Unidirectional Cross-Tolerance Between the Carbamate Insecticide Propoxur and the Organophosphate Disulfoton in Mice

Unidirectional Cross-tolerance Between the Carbamate InsecticidePropoxur and the Organophosphate Disulfoton in Mice. Costa,L.G. and Murphy, S.D. (1983). Fundam. Appl. Toxicol. 3:483–488.Previous studies have shown that subchronic treatment of micewith the organophosphate insecticide, disulfoton, or the carbamateinsecticide, propoxur, leads to the development of toleranceto their toxicity. Tolerance to disulfoton was due to a decreasein the number of muscarinic cholinergic receptors, while toleranceto propoxur appeared to be due to an induction of hepatic microsomalenzymes. In the present study we investigated if cross-tolerancebetween disulfoton and propoxur would occur. Cross-tolerancewas evaluated by measuring acute toxicities, cholinesteraseand carboxylesterase inhibition and hypothermic and antinociceptiveeffects. Mice tolerant to propoxur were cross-tolerant to thehypothermic and anticholinesterase effects of disulfoton. Similarly,when mice were pretreated with the microsomal enzyme inducer,phenobarbital, the toxicity of disulfoton was decreased. Micemade tolerant to disulfoton were cross-tolerant to the organophosphatechlorpyrifos, but were more sensitive than controls to the toxicityof propoxur. The acute toxicity of the organophosphate malathionwas also increased in disulfoton-tolerant mice. Propoxur ismetabolized by mixed function oxidases and possibly by a carboxylesterase.While hepatic microsomal enzymes appeared to be unchanged indisulfoton-tolerant mice, brain and liver carboxylesterase activitieswere significantly inhibited. Pretreatment of mice with thespecific carboxylesterase inhibitor triorthotolyl phosphateis known to greatly potentiate the toxicity of malathion andalso potentiated, to a lesser extent, the toxicity of propoxur.The results indicate that chronic exposure to an anticholinesteraseinsecticide may lead to tolerance to the toxicity of the inducingcompound by more than one mechanism and that the of other insecticidesmay be either increased or decreased.     

Evidence for a Hazardous Interaction between Ethanol and the Insecticide Endosulf an in Rats

Abstract: Protein supplemented diet was protective against the deleterious action of endosulfan on body growth and liver. Hepatomegaly and a reduction of body weight produced concurrently by endosulfan and ethanol were greater in male rats, suggesting that males are more susceptible than female rats to the metabolic stress caused by their interaction. Chronic endosulfan exposure resulted in a prolongation of ethanol sleeping time in female and not in male rats. This finding suggests failure of female rats to metabolize ethanol readily on account of their greater susceptibility than male rats to the hepatotoxic action of endosulfan.     

Reproduction Study of Dimethylacetamide following Inhalation in the Rat

Reproduction Study of Dimethylacetamide following Inhalationin the Rat. Ferenz, R. L., and Kennedy, G. L., Jr. (1986). Fundam.Appl Toxicol. 7, 132-137. Groups of 10 male and 20 female Crl:CD(SD)BRrats were exposed to vapors of dimethylacetamide (DMAC) at concentrationsof 0 (control), 30, 100, or 300 ppm. Exposures were conductedfor 6 hr/day, 5 days/week for 10 weeks (prebreeding), then 7days/week for 7 to 8 weeks (through breeding, gestation, andlactation). The exposure period was interrupted for female ratsbetween gestation Day 21 and postpartum Day 4. No compound-relatedeffects on body weight, survival, or clinical signs were detectedin parental rats. Liver weight to body weight ratios were increasedin groups where both males and females were exposed to 300 ppmbut not in groups where only males or only females were exposedto 300 ppm. No significant differences were observed betweencontrol and test rats with respect to mating performance, fertility,length of gestation, progeny numbers, structure, and viability.At 21 days postpartum, pups derived from matings involving exposureof both sexes to 300 ppm or exposure of parental females to300 ppm had lower body weights than did the controls. Grosspathologic examination of representative pups and evaluationof liver and gonad weight data did not reveal any DMAC-relatedchanges. It is concluded that reproduction in rats was not alteredby repeated inhalation exposure to up to 300 ppm DMAC.     

Modulation of lnterleukin-2-Driven Proliferation of Human Large Granular Lymphocytes by Carbaryl, an Anticholinesterase Insecticide

Modulation of Interieukin-2-Driven Proliferation of Human LargeGranular Lymphocytes by Carbaryl, an Anticholinesterase Insecticide.Bavari, S., Casale, G. P., Gold, R. E., and Vitzthum, E. F.(1991). Fundam. Appl. Toxicol. 17,61-74. Studies in other laboratorieshave provided evidence that the interleukin-2 (IL2) signalingpathway in lymphocytes includes essential, serine proteases.Since the anticholinesterase (antiCHE) insecticides are potentserine hydrolase (esterase and protease) inhibitors, we assessedthe ability of carbaryl (CA, a widely used antiCHE insecticide)and a-naphthol (NA, a major metabolite of carbaryl) to modulateIL2-driven proliferation of large granular lymphocytes (LGL)purified from human peripheral blood. These cells express nearlyall of the natural killer (NK.) activity of human peripheralWood. NK cells are normal lymphocytes that respond to IL2 byproliferating and increasing their tumoricidal activity on aper cell basis. Cultures of purified LGL, initiated in the presenceof human recombinant IL2, were harvested on culture Day 4, thenproliferation was measured as [³H]thymidine incorporation. Whenadded only at the time cultures were initiated, CA inhibitedincorporation 10-32%, 35-53%, and 54-57% at 0.5, 5.0, and 50mm, respectively. In contrast, NA had no effect at 0.5 and 5.0mm, but was inhibitory (16-17%) at 50 mm. Reexposure to CA orNA, during the incorporation assay, had little effect on theobserved inhibition profiles. Chemically induced changes incell number during an 8-day culture period reflected the chemicallyinduced changes in [³H]thymidine incorporation. Neither CA norNA produced cell death. Quantitation of both CA and NA by HPLCindicated a rapid loss of CA (ca. 95% in 24 hr) and a much slowerloss of NA from the culture medium. CA inhibited human LGL proliferationat concentrations producing little or no inhibition of serumCHE, an indicator of exposure to antiCHE insecticides.     

Reproduction and Fertility Evaluations in CD Rats following Nitrobenzene Inhalation

Reproduction and Fertility Evaluations in CD Rats followingNitrobenzene Inhalation. DODD, D. E., FOWLER, E. H., SNELLINGS,W. M., PRITTS, I. M., TYL, R. W., LYON, J. P., O'NEAL, F. O.,and KIMMERLE, G. (1987). Fundam. Appl. Toxicol. 8, 493–505.A two-generation reproduction study was performed by exposureof Sprague–Dawley CD rats to concentrations of 40, 10,1, or 0 (control) ppm of nitrobenzene (NB) vapor. No NB-relatedeffects on reproduction were observed at 10 or 1 ppm. At 40ppm, a decrease in the fertility index of the F₀ and F₁ generationsoccurred, which was associated with alterations in the malereproductive organs. Specifically, weights of testes and epididymideswere reduced and seminiferous tubule atrophy, spermatocyte degeneration,and the presence of giant syncytial spermatocytes were observed.The only significant finding in the litters derived from ratsexposed to 40 ppm was an approximate 12% decrease in the meanbody weight of F₁ pups on Postnatal Day 21. Survival indiceswere unaltered. To examine the reversibility of this selectiveeffect on male gonads, the F₁ males from the 40-ppm group wereallowed a 9-week nonexposure period and mated to naive females.An almost fivefold increase in the fertility index was observed,indicating at least partial functional reversibility upon removalfrom NB exposure. Also, the numbers of giant syncytial spermatocytesand degenerated spermatocytes were greatly reduced. The resultsof this study support the selection of 10 ppm of NB as the no-observable-effectlevel for reproduction and fertility effects in rats.     

Rapid Communication: Postmortem Distribution of Organophosphate Insecticides in Human Autopsy Tissues Following Suicide

Organophosphate insecticides (OP) are used widely in Turkey and are the most common agent employed for suicidal poisoning. At present there are limited data available on the distribution of OP in humans, and the aim of the study was to report insecticide concentrations in human autopsy tissues. With the use of gas chromatography-nitrogen phosphorous detector, the levels of fat, liver, and blood OP were determined from 32 suicide victims. In all cases OP were present and usually more than one OP was found. The concentration of OP was highest in fat and least in blood. Even 20 d postmortem OP could be detected in human autopsy tissues, but the correlation to fat content and mortality needs to be addressed.     

反相高效液相色谱法测定重组人肿瘤坏死因子衍生物

用正交试验法选择确定了反相高效液相色谱法分离测定ｒｈ－ＴＮＦ的条件，并在此条件下对３个厂家的７批产品进行了纯度测定，结果表明本法简便、准确、快速、选择性高。同时本文还确定了测定产品比例色谱的条件，测定了ｒｈ－ＴＮＦ比例色谱峰高，为产品鉴别提供了更为可靠的方法。     

七氟醚吸入不同时间对患儿顺式阿曲库铵肌松效应的影响

目的:探讨七氟醚吸入时间对患儿顺式阿曲库铵肌松效应的影响。方法:择期行颜面、颈部手术(唇裂修复术、腭裂修复术和甲舌囊肿切除术)的患儿60例,美国麻醉师协会(ASA)分级Ⅰ或Ⅱ级,年龄2～8岁,按用药情况分为吸入七氟醚30min组(S30组)、吸入七氟醚60min组(S60组)和全凭静脉麻醉组(T组),各20例。麻醉诱导后,静脉注射顺式阿曲库铵0.15mg·kg-1,S30组和S60组插管后即刻吸入七氟醚,维持呼气末浓度2.5%,分别吸入30min和60min;T组全凭静脉麻醉。行连续4个成串刺激(TOF)方式,采用肌松监测仪监测拇内收肌的肌松情况。记录肌松起效时间(Tonset)、最大效应持续时间(DURp)、临床作用时间(DURc)、恢复指数(RI)、体内作用时间(DURt)及TOFR(T4/T1)恢复至90%的时间(TOFR0.9)。结果:3组Tonset比较差异无统计学意义(P>0.05);与T组比较,S30组和S60组DURp、DURc、TOFR0.9延长,S60组DURt、RI延长(P<0.05);与S30组比较,S60组DURp、DURc、DURt和TOFR0.9延长(P<0.05)。结论:2.5%七氟醚可增强患儿顺式阿曲库铵的肌松效应,且随吸入时间延长而增强,持续吸入60min可延迟自然恢复,吸入时间不超过30min则不会。     

Assessment of Toxicity of o-Nitrochlorobenzene in Rats following a 4-Week Inhalation Exposure

Assessment of Toxicity of o-Nitrochlorobenzene in Rats followinga 4-Week Inhalation Exposure. NAIR, R.S., JOHANNSEN, F.R., LEVINSKAS,G.J., AND TERRILL, J.B. (1986). Fundam. Appl. Toxicol. 7, 609-614.o-Nitrochlorobenzene (ONCB) is a chemical intermediate usedfor the synthesis of various industrial chemicals. To evaluatethe subchronic toxicity of this compound, three groups of 15male and 15 female Sprague-Dawley rats were exposed to ONCBvapor 6 hr/day, 5 days/week for 4 weeks at target concentrationsof 10, 30, or 60 mg/m³. A control group of 15 animals/sex wasexposed to room air in a separate inhalation chamber. Concentrationsof ONCB in the chambers were determined at least three timesa day using a uv spectrophotometer. Parameters monitored inthis study included observation for signs of toxicity, bodyweights, ophthalmoscopic exam, hematology, and clinical chemistry.At necropsy, selected organ weights were recorded and over 35tissues/animal were examined microscopically for all controland high-exposure level animals. No mortality was observed inthis study. Mean body weights of all groups were comparableto controls. Animals exposed to the mid and high concentrationsof ONCB showed a significant increase in blood methemoglobinand a significant decrease in hemoglobin, hematocrit, and redblood cell counts. Spleen and liver weights (absolute and relativeto body weight) were significantly increased for these two groups.Microscopic changes, observed only in the spleen, included increaseddegree of extramedullary hematopoiesis and hemosiderosis. Thesedata suggest that the toxicity of ONCB is comparable to thatof its structural analog, p-nitrochlorobenzene. Thus these twocompounds should have similar workplace exposure limits.     

Degeneration and Recovery of Rat Olfactory Epithelium following Inhalation of Dibasic Esters

Degeneration and Recovery of Rat Olfactory Epithelium followingInhalation of Dibasic Esters. KEENAN, C. M., KELLY, D. P., ANDBOGDANFFY, M. S. (1990) Fundam. Appl. Toxicol. 15, 381–393.Dibasic esters (DBE) are solvent mixtures used in the paintand coating industry. To evaluate the potential subchronic toxicityof DBE, groups of male and female rats were exposed for periodsof up to 13 weeks to DBE concentrations of 0, 20, 76, or 390mg/m3. After approximately 7 and 13 weeks of exposure, 10 ratsper sex per group were subjected to clinical chemical, hematological,and urine analyses. Following 7 or 13 weeks of exposure, 10or 20 rats per sex per group, respectively, were euthanized.An additional 10 rats were euthanized following a 6-week recoveryperiod. A standard profile of tissues, including four levelsof nasal cavity, was evaluated histopathologically. After 7weeks of exposure, slight degeneration of the olfactory epitheliumwas observed in both male and female rats at 76 and 390 mg/m3.After 13 weeks, degeneration of the olfactory epithelium waspresent at all DBE concentrations in female rats, but only atthe mid and high concentrations in male rats. The severity andincidence of the lesions were concentration related for bothsexes with female rats being more sensitive than males. Followingthe recovery period, histological changes compatible with repairin the olfactory mucosa included an absence of degeneration,focal disorganization of the olfactory epithelium, and respiratorymetaplasia. All other tissues were macroscopically normal. Noother signs of toxicity were indicated by the other parametersevaluated. Inhalation studies of other esters demonstrate similarpathology in the olfactory epithelium. Since olfactory mucosais rich in carboxylesterase activity, acids may be the toxicmetabolites of these compounds. This hypothetical mechanismmay explain the sensitivity of olfactory tissue to the effectsof DBE     

The Immunotoxicity of Three Nickel Compounds following 13-Week Inhalation Exposure in the Mouse

The Immunotoxicity of Three Nickel Compounds following 13-WeekInhalation Exposure in the Mouse. HALEY, P. J. SHOPP, G. M.,BENSON, J. M, CHENG, Y.-S., BICE, D. E., LUSTER, M. I., DUNNICK,J. K., AND HOBBS, C. H. (1990). Fundam. Appl. Toxicol 15, 476–487.Groups of B6C3F₁, mice were exposed to aerosols of nickel subsulfide(Ni₃S₂), nickel oxide (NiO), or nickel sulfate hexahydrate (NiSO₄6H₂O)6 hr/day, 5 days per week for 65 days to determine the immunotoxicityof these compounds. Exposure concentrations were 0.11, 0.45,and 1.8 mg Ni/m³ for Ni₃S₂, 0.47, 2.0, and 7.9 mg Ni/m³ forNiO; and 0.027, 0.11, and 0.45 mg Ni/m³ for NiSO₄. Thymic weightswere decreased only in mice exposed to 1.8 mg Ni/m³ Ni₃S₂. Increasednumbers of lung-associated lymph nodes (LALN), but not spleennucleated cells, were seen with all compounds. Nucleated cellsin lavage samples were increased in mice exposed to the highestconcentrations of NiSO₄ and NiO and to 0.45 and 1.8 mg Ni/m³Ni₃S₂. Increased antibody-forming cells (AFC) were seen in LALNof mice exposed to 2.0 and 7.9 mg Ni/m³ NiO and 1.8 mg Ni/m³Ni₃S₂. Decreased AFC/10⁶ spleen cells were observed in miceexposed to NiO, and decreased AFC/spleen were seen for miceexposed to 1.8 mg Ni/m³ Ni₃S₂. Only mice exposed to 1.8 mg Ni/m³Ni₃S₂ had a decrease in mixed lymphocyte response. All concentrationsof NiO resulted in decreases in alveolar macrophage phagocyticactivity, as did 0.45 and 1.8 mg Ni/m³ Ni₃S₂. None of the nickelcompounds affected the phagocytic activity of peritoneal macro-phages.Only 1.8 mg Ni/m³ Ni₃S₂ caused a decrease in spleen naturalkiller cell activity. Results indicate that inhalation exposureof mice to nickel can result in varying effects on the immunesystem, depending on dose and physicochemical form of the nickelcompound. These nickel-induced changes may contribute to significantimmunodysfunction.     

RP-HPLC法测定鼻用重组人胰岛素粉雾剂中的相关蛋白质

分别采用并比较中国药典2005年版中重组人胰岛素中相关蛋白质测定的洗脱程序及改进后的洗脱程序考察胰岛素原药及其粉雾剂的相关蛋白含量.结果表明,采用改进法测得的胰岛素出峰时间恒定,柱效明显提高,主药峰与杂质峰分离更好,相关蛋白质检出量更高.     

吸入麻醉剂浓度及作用时间对人离体精子活率的影响

目的:研究吸入麻醉剂浓度及作用时间对人离体精子活率的影响。方法:选择人精液20份,上游法优化处理后随机分为异氟醚实验组和七氟醚实验组,各10份。分别观测5个时间点(0.5 h、1 h、2 h3、h4、h)及5个浓度水平(0、1.4%、2.8%、4.2%、5.6%)异氟醚和相似浓度七氟醚对精子活率的影响,精子运动功能采用计算机辅助精子分析系统分析。结果:1.4%~5.6%异氟醚作用于精子0.5~4 h后,精子活率显著升高,其变化趋势符合S型曲线,相同浓度异氟醚组,精子活率随放置时间的延长成直线下降。类似浓度七氟醚对精子活率无显著影响。结论:临床浓度异氟醚作用于人离体精子,可以显著升高精子活率。类似浓度七氟醚对精子活率无显著影响。     

InVitro Evaluation of Optimal Inhalation Flow Patterns for Commercial Dry Powder Inhalers and Pressurized Metered Dose Inhalers With Human Inhalation Flow Pattern Simulator

This study aimed at developing a novel analytical method to identify optimal inhalation flow patterns for commercial dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs). As typical commercial DPI and pMDI, Pulmicort^® Turbuhaler^®, and Sultanol^® Inhaler were evaluated by an in vitro inhalation performance testing system with a flow pattern simulator. An 8-stage Andersen cascade impactor (ACI) or twin stage liquid impinger (TSLI) was applied to determine the inhalation performance. The peak flow rate (PFR) of the inhalation flow pattern was set from 15 to 80 L/min in reference to our previous study. From TSLI test results, a higher PFR improved the inhalation performance of the DPI, while the performance of the pMDI was less affected by the PFR. Conversely, from ACI test results, the pMDI performance decreased with a higher PFR, while the DPI followed a similar pattern as in the TSLI test results, because ACI is a finer aerodynamic classification apparatus than TSLI. These results suggested that our in vitro system using a human inhalation flow pattern simulator successfully detected different optimal inhalation patterns between DPI and pMDI. That is, the higher PFR is better for Pulmicort^® Turbuhaler^® (DPI). Conversely, lower PFR is desirable for Sultanol^® Inhaler (pMDI).     

Evaluation of Spermatogenesis and Sperm Quality in the Rat following Acute Inhalation Exposure to Methyl Bromide

Evaluation of Spermatogenesis and Sperm Quality in the Rat followingAcute Inhalation Exposure to Methyl Bromide. HURTT, M. E., ANDWORKING, P. K. (1988). Fundam Appl Toxicol. 10, 490–498.Methyl chloride (MeCl) and methyl bromide (MeBr) have similartarget organ specificities in the male F-344 rat, and MeCl isa known reproductive toxicant in that species. Recently, bothacute and subchronic inhalation exposures to MeBr were foundto produce varying degrees of testicular alteration (S. L. Eustis,S. B. Haber, R. T. Drew, and R. S. H. Yang, 1986, Toxicologist,6, 54; N. Kato, S. Morinobu, and S. Ishizu, 1986, Ind. Health,24, 87–103; M. E. Hurtt, K. T. Morgan, and P. K. Working,1987, Fundam. Appl. Toxicol, 9, 352–365). The presentstudy examined the reproductive effects of MeBr in the maleF-344 rat. Adult males (11– 13 weeks) were exposed byinhalation to 0 or 200 ppm MeBr 6 hr/day for 5 days (first dayof exposure = Day 1). Ten animals from each group were anesthetizedwith pentobarbital and terminated on Days 1,3,5, and 8. Additionally,five males from each group were killed on Days 6, 10, 17, 24,38, 52, and 73. Plasma testosterone concentration was reducedduring and immediately following exposure (Days 1, 3, 5, and6), but returned to control levels by Day 8. Nonprotein sulfhydryl(NPSH) content of the liver and testis was reduced during exposurebut returned to control levels by Day 8 (3 days postexposure).No other reproductive indices, including testis weight, dailysperm production, cauda epididymal sperm count, sperm morphology,percentage motile sperm, linear sperm velocity, and epididymaland testicular histology, were affected by MeBr exposure atany time point examined. Thus, although MeBr causes a transientdecrease in plasma testosterone and testicular NPSH concentrationsduring acute exposure, it has no lasting effect on sperm qualityor spermatogenesis in the F-344 rat.     

Effectiveness of Oximes 2-PAM and HI-6 in Recovery of Muscle Function Depressed by Organophosphate Agents in the Rat Hemidiaphragm: An in Vitro Study

Effectiveness of Oximes 2-PAM and HI-6 in Recovery of MuscleFunction Depressed by Organophosphate Agents in the Rat Hemidiaphragm:An in vitro Study. REDDY, V. K., DESHPANDE, S. S., CINTRA, W.M., SCOBLE, G. T., AND ALBUQUERQUE, E. X. (1991). Fundam. Appl.Toxicol. 17, 746–760. Phrenic nerve diaphragm musclesof young adult rats were used to study the ability of the oximes2-PAM and HI-6 to recover muscle function depressed by organophosphate(OP) agents. The single twitch of diaphragm muscles which wereexposed to soman (0.2 mm) recovered after washing with salinefor 3 hr, but the muscles pretreated with sarin (0.4 µM),VX (0.2 µM), or tabun (0.4 µM) showed only partialrecovery. In addition, after 3 hr washing, the muscles pretreatedwith soman as well as with tabun did not recover the tetanussustaining ability (TSA), yet complete recovery was observedwith muscles pretreated with sarin and VX. These results indicatethat the OPs have different effects on muscle contractile propertiesand that VX- and sarin-pretreated muscles recover equally wellafter wash with physiological solution. The recovery of twitchtension of diaphragm muscles by 2-PAM and HI-6 was similar tothat achieved by washing with saline for 3 hr for sarin- andsoman-exposed muscles. The most remarkable differences wereseen in the recovery of TSA. Both 2-PAM and HI-6 recovered theTSA of muscles that were pretreated with sarin and VX. Although2-PAM recovered the TSA after tabun pretreatment, HI-6 had nodiscernible effect. On the other hand, HI-6 recovered the TSAof soman-pretreated muscles but 2-PAM did not. The effectivenessof muscle function recovery was not related to the oximes' abilityto reactivate AChE, thus indicating that the recovery of musclecontractility may be attributed to a direct effect of thesecompounds on the muscle.     

Evaluation of the Potential for Developmental Toxicity in Rats and Mice following Inhalation Exposure to Tetrahydrofuran

Sprague-Dawley rats and Swiss (CD-1) mice were exposed to 0,600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widelyused as an industrial solvent) vapors, 6 hr/day, 7 days/week(6–19 days of gestation (DG) for rats; 6–17 DG formice). Body weights of pregnant rats in the 5000 ppm group werereduced at euthanization. There were no effects on the percentageof live rat fetuses/litter or on the fetal sex ratio. Fetalbody weight was significantly reduced for the 5000 ppm group,but the incidence of abnormalities was not increased. Mice inthe 1800 and 5000 ppm groups were sedated during exposure; approximately27% of the mice in the 5000 ppm group died. Mean body and uterineweights of mice were reduced for the 1800 and 5000 ppm groupsat euthanization (18 DG), but adjusted maternal weight gainwas not affected at 1800 ppm. There was a reduction in the percentageof live fetuses/litter for the mice in 1800 and 5000 ppm groups(95% resorptions in the 5000 ppm group). Fetal weight and sexratio in mice were not affected. An increase in the incidenceof reduced sternebral ossifications was correlated to THF concentration,although differences between groups were not statistically significant.There were no increases in the incidences of other malformationsor variations. These results suggest that THF may be embryotoxicin mice, but if the conceptus survives, development as assessedby this experimental design continues in a normal fashion. Theno-observable-adverse-effect level (NOAEL) for maternal toxicitywas 1800 ppm in both rats and mice. The NOAEL for developmentaltoxicity was 1800 ppm in rats and 600 ppm in mice.     

Inhalation Delivery and Anti-tumor Activity of Celecoxib in Human Orthotopic Non-Small Cell Lung Cancer Xenograft Model

Purpose To determine the in vivo anti-tumor effect of aerosolized Celecoxib (Cxb) in combination with i.v Docetaxel (Doc) and compare the anti-tumor effect with oral Cxb combined with i.v Doc in human orthotopic non-small cell lung cancer (NSCLC) xenograft model.Materials and Methods Female Nu/Nu mice were implanted with orthotopic tumors by injecting A549 cells into the lung parenchyma. Seven day after tumor implantation the mice were treated with aerosolized Cxb (30 min exposure/day, 5 mg/ml solution) + i.v Doc (10 mg/kg) and the effect was compared with oral Cxb (150 mg/kg/day) + i.v Doc (10 mg/kg), for 28 days. Small-animal nose only inhalation chamber (CH Technologies, Westwood, NJ) was utilized for aerosol exposure. Therapeutic activity of Cxb (aerosol/oral) + Doc was estimated by differences in lung weight, tumor area and animal body weight. Lung tumor samples isolated from mice were analyzed for (a) PGE₂ levels by enzyme immunoassay (EIA) (b) expression of Fas and Factor VIII by immunohistochemistry (c) IL-8 expression using EIA kits and (d) mRNA expression for caspase-3 by Real-Time PCR.Results Mice treated with Cxb (aerosol/oral) + Doc showed significant reduction (P < 0.001) in lung weight and tumor area as compared to Cxb or Doc treatments. Cxb (aerosol/oral) + Doc showed increased apoptosis mediated via increased Fas and caspase-3 (P < 0.001) expression as compared to untreated control. Further, the combination treatment showed antiangiogenic effect as demonstrated by reduced expression of Factor VIII, IL-8 (P < 0.001) and PGE₂ (P < 0.001) in lung tumors as compared to untreated control. Aerosolized Cxb at a significantly lower therapeutic dose (4.56 mg/kg/day) demonstrated comparable anti-tumor efficacy to orally administered Cxb (150 mg/kg/day).Conclusion Cxb was formulated and effectively delivered via aerosolization to treat orthotopic lung tumors in combination with i.v Doc. Cxb when administered by aerosol produced same therapeutic effect as oral Cxb, but at lower therapeutic dose and thus shows promise for the treatment of lung cancer.     

Acute Changes in Muscle Blood Flow and Concomitant Muscle Damage after an Intramuscular Administration

No HeadingPurpose. The intramuscular route (IM) is widely used but commonly induces injection site muscle damage. This study investigates the hemodynamic changes in an acute lesion induced by the IM administration of propylene glycol (PG) in rabbits.Methods. Control groups received 1, 2, or 3 ml of PG (IM). Others were pretreated with pancuronium, dantrolene, indomethacin, or SR140333 and then received 2 ml of PG. The muscle blood flow (MBF) was assessed using fluorescent microspheres before and at 15, 45, 60, 90 min, 3 and 6 h after IM administration. Different areas within the muscle damage were quantified.Results. Muscle contractions as well as a transient but major MBF increase were observed at the injection site. All treatments reduced hyperemia by up to 81% (dantrolene, 15 min) at 15, 45, and 90 min (p < 0.05). MBF had returned to basal values in all groups at 6 h. The central necrotic area was not modified, but peripheral damage (8.0 ± 1.3 g) was reduced by dantrolene, indomethacin, and SR140333 (p < 0.05), but not by pancuronium.Conclusions. Muscle contraction and hyperemia are not responsible for muscle damage at the injection site, which is the multifactorial phenomenon, involving intracellular calcium and inflammation.     

Functional Assessment of Rabbit Alveolar Macrophages following Intermittent Inhalation Exposures to Sulfuric Acid Mist

Functional Assessment of Rabbit Alveolar Macrophages followingIntermittent Inhalation Exposures to Sulfuric Acid Mist. SCHLESINGER,R. B. (1987). Fundam. Appl. Toxicol. 8, 328–334. Sulfuricacid (H₂SO₄) aerosols are common in both ambient and occupationalenvironments. This study examined the numbers and selected invitro functional properties of alveolar macrophages recoveredfrom rabbits undergoing inhalation exposure to 0.5 mg/m³ submicrometer(0.3 µm) H₂SO₄ for 2 hr/day. Bronchoalveolar lavage wasperformed on Days 3, 7, and 14 during the exposure period (specifically,24 hr after either 2, 6, or 13 exposures). Total cell numbersand macrophage counts were increased on Day 3, but returnedto control levels by Day 7; no change in polymorphonuclear leukocyteswas observed at any time point. Macrophage substrate attachmentwas not affected by exposures to H₂SO₄, but random mobilitywas severely depressed at Days 7 and 14. The numbers of phagocyticallyactive macrophages and the level of such activity were increasedon Day 3, but became depressed by Day 14. These results demonstratesignificant alterations in important functional properties ofalveolar macrophages due to short-term intermittent exposuresto H₂SO₄ aerosols; these changes have implications for the abilityof the lungs to maintain adequate defense against depositedviable and nonviable particles.