Association of 2,4-dichlorophenol urinary concentrations and olfactory dysfunction in a national sample of middle-aged and older U.S. adults.

Olfaction is a key sensory mechanism in humans. Deficits in this chemosensory function have wide-ranging impacts on overall health and quality of life. This study examines the role of environmental phenols as risk factors for olfactory dysfunction among a random sample of 839 middle-aged and older U.S. adults. Olfactory function assessment was carried out using a short 8-item test, scores on which were used to classify subjects into normal or impaired olfactory function groups. Logistic regression models were used to test for associations between olfactory impairment and creatinine-adjusted urinary levels of 8 common environmental phenols, adjusting for potentially confounding covariates. A statistically significant association between 2,4-dichlorophenol levels and olfactory impairment (OR = 1.02 [95 % CI: (1.003, 1.04)]; p = 0.02) was found. 2,4-dichlorophenol is a hazardous pollutant with widespread exposure via industrial and indoor air pollution, diet, and the use of pesticides and herbicides. This study is the first to reveal its role in olfactory impairment.

Metabolism of levamisole and kinetics of levamisole and aminorex in urine by means of LC-QTOF-HRMS and LC-QqQ-MS.

The antihelminthic drug Levamisole can enhance cocaine effects by conversion into the amphetamine-like drug aminorex. We describe an LC-MS method for the determination of levamisole and its metabolite aminorex in human urine. Selectivity is given, calibration curves were linear within the calibration range 2.5-250 ng/mL; limits of the method were LoD 0.51 ng/mL, LoQ 1.02 ng/mL for levamisole and LoD 0.65 ng/mL, LoQ 0.76 ng/mL for aminorex. Precision data was in accordance with the guidelines (intraday precision for aminorex ranged between 5.75 and 11.0 % for levamisole between 8.36 and 10.9 %; interday precision for levamisole 10.9-16.9 % and for aminorex 7.64-12.7 %; accuracy data for levamisole -1.96 to -14.3 % and for aminorex-11.9 to-18.5 %). The validated method was successfully applied to study the urinary excretion of levamisole after the administration of 100 mg of levamisole orally. Levamisole and aminorex could be detected in post-administration urine samples. Levamisole could be detected up to 39 h after ingestion, while aminorex was detectable up to 54 h. Maximum aminorex concentrations were 45 ng/mL urine. Further metabolites of levamisole after oral ingestion by means of liquid chromatography hybrid quadrupole time-of-flight high-resolution mass spectrometry (LC-QTOF-HRMS) were identified. Only 0.5 % of the ingested drug was quantified as unchanged levamisole in urine. Besides aminorex, five isomers of aminorex and 4 hydroxy-metabolites of aminorex or its isomers were found. Furthermore, levamisole is also hydroxylated and eliminated free or conjugated with sulfate or glucuronide into urine.

The association between urinary concentrations of dichlorophenol pesticides and obesity in children.

BACKGROUND: Increasing prevalence of childhood obesity has been seen in the United States and other parts of the world. Environmental chemical exposures might play a role in the worldwide obesity epidemic. OBJECTIVE: This study was conducted to assess the association of exposure to environmental pesticides with childhood obesity. METHODS: A total of 6770 subjects aged 6-19 years were selected from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey (NHANES). Exposure to environmental pesticides was determined based on the concentrations of pesticide residues in urine. Multivariate logistic regression was performed using SAS 9.1.3 to assess the association between pesticide levels in urine and childhood obesity with the adjustment of potential confounders, including age, gender, race, income, and total fat intake. RESULTS: A dose-dependent increase in prevalence of obesity was observed in the groups with inter-quartile urinary concentrations of 2,5-dichlorophenol (2,5-DCP). Logistic regression revealed a significant association between adjusted third (Q3) (AOR: 1.47; 95% CI: 1.09, 1.97) and fourth (Q4) (AOR: 1.44; 95% CI: 1.06, 1.95) inter-quartile urinary 2,5-DCP levels and childhood obesity. However, urinary concentrations of 2,4-dichlorophenol were not shown to be significantly associated with childhood obesity. CONCLUSION: This study suggests a possible relationship between exposure to 2,5-DCP and obesity in children.

Metabolic fate of phenothiazine in the marmoset (Callithrix jacchus).

The fate of [35S]-phenothiazine, a veterinary anthelmintic, has been investigated in the adult male marmoset (Callithrix jacchus) following oral administration. A near complete recovery of radioactivity (c. 95%) was achieved in 0-3 days, with just over one-third of the dose (c. 37%) being present in the urine and the remainder (c. 58%) being accounted for in the faeces. The majority of the urinary radioactivity (c. 91%) was present as conjugates, tentatively identified as phenothiazine N-glucuronide and leucophenothiazone sulphate. Smaller amounts of phenothiazone, thionol, phenothiazine sulphoxide and unchanged phenothiazine were also identified. The only compound identified in the faeces was unchanged phenothiazine.

Some hepatotoxic actions of hexachloroethane and its metabolites in sheep.

1. Pentachloroethane and tetrachloroethylene were major metabolites of hexachloroethane in sheep.2. Concentrations of hexachloroethane, pentachloroethane and tetrachloroethylene were determined by gas-liquid chromatography in blood, bile, faeces, urine and tissues after oral administration of hexachloroethane emulsions to sheep.3. Increased blood concentrations of sorbitol dehydrogenase, glutamate dehydrogenase, and ornithine carbamoyl transferase were found to follow oral administration of hexachloroethane or pentachloroethane.4. The rate of bromsulphthalein transfer from liver cells to bile was found to decrease after oral administration of hexachloroethane.

Mutagenicity of antiamebic and anthelmintic drugs in the Salmonella typhimurium microsomal test system.

4 amebicides (chloroquine diphosphate, diiodohydroxyquin, iodochlorohydroxyquin and dehydroemetine) and 6 anthelmintics (bephenium hydroxynaphthoate, 4-hexylresorcinol, mebendazole, niclosamide, pyrantel pamoate and pyrvinium pamoate) were tested for mutagenicity in the Salmonella typhimurium microsomal test system. Frameshift mutations were induced by dehydroemetine and niclosamide following activation by microsomal enzymes, while pyrvinium pamoate induced both frameshift and base-pair substitution mutations with or without metabolic activation. The urine of mice treated with dehydroemetine or pyrvinium pamoate showed no mutagenic activity. However, urine obtained from mice treated with niclosamide was mutagenic in strains TA98 and TA1538. The fluctuation assay showed chloroquine diphosphate to be mutagenic in TA1537, a strain which detects frameshift mutations.

Sex differences in the disposition of albendazole metabolites in sheep.

Sex differences in the disposition of albendazole metabolites in sheep after oral administration of 20 mg/kg of netobimin have been studied. Some kinetic parameters of both metabolites show statistical differences between sexes; the sulphoxide and sulphone t1/2beta and MRT were lower in male animals than in females. Peak concentrations and AUC of sulphone metabolites were higher in males suggesting a greater oxidation rate compared with females. Urine excretion of albendazole metabolites, sulphoxide, sulphone, and amino sulphone appeared to be greater in female sheep than in males, mainly the sulphoxide metabolite. These differences between sexes can be caused by male sexual hormones, because testosterone and progesterone can induce or inhibit the microsomal Cytochrome P450 metabolism. Plasma protein-binding of albendazole sulphoxide and albendazole sulphone has been studied between male and female sheep, also their binding to sheep albumin and globulins. Both albendazole metabolites readily bind to sheep albumin and globulins. Male animals show a significantly lower binding of albendazole metabolites than females. These differences could be responsible for the non-esterified fatty acids (NEFA) present in the plasma. Males have significantly higher plasma levels of NEFA than females and which may compete with albumin for binding to albendazole metabolites.

On the metabolic detoxication of 4-iodothymol in man.

The detoxication of 4-iodothymol was investigated in man. A new metabolite was isolated as a crystalline derivative from 4-iodothymol medicated urine and identified as 4-iodothymol glucuronide as a methyl acetyl derivative. The deiodinated metabolite of 4-iodothymol, thymoquinone, was also recognized in a very small amount in 4-iodothymol medicated urine.

[Manifestation of the mutagenic effect of acemidophen depending on its metabolism in various mammalian species (acemidophen--a promutagen)]. / Proiavlenie mutagennogo éffekta atsemidofena v zavisimosti ot ego metabolizma u raznykh vidov mlekopitaiushchikh (atsemidofen--promutagen).

While studying the specific variability of metabolism of the fasciolacide anthelmintic acemidophen, it is found that it possesses no mutagenic activity. This activity is peculiar to its metabolite-free amine L2, formed in mice organism by deacetylation. Thus, acemidophen is shown to be promutagen.

Microextraction of mebendazole across supported liquid membrane forced by pH gradient and electrical field.

In the present study, extraction of mebendazole across a supported-liquid membrane (SLM) was performed based on two different driving forces: (1) pH gradient over the SLM, and (2) electrical field sustained over the SLM. The extracted drug concentration was studied using reversed-phase HPLC-UV. At passive extraction conditions, mebendazole was extracted from alkaline samples (0.01 mmol L(-1) NaOH) into 1-undecanol immobilized in the pores of a porous hollow fiber of polypropylene (SLM), and then transported into 25 µL of 100mM HCl as the acceptor solution. Under electrokinetic migration conditions, mebendazole transported under applied voltage from acidic solutions (100 mmol L(-1) HCl) through 2-nitrophenyl octyl ether (NPOE) immobilized in the pores of hollow fiber, into 25 µL of 100 mmol L(-1) HCl as the acceptor solution. The effects of several factors including the nature of organic solvent, pH of donor and acceptor solutions, extraction time and stirring speed on the extraction efficiency of the drug were investigated and optimized. Under optimal conditions, preconcentration factors (PF) of 211 and 190 were obtained for the drug based on passive transport and electromembrane extraction (EME), respectively. Also, linear range of 0.5-1000 µg L(-1) with estimation of coefficient higher than 0.994 was obtained for both of the proposed methods. The results showed that EME has higher speed in comparison with simple passive transport. The methods were successfully applied to extract mebendazole from plasma and urine samples and satisfactory results were obtained.

Levamisole-induced occlusive necrotizing vasculitis of the ears after use of cocaine contaminated with levamisole.

Based on the best available data, approximately 2.1 million Americans use illicit cocaine each month; for the last several months, 30% of that cocaine has been "cut" with a veterinary pharmaceutical, levamisole. Levamisole can cause agranulocytosis, leaving patients susceptible to fulminate and opportunistic infections and also can cause a debilitating cutaneous necrotizing vasculitis. In this manuscript, we describe a case and provide an image of levamisole-induced necrotizing vasculitis of the ears.

Pharmacokinetic behaviour of netobimin and its metabolites in sheep.

The pharmacokinetics and the profile of urine excretion of netobimin (NTB) and its metabolites were investigated after its intraruminal (i.r.) and subcutaneous (s.c.) administration to sheep at 20 mg/kg. Plasma and urine concentrations of NTB, albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) were measured serially over a 120-h period by HPLC. NTB showed a similar pharmacokinetic profile in both treatments, being detected between 0.5 and 12 h post-treatment, but the tmax was achieved significantly earlier (P less than 0.05) after s.c. treatment. ABZ was detected in plasma only after i.r. treatment, resulting in a low area under the curve (AUC). The peak plasma concentration (Cmax) and AUC for ABZSO and ABZSO2 were significantly higher after i.r. administration of NTB. In both treatments, the ABZSO Cmax was reached earlier than the ABZSO2 Cmax. The ratio of AUC ABZSO2:ABZSO was higher following s.c. administration (1.33) than following i.r. administration (0.35). The percentages of total dose excreted in the urine as NTB, ABZ, ABZSO and ABZSO2 were 17.05 (i.r.) and 8.16 (s.c.). There was a less efficient conversion of NTB into ABZ metabolites after s.c. administration. The detection of ABZ in plasma and the high ABZSO AUC obtained after i.r. treatment may be of major importance for anthelmintic efficacy.

Pesticide residues in urine of adults living in the United States: reference range concentrations.

We measured 12 analytes in urine of 1000 adults living in the United States to establish reference range concentrations for pesticide residues. We frequently found six of these analytes: 2,5-dichlorophenol (in 98% of adults); 2,4-dichlorophenol (in 64%); 1-naphthol (in 86%); 2-naphthol (in 81%); 3,5,6- trichloro-2-pyridinol (in 82%); and pentachlorophenol (in 64%). The 95th percentile concentration (95th PC) for 2,5-dichlorophenol (indicative of p-dichlorobenzene exposure) was 790 micrograms/liter; concentrations ranged up to 8700 micrograms/liter. 2,4-Dichlorophenol concentrations ranged up to 450 micrograms/ liter, and the 95thPC was 64 micrograms/liter. 1-Naphthol and 2-naphthol (indicative of naphthalene exposure) had 95thPCs of 43 and 30 micrograms/liter, respectively; concentrations of 1-naphthol ranged up to 2500 micrograms/liter. Chlorpyrifos exposure was indicated by 3,5,6-tricholoro-2-pyridinol concentrations of 13 (95thPC) and 77 micrograms/liter (maximum observed). Pentachlorophenol had a 95thPC of 8.2 micrograms/liter. Other analytes measured included 4-nitrophenol (in 41%); 2,4,5-trichlorophenol (in 20%); 2,4,6-trichlorophenol (in 9.5%); 2,4-dichlorophenoxyacetic acid (in 12%); 2-isopropoxyphenol (in 6.8%); and 7-carbofuranphenol (in 1.5%). The 95thPCs of these analytes were < 6 micrograms/liter. p-Dichlorobenzene exposure is ubiquitous; naphthalene and chlorpyrifos are also major sources of pesticide exposure. Exposure to chlorpyrifos appears to be increasing. Although pentachlorophenol exposure is frequent, exposure appears to be decreasing. These reference range concentrations provide information about pesticide exposure and serve as a basis against which to compare concentrations in subjects who may have been exposed to pesticides.

Biotransformation of methyl 5-cyclopropylcarbonyl-2-benzimidazolecarbamate (ciclobendazole) in rats and dogs.

A major metabolite of ciclobendazole (methyl 5-cyclopropylcarbonyl-2-benzimidazolecarbamate) excreted in the urine, bile, and feces of rats was methyl 5-cyclopropylcarbonyl-6-hydroxy-benzimidazolecarbamate, established by comparison of the proton magnetic resonance and mass spectra with that of the authentic compound. This compound represented 8.2% and 7.1% of the dose, respectively, in extracts of 24-hr urine and 48-hr feces samples of rats, but was only a minor metabolite in dog urine (1% of the dose). The unchanged drug was only detected in dog feces, the major route of excretion of radioactivity in the dog. 5-Cyclopropylcarbonyl-2-amino-benzimidazole was present in rat urine (2.5% of the dose). A major metabolite in dog bile was probably 5-cyclopropylcarbinol-2-aminobenzimidazole, formed by loss of the methoxycarbonyl group and reduction of the carbonyl function in the 5-position.