ABSTRACT
Chlorothalonil (CTN) is a popular fungicide widely used in the world. However, its determination in serum samples is highly challenging, preventing a reliable investigation of human CTN internal exposure. We first investigated CTN's behaviour all along this analytical process on spiked serum samples. We used a radiolabelled 14C-CTN standard to monitor CTN in spiked serum samples and observed (1) a complete degradation of CTN in deproteinised serum samples after 4 h of contact; (2) a strong interaction between serum proteins and CTN by-products, with only 20 % of the radioactivity found to be extractable after 24 h of contact and (3) a slightly improved stability of CTN in serum following a first step of acidification or EDTA addition to samples. Using liquid chromatography coupled to high resolution mass spectrometry, 4-hydroxy-2,5,6-trichloroisophthalonitrile (HCTN) was identified as the major serum by-product of CTN. A protocol was developed to monitor both extractable CTN and HCTN from serum. This method was implemented on 36 human adult serum samples from the French "Esteban" Cohort. No free CTN was identified in these serum samples. Conversely, HCTN was detected in all samples at concentrations around 15 ± 2 ng mL-1, corresponding to the extractable fraction of CTN. Thus, HCTN may constitute a relevant biomarker of human internal exposure. Of note, the potential CTN contamination during blood collection could also be a source of HCTN detection in serum samples. Finally, blood sampling in EDTA tubes would seem more appropriate than in dry tubes for any future internal exposure studies on CTN.
Subject(s)
Biological Monitoring , Fungicides, Industrial , Nitriles , Humans , Nitriles/blood , Nitriles/chemistry , Fungicides, Industrial/blood , Fungicides, Industrial/analysis , Chromatography, Liquid/methods , AdultABSTRACT
Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.
Subject(s)
Models, Biological , Triazoles , Animals , Humans , Rats , Administration, Oral , Male , Nitriles/pharmacokinetics , Nitriles/toxicity , Quantitative Structure-Activity Relationship , Caco-2 Cells , Risk Assessment , Microsomes, Liver/metabolism , Tissue Distribution , Fungicides, Industrial/pharmacokinetics , Fungicides, Industrial/toxicity , Fungicides, Industrial/administration & dosage , Fungicides, Industrial/bloodABSTRACT
Pesticide poisoning is a common occurrence due to their widespread use, easy access and high toxicity even in small concentrations. The most common poisoning fatalities have been observed due to exposure to organophosphates, carbamates and neonicotinoids, thus development of a method for the rapid determination of these compounds in blood and urine is of great importance for clinical and toxicology laboratories. A simple, fast and reliable method was developed for the determination of 9 pesticides in blood and urine using HPLC-MS/MS instrumentation. In order to find the most suitable sample pretreatment technique, three different sample preparation procedures: SPE, protein precipitation and QuEChERS were compared. The final optimized analytical method was fully validated with the values of parameters such as calibration linearity, accuracy, precision, recovery, matrix effect and stability being acceptable. The method proved reliable, accurate, robust and sensitive and was successfully applied for the quantitation of pesticides in three postmortem cases of pesticides poisoning.
Subject(s)
Chromatography, High Pressure Liquid/methods , Fungicides, Industrial , Insecticides , Tandem Mass Spectrometry/methods , Fungicides, Industrial/blood , Fungicides, Industrial/urine , Humans , Insecticides/blood , Insecticides/urine , Limit of Detection , Linear Models , Reproducibility of ResultsABSTRACT
2,4,6-tribromophenol (TBP, CAS No. 118-79-6) is widely used as a brominated flame retardant and wood antifungal agent. TBP is frequently detected in environmental matrices, biota, and humans. In female SD rats, systemically available TBP (10 µmol/kg, IV) was rapidly excreted primarily via urine, with approximately 61% of the dose recovered after 4 h, and 89%-94% in 24 h; 5% was recovered in feces; and 1%-2% in blood/tissues. TBP administered to female SD rats (0.1-1000 µmol/kg) by gavage was well absorbed, with approximately 25% eliminated via urine after 4 h and approximately 88% after 24 h. Approximately 11% of a single oral dose was recovered in bile. Male SD rats and B6C3F1/J mice of both sexes had similar disposition profiles when administered a single oral dose of TBP (10 µmol/kg). Following administration, fecal recoveries varied only slightly by dose, sex, or species. TBP readily passed unchanged through both human (ex vivo only) and rat skin with between 55% and 85% of a 100 nmol/cm2 passing into or through skin. Concentrations of TBP in blood fit a two-compartment model after IV-dosing and a one-compartment model after oral dosing. Urine contained a mixture of TBP, TBP-glucuronide, and TBP-sulfate. Fecal extracts contained only parent TBP whereas bile contained only TBP-glucuronide. TBP did not appear to bioaccumulate or alter its own metabolism after repeated administration. TBP was readily absorbed at all doses and routes tested with an oral bioavailability of 23%-27%; 49% of TBP is expected to be dermally bioavailable in humans. From these data, we conclude that humans are likely to have significant systemic exposure when TBP is ingested or dermal exposure occurs.
Subject(s)
Flame Retardants/administration & dosage , Flame Retardants/pharmacokinetics , Fungicides, Industrial/administration & dosage , Fungicides, Industrial/pharmacokinetics , Phenols/administration & dosage , Phenols/pharmacokinetics , Administration, Cutaneous , Administration, Oral , Animals , Bile/metabolism , Biological Availability , Biotransformation , Feces/chemistry , Female , Fungicides, Industrial/blood , Fungicides, Industrial/urine , Hepatobiliary Elimination , Humans , Injections, Intravenous , Intestinal Elimination , Male , Mice , Models, Biological , Phenols/blood , Phenols/urine , Rats , Rats, Sprague-Dawley , Renal Elimination , Sex Factors , Species Specificity , Tissue DistributionABSTRACT
Compounds and products in the biocide and plant protection sector can only be registered after formal risk assessment to ensure safety for users and the environment. In bird and mammal risk assessment, this is routinely done using generic focal species as models, which are of particular exposure risk. Such a species is the common vole (Microtus arvalis) due to its high food intake relative to the low body weight. For wild species, biological samples, data and hence realistic exposure estimations are particularly difficult to obtain. In recent years, advances have been made in the techniques related to serial microsampling of laboratory mice and rats that allow for a reduction in sampling volumes. Similar progress in wild species sampling is missing. This study presents a proof of concept to dose wild rodents with relevant compounds and to draw serial, low volume blood samples suitable for state-of-the art toxicokinetic analyses. For the first time, the jugular vein of common voles was used to administer compounds (two frequently used fungicidal components). This procedure and the following microsampling of blood (2 × 10 µl six times within 24 hours) from the lateral tail vein did not affect body weight and mortality of voles. Samples were sufficient to detect dissipation patterns of the compounds from blood in toxicokinetic analysis. These results suggest that microsampling can be well translated from laboratory mice to wild rodent species and help to obtain realistic exposure estimates in wild rodents for ecotoxicological studies as well as to promote the 3R concept in studies with wild rodent species.
Subject(s)
Arvicolinae/blood , Blood Specimen Collection/methods , Dioxoles/toxicity , Ecotoxicology/methods , Environmental Exposure/adverse effects , Environmental Monitoring/methods , Fungicides, Industrial/toxicity , Pyrimidines/toxicity , Pyrroles/toxicity , Administration, Intravenous , Animals , Dioxoles/administration & dosage , Dioxoles/blood , Dioxoles/pharmacokinetics , Female , Fungicides, Industrial/administration & dosage , Fungicides, Industrial/blood , Fungicides, Industrial/pharmacokinetics , Male , Pyrimidines/administration & dosage , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Pyrroles/administration & dosage , Pyrroles/blood , Pyrroles/pharmacokinetics , Reproducibility of Results , Risk Assessment , ToxicokineticsABSTRACT
A metabolite of procymidone, hydroxylated-PCM, causes rat-specific developmental toxicity due to higher exposure to it in rats than in rabbits or monkeys. When procymidone was administered to chimeric mice with rat or human hepatocytes, the plasma level of hydroxylated-PCM was higher than that of procymidone in rat chimeric mice, and the metabolic profile of procymidone in intact rats was well reproduced in rat chimeric mice. In human chimeric mice, the plasma level of hydroxylated-PCM was less, resulting in a much lower exposure. The main excretion route of hydroxylated-PCM-glucuronide was bile (the point that hydroxylated-PCM enters the enterohepatic circulation) in rat chimeric mice, and urine in human chimeric mice. These data suggest that humans, in contrast to rats, extensively form the glucuronide and excrete it in urine, as do rabbits and monkeys. Overall, procymidone's potential for causing teratogenicity in humans must be low compared to that in rats.
Subject(s)
Bridged Bicyclo Compounds/blood , Bridged Bicyclo Compounds/urine , Chimera/growth & development , Fungicides, Industrial/blood , Fungicides, Industrial/urine , Animals , Bile/chemistry , Bridged Bicyclo Compounds/toxicity , Chimera/blood , Chimera/urine , Feces/chemistry , Female , Fungicides, Industrial/toxicity , Hepatocytes/chemistry , Hepatocytes/metabolism , Humans , Mice , Rabbits , RatsABSTRACT
In recent years, serious environmental pollution has caused a decrease in the abundance of many species worldwide. Reptiles are the most diverse group of terrestrial vertebrates. There are large amounts of toxicological data available regarding myclobutanil, but the adverse effects of myclobutanil on lizards has not been widely reported. In this study, treatment groups were orally administered a single-dose of myclobutanil (20mg/kg body weight (bw)). Subsequently, it was found that there were differences in myclobutanil levels between the different tissues and concentrations also changed with degradation time. The tissue concentrations of myclobutanil decreased in the order of: stomach > liver > lung > blood > testis > kidney > heart > brain. Based on our results, the liver and testis were considered to be the main target organs in lizards, indicating that the myclobutanil could induce potential hepatic and reproductive toxicity on lizards. Meanwhile, it was also demonstrated that the toxic effects of myclobutanil was different in different species, and the distribution of different pesticides in lizards were different.
Subject(s)
Environmental Pollutants/pharmacokinetics , Fungicides, Industrial/pharmacokinetics , Lizards/metabolism , Nitriles/pharmacokinetics , Triazoles/pharmacokinetics , Animals , Environmental Pollutants/blood , Environmental Pollutants/toxicity , Fungicides, Industrial/blood , Fungicides, Industrial/toxicity , Liver/drug effects , Liver/metabolism , Lizards/blood , Male , Nitriles/blood , Nitriles/toxicity , Organ Specificity , Stereoisomerism , Testis/drug effects , Testis/metabolism , Tissue Distribution , Triazoles/blood , Triazoles/toxicityABSTRACT
Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the "expected NOEL" was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose-response curve or effects at low levels.
Subject(s)
Ecotoxicology/methods , Fungicides, Industrial/toxicity , Imidazoles/toxicity , Lactation , Models, Chemical , Nonsteroidal Anti-Androgens/toxicity , Prenatal Exposure Delayed Effects , Administration, Oral , Animals , Dose-Response Relationship, Drug , Ecotoxicology/legislation & jurisprudence , Endocrine Disruptors/administration & dosage , Endocrine Disruptors/blood , Endocrine Disruptors/toxicity , Female , Fetal Growth Retardation/blood , Fetal Growth Retardation/chemically induced , Fetal Resorption/blood , Fetal Resorption/chemically induced , Fungicides, Industrial/blood , Fungicides, Industrial/standards , Imidazoles/administration & dosage , Imidazoles/blood , Male , Nonsteroidal Anti-Androgens/administration & dosage , Nonsteroidal Anti-Androgens/blood , Pregnancy , Puberty, Delayed/blood , Puberty, Delayed/chemically induced , Random Allocation , Rats, Wistar , Toxicokinetics , Urogenital Abnormalities/blood , Urogenital Abnormalities/chemically induced , Weight Gain/drug effectsABSTRACT
We have studied rates of diabetes in 601 members of the Mohawk Nation at Akwesasne, ages 18-84 years, in relation to serum concentrations of 101 polychlorinated biphenyl (PCB) congeners and three chlorinated pesticides [dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and mirex]. Diabetes was determined from either a diagnosis by a physician or by having a fasting glucose concentration of >125 mg/dL. Rates of diabetes are high in this community. Three models were used. In the first model rate ratios (RR) were determined for quartiles of total PCBs after adjustment for age, sex, body mass index (BMI) and total serum lipids. For total PCBs RR=2.21 (1.2-4.2), while for total pesticides RR=3.75 (1.3-10.7). When the total PCB results were also adjusted for total pesticides and the total pesticide results were also adjusted for total PCBs (Model 2) the RRs were somewhat reduced. In Model 3 we considered subgroups of PCBs based on numbers of chlorines on the molecule (tri-/tetra, penta-/hexa, hepta plus) and numbers of ortho chlorines (non-/mono; di-, tri-/tetra-), and considered each of the pesticides individually after adjustment for all other contaminants as well as age, sex, BMI and serum lipids. We found a highly significant association between diabetes and PCBs with only three or four chlorines (RR=5.02), but no significant association with those with greater chlorination. When evaluating PCBs based on numbers of ortho chlorines only, those with no or one ortho chlorine showed significant associations. As mono-ortho PCBs include some with dioxin-like activity, we compared those with and without a TEF, and found that the association with diabetes was exclusively with the non-dioxin-like congeners. Of the pesticides only hexachlorobenzene showed a small but significant association with diabetes. Because lower chlorinated PCBs are more volatile and do not greatly accumulate in fish, these results suggest that inhalation is the major route of exposure to those PCBs that increase risk of diabetes.
Subject(s)
Diabetes Mellitus/epidemiology , Environmental Exposure , Environmental Pollutants/blood , Fungicides, Industrial/blood , Insecticides/blood , Polychlorinated Biphenyls/blood , Adolescent , Adult , Aged , Aged, 80 and over , Diabetes Mellitus/etiology , Dichlorodiphenyl Dichloroethylene/blood , Female , Hexachlorobenzene/blood , Humans , Indians, North American , Male , Middle Aged , Mirex/blood , Models, Theoretical , New York/epidemiology , Obesity/epidemiology , Obesity/etiology , Overweight/epidemiology , Overweight/etiology , Prevalence , Risk Factors , Young AdultABSTRACT
A simple, specific and reproducible liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of pyraoxystrobin in rat plasma and tissues. Chromatographic separation was achieved on a Zorbax Extend-C18 column (50×2.1mm I. D., 3.5µm), using a gradient mobile phase consisting of acetonitrile and 0.1% aqueous formic acid (v/v) at a flow rate of 0.5mL min(-1). Pyraoxystrobin and picoxystrobin (internal standard) were detected without interference in the selected reaction monitoring (SRM) mode with positive electrospray ionization. Further, the method was validated following FDA guideline. The calibration curves for plasma and tissues were linear over a concentration range of 1.00-200ng mL(-1), with lower limits of quantitation of 1.00ng mL(-1). Mean extraction recoveries in plasma and tissues ranged from 101.4% to 108.2% and from 49.1% to 59.4%, respectively. The intra-day and inter-day precision in plasma and tissues were within 9.9% and 8.9%, and the intra-day and inter-day accuracy ranged from 88.7% to 110.7% and 93.2% to 108.7%, respectively. Finally, the validated method was successfully applied to toxicokinetics and tissue distribution studies after oral administration of pyraoxystrobin to rats.
Subject(s)
Acrylates/analysis , Fungicides, Industrial/analysis , Pyrazoles/analysis , Acrylates/blood , Acrylates/pharmacokinetics , Acrylates/toxicity , Animals , Chromatography, High Pressure Liquid , Fungicides, Industrial/blood , Fungicides, Industrial/pharmacokinetics , Fungicides, Industrial/toxicity , Male , Pyrazoles/blood , Pyrazoles/pharmacokinetics , Pyrazoles/toxicity , Rats, Sprague-Dawley , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry , Tissue Distribution , ToxicokineticsABSTRACT
Metalaxyl [N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D,L-alaninemethylester] is a systemic fungicide widely used in agriculture. In this study, the enantioselective distribution, degradation and excretion of metalaxyl were investigated after oral gavage administration of rac-metalaxyl to mice. Concentration of metalaxyl and its enantiomers was determined by HPLC-MS/MS. The results showed that R-metalaxyl was much higher than S-metalaxyl in heart, liver, lung, urine and feces. As for the strong first pass effect, concentrations of metalaxyl in liver were much higher than those in other tissues. The total body clearance (CL) of metalaxyl in mice was 1.77 L h(-1 )kg(-1) and degradation half-lives of (t1/2) of S-metalaxyl and R-metalaxyl in liver were 2.2 h and 3.0 h, respectively. Such results indicated the enantioselectivity of metalaxyl lies in distribution, degradation and excretion processes in mice. Main metabolites were also determined and biotransformation reactions were hydroxylation, demethylation and didemethylation. Furthermore, metabolite concentrations in urine and feces were much higher than those in tissues. These results may have potential implications to predict toxicity and provide additional information associated with adverse health effects for risk assessment of metalaxyl.
Subject(s)
Alanine/analogs & derivatives , Fungicides, Industrial/chemistry , Fungicides, Industrial/pharmacokinetics , Administration, Oral , Alanine/blood , Alanine/chemistry , Alanine/pharmacokinetics , Alanine/urine , Animals , Chromatography, Liquid , Feces/chemistry , Fungicides, Industrial/blood , Fungicides, Industrial/urine , Liver/metabolism , Lung/metabolism , Male , Mice , Mice, Inbred ICR , Myocardium/metabolism , Stereoisomerism , Tandem Mass SpectrometryABSTRACT
Benalaxyl as a xylem-systemic fungicide is usually direct sprayed on the soil surface, which is potential harm to the animals lived in the soil. However, the stereoselectivity of benalaxyl in reptiles have rarely been studied. In this study, Chinese lizards (Eremias argus) were firstly used to evaluate the stereoselectivity in biodegradation and toxicity of racemate and individual enantiomers of benalaxyl. A method for determining residues of the two enantiomers of benalaxyl in lizard blood and liver by high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (HPLC-MS/MS) was developed. The degradation followed pseudo first-order kinetics and the degradation of the (S)-(+)-benalaxyl was faster than its antipode in blood and liver (Half-time t1/2 of (R)-(-)-benalaxyl and (S)-(+)-benalaxyl were 5.08 h and 3.75 h in blood, 6.21 h and 4.45 h in liver, separately). Moreover, antioxidant defenses consisting of activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and lipid peroxide malondialdehyde (MDA) were determined in 24h acute exposure. Enantioselectivity of acute toxicity depended on the concentration and form of benalaxyl. In addition, cellular degeneration, decrease of cell number, clustering phenomena of cell nuclei and preliminary liver fibrosis were observed in pathological detection at the termination of 21-d subchronic exposure (20 mg/kg(-bw) of racemate and individual enantiomers of benalaxyl). The enantiomer fractions (EFs) in racemate and individual enantiomer groups were approached both in blood and liver caused by the chiral conversion. The chiral conversion from (R)-(-)-benalaxyl to (S)-(+)-benalaxyl and (S)-(+)-benalaxyl to (R)-(-)-benalaxyl were the primary cause for no remarkable differences in toxicity between the enantiomers of benalaxyl.
Subject(s)
Alanine/analogs & derivatives , Fungicides, Industrial/metabolism , Liver/metabolism , Lizards/metabolism , Alanine/blood , Alanine/chemistry , Alanine/metabolism , Animals , Biodegradation, Environmental , Catalase/metabolism , Fungicides, Industrial/blood , Fungicides, Industrial/chemistry , Glutathione Transferase/metabolism , Kinetics , Liver/enzymology , Lizards/blood , Malondialdehyde/metabolism , Reptilian Proteins/metabolism , StereoisomerismSubject(s)
Diabetic Ketoacidosis/chemically induced , Fungicides, Industrial/poisoning , Nitriles/poisoning , Occupational Diseases/chemically induced , Occupational Exposure/adverse effects , Diabetic Ketoacidosis/blood , Fungicides, Industrial/blood , Humans , Male , Middle Aged , Nitriles/blood , Occupational Diseases/bloodABSTRACT
Partition coefficients (PCs) are used in physiologically based pharmacokinetic (PBPK) models to estimate the free concentration of a chemical in specific blood or organs. Biological PC(tissue:blood) (tissue to blood) values were determined for a series of nonvolatile herbicides, insecticides, and fungicides in liver, brain, skin, fat, kidneys, and muscle of male Sprague-Dawley rats using two different analytical methods. The free phase concentration (in phosphate-buffered saline) of a given chemical was measured in the presence and absence of tissue (including blood) and used to calculate the PC, defined as the ratio of the concentration of the chemical in saline to the concentration in the tissue. PCs were determined for 13 compounds with aqueous solubility ranging from 20 to 4100 mg/L, molecular weights from 187.3 to 342.2 g/mol, and log K (ow) values from -0.18 to 3.9. An ultrafiltration high-performance liquid chromatography (HPLC) method was implemented for compounds with log K (ow) near 0.1 or less and a negligible depletion solid-phase microextraction (nd-SPME) method for compounds with higher log K (ow). PC(tissue:saline) coefficients of variation were 0.13 (n = 3 compounds) on average for the HPLC method and 0.29 (n = 10 compounds) for the nd-SPME method. Presented here is one of the most comprehensive data sets of biological partition coefficients for herbicides, insecticides, and fungicides.
Subject(s)
Chromatography, High Pressure Liquid/methods , Environmental Monitoring/methods , Pesticides/pharmacokinetics , Adipose Tissue/metabolism , Animals , Brain/metabolism , Fungicides, Industrial/blood , Fungicides, Industrial/pharmacokinetics , Herbicides/blood , Herbicides/pharmacokinetics , Insecticides/blood , Insecticides/pharmacokinetics , Kidney/metabolism , Liver/metabolism , Male , Muscle, Skeletal/metabolism , Pesticides/blood , Rats , Rats, Sprague-Dawley , Skin/metabolism , Solid Phase Microextraction/methods , Tissue Distribution , UltrafiltrationABSTRACT
A physiologically based pharmacokinetic (PBPK) model was developed for the conazole fungicide triadimefon and its primary metabolite, triadimenol. Rat tissue:blood partition coefficients and metabolic constants were measured in vitro for both compounds. Pharmacokinetic data for parent and metabolite were collected from several tissues after intravenous administration of triadimefon to male Sprague-Dawley rats. The model adequately simulated peak blood and tissue concentrations but predicted more rapid clearance of both triadimefon and triadimenol from blood and tissues. Reverse metabolism of triadimenol to triadimefon in the liver was explored as a possible explanation of this slow clearance, with significant improvement in model prediction. The amended model was extrapolated to humans using in vitro metabolic constants measured in human hepatic microsomes. Human equivalent doses (HEDs) were calculated for a rat no observable adverse effect level (NOAEL) dose of 3.4mg/kg/day using area under the concentration curve (AUC) in brain and blood for triadimefon and triadimenol as dosimetrics. All dosimetric-based HEDs were 25-30 fold above the human oral reference dose of 0.03mg triadimefon/kg/day, but did not account for intra-human variability or pharmacodynamic differences. Ultimately, derivations of this model will be able to better predict the exposure profile of these and other conazole fungicides in humans.
Subject(s)
Fungicides, Industrial/pharmacokinetics , Models, Biological , Triazoles/pharmacokinetics , Animals , Dose-Response Relationship, Drug , Fungicides, Industrial/blood , Fungicides, Industrial/metabolism , Humans , In Vitro Techniques , Male , Metabolic Clearance Rate , Microsomes, Liver/metabolism , Organ Specificity , Rats , Rats, Sprague-Dawley , Species Specificity , Tissue Distribution , Triazoles/blood , Triazoles/metabolismSubject(s)
Environmental Monitoring/legislation & jurisprudence , Environmental Monitoring/standards , Hydrocarbons, Chlorinated/blood , Child , Dichlorodiphenyl Dichloroethylene/blood , Fungicides, Industrial/blood , Germany , Hexachlorobenzene/blood , Hexachlorocyclohexane/blood , Humans , Insecticides/blood , Polychlorinated Biphenyls/blood , Reference ValuesABSTRACT
The utility of a dynamic hollow-fibre liquid phase microextraction method (optimized using a four-variable experimental design and response surface modelling) for extracting dinitrophenolic compounds from human plasma samples was evaluated. The investigated variables were donor phase salt concentration (10-400 mM), donor phase pH (2-6), acceptor phase pH (7-12), and donor/acceptor phase flow rates (30/7.5 to 70/17.5 microL min(-1)). Four dinitrophenol pesticides were used as model substances at concentrations of 0.1 microg mL(-1) in spiked human plasma samples. Extraction efficiencies ranging from 42 to 77% with RSDs below 9 were achieved with the optimized method. The flow rate and acceptor pH were shown to strongly affect the extraction efficiency for all compounds, while the donor phase pH and salt concentration had minor effects. With a well-defined acceptor phase pH and flow rate the system exhibited high robustness. The limits of quantification for the investigated compounds, using the presented extraction method followed by liquid chromatography/electrospray ionization mass spectrometry in selected ion monitoring mode, ranged from 0.05 to 0.1 microg mL(-1) plasma.
Subject(s)
Chemical Fractionation/methods , Dinitrophenols/blood , Dinitrophenols/isolation & purification , Fungicides, Industrial/blood , Fungicides, Industrial/isolation & purification , Chromatography, Liquid , Dinitrophenols/analysis , Fungicides, Industrial/analysis , Humans , Linear Models , Spectrometry, Mass, Electrospray IonizationABSTRACT
In 137 females (F) and 94 males (M) aged 21-35 years from organochlorines (OCs) polluted area (POLL) increased thyroid volume (ThV), prevalence of antibodies to thyroperoxidase (TPOab), thyrotropin receptor (TRab) and of impaired fasting glucose (IFG) was found compared to 116 F and 107 M from background pollution area (BCGR). In F and M from POLL also strikingly increased level of PCBs, DDE and HCB was found. Such findings were compared to the generation of their parents aged 41-55 years consisting of 320F/213M from POLL and 406F/231M from BCGR. However, in spite of strikingly lower level of those OCs in young adults from POLL, they showed about the same prevalence of adverse health signs as the old generation. From such reason 44 young F and 40 young M with lowest PCBs level from POLL were selected to obtain nearly the same PCB level as found in all young F and M from BCGR. In such PCB adjusted groups the prevalence of TPOab, TRab, IFG and increased ThV was still significantly higher than that in all young subjects from BCGR. At the same time, also the level of DDE and HCB in such PCBs adjusted groups was considerably lower. It was concluded that such adverse effects in young adults from POLL possibly did not result from their actual OCs levels, but very likely from their exposure to high OCs levels of their mothers during their prenatal and perinatal life. Thus, the data may be compatible with present views on transgenerational transmission of endocrine disruptors action.
Subject(s)
Autoantibodies/blood , Environmental Pollutants/toxicity , Glucose/analysis , Hydrocarbons, Chlorinated/toxicity , Maternal Exposure , Thyroid Gland/drug effects , Adult , Aged , Chi-Square Distribution , Dichlorodiphenyl Dichloroethylene/blood , Environmental Pollutants/blood , Fasting , Female , Fungicides, Industrial/blood , Hexachlorobenzene/blood , Humans , Hydrocarbons, Chlorinated/blood , Insecticides/blood , Iodide Peroxidase/immunology , Male , Middle Aged , Organ Size , Polychlorinated Biphenyls/blood , Receptors, Thyrotropin/immunology , Young AdultABSTRACT
Studies were conducted to assess the effects of black carbon, clay type and aging (1-1.5yr) on desorption and bioavailability of hexachlorobenzene (HCB) in spiked artificial sediments. Tenax (a super sorbent)-mediated desorption was used to examine the effects of these parameters on the physicochemical availability of HCB. The Tenax-mediated desorption of HCB from the four aged artificial sediments exhibited biphasic kinetics. The fast desorbing fractions ranged from 64.8% to 22.3%, showing reductions of 4.0-18.9% compared with freshly-spiked sediments. Statistical analysis on the fast desorbing fractions showed that all three treatment effects (i.e., montmorillonite clay, black carbon content, and aging) were significant. Two sediments with higher black carbon content exhibited much greater aging effects (i.e., greater reduction in fast desorbing fraction) than the other two sediments without the addition of black carbon. For both freshly-spiked and aged sediments, the desorption resistant sediment-bound HCB (i.e., slow desorbing fraction) correlated reasonably well to previously reported rat fecal elimination of HCB, which is a measure of the non-bioavailable fraction of sediment-bound HCB. A similar correlation was also observed between fast desorbing fraction and previously reported accumulation of HCB in the rat body (carcass+skin). These observations suggest that physicochemical availability, as defined by the desorption of HCB from sediments, provides a reasonable prediction of the oral bioavailability of sediment-bound HCB to rats. These results showed that montmorillonite clay, black carbon and aging reduced physicochemical availability and ultimately bioavailability of sediment-bound HCB.
Subject(s)
Geologic Sediments/chemistry , Hexachlorobenzene/chemistry , Aluminum Silicates/chemistry , Animals , Biological Availability , Carbon/chemistry , Clay , Environmental Monitoring , Feces/chemistry , Fungicides, Industrial/blood , Fungicides, Industrial/pharmacokinetics , Fungicides, Industrial/urine , Gastrointestinal Tract/metabolism , Hexachlorobenzene/administration & dosage , Hexachlorobenzene/pharmacokinetics , Rats , Rats, Inbred F344 , Skin/metabolism , Soot/chemistry , Time Factors , Tissue DistributionABSTRACT
The fungicide Carbendazim Methyl-2-benzimidazole carbamate (MBC) is known to produce male reproductive toxicity. The present study has been undertaken to investigate the impact of vitamin E, an antioxidant against the testicular toxicity induced by MBC. HPLC analysis showed that the amount of MBC in testis and serum was 57.40 +/- 3.38 nmol/g and 14.10 +/- 0.84 nmol/ml, respectively, in rats treated with carbendazim + vitamin-E, which were significantly lower than that of rats treated with carbendazim alone (240 +/- 15.60 nmol/g and 318.70 +/- 22.52 nmol/ml, respectively). MBC treatment significantly decreased the testicular weight while co-administration of vitamin-E registered normal testicular weight. Histomorphometric analysis revealed a significant decrease (P < 0.05) in the diameter of the seminiferous tubules and lumen in MBC-treated rats compared to control whereas they remained normal in vitamin E + MBC-treated rats. Leydig cells appeared dispersed and hypertrophic after MBC treatment. Various histopathological changes were observed in testis of rats treated with MBC whereas these changes were absent in vitamin-E + MBC-treated rat testis. In conclusion protection against MBC-induced toxicity was observed with co-administration of vitamin E with MBC.