Muscle concentrations exceeded state (0.50-1.50 ppm) and federal (1.00 ppm) allowances for safe human consumption in alligators collected in the Everglades. No clinical signs of neurologic, hepatic, or renal toxicosis were detected. Because of the alligator's ability to bioaccumulate mercury, this species might be useful as a bio-monitor for environmental mercury contamination.

Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species.

The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vdss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (51/2 beta) were determined for this selected group of drugs by using the empirically determined function Y = a Wb. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric correlation, or be inconclusive due to the lack of quality data or excessive variability due to the multi-laboratory origin of the FARAD data. The results of this study show that interspecies scaling is applicable to certain veterinary drugs. The experimental determination of the coefficients of the allometric equation for relevant pharmacokinetic parameters (clearance and volume of distribution) could be an important tool in estimating dose in species where the drug has never been studied. This could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally 'well behaved.'

Oxytetracycline residues in milk after intrauterine treatment of cows with retained fetal membranes.

OBJECTIVE: To establish the maximum concentration and duration of oxytetracycline residues in milk from cows with retained fetal membranes given the antimicrobial via intrauterine infusion, and to investigate whether the number of infusions or the presence of fever (> 39.7 C) affected the duration of residues. DESIGN: Prospective study. ANIMALS: 54 Holstein cows with retained fetal membranes on a single 1,400-cow commercial dairy. PROCEDURE: Cows were treated once a day with 5 g of oxytetracycline (50 ml of 100 mg/ml solution in a povidone base) by intrauterine infusion for at least 2 days, or until the membranes were expelled. Cows that became febrile (rectal temperature > or = 39.7 C) were also given 20,000 IU of procaine penicillin G/kg of body weight, i.m., for 2 to 4 days. Milk samples were collected at 24-hour intervals during treatment. and at 12-hour intervals after the last treatment. All samples were frozen and submitted every 2 weeks for high performance liquid chromatography analysis for oxytetracycline. RESULTS: Oxytetracycline was detected in milk of all cows during treatment, at a maximum concentration ranging from 47.2 to 1,804.6 micrograms/kg (mean, 316.9 micrograms/kg). Duration of oxytetracycline residues after the last infusion ranged from 0 to 144 hours (mean, 52.3 hours). Neither the number of infusions received, nor development of rectal temperature > 39.7 C, affected the maximum concentration or the duration of oxytetracycline residues in milk. CLINICAL IMPLICATIONS: Milk obtained from cows that had been treated for retained fetal membranes by intrauterine infusion of oxytetracycline should be discarded to avoid illegal residues.

Adverse side effects of oral antibacterial therapy in dogs and cats: an epidemiologic study of pet owners' observations.

This epidemiologic study surveyed pet owners for observations of adverse reactions to oral antibacterials which were prescribed to outpatients at a university teaching hospital. Multiple questions were asked of all clients whose dog or cat was treated during the 18-month study. The questionnaire was designed prospectively to define those reactions that clearly seemed to be medication related. In this study, owners noted a significant number of adverse side effects with erythromycin stearate administration to dogs. Trimethoprim-sulfadiazine was used most often in dogs but did not result in a substantial number of adverse reactions.

Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration.

Clorsulon was measured in plasma and urine of sheep and goats after administration of a single intravenous (i.v.) and after a single oral dose of 7 mg/kg. A three-compartment model with elimination occurring from the central compartment was determined to best describe the i.v. data, whereas a one-compartment model with a single exponential absorption phase best described the oral plasma data. The bioavailability of orally administered clorsulon was approximately 55% in goats and 60% in sheep. Peak plasma concentrations occurred at 14 h and 15 h after oral administration in goats and sheep, respectively. Absorption from the gastro-intestinal tract effectively prolonged the elimination of clorsulon by increasing the elimination half-life from 17 to 28 h in sheep and from 12 to 23 h in goats for the i.v. and oral routes, respectively. In both goats and sheep, approximately 50% of the i.v. dose was recovered in urine as parent drug at 48 h after administration, whereas 41% and 30% of the dose was recovered after oral administration for goats and sheep, respectively. The elimination rate constant (kel) in goats was nearly twice as large as the value determined in sheep, and the urea under the i.v. plasma curve in goats was only 63% of the value in sheep indicating that goats are more effective in their capacity to eliminate clorsulon than are sheep. These differences in drug disposition between sheep and goats may account for the reduced efficacy of clorsulon reported in goats.

Use of the food animal residue avoidance databank.

In its extra-label drug use policy, the FDA states, as one of the criteria for permitting extra-label drug use, that a significantly extended time period be assigned for drug withdrawal prior to marketing meat, milk or eggs. The phrase "significantly extended time period" is taken to mean, at minimum, the amount of time necessary for any drug residues to deplete to subtolerance levels; however, determination of this period is left to the discretion of the veterinarian responsible for the extra-label drug use. The extended period will vary for each drug, dose, species, and route of administration. Therefore, it is unrealistic to assume that the practitioner can make a rational determination of extended drug withdrawal times without more information than is available through textbooks and professional journals. FARAD was specifically designed to provide veterinarians with the information required to determine extended withdrawal times, and thus prevent residues when drugs are used in an extra-label manner. FARAD can provide valuable residue avoidance assistance to veterinarians when drugs are administered in an extra-label manner, but it is not the answer to the national drug residue problem. Most residues result from failure to observe label-recommended withdrawal times, whereas less than 20% are thought to result from extra-label drug use. A substantial armamentarium of approved drugs is available to the veterinarian to treat most diseases in beef cattle, swine, and broiler chickens; thus, extra-label drug use in these species is unnecessary under most conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of clorsulon for the treatment of experimentally induced infections of Fasciola hepatica in goats.

A dose titration study was undertaken to determine the efficacy of clorsulon against the adult stage of Fasciola hepatica in goats. Thirty-nine goats were experimentally infected with metacercariae of F hepatica. At 14 weeks after infection, each goat was assigned randomly to 1 of 5 groups. Goats in groups 1 to 4 received a single oral administration of clorsulon at dosages of 3.5, 7, 11, and 15 mg/kg of body weight, respectively. The fifth group of goats (control group) was infected with F hepatica, but were not treated with clorsulon. Postmortem examination of goats at 3 weeks after treatment revealed mean reductions in numbers of flukes of 83, 98, 99, and 100% for groups 1 to 4, respectively. Mean percentage of reduction in eggs following treatment of groups was 82, 98, 100, and 100%, respectively. The clinical effects of clorsulon in 24 goats that were not infected with F hepatica were studied. Goats in groups 1 to 3 received a single oral administration of clorsulon at dosages of 7, 21, and 35 mg/kg, respectively, every other day for a total of 3 doses/goat. Group-4 goats (control group) received a vehicle placebo. Goats in group 3 were subject to postmortem examination at 14 days after dosing. Abnormal signs or lesions that could be attributed to clorsulon were not found in any goat.

Tolerance to ground Sesbania macrocarpa seed by broiler chicks and White Leghorn hens.

Two 21-day experiments using day-old male broiler chicks and a 28-day experiment using 35-wk-old White Leghorn hens were conducted to determine the deleterious effects of ground Sesbania macrocarpa seed in the diet. Seed levels of 0, .10, .25, .50, and 1% were used in both experiments, with a 2% level of inclusion added to Experiment 2. The hens were fed diets containing 0, 1, 2, 3, 4, 5, 6, or 7% seed. In each experiment, four replicate pens of 8 chicks or of 5 hens received each treatment diet. In both chick studies, a seed inclusion of 1% caused a significant reduction in body weight at 21 days of age. Total feed intake was significantly lowered by the inclusion of 1% seed in the first study and by 2% seed in the second study. Feed efficiency, excreta moisture, and mortality were not affected by dietary level of seed in either trial. Seed inclusion at 3% or more depressed the daily feed consumption of the hens; at 6% seed inclusion, egg production was reduced. Egg weight, egg specific gravity, mortality, and body weight change were not affected by treatment. Grains containing sufficient S. macrocarpa seed to produce finished feed with 1 or 3% seed would appear to be detrimental to broiler growth and feed intake by hens, respectively. The blending of such grains with uncontaminated stock could be a possible method of utilizing the contaminated grain.

Drug and chemical residues in livestock.

The problem of drug and chemical residues in foods of animal origin has become increasingly important to the entire livestock industry as growing consumer health concerns continue to erode the demand for these products. Although nearly 90 per cent of all drugs approved for use in livestock are available for over-the-counter sales, in the public's view, it is only the veterinarian who administers drugs to animals and who, therefore, is responsible for all drug residues in food. Congress has responded to these consumer concerns by applying increased pressure on the FDA to restrict the extra-label use of drugs by veterinarians. The veterinary profession now finds itself in a position in which it must reexamine its current drug-use policies and strive to develop policies that are more responsible to the consumer, both in appearance and substance.

Response of White Leghorn hens to various dietary levels of Cassia obtusifolia and nutrient fortification as a means of alleviating depressed performance.

Two 28-day experiments with White Leghorn hens were conducted to determine the adverse effect level of ground Cassia obtusifolia seed (coffeeweed) in the diet and to examine the nutrient fortification required to improve depressed performance due to the presence of the seed. In both experiments, five individually caged hens were used for each of the four treatment replications. Treatments for Experiment 1 consisted of a control and six diets with ground C. obtusifolia seed substituted for a filler at levels of 2, 3, 4, 5, 6, and 7%. In Experiment 2, a series of nutritionally fortified (15 to 20% higher nutrient levels) and unfortified diets coupled with seed levels of 0, 4, 6, and 8% for a total of eight treatments was used. Average daily feed intake, hen-day egg production, egg weight, egg specific gravity, and body weight change were determined during each experiment. For Experiment 1, average daily feed consumption was measured every 24 h for the first 3 days. Egg production and feed consumption were significantly reduced by 2% seed in Experiment 1. Within the first 24 h, feed intake was decreased to 37% below that of controls by increasing to the highest seed level. Egg specific gravity dropped significantly below that of controls when hens were fed 5% seed. In Experiment 2, fortification improved feed consumption, hen-day egg production, body weight change, and egg specific gravity over that of birds fed unfortified diets with the same seed level. Finished diets contaminated with 2%, or more, C. obtusifolia seed can cause reduced performance in laying hens, but nutritionally fortifying these diets can help to alleviate depressed performance.