Development of a model for nerve agent inhalation in conscious rats

Abstract

This study characterizes the development of a head-out inhalation exposure system for assessing respiratory toxicity of vaporized chemical agents in untreated, non-anesthetized rats. The organophosphate diisopropyl fluorophosphate (DFP) induces classical cholinergic toxicity following inhalation exposure and was utilized to validate the effectiveness of this newly designed inhalation exposure system. A saturator cell apparatus was used to generate DFP vapor at 9750, 10?950, 12?200, 14?625 and 19?500?mg?×?min/m³ which was carried by filtered nitrogen into a glass mixing tube, where it combined with ambient air before being introduced to the custom-made glass exposure chamber. Male Sprague-Dawley rats (250–300?g) were restrained in individual head-out plethysmography chambers, which acquired respiratory parameters before, during and after agent exposure. All animals were acclimated to the exposure system prior to exposure to reduce novel environment-induced stress. The LCt₅₀, as determined by probit analysis, was 12?014?mg?×?min/m³. Weight loss in exposed animals was dose-dependent and ranged from 8 to 28% of their body weight 24?h after exposure. Increased salivation, lacrimation, urination, defecation (SLUD) and mild muscular fasciculation were observed in all DFP-exposed animals during and immediately following exposure. In all exposed animals, DFP vapor produced significant inhibition of acetylcholinesterase (AChE) activity in cardiac blood, bronchoalveolar lavage fluid (BALF), whole brain and lung tissue as well as alterations in tidal volume and minute volume. These studies have provided valuable information leading to the initiation of studies evaluating inhalational toxicity and treatments following exposure to the more lethal and potent chemical warfare nerve agents.     

Acute pulmonary toxicity following inhalation exposure to aerosolized VX in anesthetized rats

ABSTRACT

This study evaluated acute toxicity and pulmonary injury in rats at 3, 6 and 24?h after an inhalation exposure to aerosolized O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX). Anesthetized male Sprague-Dawley rats (250–300?g) were incubated with a glass endotracheal tube and exposed to saline or VX (171, 343 and 514?mg×min/m³ or 0.2, 0.5 and 0.8?LCt₅₀, respectively) for 10?min. VX was delivered by a small animal ventilator at a volume of 2.5?ml?×?70 breaths/minute. All VX-exposed animals experienced a significant loss in percentage body weight at 3, 6, and 24?h post-exposure. In comparison to controls, animals exposed to 514?mg×min/m³ of VX had significant increases in bronchoalveolar lavage (BAL) protein concentrations at 6 and 24?h post-exposure. Blood acetylcholinesterase (AChE) activity was inhibited dose dependently at each of the times points for all VX-exposed groups. AChE activity in lung homogenates was significantly inhibited in all VX-exposed groups at each time point. All VX-exposed animals assessed at 20 min and 3, 6 and 24?h post-exposure showed increases in lung resistance, which was prominent at 20 min and 3?h post-exposure. Histopathologic evaluation of lung tissue of the 514?mg×min/m³ VX-exposed animals at 3, 6 and 24?h indicated morphological changes, including perivascular inflammation, alveolar exudate and histiocytosis, alveolar septal inflammation and edema, alveolar epithelial necrosis, and bronchiolar inflammatory infiltrates, in comparison to controls. These results suggest that aerosolization of the highly toxic, persistent chemical warfare nerve agent VX results in acute pulmonary toxicity and lung injury in rats.     

Measurement of various respiratory dynamics parameters following acute inhalational exposure to soman vapor in conscious rats

Abstract

Respiratory dynamics were investigated in head-out plethysmography chambers following inhalational exposure to soman in untreated, non-anesthetized rats. A multipass saturator cell was used to generate 520, 560 and 600?mg?×?min/m³ of soman vapor in a customized inhalational exposure system. Various respiratory dynamic parameters were collected from male Sprague-Dawley rats (300--350?g) during (20?min) and 24?h (10?min) after inhalational exposure. Signs of CWNA-induced cholinergic crisis were observed in all soman-exposed animals. Percentage body weight loss and lung edema were observed in all soman-exposed animals, with significant increases in both at 24?h following exposure to 600?mg?×?min/m³. Exposure to soman resulted in increases in respiratory frequency (RF) in animals exposed to 560 and 600?mg?×?min/m³ with significant increases following exposure to 560?mg?×?min/m³ at 24?h. No significant alterations in inspiratory time (IT) or expiratory time (ET) were observed in soman-exposed animals 24?h post-exposure. Prominent increases in tidal volume (TV) and minute volume (MV) were observed at 24?h post-exposure in animals exposed to 600?mg?×?min/m³. Peak inspiratory (PIF) and expiratory flow (PEF) followed similar patterns and increased 24?h post-exposure to 600?mg?×?min/m³ of soman. Results demonstrate that inhalational exposure to 600?mg?×?min/m³ soman produces notable alterations in various respiratory dynamic parameters at 24?h. The following multitude of physiological changes in respiratory dynamics highlights the need to develop countermeasures that protect against respiratory toxicity and lung injury.     

Aerosolized scopolamine protects against microinstillation inhalation toxicity to sarin in guinea pigs

Sarin is a volatile nerve agent that has been used in the Tokyo subway attack. Inhalation is predicted to be the major route of exposure if sarin is used in war or terrorism. Currently available treatments are limited for effective postexposure protection against sarin under mass casualty scenario. Nasal drug delivery is a potential treatment option for mass casualty under field conditions. We evaluated the efficacy of endotracheal administration of muscarinic antagonist scopolamine, a secretion blocker which effectively crosses the blood-brain barrier for protection against sarin inhalation toxicity. Age and weight matched male Hartley guinea pigs were exposed to 677.4?mg/m³ or 846.5?mg/?m³ (1.2?×?LCt₅₀) sarin by microinstillation inhalation exposure for 4?min. One minute later, the animals exposed to 846.5?mg/?m³ sarin were treated with endotracheally aerosolized scopolamine (0.25?mg/kg) and allowed to recover for 24?h for efficacy evaluation. The results showed that treatment with scopolamine increased the survival rate from 20% to 100% observed in untreated sarin-exposed animals. Behavioral symptoms of nerve agent toxicity including, convulsions and muscular tremors were reduced in sarin-exposed animals treated with scopolamine. Sarin-induced body weight loss, decreased blood O₂ saturation and pulse rate were returned to basal levels in scopolamine-treated animals. Increased bronchoalveolar lavage (BAL) cell death due to sarin exposure was returned to normal levels after treatment with scopolamine. Taken together, these data indicate that postexposure treatment with aerosolized scopolamine prevents respiratory toxicity and protects against lethal inhalation exposure to sarin in guinea pigs.     

Acute microinstillation inhalation exposure to soman induces changes in respiratory dynamics and functions in guinea pigs

We investigated the toxic effects of the chemical warfare nerve agent (CWNA) soman (GD) on the respiratory dynamics of guinea pigs following microinstillation inhalation exposure. Male Hartley guinea pigs were exposed to 841 mg/m³ of GD or saline for 4 min. At 24 and 48 h post GD exposure, respiratory dynamics and functions were monitored for 75 min after 1 h of stabilization in a barometric whole-body plethysmograph. GD-exposed animals showed a significant increase in respiratory frequency (RF) at 24 h postexposure compared to saline controls. The 24-h tidal volume (TV) increased in GD-exposed animals during the last 45 min of the 75-min monitoring period in the barometric whole-body plethysmograph. Minute ventilation also increased significantly at 24 h post GD exposure. The peak inspiratory flow (PIF) increased, whereas peak expiratory flow (PEF) decreased at 24 h and was erratic following GD exposure. Animals exposed to GD showed a significant decrease in expiratory (Te) and inspiratory time (Ti). Although end inspiratory pause (EIP) and end expiratory pause (EEP) were both decreased 24 h post GD exposure, EEP was more evident. Pause (P) decreased equally during the 75-min recording in GD-exposed animals, whereas the pseudo lung resistance (Penh) decreased initially during the monitoring period but was near control levels at the end of the 75-min period. The 48-h respiratory dynamics and function parameter were lower than 24 post GD exposures. These results indicate that inhalation exposure to soman in guinea pigs alters respiratory dynamics and function at 24 and 48 h postexposure.     

Treatment with endotracheal therapeutics after sarin microinstillation inhalation exposure increases blood cholinesterase levels in guinea pigs

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in the blood and tissues of animals that are treated with a number of endotracheally aerosolized therapeutics for protection against inhalation toxicity to sarin. Therapeutics included, aerosolized atropine methyl bromide (AMB), scopolamine or combination of AMB with salbutamol, sphingosine 1-phosphate, keratinocyte growth factor, adenosine A1 receptor antisense oligonucleotide (EPI2010), 2,3-diacetyloxybenzoic acid (2,3 DABA), oxycyte, and survanta. Guinea pigs exposed to 677.4?mg/m³ or 846.5?mg/m³ (1.2 LCt₅₀) sarin for 4?min using a microinstillation inhalation exposure technique and treated 1?min later with the aerosolized therapeutics. Treatment with all therapeutics significantly increased the survival rate with no convulsions throughout the 24?h study period. Blood AChE activity determined using acetylthiocholine as substrate showed 20% activity remaining in sarin-exposed animals compare to controls. In aerosolized AMB and scopolamine-treated animals the remaining AChE activity was significantly higher (45–60%) compared to sarin-exposed animals (p?<?0.05). Similarly, treatment with all the combination therapeutics resulted in significant increase in blood AChE activity in comparison to sarin-exposed animals although the increases varied between treatments (p?<?0.05). BChE activity was increased after treatment with aerosolized therapeutics but was lesser in magnitude compared to AChE activity changes. Various tissues showed elevated AChE activity after therapeutic treatment of sarin-exposed animals. Increased AChE and BChE activities in animals treated with nasal therapeutics suggest that enhanced breathing and reduced respiratory toxicity/lung injury possibly contribute to rapid normalization of chemical warfare nerve agent inhibited cholinesterases.     

Aerosolized delivery of oxime MMB-4 in combination with atropine sulfate protects against soman exposure in guinea pigs

We evaluated the efficacy of aerosolized acetylcholinesterase (AChE) reactivator oxime MMB-4 in combination with the anticholinergic atropine sulfate for protection against respiratory toxicity and lung injury following microinstillation inhalation exposure to nerve agent soman (GD) in guinea pigs. Anesthetized animals were exposed to GD (841?mg/m³, 1.2 LCt₅₀) and treated with endotracheally aerosolized MMB-4 (50 µmol/kg) plus atropine sulfate (0.25?mg/kg) at 30?sec post-exposure. Treatment with MMB-4 plus atropine increased survival to 100% compared to 38% in animals exposed to GD. Decreases in the pulse rate and blood O₂ saturation following exposure to GD returned to normal levels in the treatment group. The body-weight loss and lung edema was significantly reduced in the treatment group. Similarly, bronchoalveolar cell death was significantly reduced in the treatment group while GD-induced increase in total cell count was decreased consistently but was not significant. GD-induced increase in bronchoalveolar protein was diminished after treatment with MMB-4 plus atropine. Bronchoalveolar lavage AChE and BChE activity were significantly increased in animals treated with MMB-4 plus atropine at 24?h. Lung and diaphragm tissue also showed a significant increase in AChE activity in the treatment group. Treatment with MMB-4 plus atropine sulfate normalized various respiratory dynamics parameters including respiratory frequency, tidal volume, peak inspiratory and expiratory flow, time of inspiration and expiration, enhanced pause and pause post-exposure to GD. Collectively, these results suggest that aerosolization of MMB-4 plus atropine increased survival, decreased respiratory toxicity and lung injury following GD inhalation exposure.     

Younger rats are more susceptible to the lethal effects of sarin than adult rats: 24 h LC50 for whole-body (10 and 60 min) exposures

Chemical warfare nerve agents (CWNA) inhibit acetylcholinesterase and are among the most lethal chemicals known to man. Children are predicted to be vulnerable to CWNA exposure because of their smaller body masses, higher ventilation rates and immature central nervous systems. While a handful of studies on the effects of CWNA in younger animals have been published, exposure routes relevant to battlefield or terrorist situations (i.e. inhalation for sarin) were not used. Thus, we estimated the 24?h LC₅₀ for whole-body (10 and 60?min) exposure to sarin using a stagewise, adaptive dose design. Specifically, male and female Sprague-Dawley rats were exposed to a range of sarin concentrations (6.2–44.0 or 1.6–12.5?mg/m³) for either 10 or 60?min, respectively, at six different times during their development (postnatal day [PND] 7, 14, 21, 28, 42 and 70). For male and female rats, the lowest LC₅₀ values were observed for PND 14 and the highest LC₅₀ values for PND 28. Sex differences were observed only for PND 42 for the 10?min exposures and PND 21 and 70 for the 60?min exposures. Thus, younger rats (PND 14) were more susceptible than older rats (PND 70) to the lethal effects of whole-body exposure to sarin, while adolescent (PND 28) rats were the least susceptible and sex differences were minimal. These results underscore the importance of controlling for the age of the animal in research on the toxic effects associated with CWNA exposure.     

A new inhalation exposure system for the determination of inhaled doses in laboratory rats

A new inhalation exposure system has been developed which allows the determination of inhaled doses of vapors and gases by laboratory rats. The system consists of saran bags connected to head-only exposure cylinders via one-way valves. One bag serves as the source of contaminant and another receives expired air. The exposure cylinders also serve as whole body plethysmographs. Up to three rats can be exposed concurrently to the same concentration of test material. The construction of the system and its use for inhalation exposures to a direct-acting radiolabeled carcinogen are described.     

Endotracheal aerosolization of atropine sulfate protects against soman-induced acute respiratory toxicity in guinea pigs

The efficacy of endotracheal aerosolization of atropine sulfate for protection against soman (GD)-induced respiratory toxicity was investigated using microinstillation technique in guinea pigs. GD (841?mg/m³, 1.3 LCt₅₀ or 1121?mg/m³, 1.7 LCt₅₀) was aerosolized endotracheally to anesthetized male guinea pigs that were treated with atropine sulfate (5.0?mg/kg) 30 s postexposure by endotracheal microinstillation. Animals exposed to 841?mg/m³ and 1121?mg/m³GD resulted in 31 and 13% while treatment with atropine sulfate resulted in 100 and 50% survival, respectively. Cholinergic symptoms and increased body weight loss were reduced in atropine-treated animals compared to GD controls. Diminished pulse rate and blood O₂ saturation in GD-exposed animals returned to normal levels after atropine treatment. Increased cell death, total cell count and protein in the bronchoalveolar fluid (BALF) in GD-exposed animals returned to normal levels following atropine treatment. GD exposure increased glutathione and superoxide dismutase levels in BALF and that were reduced in animals treated with atropine. Respiratory parameters measured by whole-body barometric plethysmography revealed that treatment with atropine sulfate resulted in normalization of respiratory frequency, tidal volume, time of expiration, time of inspiration, end expiratory pause, pseudo lung resistance (Penh) and pause at 4 and 24?h post 841?mg/m³ GD exposure. Lung histopathology showed that atropine treatment reduced bronchial epithelial subepithelial inflammation and multifocal alveolar septal edema. These results suggest that endotracheal aerosolization of atropine sulfate protects against respiratory toxicity and lung injury induced by microinstillation inhalation exposure to lethal doses of GD.     

Adverse respiratory effects in rats following inhalation exposure to ammonia: respiratory dynamics and histopathology

Acute respiratory dynamics and histopathology of the lungs and trachea following inhaled exposure to ammonia were investigated. Respiratory dynamic parameters were collected from male Sprague–Dawley rats (300–350?g) during (20?min) and 24?h (10?min) after inhalation exposure for 20?min to 9000, 20,000, and 23,000?ppm of ammonia in a head-only exposure system. Body weight loss, analysis of blood cells, and lungs and trachea histopathology were assessed 1, 3, and 24?h following inhalation exposure to 20,000?ppm of ammonia. Prominent decreases in minute volume (MV) and tidal volume (TV) were observed during and 24?h post-exposure in all ammonia-exposed animals. Inspiratory time (IT) and expiratory time (ET) followed similar patterns and decreased significantly during the exposure and then increased at 24?h post-exposure in all ammonia-exposed animals in comparison to air-exposed controls. Peak inspiratory (PIF) and expiratory flow (PEF) significantly decreased during the exposure to all ammonia doses, while at 24?h post-exposure they remained significantly decreased following exposure to 20,000 and 23,000?ppm. Exposure to 20,000?ppm of ammonia resulted in body weight loss at 1 and 3?h post-exposure; weight loss was significant at 24?h compared to controls. Exposure to 20,000?ppm of ammonia for 20?min resulted in increases in the total blood cell counts of white blood cells, neutrophils, and platelets at 1, 3, and 24?h post-exposure. Histopathologic evaluation of the lungs and trachea tissue of animals exposed to 20,000?ppm of ammonia at 1, 3, and 24?h post-exposure revealed various morphological changes, including alveolar, bronchial, and tracheal edema, epithelial necrosis, and exudate consisting of fibrin, hemorrhage, and inflammatory cells. The various alterations in respiratory dynamics and damage to the respiratory system observed in this study further emphasize ammonia-induced respiratory toxicity and the relevance of efficacious medical countermeasure strategies.     

偏二甲基肼吸入染毒在家兔体内的毒物动力学

家兔吸入３７０±２８和７７６±５３ｍｇ·ｍ－３：以及恒速静脉输注９．７ｍｇ·ｋｇ－１·ｈ－１偏二甲基肼（ＵＤＭＨ）．均以一房室模型在体内配置；而ｉｖ３９．０ｍｇ·ｋｇ－１ＵＤＭＨ呈二房室模型。ＵＤＭＨ蒸气经家兔呼吸道的滞留率高达９５％以上，不受吸入气ＵＤＭＨ蒸气浓度Ｃ１和动物通气量Ｖｒ改变和波动的影响。由于实验期间Ｃ１和Ｖｒ基本稳定，因此ＵＤＭＨ以近似恒速即表现零级速度滞留在呼吸道，并以同样的速度特征全部迅速地被吸收入血。家兔ｉｖＵＤＭＨ在家兔体内分布很快，１３ｍｉｎ左右分布相即基本结束；呈全身分布。ＵＤＭＨ从家免体内消除较快，物质蓄积性弱；存在肾外消除途径。     

Acute respiratory toxicity following inhalation exposure to soman in guinea pigs

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m³ concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m³ soman survived, while animals exposed to 841, and 1121 mg/m³ resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt₅₀ for soman determined by probit analysis was 827.2 mg/m³. A majority of the animals that died at 1121 mg/m³ developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.     

Pulmonary toxicity and global gene expression changes in response to sub-chronic inhalation exposure to crystalline silica in rats

Exposure to crystalline silica results in serious adverse health effects, most notably, silicosis. An understanding of the mechanism(s) underlying silica-induced pulmonary toxicity is critical for the intervention and/or prevention of its adverse health effects. Rats were exposed by inhalation to crystalline silica at a concentration of 15 mg/m³, 6 hr/day, 5 days/week for 3, 6 or 12 weeks. Pulmonary toxicity and global gene expression profiles were determined in lungs at the end of each exposure period. Crystalline silica was visible in lungs of rats especially in the 12-week group. Pulmonary toxicity, as evidenced by an increase in lactate dehydrogenase (LDH) activity and albumin content and accumulation of macrophages and neutrophils in the bronchoalveolar lavage (BAL), was seen in animals depending upon silica exposure duration. The most severe histological changes, noted in the 12-week exposure group, consisted of chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis. Microarray analysis of lung gene expression profiles detected significant differential expression of 38, 77, and 99 genes in rats exposed to silica for 3-, 6-, or 12-weeks, respectively, compared to time-matched controls. Among the significantly differentially expressed genes (SDEG), 32 genes were common in all exposure groups. Bioinformatics analysis of the SDEG identified enrichment of functions, networks and canonical pathways related to inflammation, cancer, oxidative stress, fibrosis, and tissue remodeling in response to silica exposure. Collectively, these results provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic inhalation exposure to crystalline silica in rats.     

Lack of effects of nose-only inhalation exposure on testicular toxicity in male rats.

Reductions in testicular mass, sperm motility, and mating frequency have been attributed to the stresses caused by confinement of Sprague-Dawley male rats in nose-only inhalation exposure tubes. Testicular changes, including an increase in testicular atrophy, have been detected at an increased incidence in male rats used in inhalation studies as compared with rats of the same age and strain used in oral toxicity studies. This study was designed to determine whether nose-only exposure of male rats caused testicular toxicity under conditions of cooling of the exposure room and appropriate acclimation to the exposure tubes. In order to acclimate the rats to the nose-only inhalation exposure apparatus, all male rats were placed in the exposure tubes for at least four successively increasing time intervals (15, 30, 45, and 60 min) on 4 separate days, with a rest period of approximately 48 h between the first and second acclimation. Twenty male rats were exposed nose-only to filtered air for approximately 2 h per day for 28 days before cohabitation and continuing throughout a 14-day cohabitation period. To reduce thermal stress, the exposure room temperature was maintained at 64 to 70 degrees F. Twenty control rats were housed in the same room as the exposed rats but were not placed in exposure tubes. End points monitored were body weight, testicular weight, sperm count, sperm motility, and histopathology of the testes, epididymides, prostate, and seminal vesicles. The control rats gained weight more rapidly than the exposed rats. All the rats in both groups mated successfully, and testicular weights, normalized to body weight, were similar for both groups. More importantly, there were no microscopic changes that could be considered an adverse effect on the reproductive tissues in the male rats placed in exposure tubes. Thus, nose-only exposure for up to 2 h per day for a total of 42 days did not cause adverse effects on the reproductive organs, fertility, or reproductive performance of male rats under the conditions of this study.     

Effect of diesel exhaust inhalation on blood markers of inflammation and neurotoxicity: a controlled,blinded crossover study

Context: Epidemiological studies and animal research have suggested that air pollution may negatively impact the central nervous system (CNS). Controlled human exposure studies of the effect of air pollution on the brain have potential to enhance our understanding of this relationship and to inform potential biological mechanisms.

Objectives: Biomarkers of systemic and CNS inflammation may address whether air pollution exposure induces inflammation, with potential for CNS negative effects.

Materials and methods: Twenty-seven healthy adults were exposed to two conditions: filtered air (FA) and diesel exhaust (DE) (300?μg PM_2.5/m³) for 120?min, in a double-blinded crossover study with exposures separated by four weeks. Prior to and at 0, 3, and 24?h following each exposure, serum and plasma were collected and analyzed for inflammatory cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α), the astrocytic protein S100b, the neuronal cytoplasmic enzyme neuron-specific enolase (NSE), and serum brain-derived neurotrophic factor (BDNF). We hypothesized that IL-6, TNF-α, S100b and NSE would increase, and BDNF would decrease, following DE exposure.

Results: At no time-point following exposure to DE was a significant increase in concentration from baseline seen for IL-6, TNF-α, S100b, or NSE relative to FA exposure. Similarly, no significant decrease in BDNF concentration from baseline was seen following DE exposure, relative to FA. Furthermore, the repeated measures ANOVA considered for all time-points and biomarkers revealed no significant time-exposure interaction.

Discussion and conclusion: These results suggest that short-term exposure to DE amongst healthy adults does not acutely affect the systemic or CNS biomarkers that we measured.     

HI-6对梭曼染毒大鼠膈肌胆碱酯酶的重活化作用

目的研究HI-6对膈肌局部梭曼染毒大鼠膈肌胆碱酯酶的重活化作用。方法将大鼠麻醉后固定,沿腹正中线切开腹腔,暴露膈肌。梭曼局部染毒膈肌1和10min后,局部或全身给予HI-6,于给药后24和72h处死大鼠,取出中毒部位膈肌。用硫胆碱酶法显示终板的AChE活性,观察HI-6对胆碱酯酶的重活化作用。结果膈肌局部梭曼中毒1和10min后．局部给予HI-624和72h对局部中毒膈肌胆碱酯酶均没有重活化作用．在光镜下观察不到棕褐色椭圆形的运动终板：而膈肌局部梭曼中毒1和10min后,全身给予HI-6对局部中毒膈肌胆碱酯酶有明显的重活化作用,在光镜下可见到肌纤维上又出现了棕褐色椭圆形的运动终板。结论HI-6全身给药对早期膈肌局部中毒的神经运动终板胆碱酯酶有重活化作用。     

Single and 14-day repeated dose inhalation toxicity studies of hexabromocyclododecane in rats

Limited toxicological information is available for hexabromocyclododecane (HBCD),a widely used additive brominated flame retardant. Inhalation is a major route of human exposure to HBCD. The aim of this study was to determine the acute inhalation toxicity and potential subchronic inhalation toxicity of HBCD in Sprague-Dawley rats exposed to HBCD only through inhalation. The acute inhalation toxicity of HBCD was determined using the limit test method on five male and five female Sprague-Dawley rats at a HBCD concentration of 5000 mg/m³. Repeated-dose toxicity tests were also performed, with 20 males and 20 females randomly assigned to four experimental groups (five rats of each sex in each group). There were three treatment groups (exposed to HBCD concentrations of 125,500, and 2000 mg/m³) and a blank control group (exposed to fresh air). In the acute inhalation toxicity study, no significant clinical signs were observed either immediately after exposure or during the recovery period. Gross pathology examination revealed no evidence of organ-specific toxicity in any rat. The inhalation LC_50(4 h) for HBCD was higher than 5312 ± 278 mg/m3 for both males and females. In the repeated dose inhalation study, daily head/nose-only exposure to HBCD at 132 ± 8.8, 545.8 ± 35.3, and 2166.0 ± 235.9 mg/m³ for 14 days caused no adverse effects. No treatment-related clinical signs were observed at any of the test doses. The NOAEL for 14-day repeated dose inhalation toxicity study of HBCD is 2000 mg/m³.     

Behavioural effects of prenatal metallic mercury inhalation exposure in rats

The effects of administration by inhalation of metallic mercury vapour (Hg⁰) to pregnant rats, approximately corresponding to doses of 0.2 mg Hg⁰/kg /day (high dose) or 0.07 mg Hg⁰/kg/day (low dose), on the developmental and behavioural repertoire of the offspring were studied. Exposure occurred during days 11–14 plus 17–20 of gestation. The dose levels were selected so as not to induce maternal toxicity. Maturation variables such as surface righting, negative geotaxis, pinna unfolding, and tooth eruption revealed no differences between Hg⁰-treated offspring and controls. Tests of spontaneous motor activity showed that the Hg⁰-treated offspring were hypoactive at 3 months of age but hyperactive at 14 months. In spatial learning tasks the prenatally exposed offspring showed retarded acquisition in the radial arm maze but no differences in circular swim maze. A simple test of learning, habituation to a novel environment (activity chambers), indicated a reduced ability to adapt. These data suggest that prenatal exposure to Hg⁰ vapour results in similar behaviour changes in the offspring as reported for methylmercury.