SUBCHRONIC TOXICITY OF CYCLOHEXANE IN RATS AND MICE BY INHALATION EXPOSURE

Inhalation studies were conducted to determine the potential toxicity and/or potential neurotoxicity of cyclohexane. Groups of rats and mice were exposed to 0, 500, 2000, or 7000 ppm concentrations of cyclohexane vapor 6 hr/day, 5 days/week for 14 weeks. Subgroups of rats and mice were further observed during a 1-month recovery period. Functional observational battery (FOB) and motor activity (MA) behavioral tests were conducted on rats. These tests were conducted prior to the exposure series and during weeks 4, 8, and 13 on non-exposure days. Clinical pathology evaluations were conducted after approximately 7, 13, and 18 weeks. Approximately 14 and 18 weeks after study initiation, tissues from rats and mice were histologically processed and evaluated by light microscopy.

During exposure to 2000 or 7000 ppm, rats and mice had a diminished response or an absent response to delivery of a punctate auditory alerting stimulus. Immediately following removal of rats from the inhalation chambers, 7000 ppm males and females and 2000 ppm females displayed a compound-related increase in the incidence of wet and/or stained fur (which occurred in the areas of the mouth, chin, and/or perineum). These signs were transient, were not observed during exposure or prior to exposure the following day, and were not associated with any behavioral or morphological changes. During exposure sessions, mice exposed to 7000 ppm exhibited clinical signs of toxicity which included hyperactivity, circling, jumping/hopping, excessive grooming, kicking of rear legs, standing on front legs, and occasional flipping behavior. Clinical signs of toxicity observed in 7000 ppm mice immediately after exposure included hyperactivity, hyperreactivity, ruffled fur (females only), gait abnormalities, spasms in both rear legs, and excessive grooming (males only). The clinical signs observed in mice during and immediately after exposure were transient, and were not present prior to the subsequent exposure. A few mice exposed to 2000 ppm appeared hyperactive during exposure in the latter portion of the study. There were no compound-related changes in mean body weights, body weight gains, food consumption, food efficiency, or mortality; and there were no ophthalmological abnormalities in rats or mice. In addition, there were no compound-related effects on 37 different behavioral parameters assessed during the FOB or during motor activity tests in rats.

Male and female mice exposed to 7000 ppm had slight increases in measures of circulating erythrocyte mass (red blood cells, hemoglobin, hematocrit) and plasma protein concentration (males only).

Male rats and male and female mice exposed to 7000 ppm had significantly increased relative liver weights, and 7000 ppm male mice also had significantly increased absolute liver weights at the end of the exposure period. At the end of the 1-month recovery period, absolute and relative liver weights of male and female mice were similar to control. However, relative liver weights of 7000 ppm male rats continued to be significantly higher at the end of the recovery period. Male and female rats exposed to 7000 ppm had a significantly increased incidence of hepatic centrilobular hypertrophy at the end of the exposure period, which was not observed at the conclusion of the 1-month recovery period. No microscopic changes were observed in mice.

In rats, the no-observed-effect level (NOEL) for acute, transient effects was 500 ppm based on a diminished/absent response to an auditory alerting stimulus at 2000 ppm and above. The NOEL for subchronic toxicity in rats was 7000 ppm based on the lack of adverse effects on body weight, clinical chemistry, tissue morphology, and neurobehavioral parameters. In mice, the NOEL for acute, transient effects was 500 ppm based on behavioral changes during exposure at 2000 ppm and above. The NOEL for subchronic toxicity in mice is 2000 ppm based on hematological changes at 7000 ppm.     

EFFECTS OF INHALED 1,1,1-TRICHLOROETHANE ON THE REGIONAL BRAIN CYCLIC GMP LEVELS IN MICE AND RATS

As it is known that volatile organic compounds (VOCs) exhibit differential dispositions among anatomically discrete brain regions in rodents as well as in humans, potential toxicological consequences of this pharmacokinetic feature were evaluated using measurements of cyclic GMP (glucose monophosphate). With the knowledge of 1,1,1-trichloroethane (TRI) uptake and distribution in the various brain regions, cyclic GMP was evaluated due to (1) known susceptibility to the effects of organic solvents, (2) pivotal physiological role in perpetuating changes in neurochemical pathways, and (3) possible involvement with neurobehavioral functions, whose disruption is one of the primary health effects associated with solvent exposures. Male CD-1 mice and SpragueDawley rats inhaled 5000 ppm TRI for 40 and 100 min in dynamic inhalation exposure chambers, and the brain was procured from the animals immediately following termination by microwave irradiation. After 40 min of TRI inhalation, significant decreases in cyclic GMP levels were found in the cerebellum of both species, 55% and 58%, respectively, relative to the controls. There was a further decrease in both species after 100 min of TRI inhalation. Smaller decreases in cyclic GMP were seen in the cortex of both species at both time points of measurement. A decrease in cyclic GMP was observed in the medulla oblongata of mice but not in rats after 40 min of exposure. Due to its signal transduction functions, it might be expected that the effects of TRI on cyclic GMP levels could directly impact neurological function. Comparison of the results from this study with the regional brain distribution of TRI and its effects on behavioral performance seen in previous studies by this laboratory appeared to indicate that alterations in brain cyclic GMP levels are only involved with the neurobehavioral toxicity of TRI in an indirect fashion; consequently, behavioral effects and decreases in cyclic GMP do not appear to be directly related to regionally differential dispositions of TRI in rodent brain.     

A CHRONIC INHALATION TOXICITY/ONCOGENICITY STUDY OF METHYLETHYLKETOXIME IN RATS AND MICE

To evaluate the oncogenic potential of methylethylketoxime (MEKO), CD-1 mice (50/sex/group) and F-344 rats (50/sex/group) were coexposed 6 h/day, 5 days/wk for 18 mo (mice) or 26 mo (rats) via whole-body inhalation exposures to target vapor concentrations of 0, 15, 75, and 375 ppm (actual concentrations of 0, 15 ± 1, 75 ± 2, or 374 ± 10 ppm). Satellite groups of rats and mice (10/sex/group/interval) were exposed for 12 mo (mice) and 3, 12, or 18 mo (rats) to evaluate chronic toxicity. Methyl ethyl ketone (MEK), a possible hydrolysis product of MEKO, was present at less than 1%. Treatment-related effects included increased body weight (male rats only), methemoglobin formation, hematology and clinical chemistry changes, increased liver weight, and increased spleen and testes weights (rats only). A high incidence of cataracts and corneal dystrophy occurred in both control and MEKO-exposed rats, with an earlier appearance and slightly higher incidence for these ocular lesions in MEKO-exposed animals compared to controls. Degenerative and reparative changes of the olfactory epithelium in the nasal turbinates, primarily limited to the dorsal meatus, occurred in both rats (75 and 374 ppm) and mice (15, 75, and 374 ppm). In addition, in the mice, liver changes included increased incidences of pigment in reticuloendothelial cells, centrilobular hypertrophy, granulomatous inflammation, and a slightly increased incidence of necrosis (75 and 374 ppm). An increase in hepatocellular carcinomas occurred in male mice at 374 ppm. Additional MEKO-related findings in the rat included congestion of the spleen with pigment in reticuloendothelial cells and extramedullary hematopoiesis and a decreased incidence of lymphoreticular mononuclear cell leukemia. Effects observed in the liver of the rats included decreases in the incidence of both peribiliary fibrosis and hyperplasia/proliferation of the biliary duct, an increase of spongiosis hepatis in males, and an increase in the incidence of intracytoplasmic vacuoles and hepatocellular basophilic foci. The effects on the liver were generally most profound in the high-exposure groups and, with the exception of the spongiosis hepatis, occurred in both sexes. An increase in hepatocellular adenomas occurred in the male rats at 75 and 374 ppm, and hepatocellular carcinomas in the male rats at 374 ppm. In both species, the liver tumors appeared relatively late in the life of the animals, with no significant increase in tumors at 12 mo of exposure in mice and at 18 mo of exposure in rats. Lifespan shortening was not observed, as MEKO-exposed animals survived generally as well as, or slightly better than, the controls.     

COMPARISON OF THE CHEMICAL EVOLUTION OF MMVF FOLLOWING INHALATION EXPOSURE IN RATS AND ACELLULAR IN VITRO DISSOLUTION

In the process of developing new fibers or evaluating existing fibers, the dissolution coefficient is often determined using an acellular in vitro assay. This coefficient has been found useful in selecting fibers based on solubility and has been shown to be related to the clearance half-time of long fibers (>20 m) following inhalation in rats. The chemical evolution of fibers following in vitro dissolution and inhalation was examined to evaluate the comparability of these two methods. The fibers studied ranged from compositions similar to commercial insulation materials to new glasses and stone wools that have been developed for enhanced solubility. The inhalation studies were performed using Fischer 344 male rats exposed to a well-defined rat respirable aerosol (mean diameter of 1 m) at a concentration of 30 mg/m3, 6 h/day for 5 days, with postexposure sacrifices at 1 h, 1 day, 5 days, 4 wk, 13 wk, and 26 wk. The in vivo results reported have been from fibers recovered from the lung that were primarily less than 20 m in length. The in vitro dissolution measurements were performed using a continuous-flow model with simulated lung fluid based upon a modified Gamble's media using either 1- or 10- m-diameter fibers without discrimination of length. The inhalation studies show that the composition of many of the fibers recovered from the lung changes with time in the lungs, with a depletion in Na O2, CaO, and MgO and a relative enrichment in SiO2 and Al2O3, with this evolution strongly depending upon glass composition. B2O3 has been found (on 10- m-diameter fibers in vitro as analyzed by secondary ion mass spectrometry) to also be depleted. The chemical evolution of these shorter fibers (L < 20 m) is consistent with that obtained from the in vitro experiments at pH 7.4, although the rate of variation observed with the two methods varied. These results clearly demonstrate that those fibers whose composition changes quickly during in vivo studies are the same as those whose composition changes quickly during in vitro assays. These studies demonstrate that the chemical evolution of the shorter fibers recovered following in vivo inhalation studies mirrors closely the changes found from the in vitro assays. These results complement those already reported for fibers longer than 20 m, which have been shown to be removed from the lung primarily by dissolution. </abs>     

AMG-1对小鼠和大鼠缺血脑能量代谢及神经细胞损伤的影响

本文观察AMG-1对小鼠断头全脑缺血时能量代谢及大鼠大脑中动脉阻断(MCAO)后行为和病理改变影响。小鼠sc AMG-1 1～10mg/kg 30min后,能有效减少脑缺血后乳酸(LA)堆积,ATP和磷酸肌酸(PCr)的耗竭。sc AMG-1 5mg/kg和尼英地平0.5 mg/kg,可减轻大鼠MCAO后的神经症状和神经细胞缺血性损害。AMG-1的这一改善脑缺血作用与尼莫地平近似。     

AMG-1对小鼠和大鼠缺血脑能量代谢及神经细胞损伤的影响

本文观察AMG-1对小鼠断头全脑缺血时能量代谢及大鼠大脑中动脉阻断(MCAO)后行为和病理改变影响。小鼠sc AMG-1 1～10mg/kg 30min后,能有效减少脑缺血后乳酸(LA)堆积,ATP和磷酸肌酸(PCr)的耗竭。sc AMG-1 5mg/kg和尼英地平0.5 mg/kg,可减轻大鼠MCAO后的神经症状和神经细胞缺血性损害。AMG-1的这一改善脑缺血作用与尼莫地平近似。     

奥拉西坦在大鼠和小鼠的药代动力学研究

目的： 研究奥拉西坦(ORC)在大鼠和小鼠的药代动力学。方法： 采用HPLC法测定生物样品中ORC浓度, 在大鼠和小鼠进行其药代动力学、吸收、分布、排泄试验。结果： 大鼠灌胃给ORC 100,200和400 mg.kg^-1后表明, 本品po吸收速率快,达峰时间短,药物自血清消除较快。小鼠1次ig给药100 mg.kg^-1后,80%以上药物在给药后3 h内由消化道消失;药物吸收后能分布到各种组织脏器, 给药后36 h累计尿排泄原形药物量约为药物剂量的80%; 蛋白结合率低,平均结合率为10.5%。结论： 奥拉西坦是一吸收快、消除快、主要以原形药物由尿排泄、蛋白结合率低的药物。     

高三尖杉酯碱在大鼠及小鼠的代谢

本文报告³H-高三尖杉酯碱在正常大鼠、小鼠和荷瘤小鼠体内的吸收、分布和排泄。给大鼠静注后,t_1/2(α)和(β)分别为2.1和53.7分钟。静注后15分钟,以骨髓、肾和肝的放射性最高。荷瘤小鼠体内的放射性分布情况与正常大鼠的趋势相仿。静注后24小时,自大鼠尿排泄剂量的42.2%,在粪中排出6.3%,其中原形药放射性占剂量的15.9%。静注后48小时,自胆汁排泄剂量的57.7%,其中原形药放射性占剂量的20.2%。该碱经肌注也可被迅速吸收入血。     

INHALATION TOXICITY OF CYCLOOCTADIENE IN RATS

Groups of 20 male Crl:CDBR rats each were exposed, whole-body, for six hours/day, for a total of nine exposures over a two-week period to concentrations of 52, 150, or 500 ppm of 1,5-cyclooctadiene vapor. A control group of 20 male rats was exposed simultaneously to houseline air. Ten rats per group were used for standard toxicological evaluations and ten rats per group for neurotoxicity testing. In the standard toxicology group, at the end of the exposure period, blood and urine samples were collected for clinical analyses, and five rats per group were sacrificed for pathologic examination. After a two-week recovery period, the surviving rats in the standard groups were also given clinical and pathological examinations. The neurotoxicity group was given a functional observational battery (FOB) test and motor activity evaluations after the fourth and ninth exposures. In addition, six of ten neurotoxicity rats per exposure group were given neuropathology evaluations at the end of the exposure period.

In rats exposed to 500 ppm of 1,5-cyclooctadiene there was an absence of alerting response toward the end of the daily six-hour exposures. These rats appeared to recover within 1/2 hour after exposure. This effect was not observed in the other test groups.

The FOB evaluation showed an increase in the number of rats found sleeping in the 500 and 150 ppm groups compared to controls after the last exposure, but there were no treatment-related effects in the motor activity evaluation. Since there were no other neurobehavioral findings and no toxicity findings in the 150 ppm group, the sleeping behavior in the 150 ppm group was considered insufficient evidence of an adverse effect.

Clinical laboratory evaluation of the 500 ppm group showed urinary pH decreases at the end of the exposure period but not after the twoweek recovery period. There were no other toxicologically important changes in urine analysis, hematologic, or blood chemistry evaluations attributable to the test compound.

Histologic effects were found in the nose and kidneys of rats in the 500 ppm group. There was a mild degeneration/necrosis of nasal olfactory epithelium observed immediately after the exposure period and a mild degeneration/regeneration in this area observed after the two-week recovery. In addition, there were increased kidney weights in the 500 ppm group immediately after exposure along with increased hyaline droplets in the kidneys. These effects were reversible after the two-week recovery period. There were no significant nasal or kidney effects observed in the 150 and 52 ppm test groups, and no other organ weight or histological effects attributable to the test compound observed in the standard toxicology groups at either evaluation time. The neuropathologic evaluation showed only one minor lesion in one 500 ppm-group rat and this was not considered to be attributable to exposure to 1,5-cyclooctadiene.

Based on the decreased alerting response observed in rats during exposure at 500 ppm, and on the effects observed in the nose, kidney, and urine in rats at this concentration, the no-observed-adverse-effect (NOAEL) level in this study was considered to be 150 ppm.     

EXTRAPULMONARY TRANSLOCATION OF ULTRAFINE CARBON PARTICLES FOLLOWING WHOLE-BODY INHALATION EXPOSURE OF RATS

Studies with intravenously injected ultrafine particles have shown that the liver is the major organ of their uptake from the blood circulation. Measuring translocation of inhaled ultrafine particles to extrapulmonary organs via the blood compartment is hampered by methodological difficulties (i.e., label may come off, partial solubilization) and analytical limitations (measurement of very small amounts). The objective of our pilot study was to determine whether ultrafine elemental carbon particles translocate to the liver and other extrapulmonary organs following inhalation as singlet particles by rats. We generated ultrafine 13 C particles as an aerosol with count median diameters (CMDs) of 20-29 nm (GSD 1.7) using electric spark discharge of 13 C graphite electrodes in argon. Nine Fischer 344 rats were exposed to these particles for 6 h. in whole-body inhalation chambers at concentrations of 180 and 80 w g/m 3 ; 3 animals each were killed at 0.5, 18, and 24 h postexposure. Six unexposed rats served as controls. Lung lobes, liver, heart, brain, olfactory bulb, and kidney were excised, homogenized, and freeze-dried for analysis of the added 13 C by isotope ratio mass spectrometry. Organic 13 C was not detected in the 13 C particles. The 13 C retained in the lung at 0.5 h postexposure was about 70% less than predicted by rat deposition models for ultrafine particles, and did not change significantly during the 24-h postexposure period. Normalized to exposure concentration, the added 13 C per gram of lung on average in the postexposure period was ~9 ng/g organ/ w g/m 3 . Significant amounts of 13 C had accumulated in the liver by 0.5 h postinhalation only at the high exposure concentration, whereas by 18 and 24 h postexposure the 13 C amount of the livers of all exposed rats was about fivefold greater than the 13 C burden retained in the lung. No significant increase in 13 C was detected in the other organs which were examined. These results demonstrate effective translocation of ultrafine elemental carbon particles to the liver by 1 d after inhalation exposure. Translocation pathways include direct input into the blood compartment from ultrafine carbon particles deposited throughout the respiratory tract. However, since predictive particle deposition models indicate that respiratory tract deposits alone may not fully account for the hepatic 13 C burden, input from ultrafine particles present in the GI tract needs to be considered as well. Such translocation to blood and extrapulmonary tissues may well be different between ultrafine carbon and other insoluble (metal) ultrafine particles.     

INHALATION TOXICITY OF POTASSIUM OCTATITANATE FIBERS (TISMO) IN RATS FOLLOWING 13 WEEKS OF AEROSOL EXPOSURE

One hundred and forty male and 140 female rats were divided into 1 control and 3 test groups of 35 rats each, per sex, and exposed by whole-body inhalation to test compound at target concentrations of 0, 1 mg/m³ (1700 fibers/cm³, 123 WHO fibers/cm³), 10 mg/m³ (5900 fibers/cm³, 952 WHO fibers/cm³), and 100 mg/m³ (112,700 fibers/cm³, 7440 WHO fibers/cm³) for 6 h/day, 5 days/wk for 13 wk. Ten rats from each group were killed after 13 wk of exposure and 13 wk of recovery, respectively, for histopathological evaluation. The other 15 rats from each group were killed to study lung clearance after 91 days of exposure, and approximately 1.5 and 3 mo of recovery following the end of the 13 wk of exposure. The mean fiber length of the chamber atmosphere was 2.8, 2.7, and 2.8 µm, while the mean fiber width was 0.48, 0.48, and 0.45 µm for the 1-, 10-, and 100-mg/m³ chambers, respectively. In the 1-mg/m³ (123 WHO fibers/cm³) exposure group, inhaled particles were mostly retained in a few fiberladen alveolar macrophages (AMs) within the alveoli adjacent to alveolar ducts without any adverse tissue response throughout 13 wk of exposure and following 13 wk of recovery. This exposure concentration was considered to be a no-observable-adverse-effect level (NOAEL), since the alveoli containing fiber-laden AMs preserved normal structure. After 13 wk of exposure to 10 mg/m³ (952 WHO fibers/cm³), fiber-laden AMs were mainly retained at the alveoli adjacent to the alveolar ducts. Infrequently, slight fibrotic thickening was observed in the alveolar ducts and adjoining alveoli, with proliferating fibroblasts and hyperplastic Type II pneumocytes, and microgranulomas. Occasionally, trace amounts of collagenous material were deposited in the thickened alveolar ducts and adjoining alveolar walls. In addition, minimal alveolar bronchiolarization was occasionally found in the alveoli adjacent to the terminal bronchioles. The peribronchial lymphoid tissue and thymic lymph nodes contained migrated fiber-laden AMs. After 13 wk of recovery, fiber-laden AMs had mostly disappeared from alveoli located in the peripheral acini, but they localized in the alveolar ducts region, suggesting there was active lung clearance of fibers by the AMs via airways. Thickened alveolar ducts and adjacent alveoli were decreased in thickness, a reversible change manifested by reduction of proliferating Type II pneumocytes and fibroblasts. Collagenized fibrosis was slightly more pronounced in the thickened alveolar ducts and adjoining alveoli. The lung response following 13 wk of exposure to 100 mg/m³ (7440 WHO fibers/cm³) and after 13 wk of recovery was similar to those findings of the 952 WHO fibers/cm³ group but more pronounced, demonstrating a clear concentration-related response. Alveolar ducts and adjoining alveolar walls in the central acini were irregularly thickened with more frequent evidence of minimal collagenized fibrosis. The lung burden and clearance of fibers were estimated by measuring the total content of titanium (Ti) in the lungs, but high variability of Ti content in control and exposed groups prevented meaningful lung clearance analysis.     

ACUTE AND SUBCHRONIC NEUROTOXICOLOGICAL EVALUATION OF TETRAHYDROFURAN BY INHALATION IN RATS

Groups of adult male and female rats received exposure to tetrahydrofuran (THF) vapor by inhalation in acute or subchronic exposure scenarios. Acute exposure concentrations were 0, 500, 2500, or 5000 ppm for 6 hr. Evaluations conducted immediately after exposure included clinical observations, motor activity assessments (MA), and a battery of functional tests (FOB) designed to reveal nervous system dysfunction. During exposure to 2500 and 5000 ppm, rats had a diminished or absent startle response to a punctate auditory alerting stimulus. Following exposure to 5000 ppm, male and female rats were lethargic, exhibited abnormal gait or mobility, and splayed rear feet. Lethargy and splayed rear feet were also observed in females esposed to 2500 ppm. During the subsequent FOB, males exposed to 5000 ppm had a lower incidence of palpebral closure, higher incidences of slow or absent righting reflex, and a biphasic pattern of reduced motor activity followed by increased motor activity. Females exposed to 5000 ppm had increased incidences of palpebral closure in the open field, increased incidences of slow or absent righting reflex, and decreased motor activity.

During the 14-week subchronic exposure series, daily THF exposure concentrations were 0, 500, 1500, or 3000 ppm, and neurobehavioral evaluations occurred on non-exposure days at approximately monthly intervals. Diminished startle responses to an auditory alerting stimulus were observed during exposure to 1500 or 3000 ppm; however, repeated exposures did not cause additional neurobehavioral or pathological effects. This pattern of effects is suggestive of transient sedation. Despite daily reinstatement of acute sedative effects during repeated exposure with up to 3000 ppm, THF did not produce any persistent or cumulative effects on nervous system structure or function. The demonstrated no-observed-effect level of THF for both acute and subchronic exposure was 500 ppm.     

去氢骆驼蓬碱静脉注射乳剂在动物体内的药代动力学

目的：研究去氢骆驼蓬碱（harmine,HAR）静脉注射乳剂在大鼠体内的药动学和小鼠体内的组织分布。方法：HPLC法测定血药浓度,计算药动学参数;用放射性同位素示踪法测定给药后各脏器组织的分布特征。结果：iv给药,药动学过程可用三室开放模型拟合;乳剂的组织分布能力强于水溶液。iv或ig乳剂,³H-HAR定向于肝、淋巴器官分布。乳剂的LD₅₀大于水溶液。结论：将HAR制成静脉注射乳剂可改变HAR体内过程,降低其神经系统毒副作用。     

甘氨双唑钠在大鼠和小鼠体内药代动力学

目的　观察甘氨双唑钠(CMNa)在动物体内的药代动力学。方法　采用HPLC方法测定生物样品中CMNa及其代谢物甲硝唑的含量。结果　小鼠体外转化试验表明血中90 min CMNa的转化率为91.8%,甲硝唑的生成率为67.3%。小鼠iv CMNa 57.3,171.9和515.7 mg.kg^-1后CMNa的T_{1/2T1/2β约为60 min。大鼠iv CMNa 171.9 mg.kg^-1后2 min及5 min CMNa及甲硝唑在组织含量较高;药后从尿中排泄的CMNa和甲硝唑分别占给药总量的8.4%和16.7%,从胆汁排泄分别占11.5%和5.1%,从粪排泄占0.14%和0.03%。CMNa平均血浆蛋白结合率为14.2%。结论　CMNa在体内迅速代谢为甲硝唑,原型药及代谢物的Cmax和AUC均与剂量正相关,二者主要经尿和胆汁排泄。}     

REPEATED EXPOSURE INHALATION STUDY OF PENTANE IN RATS

Pentane (CAS No. 109-66-0) is a chemical being used as a co-solvent in a polymer production facility with potential for inhalation exposure in humans. To assess the toxicity of pentane, groups of 10 male rats each were exposed by inhalation, 6 hr/day, 5 days/week for 2 weeks to either 0 (control), 1,000, 3,000 or 10,000 ppm. Five rats per group were killed following the 10th exposure; the remaining 5/group were killed after a 14-day post-exposure recovery period. Parameters investigated were clinical signs of toxicity, functional behavior, body weights, clinical pathology, and gross and microscopic pathology including organ weights. No unusual clinical observations were seen in the pentane-treated rats, and body weights were not altered. Test rats generally exhibited normal behavioral responses in the functional observational battery. Increases in serum calcium and phosphorus concentrations were seen in rats exposed to either 3,000 or 10,000 ppm. These were reversible during the 2-week recovery period. No other clinical pathology changes were observed and no pentane-related tissue pathology was seen in any of the groups. The no-observed-adverse-effect level was 1,000 ppm with reversible clinical pathology changes produced at 3,000 and 10,000 ppm.     

神经妥乐平抗脑水肿的作用及机制

用阻断大鼠大脑中脑动脉及小鼠侧脑室注射角叉菜胶所致的脑水肿模型,研究神经妥乐平抗脑水肿作用及机制。结果表明,阻断大脑中动脉15min后,舌下静脉给予神经妥乐平1.5,3.0及15.0NU·kg^-1,能减轻缺血性脑水肿;小鼠侧脑室注射角叉菜胶后即刻自尾静脉给与神经妥乐平3.0,6.0及30.0NU·kg^-1,其中30.0NU·kg^-1能明显减轻脑水肿。提示神经妥乐平减轻缺血性脑水肿的机制可能与其抑制激肽—缓激肽系统的作用有关。     

EVALUATION OF THE POTENTIAL IMMUNOTOXICITY OF BROMODICHLOROMETHANE IN RATS AND MICE

In the past two decades, concern has been expressed over the potential carcinogenicity of disinfection by-products (DBPs) found in chlorinated drinking water. More recently, research efforts have expanded to include noncancer endpoints as well. The objective of the present studies was to evaluate the potential of bromodichloromethane (BDCM), one of the most prevalent DBPs, to adversely affect immune function in mice and rats following drinking water or gavage exposure. Antigen-specific immunity was assessed as the antibody response to sheep erythrocytes; responses to T-and B-cell mitogens were evaluated as a non-antigen-specific measure of the proliferative potential of splenic and mesenteric lymph node lymphocytes. In consideration of an exposure route relevant to humans, C57BL/6 mice received 0.05, 0.25, or 0.5 g BDCM/L and F344 rats received 0.07 or 0.7 g BDCM/L via drinking water. In order to evaluate the effects of higher doses, animals were administered 50, 125, or 250 mg BDCM/kg/d (mice) or 75, 150, or 300 mg BDCM/ kg/d (rats) via gavage. Under the conditions of these studies, no significant adverse effects on immune function were observed in mice. Despite some changes that were observed in non-antigen-specific immunity in rats, these experiments suggest that the immune system is not a sensitive target organ for BDCM toxicity.     

BRAIN BIOGENIC AMINES AND INTRAVENOUS SELF-ADMINSTRATION OF COCAINE IN RATS

1. The possible involvement of noradrenaline, dopamine, serotonin and 5-hydroxyindoleacetic acid in the behavioural reinforcement produced by intravenous cocaine has been investigated. 2. Rats, in Skinner boxes, were allowed to self-administer cocaine through a chronically implanted jugular vein cannula. A consistent response rate in the order of one self-administration every 10 min was observed with a dose of 3.0 mg/kg cocaine hydrochloride per response. 3. Another group of rats was cannulated and injected with a range of one to six such doses of cocaine at 10 min intervals on the basis of the responding rate, established by rats in the Skinner box. At times of 2, 5 and 8 min after each dose of cocaine, the rats were decapitated and brain concentrations of noradrenaline, dopamine, serotonin and 5-hydroxyindoleacetic acid were determined. 4. The brain levels of noradrenaline exhibited a cyclic pattern of rise and fall after each dose of cocaine, which corresponded in its time base with the time interval between responses established by the rats in the Skinner box.