Effect of prenatal exposure to combined immunosuppressive agrochemicals in a mouse model of allergic airway inflammation.

The aim of this study is to identify the combined effect of multiple chemicals to the development of allergy. In this study, the effect of prenatal exposure to an organochlorine agent methoxychlor (MXC) and/or an organophosphate agent parathion (PARA) on trimellitic anhydride-induced allergic airway inflammation was examined in mice. Eosinophil infiltration in the bronchoalveolar lavage fluid (BALF) was significantly enhanced by MXC + PARA exposure compared to that of the control, MXC, and PARA groups. In the hilar lymph node, only slight increases in B-cell infiltration, as well as IL-6 and IL-9 secretions were observed in MXC + PARA group, and no effect was observed in the individual treatment groups. Our findings imply that prenatal exposure to some combinations of multiple chemicals may exacerbate the allergic inflammatory responses including eosinophils and cytokine production.

Effects of short-term oral combined exposure to environmental immunotoxic chemicals in mice.

People are constantly exposed to environmental chemicals through contact with the atmosphere or by ingestion of food. Therefore, when conducting safety assessments, the immunotoxic effects of combinations of chemicals in addition to toxicities produced by each chemical alone should be considered. The objective of the studies reported here were to demonstrate the combined effects of three well-known environmental immunotoxic chemicals -- methoxychlor (MXC), an organochlorine compound; parathion (PARA), an organophosphate compound; and piperonyl butoxide (PBO), an agricultural insecticide synergist -- by using a short-term oral exposure method. Seven-week-old Balb/cAnN mice received daily oral exposure to either one or two of the environmental immunotoxic chemicals for 5 consecutive days. On Day 2, all mice in each group were immunized with sheep red blood cells (SRBC), and their SRBC-specific IgM responses were analyzed by using an enzyme-linked immunosorbent assay and plaque-forming cell assay. T- and B-cell counts in the mouse spleens were also assessed via surface antigen expression. Mice that received MXC + PARA and PBO + MXC treatment showed marked decreases in SRBC-specific IgM production and T- and B-cell counts compared with those in mice that received vehicle control or the corresponding individual test substance. This suggests that simultaneous exposure to multiple environmental chemicals increases the immunotoxic effects of the chemicals compared to individual exposure.

Prior oral exposure to environmental immunosuppressive chemicals methoxychlor, parathion, or piperonyl butoxide aggravates allergic airway inflammation in NC/Nga mice.

BACKGROUND: Immunosuppressive environmental chemicals may increase the potency of allergens and thereby play a role in the development of respiratory tract allergies, such as allergic rhinitis and asthma. OBJECTIVES: We investigated the association between environmental immunosuppressive chemicals and the allergic airway inflammation development. METHODS: We used a mouse model of ovalbumin (OVA)-induced allergic airway inflammation. NC/Nga mice were exposed orally to pesticides parathion (an organophosphate compound) or methoxychlor (an organochlorine compound), or to an insecticide synergist piperonyl butoxide, prior to OVA intraperitoneal sensitization and inhalation challenge. We assessed serum IgE levels, B-cell counts, cytokine production, IgE production in hilar lymph nodes, eosinophil counts, chemokine levels in bronchoalveolar lavage fluid, and cytokine gene expression in the lung. RESULTS: Exposure to environmental immunosuppressive chemicals markedly increased serum IgE - IgE-positive B-cells, IgE and cytokines in lymph nodes - eosinophils and chemokines in BALF - IL-10a and IL-17 in the lung. CONCLUSIONS: Allergic airway inflammation can be aggravated by prior exposure to immunosuppressive environmental chemicals.

An unusual case of attempted suicide by rectal administration of parathion.

Although organophosphate (OP) poisoning is well known, unusual routes of administration of OP compounds are reported occasionally. Herein, a case of self administration of parathion, an OP compound, into the rectum using a six inches (15 cm) nozzle of a sprayer in a 35-year-old man is highlighted along with probable mechanisms for rapid absorption and severe systemic toxicity.

Cytochrome P450-specific human PBPK/PD models for the organophosphorus pesticides: chlorpyrifos and parathion.

Organophosphorus pesticides (OPs) remain a potential concern to human health because of their continuing use worldwide. Phosphororthioate OPs like chlorpyrifos and parathion are directly activated and detoxified by various cytochrome P450s (CYPs), with the primary CYPs involved being CYP2B6 and CYP2C19. The goal of the current study was to convert a previously reported human pharmacokinetic and pharmacodynamic (PBPK/PD) model for chlorpyrifos, that used chlorpyrifos metabolism parameters from rat liver, into a human CYP based/age-specific model using recombinant human CYP kinetic parameters (V(max), K(m)), hepatic CYP content and plasma binding measurements to estimate new values for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition and to use the model as a template for the development of a comparable parathion PBPK/PD model. The human CYP based/age-specific PBPK/PD models were used to simulate single oral exposures of adults (19 year old) and infants (1 year) to chlorpyrifos (10,000, 1000 and 100 µg/kg) or parathion (100, 25 and 5 µg/kg). Model simulations showed that there is an age dependency in the amount of blood cholinesterase inhibition observed, however additional age-dependent data are needed to further optimize age-specific human PBPK/PD modeling for these OP compounds. PBPK/PD model simulations estimated that a 4-fold increase or decrease in relative CYP2B6 and CYP2C19 content would produce a 9-22% inhibition in blood AChE activity following exposure of an adult to chlorpyrifos (1000 µg/kg). Similar model simulation produced an 18-22% inhibition in blood AChE activity following exposure of an adult to parathion (25 µg/kg). Individuals with greater CYP2B6 content and lower CYP2C19 content were predicted to be most sensitive to both OPs. Changes in hepatic CYP2B6 and CYP2C19 content had more of an influence on cholinesterase inhibition for exposures to chlorpyrifos than parathion, which agrees with previously reported literature that these CYPs are more reaction biased for desulfurization (activation) and dearylation (detoxification) of chlorpyrifos compared to parathion. The data presented here illustrate how PBPK/PD models with human enzyme-specific parameters can assist ongoing risk assessment efforts and aid in the identification of sensitive individuals and populations.

Organophosphorus pesticides decrease M2 muscarinic receptor function in guinea pig airway nerves via indirect mechanisms.

BACKGROUND: Epidemiological studies link organophosphorus pesticide (OP) exposures to asthma, and we have shown that the OPs chlorpyrifos, diazinon and parathion cause airway hyperreactivity in guinea pigs 24 hr after a single subcutaneous injection. OP-induced airway hyperreactivity involves M2 muscarinic receptor dysfunction on airway nerves independent of acetylcholinesterase (AChE) inhibition, but how OPs inhibit neuronal M2 receptors in airways is not known. In the central nervous system, OPs interact directly with neurons to alter muscarinic receptor function or expression; therefore, in this study we tested whether the OP parathion or its oxon metabolite, paraoxon, might decrease M2 receptor function on peripheral neurons via similar direct mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Intravenous administration of paraoxon, but not parathion, caused acute frequency-dependent potentiation of vagally-induced bronchoconstriction and increased electrical field stimulation (EFS)-induced contractions in isolated trachea independent of AChE inhibition. However, paraoxon had no effect on vagally-induced bradycardia in intact guinea pigs or EFS-induced contractions in isolated ileum, suggesting mechanisms other than pharmacologic antagonism of M2 receptors. Paraoxon did not alter M2 receptor expression in cultured cells at the mRNA or protein level as determined by quantitative RT-PCR and radio-ligand binding assays, respectively. Additionally, a biotin-labeled fluorophosphonate, which was used as a probe to identify molecular targets phosphorylated by OPs, did not phosphorylate proteins in guinea pig cardiac membranes that were recognized by M2 receptor antibodies. CONCLUSIONS/SIGNIFICANCE: These data indicate that neither direct pharmacologic antagonism nor downregulated expression of M2 receptors contributes to OP inhibition of M2 function in airway nerves, adding to the growing evidence of non-cholinergic mechanisms of OP neurotoxicity.

Neonatal parathion exposure and interactions with a high-fat diet in adulthood: Adenylyl cyclase-mediated cell signaling in heart, liver and cerebellum.

Organophosphates are developmental neurotoxicants but recent evidence points to additional adverse effects on metabolism and cardiovascular function. One common mechanism is disrupted cell signaling mediated through cyclic AMP, targeting neurohumoral receptors, G-proteins and adenylyl cyclase (AC) itself. Earlier, we showed that neonatal parathion evokes later upregulation of the hepatic AC pathway in adolescence but that the effect wanes by young adulthood; nevertheless metabolic changes resembling prediabetes persist. Here, we administered parathion to neonatal rats (postnatal days 1-4, 0.1 or 0.2 mg/kg/day), straddling the threshold for cholinesterase inhibition, but we extended the studies to much later, 5 months of age. In addition, we investigated whether metabolic challenge imposed by consuming a high-fat diet for 7 weeks would exacerbate neonatal parathion's effects. Parathion alone increased the expression or function of G(i), thus reducing AC responses to fluoride. Receptors controlling AC activity were also affected: beta-adrenergic receptors (betaARs) in skeletal muscle were increased, whereas those in the heart were decreased, and the latter also showed an elevation of m(2)-muscarinic acetylcholine receptors, which inhibit AC. The high-fat diet also induced changes in AC signaling, enhancing the hepatic AC response to glucagon while impairing the cardiac response to fluoride or forskolin, and suppressing betaARs and m(2)-muscarinic receptors; the only change in the cerebellum was a decrease in betaARs. Although there were no significant interactions between neonatal parathion exposure and a high-fat diet, their convergent effects on the same signaling cascade indicate that early OP exposure, separately or combination with dietary factors, may contribute to the worldwide increase in the incidence of obesity and diabetes.

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.

Neonatal exposure to parathion alters lipid metabolism in adulthood: Interactions with dietary fat intake and implications for neurodevelopmental deficits.

Organophosphates are developmental neurotoxicants but recent evidence also points to metabolic dysfunction. We determined whether neonatal parathion exposure in rats has long-term effects on regulation of adipokines and lipid peroxidation. We also assessed the interaction of these effects with increased fat intake. Rats were given parathion on postnatal days 1-4 using doses (0.1 or 0.2mg/kg/day) that straddle the threshold for barely detectable cholinesterase inhibition and the first signs of systemic toxicity. In adulthood, animals were either maintained on standard chow or switched to a high-fat diet for 7 weeks. We assessed serum leptin and adiponectin, tumor necrosis factor-alpha (TNFalpha) in adipose tissues, and thiobarbituric acid reactive species (TBARS) in peripheral tissues and brain regions. Neonatal parathion exposure uncoupled serum leptin levels from their dependence on body weight, suppressed adiponectin and elevated TNFalpha in white adipose tissue. Some of the effects were offset by a high-fat diet. Parathion reduced TBARS in the adipose tissues, skeletal muscle and temporal/occipital cortex but not in heart, liver, kidney or frontal/parietal cortex; it elevated TBARS in the cerebellum; the high-fat diet again reversed many of the effects. Neonatal parathion exposure disrupts the regulation of adipokines that communicate metabolic status between adipose tissues and the brain, while also evoking an inflammatory adipose response. Our results are consistent with impaired fat utilization and prediabetes, as well as exposing a potential relationship between effects on fat metabolism and on synaptic function in the brain.

Persistent behavioral alterations in rats neonatally exposed to low doses of the organophosphate pesticide, parathion.

Although developmental exposures of rats to low levels of the organophosphate pesticides (OPs), chlorpyrifos (CPF) or diazinon (DZN), both cause persistent neurobehavioral effects, there are important differences in their neurotoxicity. The current study extended investigation to parathion (PTN), an OP that has higher systemic toxicity than either CPF or DZN. We gave PTN on postnatal days (PND) 1-4 at doses spanning the threshold for systemic toxicity (0, 0.1 or 0.2 mg/kg/day, s.c.) and performed a battery of emotional and cognitive behavioral tests in adolescence through adulthood. The higher PTN dose increased time spent on the open arms and the number of center crossings in the plus maze, indicating greater risk-taking and overall activity. This group also showed a decrease in tactile startle response without altering prepulse inhibition, indicating a blunted acute sensorimotor reaction without alteration in sensorimotor plasticity. T-maze spontaneous alternation, novelty-suppressed feeding, preference for sweetened chocolate milk, and locomotor activity were not significantly affected by neonatal PTN exposure. During radial-arm maze acquisition, rats given the lower PTN dose committed fewer errors compared to controls and displayed lower sensitivity to the amnestic effects of the NMDA receptor blocker, dizocilpine. No PTN effects were observed with regard to the sensitivity to blockade of muscarinic and nicotinic cholinergic receptors, or serotonin 5HT(2) receptors. This study shows that neonatal PTN exposure evokes long-term changes in behavior, but the effects are less severe, and in some incidences opposite in nature, to those seen earlier for CPF or DZN, findings consistent with our neurochemical studies showing different patterns of effects and less neurotoxic damage with PTN. Our results reinforce the conclusion that low dose exposure to different OPs can have quite different neurotoxic effects, obviously unconnected to their shared property as cholinesterase inhibitors.

Comparative in vivo effects of parathion on striatal acetylcholine accumulation in adult and aged rats.

Aged rats are more sensitive to the acute toxicity of the prototype organophosphate insecticide, parathion. We compared the acute effects of parathion on diaphragm and brain regional cholinesterase activity, muscarinic receptor binding and striatal acetylcholine levels in 3- and 18-month-old male Sprague-Dawley rats. Adult and aged rats were surgically implanted with a microdialysis cannula into the right striatum 5-7 days prior to parathion treatment. Rats were given either vehicle (peanut oil, 2 ml/kg) or one of a range of dosages of parathion (adult: 1.8, 3.4, 6.0, 9.0, 18 and 27 mg/kg, s.c.; aged: 1.8, 3.4, 6 and 9 mg/kg, s.c.) and body weight, functional signs of toxicity, and nocturnal motor activity were recorded for seven days. Three and seven days after parathion treatment, microdialysis samples were collected and rats were subsequently sacrificed for biochemical measurements. Higher dosages of parathion led to significant time-dependent reductions in body weight in both age groups. Rats in both age groups treated with lower dosages showed few overt signs of cholinergic toxicity while equitoxic high dosages (adult, 27 mg/kg; aged, 9 mg/kg) elicited marked signs of cholinergic toxicity (involuntary movements and SLUD [i.e., acronym for Salivation, Lacrimation, Urination and Defecation] signs) with peak effects being noted 3-4 days after treatment. Nocturnal activity (ambulation and rearing) was reduced in both age groups following parathion dosing, with more prominent effects in adults and rearing being more consistently affected. Dose- and time-dependent inhibition of cholinesterase activity was noted in both diaphragm and striatum. Total muscarinic receptor ([(3)H]quinuclidinyl benzilate, QNB) binding was significantly lower in aged rats, and both total binding and muscarinic agonist ([(3)H]oxotremorine methiodide] binding was significantly reduced in both age-groups treated with the highest dosages of parathion (adult, 27 mg/kg; aged, 9 mg/kg). In contrast to relatively similar levels of cholinesterase inhibition, striatal extracellular acetylcholine levels were significantly lower (2.2- to 2.9-fold) in aged rats at both 3 and 7 day time-points compared to adult rats treated with equitoxic dosages (i.e., 9 and 27 mg/kg, respectively). No age-related differences in in vitro striatal acetylcholine synthesis or in vivo acetylcholine accumulation following direct infusion of the cholinesterase inhibitor neostigmine (1 microM) were noted. While aged rats are more sensitive than adults to the acute toxicity of parathion, lesser acetylcholine accumulation was noted in the striatum of aged rats exhibiting similar levels of cholinesterase inhibition. These findings suggest that lesser acetylcholine accumulation may be required to elicit cholinergic signs in the aged rat, possibly based on aging-associated changes in muscarinic receptor density.

Time course of brain cholinesterase inhibition and recovery following acute and subacute azinphosmethyl, parathion and carbaryl exposure in the goldfish (Carassius auratus).

Laboratory toxicity data contrasting mortality and brain cholinesterase inhibition in the goldfish (Carassius auratus) are presented. Brain cholinesterase (ChE) was greatly reduced after 96 h of exposure in vivo at sublethal concentrations of azinphosmethyl and parathion. The inhibition of the enzyme was dose dependent, and concentrations higher than 0.1mg/L caused more than 90% inhibition. The effect of carbaryl was less pronounced, achieving an 86% inhibition at concentrations corresponding to the 96-h LC50. After in vivo exposure to sublethal concentrations of parathion and azinphosmethyl (0.1 mg/L) and carbaryl (3.0 mg/L), the activity of the goldfish brain ChE was greatly reduced. In the following 96 h of recovery, the enzyme inhibited with carbaryl was restored to 75% activity, while the enzyme inhibited with organophosphates (OPs) required more than 35 days for recovery. Goldfish were able to withstand high percentages of brain ChE inhibition without mortality, suggesting that another target may be responsible for the lethal effects. However, the enzyme is a good biomarker of acute and subacute exposure to OPs and carbamates.

In vivo interaction between chlorpyrifos and parathion in adult rats: sequence of administration can markedly influence toxic outcome.

Organophosphorus insecticides (OPs) generally act through a common mechanism of toxicity initiated by inhibition of acetylcholinesterase (AChE). We studied the in vivo interactive toxicity of two common OPs, chlorpyrifos (CPF) and parathion (PS), in adult male rats. Dose-response studies estimated the acute oral LD1 values for the two OPs (CPF = 80 mg/kg po; PS = 4 mg/kg po) and these dosages or relative proportions were used to evaluate interactive toxicity. Three treatment strategies were evaluated: CPF followed by PS 4 h later (CPF-1st), PS followed by CPF 4 h later (PS-1st), and simultaneous (concurrent) exposures. Using LD1 dosages, rats in the CPF-1st and concurrent groups exhibited more cholinergic toxicity (i.e., salivation, lacrimation, urination, and diarrhea signs and involuntary movements) and higher lethality (7/8 and 6/8, respectively, beginning 1 h after PS) than those in the PS-1st group (2/8 lethality, beginning 3 days after CPF). Sequential exposures to lower dosages (CPF vs PS: 60 vs 3 mg/kg; 40 vs 2 mg/kg) led to more extensive neurotoxicity in the CPF-1st group compared to the other groups. Following lower dosages (40 vs 2 mg/kg), brain ChE inhibition was more extensive in the CPF-1st group at all time points (64-85%) and the concurrent group at 4 and 24 h after exposure (46-83%) compared to rats receiving PS first (7-48%). No differences were noted however, in plasma (71-93% inhibition) or liver (72-81%) cholinesterase activities nor were there group-related differences in plasma (50-60% inhibition) or liver (>85% inhibition) carboxylesterase activities. Incubation of liver samples with oxons in the presence or absence of calcium (i.e., 2 mM CaCl(2) or EGTA) prior to addition of ChE (striatal sample) substantially blocked ChE inhibition by CPO (IC50: without liver = 4 nM; liver + calcium = 279 nM; liver + EGTA = 48 nM) but had lesser effects on PO-mediated inhibition (IC50: without liver = 17 nM; liver + EGTA = 56 nM; liver + calcium = 57 nM). Liver homogenate from animals preexposed to PS substantially decreased ChE inhibition by CPO when calcium was included (IC50: +EGTA = 8 nM; +calcium = 225 nM), but liver homogenate from animals preexposed to CPF was ineffective at blocking PO-induced inhibition (IC50: +EGTA = 16 nM; +calcium = 16 nM). We conclude that prior inhibition of carboxylesterase activity impacts toxicity of subsequent exposure to PS more than CPF because of more active detoxification of CPO by A-esterase. Together, these findings indicate that interactive toxicity from combined exposures to two OP insecticides can be markedly influenced by the sequence of administration.

Effects of subchronic parathion exposure on cyclosporine pharmacokinetics in rats.

Parathion undergoes enzymatic oxidation by hepatic cytochrome P-450 (CYP450) enzymes to the active metabolite paraoxon. Consequently, alterations in CYP450-dependent oxidation may affect the pharmacokinetics and pharmacodynamics of drugs that are metabolized in the liver. The CYP3A family is known to be responsible for the majority of cyclosporine metabolism. The aim of the present study was to assess the disposition kinetics of cyclosporine during subchronic parathion exposure. Male Wistar rats were administered either water or two different doses of parathion (1/100 LD50, 1/25 LD50; LD50 = 14 mg/kg) by gavage for 6 wk. Subsequently, rats in each experimental group received a single oral dose of cyclosporine (10 mg/kg), and serial blood samples were drawn from the carotid artery over a period of 48 h. Pharmacokinetic analysis showed that parathion increased the blood cyclosporine concentration twofold as evidenced by AUC (area under the curve), half life (t 1/2) and peak plasma concentration (Cmax). This may be due to inhibition of cyclosporine metabolism, an interaction that may be of clinical relevance in immunosuppression therapy.

Effects of neostigmine on the pharmacokinetics of intravenous parathion in rats.

It was reported that the area under the plasma concentration-time curve from time zero to time infinity (AUC) of parathion was significantly smaller and the time-averaged total body clearance (CL) of parathion was significantly faster after intravenous administration of parathion to rats pretreated with dexamethasone than those in control rats. This was supported by significantly faster intrinsic clearance of parathion to form paraoxon in hepatic microsomal fraction of rats pretreated with dexamethasone. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible hepatic cytochrome P450 (CYP) 3A in rats. The purpose of this study is to explain the protective effects of neostigmine against paraoxon toxicity by suppressing CYP3A and hence decreasing formation of toxic metabolite, paraoxon by neostigmine. The pharmacokinetic changes of parathion and its active metabolite, paraoxon, were investigated after intravenous administration of parathion, 3 mg/kg, to control Sprague-Dawley rats and the rats pretreated with neostigmine (200 microg/kg, intraperitoneal injection 30 min before parathion administration). After 1-min intravenous infusion of parathion to rats pretreated with neostigmine, the AUC of parathion (65.1 versus 74.3 microg min/ml) was significantly greater and the CL of parathion (45.1 versus 40.4 ml/min/kg) was significantly slower than those in control rats. Based on in vitro hepatic microsomal studies, neostigmine inhibited significantly the erythromycin N-demethylase activity (1.03 versus 0.871 nmol/mg protein/min), mainly mediated by hepatic cytochrome P450 3A in rats. The above data suggested that the formation of paraoxon was inhibited in rats pretreated with neostigmine by inhibiting CYP3A.

Acute effect of parathion on the seminiferous epithelium of immature mice

En el presente se estudió el efecto tóxico para la esparmatogenesis, de una inyección única del agropesticida organofosforado parathion, administrada a ratones inmaduros. Animales de 7 días de edad fueron inyectados por vía intraperitoneal con 1/3 de la LD50. Fue medido el peso corporal y testicular. Se efectúo un análisis cuali y cuantitativo de los túbulos seminíferos y de las poblaciones de células germinales en ratones controles y tratados, a los 8, 16, 28 y 50 días post-inyección. El efecto tóxico del pesticida se demuestra por una disminución del peso corporal y testicular y un daño temprano de las células germinales de los animales tratados. El efecto es reversible y la recuperación ocurre en los intervalos largos post-inyección

Learning and memory of rats after long-term administration of low doses of parathion.

A set of four learning and memory tests (Morris Maze I for reference memory, Morris Maze II for working memory, one-way active avoidance, and passive avoidance) were employed to address the questions whether parathion impaired cognitive functions after low, long-term exposure and could cause persistent changes in cognition. Motor activity and general behavior were investigated in a functional observational battery. Parathion was administered in rat food in low doses which caused no clinical symptoms and no or borderline brain acetylcholinesterase inhibition. Parathion doses of 0.5, 2, or 8 ppm in rat food produced the averaged uptake of 24, 100, or 400 microg/kg body weight per group per day in male rats and 36, 152, or 550 microg/kg per day in female rats in week 13. Learning tests were performed in weeks 1 to 4 and 10 to 14, as well as 30 to 34 weeks after the end of treatment, when the male and female rats were about 13 months old. Low doses of parathion given daily for 13 weeks had no cumulative or adverse effects on learning and memory, either during treatment or after the extended treatment-free period, in any of the tests. A significant improvement of learning compared to control observed in the Morris Water Maze I during the first week of treatment (males dose group 0.5 ppm) shows that parathion can improved cognitive functions in rats. Results of the study indicate that adverse effects changing learning and memory in animals may occur only at higher doses of organophosphates, at which the peripheral and brain acetylcholinesterases are inhibited to a greater extent than those in the present study.

Evaluation of the role of formulation on parathion toxicity.

The influence of the vehicle on the toxicity of parathion was evaluated by determining the oral and dermal LD50 in rats. The assessment of dermal absorption was performed by measuring the inhibition of plasma cholinesterase activity. The test vehicles were arol and xylene. The data obtained indicated that the acute oral and dermal toxicities are higher in xylene than in arol, but no differences were observed on plasma cholinesterase activity.

Toxicokinetics of parathion and paraoxon in rainbow trout after intravascular administration and water exposure.

Fish are less sensitive than mammals to organophosphate insecticide toxicity. The species differences have been mainly investigated by biochemical studies of AChE and organophosphate interaction. To examine whether species differences in the toxicokinetics of the organophosphate insecticides were also involved in their differential toxicity, rainbow trout were fitted with a dorsal aorta cannula and administered parathion and its active metabolite paraoxon intraarterially (ia) and via water exposure. Serial blood samples were removed and the plasma concentrations of parathion and paraoxon were determined by capillary GC with EC detection. Plasma protein binding was determined by equilibrium dialysis and ultrafiltration. After ia injection the plasma concentration-time profiles of parathion and paraoxon were multiexponential, with a terminal t1/2 of 56.1 and 0.528 hr. The steady-state volumes of distribution and total body clearances (CLb) for parathion and paraoxon were 1370 and 1080 ml kg-1 and 21.4 and 3020 ml hr-1 kg-1; the plasma unbound fractions were 1.23 and 52.5%. The large difference in CLb between parathion and paraoxon appeared to result primarily from differences in plasma protein binding. Parathion had greater persistence in trout than rat, suggesting that sensitivity difference were unrelated to toxicokinetic differences.

Coefficient of distribution of some organophosphorous pesticides in rat tissue.

Coefficient of distribution in tissue is proposed as an indicator of the affinity of xenobiotics for different tissues and their tendency to accumulate. The present study shows the distribution of some organophosphorous pesticides in rat tissues. Using the coefficient of distribution we established the preference of these insecticides for the various tissues. Each pesticide had a specific pattern of affinity for different tissues.