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.     

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.     

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.     

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.     

Metabolic fate and elimination in milk, urine and bile of deoxynivalenol following administration to lactating sheep

Using a combination of radioisotopic counting and chromatographic detection techniques, the kinetics and metabolic fate of deoxynivalenol (DON) in plasma, urine and bile were studied in lactating sheep, as was the transmission of residues to milk. Following intravenous administration, the plasma clearance of 14C-DON-derived radioactivity was rapid and followed a tri-phasic decay curve comprised of a bi-exponential decrease in DON (rapid distribution phase, t1/2 alpha = 16.2 min; slower elimination phase t1/2 beta = 66.5 min) and the formation and elimination (t1/2 beta = 188.0 min) of its major plasma metabolite, DON-glucuronide conjugate, which accounted for 13% of the plasma radioactivity levels. DON was rapidly cleared from the body by metabolism to 7 possible metabolites, which were excreted essentially in the urine (91%) and to a lesser extent in the bile (6%). Most (67%) of the recovered radioactivity was in the form of the glucuronide conjugates of DON (54%) and the de-epoxide metabolite, DOM-1 (13%). Excretion of unmetabolized DON accounted for 11%. The remaining recovered dose (18%) comprised of minor amounts of DOM-1 (6%), DON-sulfate conjugate (2%) and 3 unidentified radioactive components (10%). Studies on the presence of DON-derived residues in milk indicated that, relative to the dose, only trace amounts were transmitted following either oral or iv administration of the toxin.     

Transfer of methyl chloroform, trichloroethylene and tetrachloroethylene to milk, tissues and expired air following intraruminal or oral administration in lactating goats and milk-fed kids

The distribution of methyl chloroform was determined (MCF), trichloroethylene (TRI) and tetrachloroethylene (PCE) in milk, tissues and expired air by intraruminally administering 0.625 ml kg(-0.75) of an equal-volume mixture of the three compounds to lactating goats. The milk secreted during 24 h after the intraruminal administration contained 1.42 mg of MCF, 1.87 mg of TRI, 6.43 mg of PCE and 0.33 mg of trichloroethanol (TCE). MCF, TRI and PCE appeared in the blood less than 30 min after administration. Oral administration of these chemicals to milk-fed kids showed that at 3.5 h post-administration, the liver contained these chemicals in greatest abundance. The adaptation of milk-fed kids to 3 weeks administration of small amounts of propylene glycol stimulated the metabolic conversion of TRI to TCE. There were linear relationships between the blood concentrations of these chemicals and the expiration rates after oral administration of 0.4 ml kg(-1) of each chemical to milk-fed kids. The expiration rates of MCF, TRI and PCE were 605, 122 and 46 microg min(-1) kg(-1) at 2 microg ml(-1) blood concentrations of MCF, TRI and PCE, respectively. These results suggested that MCF is little metabolized, being most readily exhaled in expired air, while PCE demonstrates the greatest tissue-partitioning, being largely secreted into the milk or retained in the liver. TRI can be extensively metabolized to other compounds such as TCE in milk-fed kids.     

Platinum and Palladium transfer to milk, organs and tissues after a single oral administration to lactating goats

Platinum (Pt) and Palladium (Pd) are massively used in catalytic converters, emitted with exhaust fumes and deposited on roadsides in particle sizes. If they are ingested by ruminants grazing in agricultural fields located along roads they may enter the food chain. The objective of this study is to assess the potential transfer of Pt (PtCl(2)) and Pd (PdCl(2)) towards milk, tissues (muscle) and organs (kidney, liver and mammary gland). Three lactating goats received orally a single dose of 200mg of Pd and 200mg of Pt at the beginning of the experiment. The milk was collected each day during eight days. On the eighth day, organs and tissues were sampled to analyse the metal concentrations by ICP-MS (quantification limit of 0.25ng/g for Pd and Pt, detection limit of 0.08ng/g). The experiment demonstrated a significant transfer of Pd and Pt to kidney. The detected concentration was, respectively, of 73.9ng/g DW and 268.5n/g DW (factor 22 and factor 73 compared to the control kidney). The amounts of metals were : in the liver,18.1ng/g DW for the Pd and 8.1ng/g DW for the Pt, in the mammary gland, 14.9ng/g DW fort the Pd and 2.5ng/g DW for the Pt and in the muscle, 4.9ng/g DW for the Pd and 0.6ng/g DW for the Pt. The Pd concentration detected in milk was higher (from 5ng/g DW to 9ng/g DW) than in control milk but the transfer factor remained very low (0.02%). The Pt in milk could not be detected because it was below the quantification limit (<0.25ng/g DW).     

Effect of dietary protein on the distribution of cadmium,zinc and copper in rats following the oral administration of cadmium

Cadmium, 100 μg/rat/day, was administered orally 100 times (total amount of Cd administered, 10 mg), under conditions of low protein intake. The total amount of Cd in the liver and kidneys was as follows: females fed 20% protein diets > females fed 5% protein diets > males fed 20% protein diets ≒ males fed 5% protein diets. A decreased Zn concentration was found in the liver of males and the pancreas of males and females fed with the 5% protein diet. The Cu concentration in the kidneys was markedly influenced by low protein intake.     

Contributions to ecological chemistry CXLII: Separation and identification of metabolites excreted by rats after long term oral administration of imugan-14C

Rapid conversion and high rate of excretion of the fungicide, Imugan- ¹⁴C (N-formyl-N′ - (3,4-dichlorophenyl)-2, 2, 2-trichloroacetaldehydeaminal, Fig. 1) has been observed in rats upon long term oral administration². In simulated waste composting experiments³ this fungicide is metabolized to 3,4-dichloroaniline (3,4-DCA). 3,4-DCA and 3,3′, 4,4′-tetrachloroazobenzene (3,3′, 4,4′-TCAB) have been isolated from soil treated with it⁴. Algae have been found to convert it to a ring hydroxylated monohydroxy 3,3′,4,4′-TCAB⁵. In this work, the isolation and structure elucidation of metabolites of Imugan excreted with urine and faeces of rats are reported.     

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).     

Uptake,elimination and biochemical effects of azadirachtin and tebufenozide in algae

Abstract

Effects of azadirachtin (isomer A, AZ‐A) and tebufenozide (TF) on freshwater algae were investigated using indoor aquatic microcosms. AZ‐A and TF were dosed at different concentrations to 10‐L microcosms. Chlorophyll and protein contents of the algae, and the concentrations of the insecticides in water and algae were monitored at intervals of time up to 20 d. Chlorophyll and protein contents in algae were inhibited at treatment levels of 3.0 and 4.5 μg AZ‐A/mL, whereas at 1.5 μg/mL, the chemical stimulated the chlorophyll production. The partition of AZ‐A between water and algae was reversible, and the bioconcentration factor (BCF) was low. In contrast, TF dosed at 0.25 to 0.75 μg/mL stimulated algal growth, probably due to its utilization of carbonaceous and nitrogenous intermediates and other breakdown products of TF as nutrients. The BCF was high and the organism functioned as a sink for the chemical. Extension of the laboratory findings to complex outdoor systems are discussed.     

Uptake, absorption efficiency and elimination of DDT in marine phytoplankton, copepods and fish

Uptake, absorption efficiency and elimination of DDT were measured in marine phytoplankton, copepods (Acartia erythraea) and fish (mangrove snappers Lutjanus argentimaculatus). The uptake rate constant of DDT from water decreased with increasing trophic level. The dietary absorption efficiency (AE) of DDT was 10-29% in copepods and 72-99% in fish. Food concentration did not significantly affect the AEs of DDT, but the AEs varied considerably among the different food diets. The elimination rate constants of DDT by the copepods were comparable following uptake from the diet and from the water. Elimination of DDT from the fish was exceedingly low. Both aqueous and dietary uptake are equally important for DDT accumulation in the copepods. In fish, dissolved exposure is a more significant route than intake from the diet. The predicted trophic transfer factors in the copepods and the fish are consistent with the field measurements in marine zooplankton and fish.     

Tissue distribution and elimination of trichlorobenzenes in the rat

The tissue distribution and excretion of three trichlorobenzene isomers (TCB) were investigated in the rat. Single doses of TCBs were administered orally to groups of 5 fasted rats at 10 mg/kg body weight. Serial sacrifices were carried out and the radioactivity contents were determined in tissues and blood. For all three TCB isomers, radioactivity appeared in the blood and tissues at 0.5 h, and peaked around 2-4 h after dosing. Fat, skin, and liver had high concentrations of the parent compound while kidney and muscle had high levels of metabolites. Elimination of TCB from tissues and blood can best be described by a two-compartmental open pharmacokinetic model. The terminal half-lives were 145, 93 and 68 h for 1,2,3-, 1,2,4 and 1,3,5-TCB isomer respectively. Ninety-five percent of the administered 1,2,3- and 89% of the 1,3,5-isomers were eliminated within 48 h in the urine and feces with the former being the major route.     

Uptake and elimination,and effect of estrogen-like contaminants in estuarine copepods: an experimental study

Background, aim, and scope  

In recent years, anthropogenic chemicals which can disrupt the hormonal systems of both humans and wildlife have been raised to a major cause of concern. The aim of the present work was to determine the bioconcentration factors of the two major alkylphenols (AP) of the Seine Estuary [4-nonylphenol (4 NP) and nonylphenol acetic acid (NP1EC)] and of the synthetic estrogen, estrogen ethinylestradiol (EE2), in Eurytemora affinis after exposure in a continuous flow-through system under environmental realistic conditions. Moreover, the elimination of these compounds in copepods from the Seine Estuary has been investigated by measuring concentrations after 1 week in clean water in comparison to background levels.     

Uptake and enantioselective elimination of chlordane compounds by common carp (Cyprinus carpio, L.)

An analytical method involving supercritical fluid extraction (SFE) followed by a two-dimensional gas chromatography (2D-GC) analysis was developed to determine the concentration (first GC) and enantiomeric ratio (second GC) of cis- and trans-chlordanes at the ppb (ng/g) level in fish tissue. The SFE method allowed concentration of the compounds of interest, and reduced the number of extraction and sample clean-up manipulations as compared to classical solvent extraction techniques. Four hundred common carp fingerling (Cyprinus carpio, L.) were exposed for three days to water containing 5 ppb (5 ng/g) technical grade chlordane containing about 1 ppb of chlordane isomers. The fish concentrated the pesticides more than 200 times (162 and 312 ng/g of cis- and trans-chlordane, respectively). However, the uptake is not enantioselective. The concentration of the principle constituents and their enantiomeric ratio was followed during a fifty days growth period in chlordane free water. The first order decay of concentration was observed with a half time of about 18 days for both the cis- and trans-chlordane isomers. However it was found that the enantiomeric ratio of the trans-chlordane was significantly altered during this short period of time, decreasing from ER=1 to ER=0.7, while no enantiomeric changes were observed for the cis-chlordane. It seems that the (-)-trans-chlordane is metabolized significantly faster (t(1/2-)=15 days) in the river carp fish than the (+)-trans-enantiomer (t(1/2+)=20 days).     

Dietary exposure of rainbow trout to 8:2 and 10:2 fluorotelomer alcohols and perfluorooctanesulfonamide: Uptake, transformation and elimination

The bioaccumulation of perfluorooctanesulfonamide (PFOSA) and two fluorotelomer alcohols (8:2 FTOH, 10:2 FTOH) by rainbow trout (Oncorhynchus mykiss) through dietary exposure, including depuration rates and metabolism was investigated. Concentrations in the spiked feed ranged from 10.9 μg g⁻¹ wet weight (wet wt) for PFOSA and 6.7 μg g⁻¹ wet wt for 8:2 FTOH to 5.0 μg g⁻¹ wet wt for 10:2 FTOH. Trout was fed at 1.5% body weight per day for 30 d and depuration was followed for up to 30 d following previously published dietary exposure protocols. Perfluorooctanesulfonate (PFOS) was the major perfluoroalkylsulfonate (PFSA) detected in fish following dietary exposure to PFOSA. Half-lives of PFOS and PFOSA were 16.9 ± 2.5 and 6.0 ± 0.4 d, respectively. A biomagnification factor (BMF) of 0.023 was calculated for PFOSA which indicates that dietary exposure to PFOSA does not result in biomagnification in the rainbow trout. PFOS had a BMF of 0.08. The fluorotelomer saturated acids (8:2 FTCA, 10:2 FTCA) and fluorotelomer unsaturated acids (8:2 FTUCA, 10:2 FTUCA) were the major products detected in rainbow trout following dietary exposure to 8:2 FTOH and 10:2 FTOH, respectively. Half-lives were 3.7 ± 0.4, 2.1 ± 0.5, 3.3, and 1.3 d for 10:2 FTCA, 10:2 FTUCA, 8:2 FTCA, and 8:2 FTUCA, respectively. Small amounts of perfluorooctanoate (PFOA) and perfluorodecanoate (PFDA) were also detected in the FTOH exposed fish.     

Toxicity of organophosphorus esters to laying hens after oral and dermal administration

Fourteen organophosphorus esters (OPs) were evaluated for their potential to cause organophosphorus ester induced delayed neurotoxicity (OPIDN) when administered dermally and/or orally to white leghorn hens. The compounds were chlorpyrifos, DEF, dichlorvos, dimethoate, EPN, ethoprop, fenthion, isofenphos, leptophos, merphos, ronnel, tetrachlorvinphos, terbufos, and trichlorfon. DEF induced ataxia if given dermally or orally at over 21 mg/kg/day for up to 90 days. Hens treated with EPN developed irreversible ataxia after repeated exposure to as little as 1.3 mg/kg dermally or 5 mg/kg/day orally, while leptophos was neurotoxic at doses of 6-7 mg/kg/day dermally and 10 mg/kg/day orally. Multiple treatments of chlorpyrifos, terbufos, dichlorvos and dimethoate caused death after varying periods of increasing debility; although birds had difficulty walking, they did not display typical symptoms of OPIDN. Fenthion and isofenphos induced drastic weight loss in hens at low levels of treatment; Isofenphos treated hens developed OPIDN, but died soon afterwards. Dichlorvos given at greater than 6 mg/kg/day po or dermally at 1 mg/kg/day produced cholinergic symptoms and most hens died before the end of the treatment period. At lower levels, dichlorvos did not induce overt ataxia. None of the other compounds in this series induced consistent ataxia whether administered orally or dermally. Ethoprop, with an acute oral LD50 near 5 mg/kg and an acute dermal LD50 of approximately 3 mg/kg, was the most toxic compound tested and could not be fully evaluated for its potential to cause OPIDN.