Plasma pharmacokinetics of the mycotoxin deoxynivalenol following oral and intravenous administration to sheep

The pharmacokinetics of deoxynivalenol (DON) were studied in sheep after administrating intravenous and oral doses (0.5 and 5.0 mg/kg, respectively). The plasma concentrations were measured using an electron-capture gas chromatographic method. After iv administration DON plasma levels were found to decrease biexponentially, showing a rapid distribution phase (t 1/2 alpha = 12-23 min), followed by a slower elimination phase (t 1/2 beta = 57-78 min). Only trace levels of DON could be detected in plasma 7 hr post-dosing. Further pharmacokinetic data suggest that DON was confined mainly to extracellular fluid, and did not appear to undergo any significant binding or uptake by tissue. After oral dosing, DON was quickly absorbed (t-max 4.0-5.3 hr), but had a systemic bioavailability of only 7.5%; due in part to its rapid and efficient metabolism by rumen microorganisms. Half-life of elimination (t 1/2 beta) was 100-125 min following oral administration, and depending on the animal, required 20-30 hr to be cleared from the system. The metabolic formation of the glucuronide conjugate after iv and oral administration of DON appeared to occur quite efficiently (iv, 21%; oral, 75%), and its elimination half-lives (iv, 150-200 min; oral 6.1-7.1 hr) were considerably longer than that of the parent toxin. Detection in plasma of the de-epoxide metabolite, DOM-1, accounted for only a minor portion of the dose after either dosing regimen (iv, less than 2.0%; oral, less than 0.3%), occurring predominantly as the glucuronide conjugate.     

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.     

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.     

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.     

Distribution of deoxynivalenol in cerebral spinal fluid following administration to swine and sheep 1

Abstract

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 (<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 (Vdγ = 1.13 1 kg^‐1) may be slowing the rate of diffusion of the toxin into the CSF compared to sheep (Vd_β = 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 (γ) 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.     

Nontransmission of deoxynivalenol (vomitoxin) to milk following oral administration to dairy cows

The absorption of deoxynivalenol (DON; vomitoxin), a trichothecene mycotoxin produced by Fusarium species, was studied in the dairy cow. Serum and milk DON levels were quantitated following a single oral dose of 920 mg DON to each of two lactating cows of similar weight. Maximum blood levels for the two animals following DON administration were 200 and 90 ng/ml serum, occurring at times 4.7 and 3.5 hr, respectively. By 24 hr after dosing only trace levels (less than 2 ng/ml) were still detectable. DON in its conjugated form accounted for 24-46% of the total levels present in serum. Free and conjugated DON were also present in cow's milk, but only extremely low amounts (less than 4 ng/ml) were detected. Detection of DON was carried out utilizing Sep-Pak C18 extraction cartridges for isolation, with additional purification of the sample achieved by passing the extract through a short charcoal/alumina column. The extract was then reacted with N-heptafluorobutyrylimidazole prior to quantitation of the resulting DON-tris-heptafluorobutyrate derivative by combined gas chromatography-quadrupole mass spectrometry, using multiple selected ion monitoring. Detection limits were as low as 1 ng/ml (1 ppb).     

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.     

Detection of pentachlorophenol and its glucuronide and sulfate conjugates in fish bile and exposure water

The glucuronide and sulfate conjugates of pentachlorophenol (PCP) that were present in the bile and exposure water of goldfish (Carassius auratus) were used to develop methodology to quantify PCP and its metabolites. Reverse phase HPLC with radioactivity detection separated PCP and its metabolites, and was used to verify a method of quantification that used differential extraction and scintillation counting. Extractions of aqueous phase at pH 2 or 8, with butanol, ethyl acetate, or ether indicated that ether at pH 8 best separated PCP from its metabolites. The sulfate conjugate of PCP was the major metabolite produced when goldfish were exposed to 125 micrograms 14C-PCP/l. It was present primarily in the exposure water, but also appeared in the bile.     

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.     

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.     

Phthalate exposure in pregnant women and their children in central Taiwan

Phthalate exposure was found to be associated with endocrine disruption, respiratory effects, reproductive and developmental toxicity. The intensive use of plastics may be increasing the exposure to phthalates in Taiwanese population, particularly for young children.We studied phthalate metabolites in pregnant women and their newborns in a prospective cohort from a medical center in Central Taiwan. One hundred maternal urine samples and 30 paired cord blood and milk samples were randomly selected from all of participants (430 pregnant women). Eleven phthalate metabolites (MEHP, 5OH-MEHP, 2cx-MEHP, 5cx-MEPP, 5oxo-MEHP, MiBP, MnBP, MBzP, OH-MiNP, oxo-MiNP, and cx-MiNP) representing the exposure to five commonly used phthalates (DEHP, di-isobutyl phthalate (DiBP), DnBP, BBP, DiNP) were measured in urine of pregnant women, cord serum and breast milk after delivery, and in urine of their children. Exposure was estimated with excretion factors and correlation among metabolites of the same parent compound. Thirty and 59 urinary samples from 2 and 5 years-old children were randomly selected from 185 children successfully followed.Total urinary phthalate metabolite concentration (geometric mean, μg L⁻¹) was found to be higher in 2-years-olds (398.6) and 5-years-olds (333.7) than pregnant women (205.2). Metabolites in urine are mainly from DEHP. The proportion of DiNP metabolites was higher in children urine (4.39 and 8.31%, ages 2 and 5) than in adults (0.83%) (p < 0.01). Compared to urinary levels, phthalate metabolite levels are low in cord blood (37.45) and milk (14.90). DEHP metabolite levels in women’s urine and their corresponding cord blood are significantly correlated. Compared to other populations in the world, DEHP derived metabolites in maternal urine were higher, while phthalate metabolite levels in milk and cord blood were similar. The level of phthalate metabolites in milk and cord blood were comparable to those found in other populations. Further studies of health effects related to DEHP and DiNP exposure are necessary for the children.     

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.     

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.     

Contributions to ecological chemistry CVII1. Fate of lindane-14C in lettuce, endives and soil under outdoor conditions.

In seven successive outdoor experiments, lindane-14C was applied to lettuce or endive leaves as an aqueous formulation (about 12 mg on 20 plants for each experiment). The growing periods varied between 21 and 37 days. After this time, between 4.5% and 13.9% of the applied radiocarbon was recovered from the plants. Conversion rates to soluble metabolites as well as to unextractable residues appeared to be dependent on weather conditions. During the summer months, the radiocarbon in plants consisted of 36% soluble metabolites and of 30% unextractable residues (average of 4 experiments); in autumn, the conversion rates were much lower. The following metabolites were identified in both plant species by gas chromatography/mass spectrometry: a polar group (a free trichlorophenol, 2,3,4,6-tetrachlorophenol, pentachlorophenol, conjugates of the latter two compounds, and unidentified water-soluble products) amounting to 35% of the radioactivity in plants cultivated in summer, and a nonpolar group (a dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, 1,2,3,5, and/or 1,2,4,5-tetrachlorobenzene, pentachlorobenzene, hexachlorobenzene, and gamma-pentachlorocyclohexene) amounting to 1% of the radioactivity in plants cultivated in summer. The 20 cm top-soil layer had about 14% of the total radioactivity applied to all plants. Six % of the radioactivity recovered from the soil was soluble metabolites and about 50% was not extractable. The soluble metabolites comprised a polar group (free and conjugated 2,3,4,6-tetrachlorophenol, pentachlorophenol, and unidentified water soluble products) amounting to 5% of the radioactivity in the soil as well as a nonpolar group (1,2,3-trichlorobenzene, 1,2,3,4-tetrachlorobenzene, 1,2,3,5 and/or 1,2,4,5-tetrachlorobenzene, pentachlorobenzene, hexachlorobenzene, and gamma-pentachlorocyclohexene) amounting to 1% of the radioactivity in the soil.     

Bioavailability and toxicological potential of sunflower-bound residues of (14)C-chlorpyrifos insecticide in rats

Sunflower plants were treated with (14)C-chlorpyrifos under conditions simulating local agricultural practice. Residues present in the oil, methanol extract and cake of the treated sunflower seeds were 7.2, 2.8, and 12 ppm, respectively. When rats fed on sunflower cake containing bound residues for three days, the animals eliminated 46 % of the radioactivity in urine, 25 % in feces and 10 % in the expired air. A further bioavailable amount of 8 % was found in selected organs indicating that the bound residues were highly bioavailable. Chromatographic analysis of urine extract revealed the presence of the parent compound, its oxon, desethyl chlorpyrifos and desethyl chlorpyrifos oxon as free metabolites in addition to a conjugated metabolite. It was liberated by acid hydrolysis and identified as 3,5,6-trichloro-2-hydroxypyridine. Bound residues were found to have biological effects such as inhibition of rat plasma ChE, elevations of liver parameters (ALT, AST, and ALP), decrease in total protein and albumin content suggesting a hepatotoxic potential. A significant increase in the values of creatinine, urea, cholesterol, triglycerides and significant decrease in Catalase and Glutathion-S-Transfrase were observed in treated rats.     

The degradation of dissolved organic nitrogen associated with melanoidin using a UV/H2O2 AOP

The aim of this study was to examine the simultaneous degradation of dissolved organic nitrogen (DON) and associated colour from wastewater containing melanoidins by an advanced oxidation process (AOP). UV irradiation of H2O2 was used as the mechanism to create the hydroxyl radical for oxidation. Melanoidins are large nitrogenous organic compounds that are refractory during biological wastewater treatment processes. The simultaneous degradation of DON and colour, present as a result of these compounds, was investigated using an AOP. The oxidation process was much more capable of removing colour (99% degradation), dissolved organic carbon (DOC) (50% degradation) and DON (25% degradation) at the optimal applied dose of hydrogen peroxide for the system (3300 mg l(-1)). This indicated that colour and DON removal were decoupled problems for the purpose of treating melanoidin by an AOP and thus colour removal can not be used as an indication of DON removal Colour was caused by organic molecules with molecular weight greater than 10 kDa. Oxidation caused a partial reduction of the DON (41-15% of the total dissolved nitrogen) and DOC (29-14% of the DOC) associated with the large molecular weight fraction (>10 kDa) and almost complete colour removal (87-3% of the total colour). The degraded DON was mostly accounted for by the formation of ammonia (31% of the nitrogen removed from the large fraction) and small molecular weight compounds (66% of the nitrogen removed from the large fraction). The degraded DOC appeared to be mostly mineralised (to CO2) with only 20% of the degraded compounds appearing as small molecular weight DOC.     

Chemistry of fog waters in California's Central Valley—Part 3: concentrations and speciation of organic and inorganic nitrogen

Although organic nitrogen (ON) has been found to be a ubiquitous and significant component in wet and dry deposition, almost nothing is known about its concentration or composition in fog waters. To address this gap, we have investigated the concentration and composition of ON in fog waters collected in Davis, in California's Central Valley. Significant quantities of dissolved organic nitrogen (DON) were found in these samples, with a median concentration of 303 μM N (range=120–1630 μM N). DON typically represented approximately 16% of the total dissolved nitrogen (inorganic+organic) in Davis fog waters. The median concentration of nitrogen in free amino acids and alkyl amines was 16 μM N (range=3.8–120 μM N), which accounted for 3.4% of the DON in Davis fogs. Thus, although the absolute concentrations of free amino compounds were significant, they were only a minor component of the DON pool. Combined amino nitrogen (e.g., proteins and peptides) was present at higher concentrations and accounted for 6.1–29% (median=16%) of DON. Overall, free and combined amino compounds typically accounted for a median value of 22% of DON in the fog waters.The high concentrations of DON found, and the fact that amino and other N-containing organic compounds can serve as nitrogen sources for microorganisms and plants, indicate that atmospheric ON compounds likely play an important role in nitrogen cycling in the Central Valley. In addition, due to the basicity of some N functional groups, ON compounds likely contribute to the previously observed acid buffering capacity of Central Valley fog waters. Finally, a comparison of fog waters with fine particles (PM_2.5) collected from the same site during the same period of time indicated that the median concentrations (mol N m⁻³-air) of total water-soluble ON, free amino nitrogen and total amino nitrogen were very similar in the fog water and PM_2.5. Given the high water solubility of many organic N compounds, this result suggests that ON might contribute to the hygroscopic properties of atmospheric particles.     

Determination and characterization of chloroguaiacol conjugates in fish bile by HPLC

In this study a small-scale technique for direct analysis of metabolic conjugates of 4,5,6-trichloro- (CG-3) and tetrachloroguaiacols (CG-4) in fish bile by RP-HPLC is presented. Only one metabolite, glucuronic acid conjugate, was demonstrated in two Lake Baikal fishes (Leuciscus leuciscus baikalensis and Cottus kessleri) exposed to CG-3 or CG-4 at 6 degrees C for 1-2 days. In Leuciscus the ratio between free CG-4 in the ambient water and conjugated CG-4 in the bile averaged 264,000. Intraperitoneal injections of tetrachloroveratrol (CV-4) into Thymallus arcticus baikalensis did not reveal any traces of free CV-4 or CG-4 glucuronide in the bile in 2 days at 5 degrees C. We therefore suggest that CV-4 was not demethylated and subsequently conjugated with glucuronic acid in the liver of this fish species.     

Influence of the composition and removal characteristics of organic matter on heavy metal distribution in compost leachates

Compost leachates were collected to investigate the influence of the composition and removal of volatile fatty acids (VFAs), humic-like substances (HSs), and dissolved organic nitrogen (DON) on heavy metal distribution during the leachate treatment process. The results showed that acetic and propionic acids accounted for 81.3 to 93.84 % of VFAs, and that these acids were removed by the anaerobic-aerobic process. Humic- and fulvic-like substances were detected by excitation–emission matrix spectroscopy coupled with parallel factor analysis, and their content significantly decreased after the anaerobic and membrane treatments. DON in compost leachates ranged from 26.53 mg L^-1 to 919.46 mg L^-1, comprised of dissolved free amino acids and the protein-like matter bound to humic- and fulvic-like substances, and was removed by the aerobic process. Correlation analysis showed that Mn, Ni, and Pb were bound to VFAs and protein-, fulvic-, and humic-like substances in the leachates. Co was primarily bound to fulvic- and humic-like matter and inorganic sulfurs, whereas Cu, Zn, and Cd interacted with inorganic sulfur.     

Bioavailability and toxicological potential of sunflower-bound residues of 14C-chlorpyrifos insecticide in rats

Sunflower plants were treated with ¹⁴C-chlorpyrifos under conditions simulating local agricultural practice. Residues present in the oil, methanol extract and cake of the treated sunflower seeds were 7.2, 2.8, and 12 ppm, respectively. When rats fed on sunflower cake containing bound residues for three days, the animals eliminated 46 % of the radioactivity in urine, 25 % in feces and 10 % in the expired air. A further bioavailable amount of 8 % was found in selected organs indicating that the bound residues were highly bioavailable. Chromatographic analysis of urine extract revealed the presence of the parent compound, its oxon, desethyl chlorpyrifos and desethyl chlorpyrifos oxon as free metabolites in addition to a conjugated metabolite. It was liberated by acid hydrolysis and identified as 3,5,6-trichloro-2-hydroxypyridine. Bound residues were found to have biological effects such as inhibition of rat plasma ChE, elevations of liver parameters (ALT, AST, and ALP), decrease in total protein and albumin content suggesting a hepatotoxic potential. A significant increase in the values of creatinine, urea, cholesterol, triglycerides and significant decrease in Catalase and Glutathion-S-Transfrase were observed in treated rats.