The effect of acute administration of the mycotoxin zearalenone to female pigs

Crystalline zearalenone was administered to young female pigs at dose levels of 0, 3.5, 7.5 and 11.5 mg zearalenone/kg body weight. All animals receiving the mycotoxin exhibited vulva vaginitis and had enlarged reproductive tracts, 1 week after dosing. Free zearalenone was found in the blood, feces and urine of dosed animals. The highest zearalenone level detected was 2.61 ng/ml from a pig that received the 7.5 mg/kg dose. After 24 hours, feces collected contained on average upto 308 ng zearalenone per g of dried feces. Zearalenone levels of up to 59 ng/ml, and alpha-zearalenol levels of up to 155 ng/ml urine were found. beta-zearalenol was also detected in the urine.     

Metabolism, tissue disposition, and excretion of 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) in male Sprague-Dawley rats

A single oral dose of [14C] 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) was administered to conventional and bile-duct cannulated male Sprague-Dawley rats. Tissue disposition, excretion and metabolism was determined. BTBPE is a low-volume brominated flame retardant used in resins or plastics, and toxicity data in peer-reviewed journals is extremely limited. BTBPE was fairly insoluble in lipophilic solutions, which made dose preparation difficult. The great majority of 14C (>94%) was excreted in the feces of both groups of rats at 72 h, and tissue retention was minimal. Lipophilic tissues contained the highest concentrations of BTBPE, e.g. thymus, adipose tissue, adrenals, lung, and skin. Metabolites were excreted in the urine, bile and feces, but at a very low level. Fecal metabolites were characterized as monohydroxylated, monohydroxylated with debromination, dihydroxylated/debrominated on a single aromatic ring, monohydroxylated on each aromatic ring with accompanying debromination, and cleavage on either side of the ether linkage to yield tribromophenol and tribromophenoxyethanol. Despite a limited quantity of stable metabolites extractable in the feces, non-extractable 14C levels were relatively high (39% of the 0-24 h fecal 14C), which suggested that BTBPE could be metabolically activated in the rat and covalently bound to fecal proteins and/or lipids. It was concluded that limited absorption and metabolism of BTBPE would occur by ingestion in mammals.     

Metabolism of bis-methylthiotetrachlorobenzene in rats

Oral doses of bis-methylthiotetrachlorobenzene (bis-MTTCB) given to control rats and rats with cannulated bile ducts showed that at least 50% of the dose, although excreted mainly as bis-MTTCB in the feces, was metabolized. The metabolism involved replacement of one of the methylthio groups with glutathione, biliary excretion of the mercapturic acid pathway metabolites, and subsequent reformation of bis-MTTCB which is excreted with the feces.     

The effect of acute administration of the mycotoxin zearalenone to female pigs∗

Abstract

Crystalline zearalenone was administered to young female pigs at dose levels of 0, 3.5, 7.5 and 11.5 mg zearalenone/kg body weight. All animals receiving the mycotoxin exhibited vulva vag‐initis and had enlarged reproductive tracts, 1 week after dosing. Free zearalenone was found in the blood, feces and urine of dosed animals. The highest zearalenone level detected was 2.61 ng/ml from a pig that received the 7.5 mg/kg dose. After 24 hours, feces collected contained on average up to 308 ng zearalenone per g of dried feces. Zearalenone levels of up to 59 ng/ml, and a ‐zearalenol levels of up to 155 ng/ml urine were found. ß ‐zearalenol was also detected in the urine.     

The metabolic fate of N-isopropyl-N-phenyloxamic acid in the rat and the milk goat.

Rats excreted the 14C from a single oral dose of N-isopropyl-N-[14C]phenyloxamic acid [I, a soil metabolite from 2-chloro-N-isopropylacetanilide (propachlor)] in approximately equal quantities in the urine (49.2%) and feces (48.2%). A milking goat given daily oral doses of [14C]-I (1 mg of I three times daily) excreted more 14C in the feces (56.6%) than it excreted in the urine. From both species, I accounted for 97 to 100% of the urinary 14C, and all of the 14C that was extractable from the feces (73 to 75% of the 14C in feces was extractable with methanol). Goat milk samples collected 16 hr after the last dose contained no detectable 14C. Tissue residues of 14C were determined.     

Fate of ochratoxin A in goats.

The fate of ochratoxin A (OA) was studied in goats given a single oral dose of 3H-OA (0.5 mg/kg). More than 90% of the radioactivity was found to be excreted in 7 days and the majority (53%) was found in feces. Thirty-eight percent, 6% and 2.26% of the activity was found in urine, milk and serum, respectively. The radioactivity in the liver and kidney 6 hours after feeding amounted to 1.5 and 0.5% of the total dose administered, respectively. Subsequent fractionation of liver and kidney homogenates revealed that microsomes, ribosomes and post-ribosomal supernatant fractions contained most radioactivity. Thin layer chromatographic analyses revealed two additional radioactive spots with Rf values and fluorescent characteristics different from OA, Oalpha and 4-OH-OA. Whereas OA was found as the unaltered molecule in feces, the metabolites were primarily found in urine and milk. Less than 0.03% of free OA was found in milk during the 7-day period.     

Identification of the major urinary and fecal metabolites of 3,5-dinitrobenzamide in chickens and rats

Colostomized chickens given oral doses of 3,5-dinitrobenzamide (nitromide) cleared nitromide predominantly through the urine (58% of dose) and feces (21% of dose). Rats cleared 52% of nitromide via urinary excretion and 44% via feces. Major urinary metabolites for both chickens and rats include: 3-amino-5-nitrobenzamide, 3-acetamido-5-nitrobenzamide, 3-acetamide-5-aminobenzamide, and 3,5-diacetamidobenzamide. The major fecal metabolite in chickens was 3-acetamido-5-nitrobenzamide (67% of fecal 14C) and 3-acetamido-5-aminobenzamide in rats (approximately 50%).     

Distribution and toxicity of monosodium methanearsonate following oral administration of the herbicide to dairy sheep and goats

Iranian fat-tailed sheep and dairy goats were administered the herbicide monosodium methanearsonate orally at a dose of 10 mg. MSMA (as arsenic) per kg. of body weight. The concentration time curves of MSMA in the blood of sheep and goats followed a first order composite exponential equation of the form: Cb(t) = Ae- alpha t + Be- beta t - C degrees be-kat. Absorption, distribution and elimination of MSMA, therefore, corresponds to an open two-compartment model. Arsenic from MSMA was readily absorbed from gastrointestinal tract and distributed in the body fluids and the various tissues. Approximately 90% of the arsenic was excreted in the urine within 120 hrs and small amounts were also recovered in feces. Arsenic accumulation in the tissues was low and urinary excretion was the most important exit route. Arsenic concentrations in milk were low when compared to the controls, which indicates that arsenic is not excreted in the milk to significant levels. The absorption, distribution and overall elimination rate constants for the two animal species studied were statistically different at the 0.95 level of confidence which indicates that there are apparently differences in MSMA metabolism by sheep and goats.     

Metabolism of crufomate (4-tert-butyl-2-chlorophenyl methyl methylphosphoramidate) administered topically to a sheep.

A sheep dosed topically with 14C-crufomate (4-tert-butyl-2-chlorophenyl methyl methylphosphoramidate) excreted 45.5% of the 14C dose in the urine within 9 days. The feces contained 1.2% and the carcass 40.4% (this included the 37.7% of the dose remaining on the skin in the dosing area) of the dose. At sacrifice, the fat, liver, kidney, lung, and skin (where the dose was applied) contained the highest concentrations of 14C. Fourteen urinary metabolites were isolated and characterized by mass spectrometry. The metabolic reactions involved were oxidations of the t-butyl moiety, O-demethylation, replacement of the H-N-CH3 moiety with a hydroxyl group, oxidation of the N-methyl group to yield N-formyl phosphoramidates, hydrolysis of the phosphoramidate moiety to yield phenols, conjugation with glucuronic acid and combinations of these reactions.     

Fate of ochratoxin a in goats

Abstract

The fate of ochratoxin A (OA) was studied in goats given a single oral dose of ³H‐OA (0.5 mg/kg). More than 90% of the radioactivity was found to be excreted in 7 days and the majority (53%) was found in feces. Thirty‐eight percent, 6% and 2.26% of the activity was found in urine, milk and serum, respectively. The radioactivity in the liver and kidney 6 hours after feeding amounted to 1.5 and 0.5% of the total dose administered, respectively. Subsequent fractionation of liver and kidney homogenates revealed that microsomes, ribosomes and post‐ribosomal supernatant fractions contained most radioactivity. Thin layer chromatographic analyses revealed two additional radioactive spots with Upvalues and fluorescent characteristics different from OA, Oα and 4‐OH‐OA. Whereas OA was found as the unaltered molecule in feces, the metabolites were primarily found in urine and milk. Less than 0.03% of free OA was found in milk during the 7‐day period.     

Identification of the dimethylbenzyl mercapturic acid in urine of rats treated with 1,2,3-trimethylbenzene.

The structure was investigated of the mercapturic acid excreted in urine of rats after the i.p. administration of 1,2,3-trimethylbenzene. Of the two regioisomeric mercapturic acids, i.e. N-acetyl-S-(2,3-dimethylbenzyl)-L-cysteine and N-acetyl-S-(2,6-dimethyl-benzyl)-L-cysteine, only the former was isolated by preparative HPLC and identified, by comparison with an authentic specimen. The excretion rate of the mercapturate was estimated to be approximately 5% of dose, not a substantial metabolic route.     

Metabolism of beta-hexachlorocyclohexane-14C in rats following low dosing in the daily diet

beta-Hexachlorocyclohexane-14C (1.5 ppm) was administered in the diet to rats for one week. During the elimination phase three therapeutic agents were fed to enhance the clearance. Renal and fecal excreted radioactive products were collected for 8 weeks and extracted. Although significant differences in the total excreted amount of radioactivity were registered between controls and treated rats, there were no quantitative differences in the extractability of the excreta and no differences in the chemical nature of metabolites found. Radioactivity in urine consisted to 100% of conversion products, about 30% of which were unextractable residues. In the organic soluble fraction the 2,4,6-trichlorophenol was the major metabolite in urine and the only metabolite detected in feces. Minor conversion products of beta-HCH in urine were a trichlorohydroxyme-thoxybenzene, a dichlorophenol and a trace of a tetrachlorocyclohexane-isomer.     

Fate of 14C-ethyl prothiofos insecticide in canola seeds and oils

Canola plants were treated with ¹⁴C- prohiofos under conditions simulating local agricultural practices. ¹⁴C-residues in seeds were determined at different time intervals. At harvest time about 32 % of ¹⁴C-activity was associated with oil. The methanol soluble ¹⁴C-residues accounted for 12 % of the total seed residues after further seeds extraction, while the cake contained about 49 % of the total residues. About 69 % of the ¹⁴C-activity in the crude oil could be eliminated by simulated commercial processes locally used for oil refining. Chromatographic analysis of crude and refined oil revealed the presence of the parent compound together with three metabolites which were identified as prothiofos oxon, O-ethyl phosphorothioate and O-ethyl S-propyl phosphorothioate, besides one unknown compound. While methanol extract revealed the presence of despropylthio prothiofos and O-ethyl phosphoric acid as free metabolites acid hydrolysis of the conjugated metabolites in the methanol extract yielded 2, 4-dichlorophenole which was detected by color. When rats were fed the extracted cake for 72 hours, the bound residues were found to be bioavailable. The main excretion route was via the expired air (42 %), while the ¹⁴C-residues excreted in urine and feces were 30 % and 11 %, respectively. The radioactivity detected among various organs accounted to 7.5 %.Chromatographic analysis of urine indicated the presence of prothiofos oxon, O-ethyl phosphoric acid and 2, 4-dichlorophenole as main degradation products of prothiofos in free and conjugated form.     

Tissue distribution, excretion, and metabolism of 1,2,7,8-tetrachlorodibenzo-p-dioxin in the rat

A tissue distribution, excretion, and metabolism study was conducted using a relatively non-toxic dioxin congener, i.e., 1,2,7,8-tetrachlorodibenzo-p-dioxin (1278-TCDD), to gain a better understanding of mammalian metabolism of dioxins. Conventional, bile duct cannulated, and germ free male rats were administered mg/kg quantities as a single oral dose. Elimination of 1278-TCDD was largely complete by 72 h. Distribution of [¹⁴C]1278-TCDD was low in all tissues examined. Metabolites were identified in urine, bile, and feces by negative ion FAB-MS and ¹H-NMR, or GC/MS. The major fecal metabolite was a NIH-shifted hydroxylated TCDD. The bile contained a glucuronide conjugate of this hydroxy TCDD, and a diglucuronide conjugate of a dihydroxy-triCDD. The major metabolites in urine were glucuronide and sulfate conjugates of 4,5-dichlorocatechol.     

Toxicological evaluation of sulfur-containing metabolites of 2,5,2′,5′-tetrachlorobiphenyl in rats

Sulfur-containing metabolites of 2,5,2′,5′-tetrachlorobiphenyl (TCB), 4-methylthio-TCB (MT-TCB), 4-methylsulfoxyl TCB (MSX-TCB) and 4-methylsulfonyl TCB (MS-TCB) were examined for their acute toxicities, hepatic enzyme inducing activities, accumulation in the liver and lung, and excretion to the feces in rats. TCB and MT-TCB suppressed body weight and recovery of body weight gain was delayed in the MT-TCB-treated rats. MT-TCB and MS-TCB caused an increase in total liver lipid and only MT-TCB brought about an atrophy of the thymus. Treatment with MT-TCB increased cytochrome P-450 content and benzphetamine N-demethylase activity. The same enzymes were also induced by treatment with MSX-TCB. Although TCB administered was excreted mostly as hydroxylated TCB, a part was excreted as unchanged and a very small portion as the sulfur-containing metabolites. MT-TCB, MSX-TCB and MS-TCB were excreted from the MT-TCB- and MSX-TCB-treated rats. The MS-TCB-treated rats excreted only MS-TCB. The same compounds as found in the feces were identified in the liver and lung of the rats treated with those compounds except in the liver of TCB-treated rats. These results indicate that sulfur-containing metabolites, especially MT-TCB, were more important than their parent compound, TCB, from a toxicological point of view.     

Uptake, distribution and elimination of monosodium methanearsonate following long term oral administration of the herbicide to sheep and goats

The rate and extent of accumulation and washout of arsenic, during daily oral administration of the herbicide monosodium methanearsonate (MSMA) were evaluated in Iranian dairy sheep and goats. Subjects received a dose of 10 mg of MSMA as arsenic per kg of body weight daily for 28 consecutive days. The total arsenic concentration in blood and milk was measured during and after the period of MSMA administration while arsenic in urine and feces was measured for 10 days following administration of last dosage of MSMA. Arsenic was accumulated slowly during 28 days of MSMA administration and steady states were essentially complete in sheep after 20 days and in goats following 25 days of MSMA administration. Blood arsenic concentration decreased rapidly after termination of MSMA administration. In both test animals, the half-lives of washout were smaller than accumulation. The concentration of arsenic in the urine and feces of both species did not increase significantly over controls and animals were free of arsenic relatively shortly after administration stopped. These data indicate that arsenic from MSMA is mainly absorbed from gastrointestinal tract and is not significantly accumulated in the body. Arsenic is eliminated from body by way of urine and feces with urinary excretion being the most important route.     

Distribution and toxicity of monosodium methanearsonate following oral administration of the herbicide to dairy sheep and goats

Abstract

Iranian fat‐tailed sheep and dairy goats were administered the herbicide monosodium methanearsonate orally at a dose of 10 mg. MSMA (as arsenic) per kg. of body weight. The concentration time curves of MSMA in the blood of sheep and goats followed a first order composite exponential equation of the form: ^Cb(t) = Ae^‐ αt + B_e ^‐βt ‐ C°be^‐kat.

Absorption, distribution and elimination of MSMA, therefore, corresponds to an open two‐compartment model.

Arsenic from MSMA was readily absorbed from gastrointestinal tract and distributed in the body fluids and the various tissues. Approximately 90% of the arsenic was excreted in the urine within 120 hrs and small amounts were also recovered in feces. Arsenic accumulation in the tissues was low and urinary excretion was the most important exit route. Arsenic concentrations in milk were low when compared to the controls, which indicates that arsenic is not excreted in the milk to significant levels.

The absorption, distribution and overall elimination rate constants for the two animal species studied were statistically different at the 0.95 level of confidence which indicates that there are apparently differences in MSMA metabolism by sheep and goats.     

Uptake,distribution and elimination of monosodium methanearsonate following long term oral administration of the herbicide to sheep and goats

Abstract

The rate and extent of accumulation and washout of arsenic, during daily oral administration of the herbicide monosodium methanearsonate (MSMA) were evaluated in Iranian dairy sheep and goats. Subjects received a dose of 10 mg of MSMA as arsenic per kg of body weight daily for 28 consecutive days. The total arsenic concentration in blood and milk was measured during and after the period of MSMA administration while arsenic in urine and feces was measured for 10 days following administration of last dosage of MSMA.

Arsenic was accumulated slowly during 28 days of MSMA administration and steady states were essentially complete in sheep after 20 days and in goats following 25 days of MSMA administration. Blood arsenic concentration decreased rapidly after termination of MSMA administration. In both test animals, the half‐lives of washout were smaller than accumulation. The concentration of arsenic in the urine and feces of both species did not increase significantly over controls and animals were free of arsenic relatively shortly after administration stopped.

These data indicate that arsenic from MSMA is mainly absorbed from gastrointestinal tract and is not significantly accumulated in the body. Arsenic is eliminated from body by way of urine and feces with urinary excretion being the most important route.     

Metabolism of 2-chloro-N-isopropylacetanilide in chickens

2-Chloro- -isopropylacetanilide was quantitatively metabolized in chickens in the mercapturic acid pathway (MAP). The MAP metabolites (cysteine conjugate, -carboxymethyl- -acetyl cysteine, -acetyl cysteine conjugate, and -acetyl cysteine sulfoxide conjugate) were excreted mainly with the urine with minor amounts (less than 7% of the dose) excreted with bile. The cysteine conjugate was precursor for all the MAP metabolites, as well as, for -isopropyloxanilic acid and -isopropylacetanilide. Cysteine conjugate β-lyase activity was detected in the intestinal contents in vitro but was not manifested in vivo when the cysteine conjugate was injected intracecally.     

Mutagenicity and organic halogen determination in body fluids and tissues of rats treated with drinking water and pulp mill bleachery effluent concentrates

Concentrates of either drinking water or chlorination stage pulp mill effluent were injected intraperitonally into rats. Urine, feces, liver, and adipose tissues were tested for mutagenic activity and analysed for organic halogen. For both sample types nearly all the organic halogen taken up, eighteen percent from the chlorination stage sample and four percent from the drinking water sample, was excreted via the urine during the first day. Weak mutagenic activity could only be found in the urine collected the first day from animals treated with the highest dose of drinking water.