Butyrylcholinesterase in Guinea Pig Lung Lavage: A Novel Biomarker to Assess Lung Injury Following Inhalation Exposure to Nerve Agent VX

Respiratory disturbances play a central role in chemical warfare nerve agent (CWNA) induced toxicity; they are the starting point of mass casualty and the major cause of death. We developed a microinstillation technique of inhalation exposure to nerve agent VX and assessed lung injury by biochemical analysis of the bronchoalveolar lavage fluid (BALF). Here we demonstrate that normal guinea pig BALF has a significant amount of cholinesterase activity. Treatment with Huperzine A, a specific inhibitor of acetylcholinesterase (AChE), showed that a minor fraction of BALF cholinesterase is AChE. Furthermore, treatment with tetraisopropyl pyrophosphoramide (iso-OMPA), a specific inhibitor of butyrylcholinesterase (BChE), inhibited more than 90% of BChE activity, indicating the predominance of BChE in BALF. A predominance of BChE expression in the lung lavage was seen in both genders. Substrate specific inhibition indicated that nearly 30% of the cholinesterase in lung tissue homogenate is AChE. BALF and lung tissue AChE and BChE activities were strongly inhibited in guinea pigs exposed for 5 min to 70.4 and 90.4 μ g/m³ VX and allowed to recover for 15 min. In contrast, BALF AChE activity was increased 63% and 128% and BChE activity was increased 77% and 88% after 24 h of recovery following 5 min inhalation exposure to 70.4 μ g/m³ and 90.4 μg/m³, respectively. The increase in BALF AChE and BChE activity was dose dependent. Since BChE is synthesized in the liver and present in the plasma, an increase in BALF indicates endothelial barrier injury and leakage of plasma into lung interstitium. Therefore, a measure of increased levels of AChE and BChE in the lung lavage can be used to determine the chronology of barrier damage as well as the extent of lung injury following exposure to chemical warfare nerve agents.     

Acute Toxic Effects of Nerve Agent VX on Respiratory Dynamics and Functions Following Microinsillation Inhalation Exposure in Guinea Pigs

Exposure to a chemical warfare nerve agent (CWNA) leads to severe respiratory distress, respiratory failure, or death if not treated. We investigated the toxic effects of nerve agent VX on the respiratory dynamics of guinea pigs following exposure to 90.4 μg/m³ of VX or saline by microinstillation inhalation technology for 10 min. Respiratory parameters were monitored by whole-body barometric plethysmography at 4, 24, and 48 h, 7 d, 18 d, and 4 wk after VX exposure. VX-exposed animals showed a significant decrease in the respiratory frequency (RF) at 24 and 48 h of recovery (p value.0329 and.0142, respectively) compared to the saline control. The tidal volume (TV) slightly increased in VX exposed animals at 24 and significantly at 48 h (p = .02) postexposure. Minute ventilation (MV) increased slightly at 4 h but was reduced at 24 h and remained unchanged at 48 h. Animals exposed to VX also showed an increase in expiratory (Te) and relaxation time (RT) at 24 and 48 h and a small reduction in inspiratory time (Ti) at 24 h. A significant increase in end expiratory pause (EEP) was observed at 48 h after VX exposure (p = .049). The pseudo lung resistance (Penh) was significantly increased at 4 h after VX exposure and remained slightly high even at 48 h. Time-course studies reveal that most of the altered respiratory dynamics returned to normal at 7 d after VX exposure except for EEP, which was high at 7 d and returned to normal at 18 d postexposure. After 1 mo, all the monitored respiratory parameters were within normal ranges. Bronchoalveolar lavage (BAL) 1 mo after exposure showed virtually no difference in protein levels, cholinesterase levels, cell number, and cell death in the exposed and control animals. These results indicate that sublethal concentrations of VX induce changes in respiratory dynamics and functions that over time return to normal levels.     

Blood and Bronchoalveolar Lavage Fluid Acetylcholinesterase Levels Following Microinstillation Inhalation Exposure to Sarin in Guinea Pigs

We determined acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in the bronchoalveolar lavage fluid (BALF) following inhalation exposure to chemical threat nerve agent (CTNA) sarin. Age- and weight-matched male guinea pigs were exposed to five different doses of sarin (169.3, 338.7, 508, 677.4, and 846.5 mg/m³) using a microinstillation inhalation exposure technique for 4 min. The technique involves aerosolization of the agent in the trachea using a microcatheter with a center hole that delivers the agent and multiple peripheral holes that pumps air to aerosolize the agent at the tip. Animals exposed to higher doses of sarin occasionally developed seizures and succumbed to death within 15 min after exposure. The LCt₅₀ for sarin using the microinstillation technique was determined to be close to 677.4 mg/m³. Ear blood AChE activity showed a dose-dependent inhibition at 15 min postexposure. The inhibition of blood AChE remained constant over 35 and 55 min after sarin exposure indicating that there was no lung depot effect. Cardiac blood AChE and butyrylcholinesterase (BChE) activity in surviving animals euthanized at 24 h postexposure showed a dose-dependent inhibition with an inhibition of 60% at 677.4 and 846.5 mg/m³ sarin exposure. AChE and BChE activity in bronchoalveolar lavage fluid (BALF) showed a slight increase at 338.7 to 677.4 mg/m³ sarin exposure but a marginal inhibition at 169.3 mg/m³. In contrast, the AChE protein levels determined by immunoblotting showed an increase at 169.3 mg/m³ in the BALF. The BALF protein level, a biomarker of lung injury, was increased maximally at 338.7 mg/m³ and that increase was dropped with an increase in the dose of sarin. The BALF protein levels correlated with the AChE and BChE activity. These data suggest that sarin microinstillation inhalation exposure results in respiratory toxicity and lung injury characterized by changes in lavage AChE, BChE, and protein levels.     

Autoradiographic Analyses of Guinea Pig Airway Tissues Following Inhalation Exposure to 14C-Labeled Methyl Isocyanate

Through the use of radioactively labeled methyl isocyanate (MIC),the deposition, penetration, and clearance of this highly reactivecompound in the airway at the tissue and cellular levels havebeen directly examined. Guinea pigs were exposed to ¹⁴C-MICvapors at concentrations ranging from 0.38 to 15.2 ppm for periodsof 1–6 hr. Solubilization of tissues from these animalsshowed the airway tissues to have the highest level of radioactivity.In the nasal region, ¹⁴C deposition, as monitored by histoautoradiography,was limited to the epithelial layer, was related to dose, andwas dependent on the specific epithelial cell type. The squamousepithelium was minimally labeled on the surface and the labeldid not penetrate the cell layer. However, radioactivity wasdetected throughout the entire nasal respiratory epitheliallayer. The lack of nasal deposition in tracheotomized animalsdemonstrated that the ¹⁴C accumulation at this site was dueto the scrubbing action of the nasal region with no contributionfrom blood recirculation. Cellular localization in the tracheobronchialregion showed epithelial and subepithelial deposition in a dose-dependentmanner with accumulation of the label at the subepithelial region.Radioactivity penetrated to the level of the terminal bronchiolebut was not detected in the alveolar region. The persistenceof airway radioactivity over the 48-hr postexposure period monitoredsuggests the covalent modification of airway macromolecules.Despite its broad specificity and high reactivity, MIC undergoesselective reactions in the airways which are dependent on respiratoryregion and cell type.     

Lung Response to Ultrafine Kevlar Aramind Synthetic Fibrills Following 2-Year Inhalation Exposure in Rats

Lung Response to Ultrafine Kevlar Aramid Synthetic Fibrils following2-Year Inhalation Exposure in Rats. LEE K. P., KELLY D.P. O'NEALF. O., STADLER, J. C., AND KENNEDY G. L., JR (1988). Fundam.Appl. Toxicol. 11, 1-20. Four groups of 100 male and 100 femalerats were exposed to ultrafine Kevlar fibrils at concentrationsof 0, 2.5,25, and 100 fibrils/cc for 6 hr/day, 5 days/week for2 years. One group was exposed to 400 fibrils/cc for 1 yearand allowed to recover for 1 year. At 2.5 fibrils/cc, the lungshad normal alveolar architecture with a few dust-laden macrophages(dust cell response) in the alveolar airspaces. At 25 fibrils/cc,the lungs showed a dust cell response, slight Type II pneumocytehyperplasia, alveolar bronchiolariation, and a negligible amountof collagenized fibrosis in the alveolar duct region. At 100fibrils/cc, the same pulmonary responses were seen as at 25fibrilsol;cc. In addition, cystic keratinizing squa- mous cellcarcinoma (CKSCC) was found in 4 female rats, but not in malerats. Female rats had more prominent foamy alveolar macrophages,holesterol granulomas, and alveolar bronchio-larization. Thesepulmonary lesions were related to the development of CKSCC.The lung tumors were derived from metaplastic squamous cellsin areas of alveolar bronchiolarization. At 400 fibrils/cc following1 year of recovery, the lung dust content, average fiber length,and the pulmonary lesions were markedly reduced, but slightcentriacinar emphysema and minimal collagenized fibrosis werefound in the alveolar duct region. One male and 6 female ratsdeveloped CKSCC. The lung tumors were a unique type of experimentallyinduced tumors in the rats and have not been seen as spontaneoustumors in man or animals. Therefore, the relevance of this typeof lung tumor to the human situation is minimal.     

Asthmalike Symptoms Following Intratracheal Exposure of Guinea Pigs to Sulfur Mustard Aerosol: Therapeutic Efficacy of Exogenous Lung Surfactant Curosurf and Salbutamol

The purpose of the present study was to investigate: (1) the acute effects of sulfur mustard on airway, lung, and surface tension of bronchoalveolar lavage fluid (BALfluid) in guinea pigs following intratracheal (i.t.) exposure to 1LD50 of an aerosolized solution of sulfur mustard in saline, and (2) the therapeutic efficacy of i.t. administration of the natural surfactant Curosurf and the broncholytic Salbutamol. Intratracheally aerosolized sulfur mustard solution induced two clinically relevant symptoms, that is, asthmalike symptoms reflected by an early bronchoconstriction and “late asthmatic responses” (LAR), and ARDS-like symptoms, that is, pulmonary edema and damage to the lung surfactant. The respiratory minute volume (RMV) was enhanced. Histologically, inflammation and severe epithelial injury in the upper airways were observed, whereas the lungs were homogeneously affected. The surface tension of BAL fluid derived at 24 h after sulfur mustard exposure was much higher (20 ± 1 mN/m) than that of unexposed control animals (about 1.0 ± 0.5 mN/m), indicating that the lung surfactant had been altered, and justifying treatment with exogenous surfactant. Intratracheal nebulization of a Salbutamol solution (10 μ g/kg), or i.t. bolus administration of Curosurf (62.5 or 125 mg/kg), tended to reduce mortality, although Salbutamol appeared to be more effective than Curosurf in this respect. Although the present study does not give a definite answer to the question of whether the animal model used would be the most relevant for humans, a number of considerations in favor of i.t. aerosolization of sulfur mustard are discussed. Since it was noticed that sulfur mustard exposure induced damage to the lung surfactant, severe bronchoconstriction, and inflammation of the respiratory tract, the effectiveness of a combined treatment consisting of exogenous surfactant, anti-inflammatory drugs, and broncholytics is recommended to be further investigated.     

Kinetics of Sarin (GB) Following a Single Sublethal Inhalation Exposure in the Guinea Pig

To improve toxicity estimates from sublethal exposures to chemical warfare nerve agents (CWNA), it is necessary to generate mathematical models of the absorption, distribution, and elimination of nerve agents. However, current models are based on representative data sets generated with different routes of exposure and in different species and are designed to interpolate between limited laboratory data sets to predict a wide range of possible human exposure scenarios. This study was performed to integrate CWNA sublethal toxicity data in male Duncan Hartley guinea pigs. Specific goal was to compare uptake and clearance kinetics of different sublethal doses of sarin (either 0.1 × or 0.4 × LC₅₀) in blood and tissues of guinea pigs exposed to agent by acute whole-body inhalation exposure after the 60-min LC₅₀ was determined. Arterial catheterization allowed repeated blood sampling from the same animal at various time periods. Blood and tissue levels of acetylcholinesterase, butyrylcholinesterase, and regenerated sarin (rGB) were determined at various time points during and following sarin exposure. The following pharmacokinetic parameters were calculated from the graph of plasma or RBC rGB concentration versus time: time to reach the maximal concentration; maximal concentration; mean residence time; clearance; volume of distribution at steady state; terminal elimination-phase rate constant; and area under plasma concentration time curve extrapolated to infinity using the WinNonlin analysis program 5.0. Plasma and RBC t_1/2 for rGB was also calculated. Data will be used to develop mathematical model of absorption and distribution of sublethal sarin doses into susceptible tissues.     

Respiratory and Immunological Responses of Guinea Pigs to Enzyme-Containing Detergents: A Comparison of Intratracheal and Inhalation Modes of Exposure

Guinea pigs were exposed once a week for 10 weeks by intratrachealexposure to solutions of 3, 1, 0.3, or 0.1 µg of the enzymeprotein, Subtilisn Carlsberg (Alcalase), in 250 µg ofa detergent base. Other groups of guinea pigs were exposed byinhalation (6 hr per day, 4 days a week) to 1 mg/m³ of the aerosolizeddetergent base containing either 3.5, 1.1, 0.3, or 0.1% Alcalaseprotein. Evaluations of gross respiratory responses immediatelyfollowing each intratracheal exposure revealed a significantdose response in respiratory symptoms measurable after the fourthexposure and continuing throughout the study. In the inhalationexperiment, during Weeks 4 through 10, animals were observedto have respiratory symptoms which were dependent upon boththe dose of enzyme and on total exposure to the enzyme/detergentatmosphere. For both intratracheal and inhalation routes ofexposure, the initial appearance of respiratory symptoms coincidedwith the first appearance of measurable serum allergic antibodiesspecific to Alcalase. The allergic antibody levels increasedwith time and dosage by both routes of exposure, and the antibodytiters generated by the intratracheal administration of antigenwere comparable to those generated by the inhalation route ofexposure. These results indicate that the intratracheal techniqueis appropriate for the evaluation of the respiratory allergicresponse to a protein.     

喘可治注射液雾化吸入给药对豚鼠肺指数及气管、肺、食管组织形态学的影响

目的:观察喘可治注射液雾化吸入给药对豚鼠肺指数及气管、食管等器官组织形态学的影响。方法:将40只豚鼠随机均分为空白对照组(生理盐水)和喘可治高、中、低(2.48、1.24、0.62 ml/kg)剂量组,雾化喷雾吸入给药,20 ml/kg,每天1次,连续给药2周。每次给药1 h后观察豚鼠一般情况;末次给药1 h后检测豚鼠肺指数,并采用苏木精-伊红(HE)染色观察豚鼠左肺、右肺、气管及食管的组织形态学变化。结果:与正常对照组比,喘可治高、中、低剂量组豚鼠的一般情况均正常;肺指数无差异,均为0.653左右;组织切片染色结果显示各组织未见异常病变。结论:喘可治注射液雾化吸入给药2周对豚鼠肺指数及气管、肺、食管等器官组织形态学无明显影响。     

Short-Term Exposure to Diesel Exhaust Induces Nasal Mucosal Hyperresponsiveness to Histamine in Guinea Pigs

The increasing prevalence of allergic rhinitis in many countriesis becoming a social problem. It is important to determine whetherair pollutants are related to the increase in the prevalencerate of allergic rhinitis or not. In this respect, it is necessaryto elucidate whether exposure to air pollutants affects thenasal mucosa and causes nasal mucosal hyperresponsiveness tochemical mediators released by antigen-antibody reactions. Aprevious study revealed that diesel exhaust participates arepotent in augmenting increases in nasal congestion and nasalsecretion induced by histamine (T. Kobayashi and T. Ito, 1995,Fundam. Appl. Toxicol. 27,195–202). In the present study,using a rhinitis model of guinea pigs, we investigated whethershort-term (3-hr) exposure to diesel exhaust induces nasal mucosalhyperresponsiveness to histamine. Guinea pigs of each groupwere exposed to filtered air or to a low or high concentrationof diesel exhaust (1 and 3.2 mg/m³ particulates in diluted dieselexhaust, respectively) for 3 hr. After diesel exhaust exposure,sneezing frequency, nasal secretion from the nostril, and intranasalairway resistance induced by histamine were measured as indicesof sneezing response, rhinorrhea, and nasal congestion, respectively.Short-term exposure to a low or high concentration of dieselexhaust itself did not induce sneezing, nasal secretion, ornasal congestion. However, short-term exposure to a high concentrationof diesel exhaust augmented sneezing and nasal secretion, butnot nasal congestion, induced by histamine. In conclusion, short-termexposure to diesel exhaust potently induces nasal mucosal hyperresponsiveness.     

Four-Week Exposure to Disel Exhaust Includes Nasal Muscosal Hyperresponsiveness to Histamine in Guinea Pigs

It has been reported that diesel exhaust (DE) particulates augmentincreases in nasal congestion and nasal secretion induced byhista-mine (His). We also showed that short-term (3-h) exposureto DE induces nasal mucosal hyperresponsiveness to His. Therefore,in the present study we investigated that whether 4-week exposureof guinea pigs to diesel exhaust would likewise induce nasalmucosal hyperresponsiveness to His. Sneezing number, nasal secretionfrom the nostril, and intranasal airway resistance induced byHis were measured as indices of sneezing response, rhinorrhea,and nasal congestion, respectively. Guinea pigs of each groupwere exposed to filtered air, with or without a low or highconcentration of DE for 3, 7, or 28 days. Exposure to a lowor high concentration of DE itself did not induce sneezing,nasal secretion, or nasal congestion. However, exposure to ahigh concentration of DE augmented that the number of sneezesinduced by His, whereas exposure to a low concentration of DEhad no significant effect. Exposure to DE for 7 and 28 daystended to augment an increase in nasal secretion induced byexposure to His aerosol in a DE concentration-dependent fashion.The augmentation, however, was not statistically significantExposure to high or low DE for 3 or 7 days had no significanteffect on the increase in intranasal pressure (INP) inducedby a 10-min exposure to His aerosol, but exposure to high DEfor 28 days augmented the increase in INP induced by His, significantly.Exposure to low DE for 28 days did not augment the increasein INP immediately after inhalation of His aerosol. These resultsreveal that 4-week exposure to high DE induces nasal mucosalhyperresponsiveness in guinea pigs.     

白藜芦醇苷对大鼠内毒素休克性肺损伤的保护作用

目的 :研究白藜芦醇苷 (PD)对内毒素休克大鼠肺损伤的保护作用。方法 :将大鼠随机分为单纯手术组、内毒素休克组、PD预防组和PD治疗组4组。利用静脉注射内毒素复制大鼠内毒素休克的动物模型。对各组大鼠平均动脉压 (MAP)的动态变化、肺系数、肺通透指数、肺泡灌洗液 (BALF)中蛋白含量、肺组织一氧化氮合酶 (NOS)含量等指标进行观测 ,并结合光镜下肺组织的病理变化 ,探讨PD对内毒素休克性肺损伤的保护作用。结果 :PD可不同程度地阻止内毒素引起的血压下降 ,明显降低内毒素导致的肺系数、肺通透指数、BALF中蛋白含量、NOS含量的增高 ,从而减轻内毒素导致肺组织病理损伤的程度 ,且PD预防组较PD治疗组的效果更好。结论 :PD对大鼠内毒素休克性肺损伤具有保护作用 ,且预防性用药效果更佳。     

Acute Inhalation Exposure to Epichlorohydrin Transiently Decreases Rat Sperm Velocity

Acute Inhalation Exposure to Epichlorohydrin Transiently DecreasesRat Sperm Velocity. Slott, V. L., Suarez, J. D., Simmons, J.E., and Perreault, S. D. (1990). Fundam. Appl. To.xicol. 15,597–606. The effect of inhaled epichlorohydrin on ratsperm motility characteristics was evaluated. Male F-344 ratswere exposed to 100 ppm epichlorohydrin via inhalation for 4hr in the morning of Day 0 and killed immediately and on Days1, 2, 6, and 14 postexposure. Videotapes of cauda epididymalsperm were analyzed (300–350 sperm/sample) with a HamiltonThorn motility analyzer (HTM-2000, Hamilton Thorn Research,Danvers, MA). Epichlorohydrin did not affect the percentageof motile sperm at any time. However, transient changes in spermvelocity were found. On Day 1 postexposure mean progressive(straight line) and mean path (smoothed curvilinear) velocitywere significantly decreased to 80 and 85% of control, respectively.The progressive velocities of sperm from both control and treatedrats were normally distributed, indicating a general effectof epichlorohydrin on all sperm as opposed to a more severeeffect on a specific sperm subpopulation. Sperm velocity wasnot significantly affected at later times. Other endpoints (testisand epididymis weights, testicular spermatid counts, and caudaepididymal sperm reserves) were unaltered by epichlorohydrin.Thus, inhaled epichlorohydrin at 100 ppm produced specific,transient decreases in rat sperm velocity. Furthermore, computer-assistedsperm analysis was able to detect these relatively subtle, toxicant-inducedchanges in rat sperm velocity, demonstrating the utility ofthis technology in reproductive toxicology studies.     

Lung Function Changes in Sprague-Dawley Rats After Prolonged Inhalation Exposure to Silver Nanoparticles

The antimicrobial activity of silver nanoparticles has resulted in their widespread use in many consumer products. However, despite the continuing increase in the population exposed to silver nanoparticles, the effects of prolonged exposure to silver nanoparticles have not been thoroughly determined. Accordingly, this study attempted to investigate the inflammatory responses and pulmonary function changes in rats during 90 days of inhalation exposure to silver nanoparticles. The rats were exposed to silver nanoparticles (18 nm diameter) at concentrations of 0.7 × 10⁶ particles/cm³ (low dose), 1.4 × 10⁶ particles /cm³ (middle dose), and 2.9 × 10⁶ particles /cm³ (high dose) for 6 h/day in an inhalation chamber for 90 days. The lung function was measured every week after the daily exposure, and the animals sacrificed after the 90-day exposure period. Cellular differential counts and inflammatory measurements, such as albumin, lactate dehydrogenase (LDH), and total protein, were also monitored in the acellular bronchoalveolar lavage (BAL) fluid of the rats exposed to the silver nanoparticles for 90 days. Among the lung function test measurements, the tidal volume and minute volume showed a statistically significant decrease during the 90 days of silver nanoparticle exposure. Although no statistically significant differences were found in the cellular differential counts, the inflammation measurements increased in the high-dose female rats. Meanwhile, histopathological examinations indicated dose-dependent increases in lesions related to silver nanoparticle exposure, such as infiltrate mixed cell and chronic alveolar inflammation, including thickened alveolar walls and small granulomatous lesions. Therefore, when taken together, the decreases in the tidal volume and minute volume and other inflammatory responses after prolonged exposure to silver nanoparticles would seem to indicate that nanosized particle inhalation exposure can induce lung function changes, along with inflammation, at much lower mass dose concentrations when compared to submicrometer particles.     

Lung Tumor Induction by Inhalation Exposure to Molybdenum Trioxide in Rats and Mice

Inhalation studies of molybdenum trioxide (MoO₃) were conductedbecause of its wide use in industry, human exposure, and lackof data on carcinogenicity. Groups of 50 male and 50 femaleF344/N rats and B6C3F1 mice were exposed to MoO₃ by inhalationat 0, 10, 30, or 100 mg/m₃, 6 h/day, 5 days/week, for 2 years.In both rats and mice, survival and mean body weights of exposedgroups of males and females were similar to those of their respectivecontrols. There were significant exposure-dependent increasesin blood molybdenum concentration in exposed rats and mice.There were no toxicological differences in bone density or curvaturebetween exposed animals and their respective controls. In rats,dose-dependent increases in incidence of hyaline degenerationin the nasal olfactory epithelium and squamous metaplasia ofthe epithelium lining the base of the epiglottis were observed.The incidence of alveolar/bronchiolar adenoma or carcinoma (combined)was marginally increased in males but not in females comparedwith controls. In mice, the incidences of squamous metaplasiaof the epithelium lining the base of the epiglottis, hyperplasiaof the laryngeal epithelium, and metaplasia of the alveolarepithelium were significantly increased in all exposed malesand females compared with controls. The incidence of alveolar/bronchiolaradenoma or carcinoma (combined) in exposed groups of males andfemales was significantly greater than that in the control groups.     

Effects of Acute Lead Acetate Exposure on Adult Guinea Pigs: Electrophysiological Study of the Inner Ear

The effects on humans of lead acetate exposure may involve thecranial nerves, since vertigo and sensory neuronal deafnesshave been reported in lead workers; however, there exist onlya few reports concerning the dose effects of lead acetate bothon the cochlea and the eighth cranial nerve. The effects oflead acetate on the cochlea and the eighth nerve were investigatedsystematically using cochlear microphonics (CM), wholenerveaction potential (AP), and endocochlear potential (EP) in guineapigs (male albino Hartley). Guinea pigs were injected with 2ml of a 1% solution of lead acetate (20 mg) once a week for1–5 weeks. The threshold of whole-nerve AP (N₁) was elevatedby injection of lead acetate, even 40 mg, and whole-nerve AP(N₁) output voltage decreased after injection of 100mg of leadacetate. On the other hand, no change was observed in CM afterlead acetate injection (100 mg) or in EP after lead acetateexposure (40 mg). The blood concentrations of lead acetate wereas follows (mean): control, 4.5 µg/dl; Expt 1, 80 µg/dl;Expt 2, 126 µg/dl; Expt 3, 142 µg/dl;. We concludethat dysfunction of the eighth nerve is induced by high-doselead exposure, but that lead exposure does not induce electrophysiologicaldysfunction of the organ of Corti and the stria vascularis.     

Clearance of Sulfuric Acid-Introduced 35S from the Respiratory Tracts of Rats, Guinea Pigs and Dogs Following Inhalation or Instillation

Clearance of Sulfuric Acid-Introduced ³⁵S from the RespiratoryTracts of Rats, Guinea Pigs and Dogs Following Inhalation orInstillation. Dahl, A.R., Felicetti, S.A., and Muggenburg, B.A.(1983). Fundam. Appl. Toxicol. 3: 293–297. The clearanceof sulfuric acid-introduced ³⁵S from the upper and lower respiratorytracts of rats, guinea pigs and dogs was measured. Sulfuricacid was administered by instillation and by inhalation foreach species. Clearance into the blood and gastrointestinaltract was measured along with determination of ³⁵S remainingat the site of administration at sacrifice. Different ratesof clearance from different sites within the dog lung were indicatedwith rates of clearance increasing with decreasing airway diameter.Half-times of clearance from all sites in the lung and for allspecies were from 2–9 min. There appeared to be some speciesdifferences, with clearance for dogs being slower than for guineapigs, which was slower than for rats. Upper respiratory tractclearance was much slower than for lung and may not have beenprimarily by way of the blood. The data indicate that the clearanceof sulfuric acid-introduced ³⁵S in vivo is faster than previousstudies in isolated perfused lungs had indicated. The resultsmay be general for water soluble, ionized chemical species.     

Acute Inhalation Studies with Methyl Isocyanate Vapor. II. Respiratory Tract Changes in Guinea Pigs, Rats, and Mice

Acute Inhalation Studies with Methyl Isocyanate Vapor. II. RespiratoryTract Changes in Guinea Pigs, Rats, and Mice. FOWLER, E. H.,AND DODD, D. E. (1986). Fundam. Appl. Toxicol. 6, 756–771.Hartley guinea pigs, Fischer-344 rats, and B6C3F1 mice of bothsexes were exposed to varying concentrations of methyl isocyanate(MIC) vapor with the highest concentration being 20.4 ppm forrats and mice and 10.5 ppm for guinea pigs. A control groupfor each species was exposed to air only. All animals were exposedfor a duration of 6 hr, and survivors were sacrificed14 daysfollowing exposure. The respiratory tract was removed and examinedmicroscopically from all animals. Guinea pigs were more sensitiveto the MIC vapor than were rats which were in turn more sensitivethan mice. Gross lesions encountered in many of the animalsthat diedconsisted of nasal discharge, often blood tinged, anddiscoloration of the lungs. Microscopic lesions included acutenecrosis of epithelial lining throughout the respiratory tractin animals that died shortly after exposure coupled with congestion,edema, and inflammation. A microscopic lesion which appearedunique to guinea pigs was bronchiolitis obliterans where thenecrosis and inflammation had completely closed the bronchioles.Additional microscopic lesions observed in some animals thatdied or were sacrificed at the end of the study (postexposureDay 14) consisted of squamous metaplasia of respiratory epitheliumin the nasal cavity, which extended into the larynx, trachea,and, in some cases, the bronchi. In addition, epithelial regenerationthroughout the tract and submucosal fibroplasia in the trachea,bronchi, and bronchioles were observed, the latter lesion beingprimarily confined to rodents. No animals exposed to 2.4 or1.0 ppm of MIC vapor died following exposure. There were minimalmicroscopic lesions at sacrifice in the 2.4ppm-exposed animalsfrom all three species. Only in guinea pigs were there lesionsin the 1.0-ppm group attributed to MIC vapor exposure.     

化学吸入性急性肺损伤/急性呼吸窘迫综合征患者的药学监护实践

摘 要 目的： 探讨临床药师对化学吸入性急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）患者的药学监护模式,保障患者用药安全、合理和有效。方法: 根据化学吸入性ALI/ARDS患者的药物治疗特点,对患者进行药学监护,有针对性提出用药建议。结果: 通过药学监护,可提高化学吸入性ALI/ARDS患者用药的安全性、合理性及有效性,减少药品不良反应的发生。结论:临床药师积极开展药学服务,协同临床医师优化给药方案,有利于患者用药安全、有效。