Biliary excretion and enterohepatic cycling of zearalenone in immature pigs.

The disposition of the estrogenic mycotoxin, zearalenone (ZEN) in female, 10- to 14-week-old Yorkshire pigs was investigated. Pigs were administered [3H]ZEN intravenously (IV; n = 4; 5 mg/kg; 15 microCi/kg), orally (n = 4; 10 mg/kg; 30 microCi/kg), or intravenously with bile removal (IVB; n = 2; 5 mg/kg; 15 microCi/kg). Plasma, urine, feces, and bile (IVB pigs only) were serially collected and analyzed for radioactivity. Metabolite profiles were determined in plasma and bile by HPLC. The biological half-life of total plasma radioactivity in IV and orally dosed pigs (86.6 hr) was much larger than that of IVB animals (3.34 hr). Metabolite profiles of plasma concentration vs time demonstrated secondary peaks in concentration during the terminal elimination phase in IV and orally dosed pigs. In IVB pigs these peaks were absent, relative metabolite profiles were altered, and ZEN and metabolites were no longer detectable after 16 hr post-dosing. Biliary recovery of radioactivity, principally as glucuronide conjugates, was extensive (45.61 +/- 4.7%) in IVB pigs and significantly greater (p < 0.05) than that of fecal recovery of radioactivity in IV (6.56 +/- 0.78) or orally dosed (21.74 +/- 1.56%) pigs. Intraduodenal administration of bile containing [3H]ZEN and metabolites resulted in recovery of 64.56 +/- 4.89% of the dose in bile, 20.78 +/- 3.94% in urine, and the presence of glucuronide conjugates of ZEN and alpha-zearalenol (ZEL) in portal and jugular plasma. Differences in metabolite profiles between administered bile and sampled plasma suggest that the intestinal mucosa was active in reducing ZEN to ZEL and conjugating these metabolites with glucuronic acid. These studies provide evidence for extensive biliary secretion and enterohepatic cycling of ZEN and metabolites in pigs.

Deltamethrin residues in milk and tissues of lactating dairy cows.

Lactating dairy cows were fed deltamethrin (2 or 10 mg kg-1 feed) for 28 consecutive days and deltamethrin residues measured in milk and tissues. Deltamethrin residues were higher relative to dose administered. The order of relative concentrations of deltamethrin in tissues, measured 1, 4, and 9 days after the last dose was: renal fat greater than subcutaneous fat greater than forequarter muscle greater than hindquarter muscle greater than liver greater than kidney. Depletion of deltamethrin residues in milk was very rapid indicating the half-life of the insectide of about 1 day. Trace amounts of deltamethrin metabolites 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (less than 0.0235 ppm) and 3-phenoxybenzoic acid (less than 0.034 ppm) were also detected in milk and tissues of treated cows.

A technique for serial sampling of cerebrospinal fluid from conscious swine and sheep.

We devised a method for the atraumatic repeated collection of cerebrospinal fluid samples from conscious swine and sheep. Indwelling needles, with injection caps, were secured intracisternally and protected with plastic "crowns" attached to their skulls. The crowns permitted the animals freer movement with minimal risk of damage to the needles. With sheep, cerebrospinal fluid was withdrawn directly by puncturing the self-sealing injection caps attached to the hubs of the fixed needles. With the pigs, which are less amenable to handling, lengths of sterile polyethylene tubing inserted into the fixed needles enable collection without continuously disturbing the pigs. Serial samples were withdrawn from sheep (.10 to .30 ml) for up to 3 weeks with no problems, and from pigs (.05 to .15 ml) for 8 to 12 days, until the cannulae failed.

Distribution of deoxynivalenol in cerebral spinal fluid following administration to swine and sheep.

Deoxynivalenol (DON) is one of the major mycotoxins produced by Fusarium fungi. In evaluating DON as a potent CNS (emetic, anorexic) agent, its cerebral spinal fluid (CSF) and plasma pharmacokinetics were studied in pigs, a species very sensitive to the effects of DON, and sheep, a more tolerant animal. After intravenous administration, DON was detected very rapidly (less than 2.5 min) in the CSF of both species, but whereas peak levels (t-max) occurred at 5-10 min in sheep, in swine it was 30-60 min. It would appear that the very rapid and extensive tissue distribution of DON in swine (Vd gamma = 1.13 1 kg-1) may be slowing the rate of diffusion of the toxin into the CSF compared to sheep (Vd beta = 0.19 1 kg-1) where the toxin is confined essentially to the extracellular compartment. Area under curve calculations indicate approximately 2 1/2 times the amount of toxin eventually reaches the pig CSF compared to sheep CSF. A good relationship between blood-CSF DON levels was apparent in both species, although limitations in detection methods made it impossible to resolve a slow terminal phase (gamma) in swine CSF which was evident in the plasma profile after iv administration. Following oral administration of DON to pigs, a close correlation between plasma and CSF DON levels was observed. The toxin could be detected in CSF for up to 20 hr post-dosing.

Pharmacokinetic fate of 14C-labeled deoxynivalenol in swine.

The pharmacokinetics of the trichothecene mycotoxin deoxynivalenol (DON) was investigated in swine following intravenous (0.30 mg, 0.35 microCi/kg) and intragastric (0.60 mg, 0.60 microCi/kg) administration of the 14C-labeled toxin. After iv dosing, plasma concentration data favored a three-compartment open model with half-life values for the rapid distribution (alpha), slower distribution (beta), and terminal elimination (gamma) phases of 5.8, 96.7, and 510.0 min, respectively. The apparent volume of distribution (V'd) was 1.34 liter/kg, the volume of the central compartment (Vc) was 0.166 liter/kg, and the plasma clearance was 1.81 ml/min/kg. DON was rapidly cleared essentially unchanged (greater than 95%), and was excreted primarily in urine (86-104%), with minor elimination in bile (3-5%). Following intragastric dosing DON was very rapidly absorbed, reaching near peak plasma levels within 15-30 min. Levels remained elevated (63-325 ng/ml) for approximately 9 hr, and began declining slowly (t1/2 beta = 7.1 hr) thereafter. The calculated systemic bioavailability (F) was between 48 and 65%, although urinary and biliary recoveries indicated marginally greater absorption actually occurred (54-85%). Overall, although DON was eliminated rapidly and completely within 24 hr following a single iv or intragastric dose, data suggest that residues may undergo temporary sequestration in a tissue depot.

Excretion profiles of the mycotoxin deoxynivalenol, following oral and intravenous administration to sheep.

The excretion profiles of deoxynivalenol (DON) and metabolites (DON glucuronide conjugate, 3 alpha, 7 alpha,15-trihydroxytrichothec-9,12-diene-8-one (DOM-1), and DOM-1 glucuronide conjugate) were defined in male sheep following either intravenous (iv) or oral administration of the toxin at levels of 0.5 and 5.0 mg DON/kg body wt, respectively. After iv dosing, urinary DON levels declined in a biphasic fashion with an average elimination half-life (terminal phase) of 1.2 hr, diminishing to baseline concentrations by 8 hr. Maximum urinary excretion rates for the two major metabolites identified (conjugated DON, conjugated DOM-1) occurred 0.5-1.5 hr after dosing, exhibiting elimination half-lives of 2.2 and 3.1 hr, respectively. Total recovery accounted for only about 66.5% of the dose: 63.0% in the urine (24.1% DON, 21.2% conjugated DON, 0.5% DOM-1, 17.2% conjugated DOM-1) and 3.5% in bile (made up almost completely of conjugated DOM-1). The peak biliary excretion rate for conjugated DOM-1 was found to occur within 1 hr postdosing, which rapidly declined to baseline levels by 5 hr. Following oral administration, urinary excretion rates of the major metabolites (DON, conjugated DON, conjugated DOM-1) reached maximum 6-9 hr post-treatment, and declined exponentially with t 1/2 values of 3.2, 4.0, and 5.0 hr, respectively. Urinary and biliary recovery of administered DON averaged approximately 7.1%: 7.0% in urine (2.1% DON, 3.6% conjugated DON, 0.06% DOM-1, 1.2% conjugated DOM-1) and 0.11% in bile (predominantly conjugated DOM-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Ingestion of vomitoxin (deoxynivalenol)-contaminated wheat by nonlactating dairy cows.

Our objective was to determine if there were serious deleterious effects of wheat naturally contaminated with vomitoxin (deoxynivalenol) on nonlactating dairy cows. Comparisons were between two Quebec spring wheat sources contaminated with Fusarium graminearum in a feeding trial involving 10 nonlactating Holstein dairy cattle offered good quality hay for ad libitum intake supplemented with wheat-oats concentrate (1 kg concentrate/100 kg body weight). Initially, for 3 wk all cows were fed hay plus wheat-oats containing 1.5 mg vomitoxin/kg. Each week thereafter two more cows, chosen at random, were switched to a second wheat-oats concentrate containing higher mycotoxin concentration (6.4 mg vomitoxin/kg). After the last two cows had been on the latter diet for 6 wk, all cows were returned to the previous wheat-oats concentrate containing the lower mycotoxin concentration (1.5 mg vomitoxin/kg). No unusual symptoms of illness that might be attributed to the mycotoxin-contaminated wheat were observed. In body weight gains, the data reflected a linear growth pattern with no apparent effect of changing from low to high vomitoxin content in the concentrate. Generally, consumption of the wheat-oats ration containing 6.4 mg vomitoxin/kg was lower than the 1.5 mg vomitoxin/kg concentrate. The progressive, linear decrease of hay consumption was not affected by source of contaminated wheat-oats diet.

Copper poisoning in a flock of sheep. Copper excretion patterns after treatment with molybdenum and sulfur or penicillamine.

During an outbreak of chronic copper poisoning, fecal and urinary copper excretion were measured following treatment with molybdenum and sulfur supplementation of the feed (0.1 g ammonium molybdate plus 1 g sodium sulfate/sheep/day) or oral penicillamine (50 mg/kg bodyweight/day) using rams in metabolism cages. Serum glutamic-oxaloacetic transaminase activities and liver levels of molybdenum and copper in sheep that died were also monitored. Within four days of starting molybdenum and sulfur supplementation a highly significant increase in fecal copper excretion was evident and the increase persisted throughout the monitoring period (five weeks - general treatment of the flock continued for another three weeks). There was no effect of the molybdenum and sulfur supplementation on urinary excretion of copper. The molybdenum and sulfur supplementation was very effective, resulting in a rapid marked decrease in mortality. Oral penicillamine treatment induced cupruresis but did not affect fecal copper excretion. The results indicated that, while the cost of penicillamine may be a limiting factor for general treatment of a flock, it may be the drug of choice for the therapy of valuable breeding animals because cupruresis may be accurately and individually controlled. Serum glutamicoxaloacetic transaminase activities were a valuable aid in diagnosing chronic copper toxicosis as well as for monitoring recovery. High initial liver copper levels were gradually reduced following molybdenum and sulfur treatment. However, at the end of the study the liver copper levels of dead sheep varied within wide limits and there were still some sheep with high liver copper levels.

Feeding trials with vomitoxin (deoxynivalenol)-contaminated wheat: effects on swine, poultry, and dairy cattle.

Nutritional and toxicologic feeding trials with 3 species of farm animals demonstrated that decreased feed consumption and reduced weight gains in pigs are the main effects of ingestion of a diet with low vomitoxin (deoxynivalenol; DON) content, eg, 2 mg of DON/kg of feed, ie, 2 ppm. The feeding trials indicated that swine can ingest up to 2 mg of DON/kg of feed without serious adverse effects. Poultry can tolerate at least 5 mg of DON/kg feed. In fact, at concentrations up to 5 mg of DON/kg feed, some beneficial effects on poultry were observed. In dairy cattle, feed consumption decreased slightly when a wheat-oats diet containing 6 mg of DON/kg was fed at the rate of 1% of body weight/day, with hay offered ad libitum. In surveys of Canadian grains carried out during the past 3 years, the DON content (maximum of 8.5 mg/kg) in eastern Canadian wheats probably was not high enough to account for reports of feed refusal, vomiting, and reproductive problems in livestock operations. This conclusion is based partly on the fact that even at the highest concentrations of DON found in wheat, formulated diets comprise, at maximum, about 70% to 80% wheat. Consequently, the actual DON content of diets fed to farm animals would be much lower.

Vitamins a, e and selenium blood levels in the fat cow syndrome.

Blood plasma analyses for vitamins A, E and selenium were performed from calving to five weeks of lactation in 29 cows. Twelve of the 29 cows had fat cow syndrome. The healthy cows had significantly higher (P<0.01) plasma vitamin A (40 mug/dL) and vitamin E (5 mug/mL) levels than the cows with fat cow syndrome (29 mug vitamin A/dL and 3 mug vitamin E/mL). At parturition, vitamin A level in plasma was low (25 mug/dL) but increased progressively thereafter (up to 51 mug/dL) in healthy cows, whereas cows with fat cow syndrome had lower levels of vitamin A, bordering on deficiency. The possible role of vitamin E in the alleviation of fat cow syndrome by affecting oxidation-reduction reactions in the liver is discussed. Significant (P<0.01) difference was not observed in selenium blood plasma level (35 ng/mL) between the two groups of cows or in another random group of 12 cows clinically affected by fat cow syndrome.

Copper toxicosis in lambs fed milk replacer.

Thirty-four hysterectomy derived, crossbred lambs were fed a commercial, lamb milk replacer, containing added copper from birth. Twenty-five lambs died, four were killed and five survived. At necropsy, generalized icterus, enlarged kidneys and enlarged or small livers were found.CLINICAL PATHOLOGY FINDINGS INCLUDED: responsive hemolytic anemia and occasional spherocytosis, hemoglobinemia, hemoglobinuria and urinary casts, leukocytosis with neutrophilia, a liver copper content range of 38-584 ppm; a kidney copper content 6-86 ppm, and serum aspartate amino-transferase level range of 150-302 I.U./L. Histopathologically there was either periacinar hepatic necrosis or widespread portal fibrosis and nephrosis.The role of age and stress in the development of toxicosis is discussed.