Continuous biodegradation of parathion by immobilized Sphingomonas sp. in magnetically fixed-bed bioreactors and evaluation of the enzyme stability of immobilized bacteria.

Magnetically-modified Sphingomonas sp. was prepared using covalent binding of magnetic nanoparticles on to the cell surface. The magnetic modified bacteria were immobilized in the fixed-bed bioreactors (FBR) by internal and external magnetic fields for the biodetoxification of a model organophosphate, parathion: 93 % of substrate (50 mg parathion/l) was hydrolyzed at 0.5 ml/min in internal magnetic field fixed-bed bioreactor. The deactivation rate constants (at 1 ml/min) were 0.97 × 10(-3), 1.24 × 10(-3) and 4.17 × 10(-3) h(-1) for immobilized bacteria in external and internal magnetic field fixed-bed bioreactor and FBR, respectively. The deactivation rate constant for immobilized magnetically modified bacteria in external magnetic field fixed-bed bioreactor (EMFFBR) was 77 % lower than that of immobilized cells by entrapping method on porous basalt beads in FBR at 1 ml/min. Immobilized magnetic modified bacteria exhibited maximum enzyme stability in EMFFBR.

Deadly drop--cholinergic syndrome from wearing a laundered uniform.

Unintentional organophosphate compound poisoning, although known, contamination of organophosphate compound through laundered uniform and subsequent transcutaneous absorption, in 30 children is reported herewith for its rarity. Emergency physicians have to recognize such entities clinically, confirm by laboratory means wherever possible, and intervene with appropriate measures.

Toward a better understanding of pesticide dermal absorption: diffusion model analysis of parathion absorption in vitro and in vivo.

Human skin absorption of radiolabeled parathion was studied in vitro at specific doses (mass loadings) of 0.4, 4.0, 41, or 117 microg/cm(2), with and without occlusion. The compound was applied in small volumes of acetone solution to split-thickness skin. Permeation of radiolabel into the receptor solutions was monitored for 76 h, after which the tissue was dissected and analyzed for residual radioactivity. For the 3 lower doses, cumulative permeation after 76 h was approximately dose-proportional, ranging from 28.5-30.5% of applied dose (unoccluded) to 45.5-55.7% (occluded). Total absorption, calculated as receptor fluid plus dermis content, followed a similar pattern. Both permeation rate and total absorption continued to increase up to the highest dose tested, consistent with results from other laboratories. These results are compared with predictions from a previously developed skin diffusion model (Kasting et al., 2008a). The model predicted total absorption to within a factor of 1.4 at 0.4 microg/cm(2) and 1.6 at 4 microg/cm(2), but substantially underpredicted absorption at the 2 higher doses. The analysis showed that parathion partitioned more favorably into the stratum corneum than the diffusion model prediction. Nevertheless, comparison of the model predictions to a previously reported human study showed that the skin absorption model, when corrected for surface losses occurring in vivo, satisfactorily described in vivo dermal absorption of parathion applied at 4 microg/cm(2) to various body sites.

In vitro dermal absorption of methyl salicylate, ethyl parathion, and malathion: first responder safety.

In vitro tests with fresh dermatomed (0.3 to 0.4 mm thick) female breast skin and one leg skin specimen were conducted in Bronaugh flow-through Teflon diffusion cells with three chemicals used to simulate chemical warfare agents: 14C-radiolabeled methyl salicylate (MES), ethyl parathion (PT), and malathion (MT), at three dose levels (2, 20, and 200 mM). Tests were conducted at a skin temperature of 29 degrees C using a brief 30-min exposure to the chemical and a 6.5-h receivor collection period. Rapid absorption of all three chemicals was observed, with MES absorbed about 10-fold faster than PT and MT. For MES, PT, and MT, respectively, there was 32%, 7%, and 12% absorption into the receivor solution (Hank's HEPES buffered saline with 4% bovine serum albumin [BSA], pH 7.4) at the low dose (2 mM), 17%, 2%, and 3% at the medium dose (20 mM), and 11%, 1%, and 1% at the high dose (200 mM) levels. Including the skin depot for MES, PT, and MT, respectively, there was 40%, 41%, and 21% (low dose), 26%, 16%, and 8% (medium dose), and 13%, 19%, and 10% (high does) absorption. Efficacy of skin soap washing conducted at the 30 min exposure time ranged from 31% to 86%, varying by chemical and dose level. Skin depot levels were highest for the relatively lipophilic PT. "Pseudo" skin permeability coefficient (K(p)) data declined with dose level, suggesting skin saturation had occurred. An in-depth comparison with literature data was conducted and risk assessment of first responder exposure was briefly considered.

Organophosphate poisonings with parathion and dimethoate.

OBJECTIVE: Organophosphate toxicity is the leading cause of morbidity and death in poisoning by insecticides. The clinical symptoms of pesticide toxicity range from the classic cholinergic syndrome to flaccid paralysis and intractable seizures. The mainstays of therapy are atropine, oximes, benzodiazepines and supportive care. The toxicokinetics vary not only with the extent of exposure, but also with the chemical structure of the agent. PATIENTS: We report two cases of poisoning with parathion-ethyl and dimethoate. The patients developed a cholinergic syndrome immediately, accompanied by bradycardia and hypotension. INTERVENTIONS: The patients were admitted to the intensive care unit (ICU) a few hours after ingestion. Atropine was administered according to the cholinergic symptoms. The patients recovered in the ICU after 10-12 days and were discharged after 3 and 4 weeks. MEASUREMENTS AND RESULTS: Organophosphate blood and urine levels were determined on admission and during hospitalisation. The pesticides were rapidly distributed and slow elimination rate of the poisons was documented. In the case of parathion-ethyl the distribution half-life estimated was t(1/2alpha) = 3.1h while the terminal half-life was t(1/2beta) = 17.9 h. Using a one-compartment model for dimethoate the elimination half-life was t(1/2beta) = 30.4 h in plasma and 23.8 h in urine. The serum pseudo-cholinesterase activity was below the limit of detection at admission and recovered during the following 3weeks.

A physiologically based pharmacokinetic model of organophosphate dermal absorption.

The rate and extent of dermal absorption are important in the analysis of risk from dermal exposure to toxic chemicals and for the development of topically applied drugs, barriers, insect repellents, and cosmetics. In vitro flow-through cells offer a convenient method for the study of dermal absorption that is relevant to the initial processes of dermal absorption. This study describes a physiologically based pharmacokinetic (PBPK) model developed to simulate the absorption of organophosphate pesticides, such as parathion, fenthion, and methyl parathion through porcine skin with flow-through cells. Parameters related to the structure of the stratum corneum and solvent evaporation rates were independently estimated. Three parameters were optimized based on experimental dermal absorption data, including solvent evaporation rate, diffusivity, and a mass transfer factor. Diffusion cell studies were conducted to validate the model under a variety of conditions, including different dose ranges (6.3-106.9 microg/cm2 for parathion; 0.8-23.6 microg/cm2 for fenthion; 1.6-39.3 microg/cm2 for methyl parathion), different solvents (ethanol, 2-propanol and acetone), different solvent volumes (5-120 microl for ethanol; 20-80 microl for 2-propanol and acetone), occlusion versus open to atmosphere dosing, and corneocyte removal by tape-stripping. The study demonstrated the utility of PBPK models for studying dermal absorption, which can be useful as explanatory and predictive tools that may be used for in silico hypotheses generation and limited hypotheses testing. The similarity between the overall shapes of the experimental and model-predicted flux/time curves and the successful simulation of altered system conditions for this series of small, lipophilic compounds indicated that the absorption processes that were described in the model successfully simulated important aspects of dermal absorption in flow-through cells. These data have direct relevance to topical organophosphate pesticide risk assessments.

A model for linking the effects of parathion in soil to its degradation and bioavailability kinetics.

Parathion is an insecticide of a group of highly toxic organophosphorus compounds. To investigate the dissipation and toxicological impact of parathion [O,O-diethyl O-(4-nitrophenyl) phosphorothioate] and its highly toxic metabolite, paraoxon, soil laboratory experiments were conducted in columns during a 19-d experiment under variably saturated conditions. Water and pesticide transport, sorption, and biodegradation of parathion were measured in three soil pools (soluble phase, weakly and strongly sorbed phases) using C-labeled pesticide. The effects of parathion and its metabolite on the mobility of soil nematodes were observed and then modeled with an effective variable, which combined pesticide concentration and time of application. Results showed that parathion was highly sorbed and slowly degraded to a mixture of metabolites. The parent compound and its metabolites remained located in the top 0.06-m soil layer. A kinetic model describing the sorption, biodegradation, and allocation into different soil pools of parathion and its metabolites was coupled with heat and water transport equations to predict the fate of parathion in soil. Simulated results were in agreement with experimental data, showing that the products remained in the upper soil layers even in the case of long-term (11-mo) simulation. The strongly sorbed fraction may be regarded as a pesticide reservoir that regularly provides pesticide to the weakly sorbed phase, and then, liquid phase, respectively. From both modeling and observations, no major toxicological damage of parathion and paraoxon to soil nematodes was found, although some effects on nematodes were possible, but at the soil surface only (0.01- and 0.02-m depth).

Role of metabolism in parathion-induced hepatotoxicity and immunotoxicity.

The objective of this study was to investigate whether metabolic activation of parathion by cytochrome P-450s (CYPs) was responsible for pesticide-induced hepatotoxicity and immunotoxicity. Initially, to investigate parathion metabolism in vitro, the production of paraoxon and p-nitrophenol, major metabolites of parathion, was determined by high-performance liquid chromatography (HPLC). Subsequently, metabolic fate and CYP enzymes involved in the metabolism of parathion were partially monitored in rat liver microsomes in the presence of the NADPH-generating system. Among others, phenobarbital (PB)-induced microsomes produced the metabolites paraoxon and p-nitrophenol to the greatest extent, indicating the involvement of CYP 2B in parathion metabolism. When female BALB/c mice were treated orally with 1, 4, or 16 mg/kg of parathion in corn oil once, parathion suppressed the antibody response to sheep red blood cells. To further investigate a possible role of metabolic activation by CYP enzymes in parathion-induced toxicity, female BALB/c mice were pretreated intraperitoneally with 40 mg/kg PB for 3 d, followed by a single oral treatment with 16 mg/kg parathion. PB pretreatment produced a decrease in hepatic glutathione content and increases in hepatotoxic paramenters in parathion-treated mice with no changes in the antibody response. In addition, greater p-nitrophenol amounts were produced when mice were pretreated with PB, compared to treatment with parathion alone. These results indicate that parathion-induced hepatotoxicity might be differentiated from immunotoxicity in mice.

Protein binding of isofluorophate in vivo after coexposure to multiple chemicals.

Full toxicologic profiles of chemical mixtures, including dose-response extrapolations to realistic exposures, is a prohibitive analytical problem, even for a restricted class of chemicals. We present an approach to probing in vivo interactions of pesticide mixtures at relevant low doses using a monitor compound to report the response of biochemical pathways shared by mixture components. We use accelerator mass spectrometry (AMS) to quantify [14C]-diisopropylfluorophosphate as a tracer at attomole levels with 1-5% precision after coexposures to parathion (PTN), permethrin (PER), and pyridostigmine bromide separately and in conjunction. Pyridostigmine shows an overall protective effect against tracer binding in plasma, red blood cells, muscle, and brain that is not explained as competitive protein binding. PTN and PER induce a significant 25-30% increase in the amount of tracer reaching the brain with or without pyridostigmine. The sensitivity of AMS for isotope-labeled tracer compounds can be used to probe the physiologic responses of specific biochemical pathways to multiple compound exposures.

An approach for the quantitative consideration of genetic polymorphism data in chemical risk assessment: examples with warfarin and parathion.

In recent years, a great deal of research has been conducted to identify genetic polymorphisms. One focus has been to characterize variability in metabolic enzyme systems that could impact internal doses of pharmaceuticals or environmental pollutants. Methods are needed for using this metabolic information to estimate the resulting variability in tissue doses associated with chemical exposure. We demonstrate here the use of physiologically based pharmacokinetic (PBPK) modeling in combination with Monte Carlo analysis to incorporate information on polymorphisms into the analysis of toxicokinetic variability. Warfarin and parathion were used as case studies to demonstrate this approach. Our results suggest that polymorphisms in the PON1 gene, that give rise to allelic variants of paraoxonase, which is involved in the metabolism of paraoxon (a metabolite of parathion), make only a minor contribution to the overall variability in paraoxon tissue dose, while polymorphisms in the CYP2C9 gene, which gives rise to allelic variants of the major metabolic enzyme for warfarin, account for a significant portion of the overall variability in (S)-warfarin tissue dose. These analyses were used to estimate chemical-specific adjustment factors (CSAFs) for the human variability in toxicokinetics for both parathion and warfarin. Implications of alternatives in the calculation of CSAFs are explored. Key decision points for applying the PBPK-Monte Carlo approach to evaluate toxicokinetic variability for other chemicals are also discussed.

Flavonoid-induced alterations in cytochrome P450-dependent biotransformation of the organophosphorus insecticide parathion in the mouse.

The majority of insecticides currently in use throughout the world belong to the class of the organophosphorus insecticides. Many of these compounds, such as the phosphorothioate insecticides, exert their mammalian toxicity only after undergoing metabolic activation by a variety of cytochrome P450 isoforms to produce their corresponding oxygen analogs (or oxons), which are potent inhibitors of the critical enzyme acetylcholinesterase. Of the many chemicals identified that can modulate cytochrome P450-dependent activities, the flavonoids represent some of the most unusual compounds in that they have been reported to both inhibit and stimulate certain activities. The present study was undertaken to determine if representative flavonoids (at in vitro concentrations of 1-100 microM) can alter the mammalian cytochrome P450-dependent biotransformation and acute toxicity of the phosphorothioate insecticide parathion. The flavonoids 5,6-benzoflavone, flavone, and quercetin had the biphasic effect of stimulating mouse hepatic microsomal parathion oxidation at a concentration of 1 microM, and inhibiting this same activity when increased to 100 microM. In contrast, 7,8-benzoflavone was only inhibitory at all concentrations examined. All the flavonoids examined except quercetin altered the ratio of activation/detoxification of parathion by mouse hepatic microsomes, but had no effect on this same ratio with human CYP1A2. These data suggest that the changes in the activation/detoxification ratio observed with mouse hepatic microsomes resulted from selective inhibition or stimulation of various cytochrome P450 isoforms rather than a flavonoid-induced alteration in the nonenzymatic rearrangement of the putative phosphooxythirane intermediate generated by cytochromes P450 from parathion. Surprisingly, however, none of the four flavonoids in the current study affected the lethality of parathion in vivo, suggesting that the flavonoid-induced alterations in cytochrome P-450-dependent metabolism of parathion documented in vitro were simply not great enough to be of any significance in vivo.

The actions of the H2-blocker cimetidine on the toxicity and biotransformation of the phosphorothioate insecticide parathion.

Parathion, like most organophosphorus insecticides currently in use, must undergo cytochrome P450(P450)-dependent activation in order to exert its acute mammalian toxicity (cholinergic crisis). Since P450 isoforms play such an important role in mediating the toxicity of parathion and related insecticides, factors which significantly alter P450 activities, such as exposure to certain xenobiotics, can also be expected to affect the toxicity of these potentially hazardous insecticides. Cimetidine is a H2-histamine antagonist that has been shown to inhibit several P450-isoforms. In addition, administration of cimetidine has been reported to result in clinically significant pharmacokinetic interactions with a wide variety of drugs. In the present study coexposure to cimetidine and parathion resulted in a moderate increase in the toxicity of this pesticide. However, coexposure to cimetidine and paraoxon did not alter the toxicity of the organophosphate, indicating that cimetidine likely affected P450-dependent formation of paraoxon from parathion. In vitro incubations of mouse hepatic microsomes demonstrated that, in addition to reducing the velocity of P450-dependent metabolism of parathion, cimetidine increased the proportion of paraoxon formed (activation). and decreased the proportion of p-nitrophenol formed (detoxification). Since parathion is not eliminated significantly by other routes in the mouse, the bulk of parathion in vivo was metabolized by P450 (although more slowly) in the presence of cimetidine, leading to a greater amount of paraoxon produced, and therefore greater toxicity. Incubations with individual P450 isoforms suggested that cimetidine could act by inhibition of P450 isoforms that detoxify parathion to a greater degree than cimetidine-resistant isoforms, and/or cimetidine could alter the proportions of detoxification versus activation of certain individual isoforms.

Percutaneous absorption, dermatopharmacokinetics and related bio-transformation studies of carbaryl, lindane, malathion, and parathion in isolated perfused porcine skin.

The percutaneous absorption of topically applied pesticides is a primary route for systemic exposure and potential toxicity. The isolated perfused porcine skin flap (IPPSF) is an in vitro model for studying percutaneous absorption of xenobiotics as well as cutaneous metabolism and toxicity in an anatomically intact viable skin preparation. In the present studies, percutaneous absorption of four different pesticides, carbaryl (C), lindane (L), malathion (M), and parathion (P), was assessed topically in an ethanol vehicle. A 4-compartment pharmacokinetic model was utilized to model their absorption profile. The order of absorption was C > P > L > M for the 8-h experimental period, but C > L > P > M for a model-extrapolated 6-day prediction. Metabolism of C and P was also assessed by high performance liquid chromatography (HPLC). The HPLC results indicate a significant first-pass effect for both pesticides after topical application, with parathion being metabolized to paraoxon and para-nitrophenol and carbaryl to naphthol. In addition, comparison of the metabolic data of P with previous results underscores the difference between non-recirculating and recirculating IPPSF systems in xenobiotic metabolism studies.

Effects of arsenite pretreatment on the acute toxicity of parathion.

Parathion (PA) is a phosphorotioate pesticide requiring P-450-mediated oxidations to become activated to paraoxon, or to be metabolised to its less toxic metabolites. On the other hand, sodium arsenite [As(III)] markedly decreases total hepatic P-450 content and dependent monoxygenase activities. Our aim was to determine the effects of As(III) pretreatment on the acute toxicity of PA and its possible relationship with the effects of As(III) on P-450-dependent monooxygenase activities. Adult male Wistar rats were pretreated with As(III) (5.6 mg As(III)/kg, s.c.), and 24 h later given PA (5 to 20 mg/kg, per os). As(III) pretreatment increased the acute toxicity of PA, reducing 38% its median lethal dose (LD50) from 11.68 to 7.21 mg PA/kg. In addition, As(III) pretreatment further decreased the inhibitory effect of PA on brain acetylcholinesterase activity, reducing 33% the median inhibitory dose (ID50) from 3.44 to 2.31 mg PA/kg. whereas As(III) alone had no significant effects. As(III) decreased the P-450 content to 87% of control values, reduced EROD activity to 74% and BROD activity to 41%; PA produced no significant effects on these parameters, whereas the joint administration of As(III)+ PA produced effects similar to those of As(III). PROD activity was reduced to 36% of control value by PA, whereas As(III) alone produced no significant effects. However, As(III) pretreatment apparently protected against the inhibition of CYP2B1-mediated PROD activity produced by PA, since PROD values were similar to those of control animals. Our results also indicated that the increase in PA toxicity caused by As(III) pretreatment, could also be related to the CYP2B2 isoform, since decreases in CYP2B2-dependent BROD activity were observed in both As(III) and As(III) + PA groups, but not in PA-treated animals, suggesting that CYP2B2 is involved in PA detoxification.

Continuous system modeling of equilibrium dialysis for determinations of tissue partitioning of parathion and paraoxon.

A tissue/blood partition coefficient, defined as the ratio of tissue chemical concentration to that of the venous outflow of the tissue when at equilibrium, is an important parameter required for physiological based pharmacokinetic models. While many techniques have been developed to quantify tissue/blood partition coefficients for various chemicals, there is no single best approach for their determination. In the current study, equilibrium dialysis of the organophosphorus insecticide parathion and its active metabolite paraoxon was undertaken to assess their partitioning into rat liver. A mass balance analysis of the contents of the dialysis cells suggested that significant levels of parathion and paraoxon were bound to the dialysis membranes. There was no evidence of metabolism of either parathion or paraoxon by the very dilute liver homogenate utilized in the dialysis. In order to investigate the potential impact of binding of a chemical to dialysis membrane during determination of partition coefficients, a computer model of a dialysis system was constructed. The model assumed that all processes occurring within the dialysis cell were first or second order in nature, and that binding to the dialysis membrane occurred symmetrically on both sides of the membrane. Variations in the total number of simulated binding sites on dialysis membrane revealed that increasing the degree of membrane binding resulted in decreased compound on the homogenate and buffer sides of the dialysis cells. However, the final tissue/buffer partition coefficient was unaffected by these alterations in membrane binding, although increased membrane binding prolonged the incubation time required to achieve equilibrium. These simulations suggest that loss of a compound to membrane binding does not preclude the use of equilibrium dialysis for determination of tissue/buffer, and therefore tissue/blood, partition coefficients, provided the dialysis system is allowed to proceed to equilibrium.

Human parathion poisoning. A toxicokinetic analysis.

The mortality rate of suicidal parathion poisoning is particularly high, the onset of fulminant cholinergic signs, and the patients frequently present to the emergency physician with life-threatening symptoms. Despite this uniformity, subsequent clinical course differs significantly among patients, mostly not as a result of different delays in treatment or insufficiency of primary care. Probably, the differences depend on the amount of poison absorbed and/or the disposition of the active poison, paraoxon. We followed the toxicokinetics of parathion and tried to quantify the actual poison load. To this end, we monitored parathion-intoxicated patients (patients requiring artificial ventilation) for plasma levels of parathion and paraoxon along with the activity of erythrocyte acetylcholinesterase and its reactivatability. Plasma obidoxime concentrations were followed as well as the cumulative urinary para-nitrophenol conjugate excretion as a measure of total poison load. All patients received a standard obidoxime scheme of a 250 mg bolus dose intravenously, followed by continuous infusion with 750 mg per 24 hours as long as reactivation could be expected (usually 1 week). All other treatment was instituted as judged by the physician. It was recommended to use atropine at low doses to achieve dry mucous membranes, no bronchoconstriction and no bradycardia. Usually 1-2 mg/h were sufficient. Seven selected cases are presented exemplifying toxicokinetic peculiarities. All patients were severely intoxicated, while the amount of parathion absorbed varied widely (between 0.12 and 4.4 g; lethal dose 0.02-0.1 g) and was generally much lower than anticipated from the reports of relatives. It remains open whether the discrepancies between reports and findings were due to exaggeration or to effective decontamination (including spontaneous vomiting, gastric lavage and activated charcoal). Absorption of parathion from the gastrointestinal tract was sometimes retarded, up to 5 days, resulting in fluctuating plasma profiles. The volume of distribution at steady-state (Vdss) of parathion was around 20 L/kg. Post-mortem analysis in one patient revealed a 66-fold higher parathion concentration in fat tissue compared with plasma, 16 days after ingestion. Biotransformation of parathion varied widely and was severely retarded in one patient receiving fluconazole during worsening of renal function, while phenobarbital (phenobarbitone) sedation (two cases) had apparently no effect. The proportion of plasma parathion to paraoxon varied from 0.3-30, pointing also to varying paraoxon elimination, as illustrated by one case with particularly low paraoxonase-1 activity. Obidoxime was effective at paraoxon concentrations below 0.5 microM, provided aging was not too advanced. This concentration correlated poorly with the paration concentration or the poison load. The data are discussed in light of the pertinent literature.

Significant effects of application site and occlusion on the pharmacokinetics of cutaneous penetration and biotransformation of parathion in vivo in swine.

Increasing attention has been paid to the variables of application site and dosing method in quantitation of chemical percutaneous absorption. Following topical and intravenous application of [ring-U-14C]parathion (PA) in weanling pigs, we have determined, in a previous publication, the profiles of 14C and HPLC-separated paraoxon (PO), p-nitrophenol (PNP), and p-nitrophenyl beta-D-glucuronide (PNP-G) in plasma, urine, tissues, and dosing device. The purpose of the present paper was to analyze these data further, focusing on a quantitation of the effects of application site (back versus abdomen) and dosing method (occluded versus nonoccluded) on in vivo disposition of both the parent PA and its sequential metabolites PO, PNP, and PNP-G. Cutaneous and systemic disposition parameters were determined using a numerical simulation modeling approach and moments analysis. Mean systemic bioavailability values of 8.9-9.2% for abdomen and 14.7-19.7% for back were determined. Under different dosing conditions, 1-35% of the topical dose was metabolized dermally, and 9-19% systemically. Radioactivity in plasma and urine was predominantly contributed by PNP-G and PNP. Site differences in 14C percutaneous absorption were governed by the differences in transport of PA, PO, and PNP from epidermis into blood, by local tissue distribution, and by the cutaneous metabolism to PNP. Systemic bioavailability of PA was higher from the back than from the abdomen. Occlusion not only increased the amount of 14C absorption and shortened the mean residence time in most compartments but also altered the systemic versus cutaneous biotransformation pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Percutaneous penetration and skin retention of topically applied compounds: an in vitro-in vivo study.

Radiolabeled compounds with varying partition coefficients (paraoxon, benzoic acid, parathion, and DDT) were chosen to study the percutaneous penetration and extent of dermal retention in pig skin both in vitro and in vivo. Radiolabel distributions within the skin were determined from 1 min to 24 h after application in ethanol. The distribution of radioactivity in the skin during the first 4 h was comparable between in vitro and in vivo experiments. At 24 h, radioactive residues in the dermis were significantly higher in vitro than in vivo for DDT, the most lipophilic compound. Increasing air flow over the skin surface significantly increased evaporative loss for volatile compounds (benzoic acid, N,N-diethyl-m-toluamide, malathion, parathion, and DDT), significantly decreased the residues in the upper skin layer for N,N-diethyl-m-toluamide, malathion, parathion, and DDT, significantly decreased the dermal residue for malathion, and significantly decreased the penetration of N,N-diethyl-m-toluamide, malathion, and parathion. On a percentage basis, increasing the dose of parathion and paraoxon from 4 to 1000 micrograms/cm2 resulted in significantly lower residues in the dermis. When applied to the dermis, the more hydrophilic benzoic acid and paraoxon better penetrated the dermis than the more hydrophobic parathion and DDT. An ethanol vehicle facilitated the penetration of parathion into the dermis and receptor fluid. These results indicate that the dermis interacted with the penetrant during both in vitro and in vivo percutaneous absorption. Factors such as partition coefficient and dose of the penetrant, air flow over the skin, and vehicle changed the distribution of penetrants in the skin and percutaneous penetration.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo percutaneous absorption of chemicals: a multiple dose study in rhesus monkeys.

The effect of daily topical application on the in vivo percutaneous absorption of benzoic acid, parathion and salicylic acid in rhesus monkeys has been investigated. The study was designed to test further the hypothesis that topical bioavailability, or body burden, of a chemical following chronic exposure may be accurately predicted from the result of a single acute-dose experiment. No significant change in percutaneous absorption from that following the initial dose was observed following the eighth daily dose of a 14-day multidose regimen for each of the three penetrants considered. The results are consistent with those of recent experiments in humans with malathion and steroids, but not entirely consistent with the results of other animal studies.

Glucose feeding exacerbates parathion-induced neurotoxicity.

Excessive dietary intake of sugars could alter various biotransformation processes and the pharmacological and toxicological properties of numerous xenobiotics. In the present study, the effects of glucose supplementation were examined on the neurotoxicity of the organophosphorus (OP) pesticide parathion (PS) and its active metabolite, paraoxon (PO), a potent inhibitor of acetylcholinesterase (AChE). Rats (n = 6-12/treatment group) were given free access to tap water or 15% glucose (w/v) in tap water beginning 7 d prior to OP toxicant exposure. Food, caloric intake, and body weight were measured daily. Animals were challenged with either PS (4.5, 9, or 18 mg/kg, sc) or PO (0.3 0.5, or 0.7 mg/kg, sc) and clinical signs of neurotoxicity (i.e., autonomic dysfunction, involuntary movements) were recorded daily for the following 13 d. Glucose feeding was associated with a dramatic drop (approximately 50%) in feed intake and an increase (approximately 20% in total caloric consumption over the 7 d prior to OP exposure. Functional toxicity associated with PS exposure was increased in glucose-fed (GF) rats, but the glucose diet had no apparent effect on clinical signs of toxicity following PO treatment. Glucose feeding increased the magnitude of AChE inhibition in the frontal cortex and plasma at lower dosages (i.e., 4.5 and 9 mg/kg) 3 d following PS treatment. Time-course studies (3, 7, and 11 d after PS exposure, 18 mg/kg, sc) indicated significantly greater brain and plasma AChE inhibition in glucose-fed animals at later time points. In contrast, glucose feeding had no effect on the degree of AChE inhibition following PO exposure. Neither liver microsomal oxidative desulfuration of PS, nor liver or plasma paraoxonase, nor liver or plasma carboxylesterase activities were measurably affected by glucose feeding. Downregulation of muscarinic receptors 7 d after PS exposure (18 mg/kg, sc) was more extensive in GF rats. It is postulated that excessiveglucose consumption decreases the intake of other dietary components, in particular amino acids, limiting the de novo synthesis of AChE and consequent recovery of synaptic transmission. Due to the shorter duration of inhibition following PO exposure, sponta neous reactivation of AChE may be more important than de novo protein synthesis in recovery of function, and thus with the effects of glucose feeding on its toxicity. Individuals that derive a large proportion of their calories from sugars may be at higher risk of acute toxicity from organophosphorus pesticides such as PS.