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.     

Zearalenone metabolism and excretion in the rat: effect of different doses

Young female rats were orally dosed with either 1 or 100 mg zearalenone kg-1 body weight; zearalenone and metabolites were measured in a 96-h collection of urine and feces by HPLC analysis. Dose had little effect on metabolites formed, or excretion route. In both treatment groups, about 55% of the oral dose was excreted in the feces, while the urine was also a major route of excretion accounting for 15-20% of the administered dose. Zearalenone and metabolites were excreted mainly in the free form, with the production of alpha-zearalenol, the most potent estrogenic metabolite, being greater than 10% of the zearalenone dose.     

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.     

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.     

Bioavailability of bound 14C residues in rats from bean plants treated with 14C-deltamethrin

Bean plants were treated with deltamethrin labeled with ¹⁴C at the methyl or benzylic position. The aerial portion of the plants was exhaustively extracted with solvents and the extracted material containing bound ¹⁴C residues was fed to rats. After 4 days 60% and 53% of the dose was excreted in feces and 31% and 20% in the urine from rats fed extracted bean plants treated with deltamethrin labeled at the methyl and benzylic position, respectively. The data demonstrated that bound residues in bean plants treated with deltamethrin may be bioavailable in rats.     

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.     

Tissue distribution and excretion of hexabromobenzene (HBB) and hexachlorobenzene (HCB) administered to rats

Tissue distribution and excretion of hexabromobenzene (HBB) and hexachlorobenzene (HCB) were studied in Wister male rats, after oral administration of these chemicals.There was no difference in the amount of two chemicals excreted in feces for seven days. Their absorption rates through intestine were the same. HBB and HCB also were excreted in urine, but their amounts were very low. Therefore, both chemicals seem to be mainly excreted via feces. HBB and HCB were found to be transported rapidly to all tissues, but the concentrations of HCB were higher than those of HBB in all tissues, indicating the rapid metabolism of HBB. This might be due to the lower bonding energy between bromine and carbon atoms (C₆H₆-Br: 71kcal/mol) compared to that of chlorine and carbon atoms (C₆H₆Cl: 86kcal/mol). The half-lives were 0.7 (phase I) and 48 days (phase II) for HBB and 20 days for HCB in whole body. It is noteworthy that the half-life of HBB at phase II is longer than that of HCB.     

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.     

Occurrence of free estrogens,conjugated estrogens,and bisphenol A in fresh livestock excreta and their removal by composting in North China

An efficient pretreatment and analytical method was developed to investigate the occurrence and fate of four free estrogens (estrone (E1), 17β-estradiol (17β-E2), estriol (E3), and 17α-ethinylestradiol (EE2)), four conjugated estrogens (estrone-3-sulfate sodium salt (E1-3S), 17β-estradiol-3-sulfate sodium salt (E2-3S), estrone-3-glucuronide sodium salt (E1-3G), and 17β-estradiol-3-glucuronide sodium salt (E2-3G)), and bisphenol A (BPA) in three livestock farms raising beef cattle, cows, sheep, swine, and chickens in Qi County, which is located in North China. The results demonstrated that one cow and one beef cattle excreted 956.25–1,270.41 and 244.38–319.99 μg/day of total (free and conjugated) estrogen, respectively, primarily through feces (greater than 91 %), while swine excreted 260.09–289.99 μg/day of estrogens, primarily through urine (98–99 %). The total estrogen excreted in sheep and broiler chicken feces was calculated to be 21.64–28.67 and 4.62–5.40 μg/day, respectively. It was determined that conjugated estrogens contributed to 21.1–21.9 % of the total estrogen excreted in cow feces and more than 98 % of the total estrogen excreted in swine urine. After composting, the concentration of total estrogen decreased by 18.7–59.6 %; however, increased levels of BPA were measured. In treated compost samples, estrogens were detected at concentrations up to 74.0 ng/g, which indicates a potential risk of estrogens entering the surrounding environment.     

Biliary secretion,retention and excretion of five 14C-labelled polychlorinated biphenyls in the rat

Five ¹⁴C-labelled polychlorinated biphenyls: 2,4′,5-trichlorobiphenyl, 2,2′,4,5′-tetrachlorobiphenyl, 2,2′,4,5,5′-pentachlorobiphenyl, 2,2′,3,4,4′-pentachlorobiphenyl and 2,2′,4,4′,5,5′-hexachlorobiphenyl were administered orally to bile-cannulated rats. The activity secreted in the bile, excreted in the feces and the urine was determined. Residues of radioactivity in certain tissues and the carcass were also measured.The trichlorobiphenyl showed the highest absorption (93.8%±5.4) from the gastrointestinal tract and biliary secretion of radioactivity (87.6%±6.1 of the dose). The hexachlorobiphenyl showed the lowest absorption and biliary secretion, 28.2%±1.4 and 18.6%±1.3, respectively. The urinary excretion was low and the radioactive residues in the eviscerated carcasses increased with the chlorine content of the biphenyls.     

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.     

Clearance of PCDD/Fs via the gastrointestinal tract in occupationally exposed persons.

A digestive tract mass balance was performed on six men with high body burdens of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). Intake via food was measured by analyzing duplicate portions of the food consumed by the volunteers and excretion via feces was determined by quantitative collection and analysis of the feces. Blood samples were taken to determine the current body burden. The results showed that the quantity of non-metabolized chemical excreted in the feces clearly exceeded the uptake via food for all of the 2,3,7,8-substituted PCDDs and some of the PCDFs, indicating a significant clearance across the gastrointestinal tract. The concentrations of these PCDD/F congeners in blood and feces were highly correlated (r > 0.8), demonstrating that the fecal PCDD/F content was determined by the body burden. The half lives in the test persons due to fecal clearance of non-metabolized chemical were estimated from the excretion rate and the current body burden and ranged between 10 years (Cl8DD) and 33 years (2,3,4,7,8-Cl5DF). These were compared with the overall contaminant half-lives due to all clearance processes which were calculated from the body burden and the decrease in blood concentrations measured over several years. The fecal clearance of non-metabolized PCDD/F contributed on average between 37% (2,3,7,8-Cl4DD) and 90% (Cl8DD) to the total elimination. This indicates that the gastrointestinal pathway plays a decisive role in the clearance of most 2,3,7,8-subsituted PCDD/F congeners.     

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%).     

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 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.     

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.     

Metabolic conversion of 14C-chloralkylene - 9

¹⁴C-Chloralkylene-9 was applied to rats for 35 days (2 ppm/day/animal)². GC-Mass Spectra indicated oxygenated components of chloralkylene-9 in urine and feces. The urinary metabolites were characterized to be mono-, di- and trihydroxy 2,4′-dichlorobiphenyls. The feces contained mainly those metabolites in which the side chain of mono-, di- and tri-isopropyl 2,4′-dichlorobiphenyl was oxidized. Different metabolic products containing alcoholic, aldehydic and carboxylic side chains were detected. Metabolites with unsaturated side chains were also detected.The GC-Mass spectroscopic analysis of chloroalkylene-9 residue showed the major component consisted of di- and tri-isopropyl 2,4′-dichlorobiphenyl. 2,4′-dichlorobiphenyl and monoisopropyl 2,4′-dichlorobiphenyl were found to comprise a smaller percentage of the total residue. There was also an indication of isomerization of 2,4′-dichlorobiphenyl.     

Bioavailability and toxicity to rats of bound residues of 14C-pirimiphos-methyl in stored wheat.

Wheat grains were treated with 14C-pirimiphos-methyl to generate bound residues for testing their bioavailability to rats. Bound residues accounted for 25% of the applied dose (50 ppm) at the end of one year. When the grain bound residues were fed to rats for 48 hours the animals eliminated 30 and 40% of the administered dose in urine and feces respectively, after 5 days. Radioactivity in some selected organs and blood accounted for 37% of the administered dose after 2 days, which gradually declined to 1% after 5 days. These data indicate that wheat-bound pirimiphos-methyl residues are moderately bioavailable to rats. In a 90-day feeding study, inhibition of plasma cholinesterase and brain acetylcholinesterase strongly suggest that the bound residues possess a toxicological potential.     

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.     

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.