Respiratory retention of inhaled toluene and benzene in the dog.

This study deals with the inhalation of toluene and benzene found in the vapor phase of cigarette smoke. Determined in this study were the uptake of each substance by the total respiratory tract and by the upper and lower portions under varying conditions of ventilatory rate, tidal volume, and concentration inhaled. Retention by the total tract of toluene fell within the range of 91-94% at all ventilatory rates seen, indicating no relationship between rate and retention. With benzene, total tract retention varied from 88 to 68% with an inverse relationship between retention and rate apparent. This relationship was seen in all types of experiments conducted with benzene. Upper tract retention revealed an uptake of about 89% for both one- and two-way experiments with toluene. In the benzene experiments retention varied from 80 to 61% and from 81 to 63% in the one- and two-way procedures, respectively. Mean lower tract retention was 90% with toluene at all ventilatory rates considered. Benzene retention varied from 74 to 61% as the rate increased from 6 to 18 inhalations/min.     

Developmental toxicity evaluation of inhaled toluene diisocyanate vapor in CD rats.

Mated female CD (Sprague-Dawley) rats, 25/group, were exposed to toluene diisocyanate (TDI) vapor, for six h/day on gestational days (gd) 6 through 15, at 0.00, 0.02, 0.10, or 0.50 p.p.m.. Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gd 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified: resorptions and dead and live fetuses. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre- and postimplantation loss, sex ratio/litter, or fetal body weights/litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapor by inhalation, during major organogenesis in CD rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm no observed adverse effect level (NOAEL) for maternal and developmental toxicity was 0.10 ppm. No treatment-related embryotoxicity or teratogenicity was observed.     

Two-generation reproductive toxicity study of inhaled toluene diisocyanate vapor in CD rats.

Twenty-eight 42-day-old pups/sex/group (F0) were exposed to toluene diisocyanate vapor (TDI; 80% 2,4-TDI, 20% 2,6-TDI) by inhalation at 0.0, 0.02, 0.08, or 0.3 ppm, 6 h/day, 5 days/week, for 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapor, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.     

A dosimetric analysis of the acute behavioral effects of inhaled toluene in rats.

Knowledge of the appropriate metric of dose for a toxic chemical facilitates quantitative extrapolation of toxicity observed in the laboratory to the risk of adverse effects in the human population. Here, we utilize a physiologically based toxicokinetic (PBTK) model for toluene, a common volatile organic compound (VOC), to illustrate that its acute behavioral effects in rats can be quantitatively predicted on the basis of its concentration in the brain. Rats previously trained to perform a visual signal detection task for food reward performed the task while inhaling toluene (0, 1200, 1600, 2000, and 2400 ppm in different test sessions). Accuracy and speed of responding were both decreased by toluene; the magnitude of these effects increased with increasing concentration of the vapor and with increasing duration of exposure. Converting the exposure conditions to brain toluene concentration using the PBTK model yielded a family of overlapping curves for each end point, illustrating that the effects of toluene can be described quantitatively by its internal dose at the time of behavioral assessment. No other dose metric, including inhaled toluene concentration, duration of exposure, the area under the curve of either exposure (ppm h), or modeled brain toluene concentration (mg-h/kg), provided unambiguous predictions of effect. Thus, the acute behavioral effects of toluene (and of other VOCs with a similar mode of action) can be predicted for complex exposure scenarios by simulations that estimate the concentration of the VOC in the brain from the exposure scenario.     

Estimating in vivo airway surface liquid concentration in trials of inhaled antibiotics.

Antibiotic drugs exhibit concentration dependence in their efficacy. Therefore, ensuring appropriate concentration of these drugs in the relevant body fluid is important for obtaining the desired therapeutic and physiological action. Until recently there had been no suitable method available to measure or estimate concentration of drugs in the human airways resulting from inhaled aerosols or to determine the amount of inhaled antibiotics required to ensure minimum inhibitory concentration of a drug in the airway surface liquid (ASL). In this paper a numerical method is used for estimating local concentration of inhaled pharmaceutical aerosols in different generations of the human tracheobronchial airways. The method utilizes a mathematical lung deposition model to estimate amounts of aerosols depositing in different lung generations, and a recent ASL model along with deposition results to assess the concentration of deposited drugs immediately following inhalation. Examples of concentration estimates for two case studies: one for the antibiotic tobramycin against Pseudomonas aeruginosa, and another for taurolidine against Burkholderia cepacia are presented. The aerosol characteristics, breathing pattern and properties of nebulized solutions were adopted from two recent clinical studies on efficacy of these drugs in cystic fibrosis (CF) patients and from other sources in the literature. While the clinically effective tobramycin showed a concentration higher than the required in vivo concentration, that for the ineffective taurolidine was found to be below the speculated required in vivo concentration. Results of this study thus show that the mathematical ASL model combined with the lung deposition model can be an effective tool for helping decide the optimum dosage of inhaled antibiotic drugs delivered during human clinical trials.     

异丙酚与瑞芬太尼联合进行喉罩麻醉的效果分析

目的调查分析联合使用异丙酚与瑞芬太尼进行喉罩麻醉的效果。方法将2010年6月～2011年8月来本院进行手术的患者124例随机平均分为两组,联合组使用靶控输注异丙酚与瑞芬太尼联合进行喉罩麻醉,对照组单一输注异丙酚进行喉罩麻醉。通过相关参数比较两组麻醉效果。结果异丙酚与瑞芬太尼联合进行喉罩麻醉效果在血流动力学稳定性、麻醉所用时间、术后清醒时间、减少丙泊酚的用量和并发症方面与单纯运用丙泊酚相比,差异均有统计学意义（P〈0.05）。结论异丙酚与瑞芬太尼联合进行喉罩麻醉效果较好,血流动力学变化较小,术后恢复迅速,异丙酚用量少,副作用小,可在喉罩麻醉中给予推广。     

哮喘患儿吸入糖皮质激素的调查分析

目的：了解哮喘儿童吸入糖皮质激素应用情况。方法：对来咳喘专科就诊的患儿应用统一的调查表,内容包括吸入情况、发作情况、中断情况、再吸情况。结果：172例患者中有持续吸入史者仅28．5％,而其中仅44．9％坚持用药1年以上,停药后再用药有效。结论：实际应用情况不尽人意。     

Inhibition of inhaled metabisulphite-induced bronchoconstriction by inhaled frusemide and ipratropium bromide.

1. The effect of inhaled frusemide and high dose inhaled ipratropium bromide on bronchoconstriction induced by inhaled metabisulphite was studied in 10 atopic volunteers. 2. Frusemide (40 mg), ipratropium bromide (0.5 mg) or saline placebo were administered by nebuliser in a double-blind fashion, prior to construction of a dose-response curve to metabisulphite (2.5-100 mg ml-1). 3. Geometric mean of the provocative dose of metabisulphite that caused a 35% fall in specific airways resistance (sGaw) after placebo was 13 (95% confidence intervals CI 4-36 mumol) compared with 36 (16-78) mumol after ipratropium bromide and 45 (22-94) mumol after frusemide. 4. Mean maximum fall in sGaw was 49 (40-57)% after placebo, 11 (0-22)% after frusemide and -1 (-25-22)% after ipratropium bromide. 5. Frusemide significantly protected against metabisulphite induced bronchoconstriction (P less than 0.005). The protection from high dose ipratropium bromide was also significant (P less than 0.05), but the response was more variable between subjects.     

Cost implications of using inhaled nitric oxide compared with epoprostenol for pulmonary hypertension.

OBJECTIVE: To compare the cost of using intravenous epoprostenol with that of inhaled nitric oxide (NO) for treating episodes of pulmonary hypertension in children with congenital heart disease. DESIGN: An analysis of the cost of epoprostenol and NO use over the previous 18 months was performed. Three 6-month periods were identified, two in which epoprostenol was used and the third in which inhaled NO was introduced for the treatment of pulmonary hypertension. SETTING: A 10-bed pediatric cardiac intensive care unit, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, England. SUBJECTS: Children with congenital heart disease and persistently elevated pulmonary artery pressure following cardiac surgery. MAIN OUTCOME MEASURES: The total duration of use of epoprostenol and inhaled NO was documented. The costs per hour for epoprostenol and inhaled NO were calculated and the annual cost of each agent was estimated. RESULTS: In the two 6-month periods prior to the introduction of inhaled NO, epoprostenol was used on 14 occasions (5 in the first period, 3 in the second). In the last 6-month period, nine children required pulmonary vasodilator therapy on 14 occasions. All nine children were treated successfully with inhaled NO; none were given or needed epoprostenol, as NO always was effective in providing pulmonary vasodilatation. For resistant pulmonary hypertension, increasing the concentration of NO would have been the next therapeutic option. The cost for the two 6-month periods using epoprostenol was $19,483.48 for the drug and $283.25 for equipment costs (total cost $19,766.73). There was no expenditure on epoprostenol in the final 6-month period. The cost of NO was $465. However, the total expenditure, including the delivery and monitoring system, was $4,722.85. CONCLUSIONS: Using inhaled NO in our pediatric cardiac intensive care unit abolished the use of epoprostenol during the reported monitoring period. The cost savings were significant, amounting to 12% of the annual drug budget for the unit. The cost of setting up the inhaled NO delivery system is recouped rapidly. The ease of delivery and measurement of inhaled NO also may have contributed to its increased clinical use.     

Extraction and determination of trace amounts of chlorpromazine in biological fluids using hollow fiber liquid phase microextraction followed by high-performance liquid chromatography

In the present work, hollow fiber liquid phase microextraction (HF-LPME) in conjunction with reversed-phase HPLC/UV was developed for extraction and determination of trace amounts of chlorpromazine in biological fluids. The drug was extracted from an 11 ml aqueous sample (source phase; SP) into an organic phase impregnated in the pores of the hollow fiber (membrane phase; MP) followed by the back-extraction into a second aqueous solution (receiving phase; RP) located in the lumen of the hollow fiber. The effects of several factors such as the nature of organic solvent, compositions of SP and RP solutions, extraction time, ionic strength and stirring rate on the extraction efficiency of the drug were examined and optimized. Under the optimal conditions, enrichment factor of 250, dynamic linear range of 1–500 μg l⁻¹, and limit of detection of 0.5 μg l⁻¹ were obtained for the drug. The percent relative intra-day and inter-day standard deviation (R.S.D.%) based on three replicate determinations were 6.7 and 10.3%, respectively. The method was applied to drug level monitoring in the biological fluids and satisfactory results were obtained.     

Early damage indicators in the lung. III. Biochemical and cytological response of the lung to inhaled metals salts.

The validity of using the enzymatic and cytologic profile of airway fluids to indicate lung damage was tested in animals exposed by inhalation to either a known toxic metallic salt (CdCl₂) or a relatively innocuous salt (CrCl₃). The enzymatic and cytologic response of the airways was compared to histopathological evaluation of lung damage. Syrian hamsters were exposed to an aerosol of CdCl₂ (aerodynamic diameter = 1.7 μm, $\text{σ}{}_{\mathrm{g}}\text{? 1.7}$) to achieve an initial lung burden (ILB) of 0.6 ± 0.3 and 4.4 ± 1.2 μg of CdCl₂ or to an aerosol of CrCl₃ (count median diameter = 1.2 μm, $\text{σ}{}_{\mathrm{g}}\text{? 1.5}$) to achieve an ILB of 0.7 ± 0.2 or 20 ± 10 μg of CrCl₃. Animals were sacrificed at 2 hr, 1, 7, and 21 days after exposure. A sample of airay fluid was obtained by bronchopulmonary lavage and examined for the enzymatic profile of the cell-free fraction and the cytological profile of the cell fraction. Lung tissue enzyme activities were also measured and histopathologic evaluations were made on lung tissue from exposed, but nonlavaged, animals. In the lavage fluid from animals exposed to CdCl₂, the enzymatic and cytologic data demonstrated a dose-response pattern and the airway response preceded enzymatic changes in the lung tissue. Tissue morphological changes correlated well with the biochemical changes. The response of the lung to CrCl₃ was minimal by both morphological and biochemical evaluations. Airway enzymatic and cytologic responses were shown to be potentially useful as indicators of lung damage in toxicological screening programs.     

Determination of volatile organic compounds in biological samples using headspace solid-phase microextraction and gas chromatography: toluene and styrene

Epidemiological and laboratory investigations have shown that toluene and styrene are toxic compounds that lead to impairment of the nervous system. To quantitate toluene and styrene in biological samples, liquid-liquid phase, headspace (HS), and solid-phase microextraction (SPME) methods are generally used. Most of these methods are not sensitive enough for applications involving small sample volumes. Here, we present a method for quantitative analysis of low concentrations of styrene and toluene in very small volumes of biological samples using HS-SPME and gas chromatography (GC) equipped with a flame-ionization detector. The method was developed by optimizing operating parameters that affect the HS-SPME-GC process [i.e., desorption time (30 s), depth of the fiber in the GC injection port (3.7 cm), adsorption time (4 min), and adsorption temperature (room temperature)]. It has a wide range of linearity (0.5-500 ng/10 microL), high precision (coefficient of variation < 5%), good accuracy (deviation < 11%), and low detection limits of 0.13 and 0.08 ng/10 microL for styrene and toluene in serum, respectively. This analytical technique can be applied to the estimation of styrene and toluene in small volumes of biological fluids (blood, serum, and perilymph) and tissues of low lipid content (cochlea).     

The role of biological monitoring in the health management of lead-exposed workers.

In 1967, the problem of occupational lead exposure came to public attention in Korea. Since then, regular progress has been made in lowering workplace lead exposures, instituting new workplace controls, and implementing health examinations of exposed workers. Serious lead poisoning episodes led to the introduction of biological monitoring programs on a voluntary basis in high lead exposure facilities in Korea. Occupational health services for lead workers in Korea during the last 10 years could be categorized into three phases. During the first phase (1988-1993), effort was directed at increasing awareness among workers concerning the hazards of lead exposure, biological monitoring was commenced with zinc protoporphyrin (ZPP), and a respiratory protection program was introduced. During the second phase (1994-1996), a computerized health management system of lead workers was developed, blood lead measurement was added for biological monitoring, and engineering controls were introduced in the workplace to lower air lead levels to comply with air lead regulations. Finally, during the third phase (1997-present), bone lead measurement by X-ray fluorescence was introduced to evaluate total body lead burden. During the period 1988-1998, air lead levels have remained generally steady and above the permissible exposure level (PEL), but ZPP and blood lead levels have shown a steady decline. It was discovered that in a developing country like Korea, which cannot introduce engineering controls quickly to protect lead workers, biological monitoring was very useful in identifying and lowering excess lead absorption. In the future, as average exposure duration continues to rise, bone lead measurement may be recommended to adequately protect the long-term health of lead workers.     

Multicenter field trial on possible health effects of toluene. I. Toluene body burdens in workers of the rotogravure industry

Ambient air toluene concentrations as well as corresponding individual blood toluene levels were measured under conditions of a field trial, as basis for a correlation with possible acute effects. While the results of various psycho-physiological and medical evaluations after acute (Neubert et al., 2001) and long-term toluene exposure (Gericke et al., 2001) are published in accompanying papers, this publication deals with the exposure levels and body burdens characteristic of workers in the rotogravure industry in Germany at the time of the investigation (1993-1995). Besides providing some information on the exposure at various work-areas under occupational conditions, the correlation between a time-weighted average of the ambient air concentration with the corresponding blood toluene levels is analyzed. Limitations of such an attempt and possible pitfalls are discussed. In the largest field study so far performed on toluene exposure, 12 companies of the German rotogravure industry (and a total of 1528 volunteers) participated. Altogether, complete data sets, i.e. on both ambient air as well as blood toluene levels, were obtained from 1244 male and 124 female participants of the rotogravure industry with quite different degrees of toluene exposure. Rotogravure printers and their helpers were exposed to the highest toluene concentrations in ambient air. On the day of the evaluation, of 806 male volunteers within this group (of 1261 with verified exposure in air), 35 were exposed to a time-weighted average of 100 ppm (i.e. 375 mg/m(3)) or above, and 155 of the printers to concentrations between 50 and 100 ppm. Of the remaining 455 male participants of the rotogravure factories ('non-printers and helpers'), only three were exposed to toluene concentrations above 50 ppm. Only one of the 124 women working in the rotogravure factories was exposed to an average toluene concentrations above 100 mg/m(3) (i.e. 27 ppm). In 66 of the male volunteers toluene levels in blood of >850 microg/l were measured and 14 showed levels exceeding 1700 microg/l. When attempting to predict the resulting individual blood toluene levels from measurements of ambient air concentrations under field conditions, a considerable uncertainty is to be expected. We found a correlation coefficient of the regression curve of about 0.70, with numerous outliers (and a variation of the 12 factories between 0.52 and 0.88).     

Effects of mouth washing procedures on removal of budesonide inhaled by using Turbuhaler

Mouth washing after inhalation of corticosteroids is effective for prevention of local adverse effects. We determined the amounts of drug residues remaining on the oropharyngeal mucosa following inhalation of budesonide (BUD) via a Turbuhaler (BUD-TH) (100 microg). Further, we studied the effects of mouth washing on the removal of drug residues by quantification of BUD in expectorated wash solution using an HPLC method. The amount of BUD recovered after gargling and rinsing for 5 s each was 19.4+/-9.4 microg, as compared to 23.8+/-13.6 microg after rinsing alone for 10 s and 18.3+/-8.9 microg after gargling alone for 10 s, though the differences were not significant. Our results indicated that about 20% of the dose was remaining on the oropharyngeal mucosa after inhalation. In a comparison of washing times, the amounts of BUD recovered were 26.3+/-3.2 microg after gargling and rinsing for 3 s each, and 19.4+/-9.3 microg after those for 5 s each. As for the effect of lag time before beginning mouth washing, the ratio of BUD recovered following mouth washing with a lag time of 1 min was 73.2%, while it was reduced to 27.8% after 10 min, as compared to immediate mouth washing following administration. Our results suggest that the amount of BUD removed by mouth washing is associated with the lag time between inhalation and mouth washing, however, not with the duration of mouth washing. We concluded that immediate mouth washing after inhalation is most useful for the removal of drugs following BUD-TH administration.     

Interaction of chlorpromazine with biological membranes. A photochemical study using spin labels.

Fatty acid spin labels have been included into erythrocyte ghosts and synaptic plasma membranes in order to study the interaction of phenothiazine derivatives (particularly chlorpromazine— CPZ) with these membranes. The following results have been obtained. (1) Weak modifications of the spin label spectroscopic response are observed only on the label of the polar part of the membrane and with CPZ concentrations higher than 5 × 10^?4 M. (2) Under ultraviolet irradiation (λ = 310 nm) phenothiazine derivatives reduce fatty acids spin labels. Measurement of the reduction kinetic constants of two different types of spin labels give information about the location of the drugs inside the membranes. The photochemical interaction is influenced by the membrane proteins. These results suggest that, in the pharmacologically active concentration range, chlorpromazine seems to localize at the interface between the phospholipids and the proteins of the membranes.     

Dose-dependent inhibitory effect of inhaled beclomethasone on late asthmatic reactions and increased responsiveness to methacholine induced by toluene diisocyanate in sensitised subjects

To determine whether inhaled beclomethasone, both at low and at high doses, inhibits late asthmatic reactions and the associated increase in airway responsiveness induced by toluene diisocyanate (TDI), we studied 9 sensitised subjects. Low dose beclomethasone (200 μg bid), high dose beclomethasone aerosol (1000 μg bid), and placebo were administered for 7 days before TDI inhalation challenge to each subject, according to a double-blind, crossover study design. The washout period between the treatments was at least 1 week. When the subjects were treated with placebo, forced expiratory volume in 1 sec (FEV₁) markedly decreased after exposure to TDI. By contrast, high dose beclomethasone prevented the late asthmatic reaction and the low dose partially inhibited the reaction. With placebo the mean (±SE) value of FEV₁ 4 h after exposure to TDI was 2.6 ± 0.17 L, which went to 3.3±0.12 after low dose beclomethasone, and to 3.5±0.15 L after high dose of beclomethasone (significant difference in the decrease of FEV₁ in the 8 h after exposure to TDI, between treatments: F = 9.87, (P < 0.001), After treatment with placebo or with low dose beclomethasone, airway responsiveness to methacholine increased 8 h after exposure to TDI. With placebo, the PD₂₀ decreased from 0.66 mg (Geometric Standard Error of the Mean [GSEM], 1.38) to 0.18 mg (GSEM, 1.46); with low dose inhaled beclomethasone, the PD₂₀ decreased from 0.93 mg (GSEM, 1.42) to 0.36 mg (GSEM, 1.63). By contrast, airway responsiveness to methacholine did not change 8 h after exposure to TDI in subjects treated with high dose inhaled beclomethasone: the PD₂₀ was 0.78 mg (GSEM, 1.51) before and 0.71 mg (GSEM, 1.58) after exposure to TDI. The protective effect of beclomethasone was obtained without side effects and without changes in serum cortisol levels (08.00) in any of the nine examined subjects. These results suggest that the inhibitory effect of inhaled beclomethasone on TDI-induced late asthmatic reactions and increased responsiveness is dose-dependent.     

Sensitivity testing of bacteria to ceftriaxone using discs with different amounts of antibiotic

Studies were performed to compare the results of sensitivity testing of bacteria to ceftriaxone using discs containing 10, 20, 30 and 40 micrograms of the antibiotic. The highest correlation between diameters of zone inhibition and MIC values was found with discs containing 30 micrograms of ceftriaxone. The lowest percentage of false results was also obtained with 30 micrograms discs.