Endosulfan, an organochlorine (OC) insecticide that belongs to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. Porcine brain microvascular endothelial cells were used to develop a model to study the effects of endosulfan on the permeability of tight junctions in the blood-brain barrier (BBB). BBB permeability, measured as transendothelial electrical resistance, decreased in a dose- and time-dependent manner when treated with alpha-endosulfan, beta-endosulfan, or endosulfan sulfate. Cytotoxicity testing revealed that the three endosulfans did not cause cell death at concentrations of 10 microM and below. The ratio of the average permeability of the filter-grown endothelial cell monolayer to 14C-endosulfan (Pe) going from the outer to the inner compartments with that going from the inner to the outer compartments was approximately 1:1.2-2.1 after exposure to concentrations of 0.01-10 microM. alpha-Endosulfan, beta-endosulfan, and endosulfan sulfate had cytotoxic effects on rat glial (C6) and neuronal (PC12) cell cultures as well as on human glial (CCF-STTG1) and neuronal (NT2) cell cultures. The effects of alpha-endosulfan were highly selective, with a wide range of LC50 values found in the different cultures, ranging from 11.2 microM for CCF-STTG1 cells to 48.0 microM for PC12 cells. In contrast, selective neurotoxicity was not so manifest in glial and neuronal cell cultures after exposure to endosulfan sulfate, as LC50 values were in the range of 10.4-21.6 microM. CCF-STTG1 cells were more sensitive to alpha-endosulfan and endosulfan sulfate, whereas NT2 cells were more sensitive to beta-endosulfan.
Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and risk assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.
A method has been developed for the determination of trace levels of alpha-endosulfan, beta-endosulfan, endosulfan sulfate, and endosulfan diol in rat plasma and tissue samples. Endosulfan and its metabolites in the plasma samples were extracted with solid-phase extraction Chromabond-end-capped C18 cartridges and analyzed by a Shimadzu QP-5050A gas chromatograph-mass spectrometer (GCMS) with quadrupole detector in selected-ion-monitoring mode. The analysis of endosulfan and its metabolites in liver and kidney samples involved solvent extraction, Florisil solid-phase-extraction cleanup, and quantitation by GCMS. Recovery experiments for the plasma and tissue samples were conducted over concentration ranges of 10-100 ng mL(-1) and 100-1000 ng mL(-1), respectively. The method was applied to the analysis of trace levels of endosulfan and its metabolites in plasma and tissue samples collected from an animal study. Trace levels of alpha-endosulfan and beta-endosulfan in the ranges of undetectable to 3.11 microg g(-1) and undetectable to 1.19 microg g(-1), respectively, were detected in the kidney samples, whereas trace levels of endosulfan sulfate in the range of 0.02-0.22 microg g(-1) were detected in the liver samples of rats. Neither endosulfan nor its metabolites was detected in any of the plasma samples.
A growing body of evidence has found that mortality rates are positively correlated with social inequalities, air pollution, elevated ambient temperature, availability of medical care and other factors. This study develops a model to predict the mortality rates for different diseases by county across the US. The model is applied to predict changes in mortality caused by changing environmental factors. A total of 3,110 counties in the US, excluding Alaska and Hawaii, were studied. A subset of 519 counties from the 3,110 counties was chosen by using systematic random sampling and these samples were used to validate the model. Step-wise and linear regression analyses were used to estimate the ability of environmental pollutants, socio-economic factors and other factors to explain variations in county-specific mortality rates for cardiovascular diseases, cancers, chronic obstructive pulmonary disease (COPD), all causes combined and lifespan across five population density groups. The estimated models fit adequately for all mortality outcomes for all population density groups and, adequately predicted risks for the 519 validation counties. This study suggests that, at local county levels, average ozone (0.07 ppm) is the most important environmental predictor of mortality. The analysis also illustrates the complex inter-relationships of multiple factors that influence mortality and lifespan, and suggests the need for a better understanding of the pathways through which these factors, mortality, and lifespan are related at the community level.
Endosulfan (ES), an organochlorine (OC) insecticide that belongs to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. The toxicokinetics of 14C-endosulfan following oral administration of a single dose of 5 mg/kg body weight was investigated in male Sprague-Dawley rats. Three rats were sacrificed 30 min, 1 h, 2 h, 4 h, and 8 h after dosing. 14C-endosulfan radioactivity was detected in all tissues at each time point. In a separate experiment urine and feces were collected for 96 h. The total radioactivity recovered in the excreta for 4 days was 106.8% +/- 26.2%, with fecal elimination the major route of elimination route (94.4% +/- 21.4%). The cumulative excretion in the urine for 4 days was 12.4% +/- 4.8%. Radioactivity 8 h after administration was highest in gastrointestinal (GI) tract tissue (20.28 +/- 16.35 mg ES eq./L) and lowest in muscle (0.18 +/- 0.06 mg ES eq./L). The toxicokinetic parameters obtained from 14C-endosulfan-derived radioactivity in blood were distribution half-life (T1/2 x) = 31 min and terminal elimination half-life (T1/2 y) = 193 h. Blood concentration reached its maximum (Cmax) of 0.36 +/- 0.08 mg ES eq./L 2 h after the oral dose. Endosulfan was rapidly absorbed into the GI tract in rats, with an absorption rate constant (ka) of 3.07 h(-1).
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