Lung Retention Research Articles

Calibration Study on Subchronic Inhalation Toxicity of Man-Made Vitreous Fibers in Rats

This 3-mo inhalation study investigated the biological effects of a special-purpose glass microfiber (E-glass microfiber), the stone wool fiber MMVF21, and a new high-temperature application fiber (calcium-magnesium-silicate fiber, CMS) in Wistar rats. Rats were exposed 6 h/day, 5 days/wk for 3 mo to fiber aerosol concentrations of approximately 15, 50, and 150 fibers/ml (fiber length >20 µm) for E-glass microfiber and MMVF21. For the CMS fiber only the highest exposure concentration was used. During a 3-mo postexposure period, recovery effects were studied. In the highest exposure concentration groups, gravimetric concentrations were 17.2 mg/m 3 for E-glass microfiber, 37 mg/m 3 for MMVF21, and 49.5 mg/m 3 for the CMS fiber. After 3 mo of exposure, lung retention of fibers longer than 20 µm per lung was 17 × 10 6 for E-glass microfiber, 5.7 × 10 6 for MMVF21, and 0.88 × 10 6 for CMS. After 3 mo of recovery the concentration of the long fiber fraction was decreased to 38.4%, 63.9%, and 3.0% compared to original lung burden for the E-glass microfiber, MMVF21, and CMS, respectively. Biological effects measured included inflammatory and proliferative potential, histopathology lesions, and the persistence of these effects over a recovery period of 3 mo. Generally, observed effects were higher for E-glass microfiber when compared to MMVF21. The following clear dose-dependent effects on E-glass microfiber and MMVF21 exposure were observed as main findings of the study: increase in lung weight, in measured biochemical parameters and polymorphonuclear leukocytes (PMN) in the bronchoalveolar lavage fluid (BALF), in cell proliferation (BrdU-response) of terminal bronchiolar epithelium, and in interstitial fibrosis. The values observed in the proliferation assay on the carcinogenic E-glass microfiber indicate that this assay has an important predictive value with regards to potential carcinogenicity. Surprisingly, for the biosoluble CMS fiber, fibrogenic potential was detected in this study. The results of the CMS exposure group indicate that effects may be dominated by the presence of nonfibrous particles and that fibrosis may not be a predictor of carcinogenic activity of fiber samples, if the fiber preparation contains a significant fraction of nonfibrous particles. In summary, this study demonstrates the importance of fiber dust contamination by granular components. For future subchronic studies a longer posttreatment observation period would be advisable.

Liposomal tobramycin against pulmonary infections of Pseudomonas aeruginosa: a pharmacokinetic and efficacy study following single and multiple intratracheal administrations in rats.

To determine the pharmacokinetics and efficacy of tobramycin against pulmonary infections of Pseudomonas aeruginosa in rats after intratracheal administration of conventional and liposomal formulations. Male Sprague-Dawley rats were inoculated with 10(6) cfu of a mucoid variant of P. aeruginosa (MIC of tobramycin for PA 508 = 1 mg/l) and tobramycin (conventional or liposomal formulations) was administered in single (490 microg) and multiple dose (490 microg during 4 days) experiments. Rats were killed at multiple time points to determine the residual cfu of P. aeruginosa and tobramycin amounts in lungs. Pharmacokinetic parameters were calculated using a two-compartment model with NONMEM. Mean (+/-S.D.) elimination half-life (t(1/2beta)) and pulmonary exposure (AUC) of the conventional formulation were 14.0 +/-4.0 h and 663 +/-89 microg x h/lungs, respectively. The pharmacokinetic profile of liposomal tobramycin was markedly different, with a longer t(1/2beta) (34.4 +/-5 h, P < 0.05), resulting in an increased AUC (3890 +/-560 microg x h/lungs, P < 0.05). chi(2) analyses were carried out on cfu data distributed in the following categories: below 10(3), 10(3)-10(5), and above 10(5) cfu. In the single dose experiments, approximately 90% of the observations were above 10(5) cfu for both formulations. Significant differences in cfu distribution were observed after multiple treatments, with approximately 10% of the observations falling below 10(3) cfu of P. aeruginosa for the conventional formulation versus 30% for the liposomal formulation. The liposomal formulation of tobramycin promoted drug retention in lungs and improved its efficacy after multiple treatments.

Anomalously high excretion of Pu in urine following inhalation of plutomium nitrate?

A study of the biokinetics of inhaled plutonium nitrate in two volunteers has been carried out. Low doses (approximately 80 microSv) were achievable because tracers of high isotopic purity were used: 237Pu (measurable by X ray spectrometry) and 244Pu (measurable by accelerator mass spectrometry). Lung retention, amount in blood, uptake to the liver and skeleton, and urinary and faecal excretion were measured. The measured urinary excretion rates are about a factor of three higher than those predicted from urine excretion data measured following intravenous injection of plutonium to the same volunteers. If similar biokinetic behaviour occurs in workers exposed to plutonium nitrate, intakes by inhalation and corresponding committed doses assessed by urine bioassay could be consistently overestimated by a similar factor.

Thallium-201 SPECT in advanced non-small cell lung cancer: In relation with chemotherapeutic response, survival, distant metastasis and p53 status

The aim of this study was to evaluate the relationship between 201Tl tumor uptake, chemotherapeutic response, metastasis, p53 status and survival in non-small cell lung cancer (NSCLC). A total of 23 patients underwent 201Tl SPECT. In 9 patients, 2nd 201Tl SPECT study were performed 1 week after the 3rd cycle of chemotherapy (ChT), and early (ER) and delayed (DR) tumor/normal lung ratios and retention indices (RI) were obtained. In 15 patients p53 status was assayed with immuno-histochemical staining. The patients were divided into subgroups after the 3rd cycle of ChT; responders [R(+) (n = 10)] and non-responders [R(-) (n = 13)], distant metastasis [(M1) n = 11] and [(M0) n = 12], and mutant p53 status [p(+) n = 7, p53(-) n = 8]. The differences for ER, DR and RI values between all of the subgroups were not statistically significant. ER and DR of responders decreased significantly after ChT; from to 2.46 to 1.36 (p = 0.04) and 2.29 to 1.53 (p = 0.04), respectively. In the non-responder group, both ER and DR slightly increased after ChT (p > 0.05). Our results suggest that in NSCLC, there was a weak correlation between higher 201Tl ratios and positive response to chemotherapy, absence of distant metastasis, and p53(-) status. Significant 201Tl uptake decrease after chemotherapy indicates that delayed 201Tl uptake can be used in evaluating the chemotherapeutic response.

Calibration Study on Subchronic Inhalation Toxicity of Man-Made Vitreous Fibers in Rats

This 3-mo inhalation study investigated the biological effects of a special-purpose glass microfiber (E-glass microfiber), the stone wool fiber MMVF21, and a new high-temperature application fiber (calcium-magnesium-silicate fiber, CMS) in Wistar rats. Rats were exposed 6 h/day, 5 days/wk for 3 mo to fiber aerosol concentrations of approximately 15, 50, and 150 fibers/ml (fiber length >20 µm) for E-glass microfiber and MMVF21. For the CMS fiber only the highest exposure concentration was used. During a 3-mo postexposure period, recovery effects were studied. In the highest exposure concentration groups, gravimetric concentrations were 17.2 mg/m 3 for E-glass microfiber, 37 mg/m 3 for MMVF21, and 49.5 mg/m 3 for the CMS fiber. After 3 mo of exposure, lung retention of fibers longer than 20 µm per lung was 17 × 10 6 for E-glass microfiber, 5.7 × 10 6 for MMVF21, and 0.88 × 10 6 for CMS. After 3 mo of recovery the concentration of the long fiber fraction was decreased to 38.4%, 63.9%, and 3.0% compared to original lung burden for the E-glass microfiber, MMVF21, and CMS, respectively. Biological effects measured included inflammatory and proliferative potential, histopathology lesions, and the persistence of these effects over a recovery period of 3 mo. Generally, observed effects were higher for E-glass microfiber when compared to MMVF21. The following clear dose-dependent effects on E-glass microfiber and MMVF21 exposure were observed as main findings of the study: increase in lung weight, in measured biochemical parameters and polymorphonuclear leukocytes (PMN) in the bronchoalveolar lavage fluid (BALF), in cell proliferation (BrdU-response) of terminal bronchiolar epithelium, and in interstitial fibrosis. The values observed in the proliferation assay on the carcinogenic E-glass microfiber indicate that this assay has an important predictive value with regards to potential carcinogenicity. Surprisingly, for the biosoluble CMS fiber, fibrogenic potential was detected in this study. The results of the CMS exposure group indicate that effects may be dominated by the presence of nonfibrous particles and that fibrosis may not be a predictor of carcinogenic activity of fiber samples, if the fiber preparation contains a significant fraction of nonfibrous particles. In summary, this study demonstrates the importance of fiber dust contamination by granular components. For future subchronic studies a longer posttreatment observation period would be advisable.

Evaluation of respiratory and cutaneous doses of chlorothalonil during re-entry in greenhouses

Five female workers were monitored for 5 consecutive days during re-entry into a greenhouse containing ornamental plants. Skin contamination (excluding hands) was evaluated with nine pads of filter paper placed on the skin. Hand contamination was assessed by washing with 95% ethanol. Respiratory exposure was evaluated by personal air sampling. The respiratory dose was based on a lung ventilation of 15 l/min. The doses absorbed were estimated assuming 10% skin absorption and 100% lung retention. Dislodgeable foliar residue was determined on days of re-entry to evaluate the decay of chlorothalonil. Chlorothalonil was analysed in the different matrices by GC–MS. Respiratory exposure was less than skin contamination, being 11.4±5.1% (mean±SD) of total exposure. The estimated total absorbed dose did not exceed the acceptable daily intake of 0.03 mg/kg body mass. The hands and unexposed skin of all workers were always found to be contaminated. Greater precautions are therefore needed to reduce skin exposure (clean gloves and suitable clean clothing every day).

Indomethacin attenuates the immunosuppressive and tumor-promoting effects of surgery

Abstract: We have previously shown in rats that both intrathecal and systemic analgesia regimens attenuate surgery-induced increases in tumor susceptibility. The current study used indomethacin to assess the role of prostaglandins and inflammation-associated pain in mediating the deleterious effects of surgery on immunity and tumor susceptibility. Male and female Fischer 344 rats were anesthetized with halothane and were either subjected or not to experimental laparotomy, followed by the administration of indomethacin or vehicle. Tumor susceptibility was assessed by the lung retention assay using the syngeneic MADB106 mammary adenocarcinoma cell line, a natural killer (NK)-sensitive tumor that colonizes only in the lungs. Surgery resulted in a 2- to 3.5-fold increase in lung tumor retention, and indomethacin administration significantly reduced this effect in both sexes without affecting unoperated animals. Indomethacin also attenuated the reductions in rearing behavior evident after surgery, suggesting that it relieved abdominal discomfort. Surgery increased interleukin-6 levels and suppressed NK activity per milliliter blood. Indomethacin restored NK activity in both male and female rats but attenuated surgery-induced interleukin-6 increases only in the male rats. These findings further support our previous work implicating pain in mediating the tumor-enhancing effects of surgery and implicate prostaglandins in mediating this effect. If similar relationships occur in humans, controlling postoperative pain and inflammation must become a priority in the management of cancer patients undergoing surgery. © 2002 by the American Pain Society

The development of the plutonium lung clearance model for exposure estimation of the Mayak production association, nuclear plant workers.

The purpose of this study was to develop a biokinetic model that uses urinary plutonium excretion rate data to estimate the plutonium accumulation in the human respiratory tract after occupational exposure. The model is based on autopsy and urinalysis data, specifically the plutonium distribution between the respiratory tract and the remainder of the body, taken from 543 former workers of a radiochemical facility at the Mayak Production Association (MPA) plant. The metabolism of plutonium was represented with a compartmental model, which considers individual exposure histories and the inherent solubility properties of industrial plutonium aerosols. The transport properties of plutonium-containing aerosols were estimated by experimentally defining their in vitro solubility. The in vitro solubilities were found by dialysis in a Ringer's solution. Analysis of the autopsy data indicated that a considerable fraction of the inhaled plutonium is systemically redistributed rapidly after inhalation. After the initial dynamic period, a three-compartment model describes the retention in the respiratory tract. One compartment describes the nuclide retained in the lungs, the second compartment describes a plutonium lung concentration that exponentially decreases with time, and the third compartment describes the concentration in the pulmonary lymph nodes. The model parameters were estimated by minimizing sum squared of the error between the tissue and bioassay data and the model results. The parameters reflect the inverse relationship between plutonium retention in lungs and the experimentally derived aerosol transportability. The model was validated by comparing the autopsy results with in vivo data for 347 cases. The validation indicates that the model parameters are unbiased. This model is being used to estimate individual levels of nuclide accumulation and to compute radiation doses based upon the urinary excretion rates.

Guide for the Practical Application of the ICRP Human Respiratory Tract Model: ICRP Supporting Guidance 3Approved by ICRP Committee 2 in October 2000

The ICRP Publication 66 Human Respiratory Tract Model for Radiological Protection (HRTM) has been applied to calculate dose coefficients (doses per unit intake) and bioassay functions in ICRP Publications 68, 71, 72 and 78. For these purposes, ICRP assigned numerical values to a range of model parameters, such as the size of the inhaled particles and the breathing rate of the subjects. These are known as ‘default’ or ‘reference’ values, and were chosen to be typical, representative values. In any particular situation the actual values of many parameters can be considerably different from the reference values. Usually, doses from intakes of radionuclides are low compared with the relevant limit or constraint, and the resulting difference is unimportant. There are, however, circumstances where more reliable assessments of intake and dose are desirable. This Guidance Document therefore gives advice on applying specific information within the framework of the HRTM for assessing occupational and environmental exposures and for interpreting bioassay data. Chapters on each aspect of the model (morphometry, physiology, deposition, clearance, gases and vapours, dosimetry) provide: • A summary of how the HRTM treats that topic; • Information on the reference values of relevant parameters; • Guidance on choosing between default values; • Information on how doses and bioassay quantities (lung retention, urine, and faecal excretion) vary with the values of selected parameters, giving guidance on the importance of obtaining specific information; • Simple examples of the use of specific information relating to the topic. Annexes give additional information for those directly involved in applying the HRTM to specific situations, including guidance on obtaining parameter values. A brief overview is given of the deposition, characterisation, and sampling of aerosols, with references to further information, as there are relevant text books already available. Issues specific to radioactive aerosols, such as low particle number concentrations for high specific activity materials are, however, addressed. Guidance on obtaining information about absorption of inhaled radionuclides into blood is given in greater detail, because this is a topic on which ICRP has traditionally given guidance, and because a compilation of such information is not readily available elsewhere. Several detailed examples are also provided. One involves assessment of an individual's intake and committed dose from comprehensive bioassay monitoring data. The others deal with the derivation of HRTM absorption parameter values from experimental data, and their application, with additional information on e.g. size distribution, to calculate dose coefficients and interpret bioassay data.

Determination of the physical and chemical properties, biokinetics, and dose coefficients of uranium compounds handled during nuclear fuel fabrication in France.

The introduction of new ICRP recommendations, especially the new Human Respiratory Tract Model (HRTM) in ICRP Publication 66 led us to focus on some specific parameters related to industrial uranium aerosols collected between 1990 and 1999 at French nuclear fuel fabrication facilities operated by COGEMA, FBFC, and the CEA. Among these parameters, the activity median aerodynamic diameter (AMAD), specific surface area (SSA), and parameters describing absorption to blood f(r), s(r) and s(s) defined in ICRP Publication 66 were identified as the most relevant influencing dose assessment. This study reviewed the data for 25 pure and impure uranium compounds. The average value of AMAD obtained was 5.7 microm (range 1.1-8.5 microm), which strongly supports the choice of 5 microm as the default value of AMAD for occupational exposures. The SSA varied between 0.4 and 18.3 m2 g(-1). For most materials, values of the absorption parameters f(r), s(r), and s(s) derived from the in vitro experiments were generally consistent with those derived from the in vivo experiments. Using average values for each pure compound allowed us to classify UO2 and U3O8 as Type S, mixed oxides, UF4, UO3 and ADU as Type M, and UO4 as Type F based on the ICRP Publication 71 criteria. Dose coefficients were also calculated for each pure compound, and average values for each type of pure compound were compared with those derived using default values. Finally, the lung retention kinetics and urinary excretion rates for inhaled U03 were compared using material-specific and default absorption parameters, in order to give a practical example of the application of this study.

Mucoadhesive beclomethasone microspheres for powder inhalation: their pharmacokinetics and pharmacodynamics evaluation

The feasibility of prolonging drug action and/or reducing drug dosage using mucoadhesive beclomethasone dipropionate (BDP) microspheres for powder inhalation was investigated. BDP was spray-dried from ethanol solution or aqueous suspension systems dissolving a mucoadhesive polymer, hydroxypropylcellulose (HPC); this resulted in amorphous and crystalline BDP incorporation in the HPC microspheres (aBDP/HPC and cBDP/HPC; BDP-HPC ratio=1:4), respectively. These microspheres were administered as powder aerosols to healthy or antigen-induced, asthmatic guinea pigs, and BDP’s retention in the lung (pharmacokinetics) and inhibitory duration with respect to eosinophil infiltration into the airways (pharmacodynamics) were compared to those for pure crystalline BDP (cBDP; ‘control’). Both BDP/HPC microspheres were prepared within a respirable-size range of 2.5–2.9 μm. BDP’s aqueous solubility was increased 25 times for aBDP/HPC, compared to crystalline counterpart. Pharmacokinetic profiles for three powders were dissolution-modulated. aBDP/HPC showed rapid BDP absorption from the lung (≥95% absorption for 180 min) with a greater metabolite (B17MP) formation, compared to cBDP, primarily due to the increased dissolution of amorphous BDP. In contrast, 86.0% of BDP remained at 180 min following cBDP/HPC administration, demonstrating the prolonged BDP’s retention in the lung by virtue of poor dissolution (and/or release) and retarded mucociliary clearance. As a result, while cBDP (1.37 mg/kg) significantly inhibited eosinophil infiltration into the lungs of antigen-sensitized and -challenged guinea pigs for only 1–6 h, cBDP/HPC, despite a much lower drug dosage (0.25 mg/kg), was capable of maintaining such inhibitory effects for 24 h following administration. It appeared therefore that the prolonged lung retention of BDP by the use of the HPC microspheres (cBDP/HPC) was attributed to prolonging its pharmacological duration without requiring increased drug dosage.

Activated polymorphonuclear cells increase sickle red blood cell retention in lung: role of phospholipids

This study investigates the role of the activated polymorphonuclear cell (APMN) products on sickle red blood cell (SRBC) retention/adherence in the pulmonary circulation. Isolated rat lungs were perfused with (51)Cr-labeled normal RBCs (NRBC) or SRBCs (10% hematocrit) suspensions +/- PMNs. Specific activities of lung and perfusate were measured and retention (the number of SRBC/g lung) was calculated. SRBC retention was 3.5 times greater than NRBC retention. PMN activation was required to increase SRBC retention. Supernatants from APMN increased SRBC retention, which suggested soluble products such as oxidants, PAF, and/or leukotriene (LTB(4)) are involved. Heat inactivation of PMN NADPH oxidase had no effect on retention. Whereas neither platelet-activating factor (PAF) nor LTB(4) (secreted by APMN) increased SRBC retention, PAF+LTB(4) did. The PAF antagonist, WEB-2170, attenuated SRBC retention mediated by PAF+LTB(4) and APMNs. Similarly, zileuton (5-lipoxygenase inhibitor) attenuated APMN-mediated SRBC retention. We conclude the concomitant release of PAF and LTB(4) from APMN is involved in the initiation of microvascular occlusion by SRBCs in the perfused rat lung.

Pulmonary involvement in Behçet's disease: evaluation of 123 I-MIBG retention.

Pulmonary involvement in Behçet's disease (BD) is reported to indicate poor prognosis and high mortality. Our aim was to evaluate the pulmonary vascular status in BD. As 123I-meta-iodobenzylguanidine (123I-MIBG) shares the same uptake, storage and release mechanisms as norepinephrine, associated with the functional state of pulmonary endothelium, it may reflect endothelial injury. Twenty-five patients (13 males, 12 females; mean age, 36.44 years) and 12 age-matched controls were included. After intravenous injection of 123I-MIBG, thorax images were taken at 15 min and 4 h. Appropriate regions of interest were drawn, and heart to mediastinum (H/M) ratios and lung retention indices (LRI) were calculated. The difference between the LRI of controls (75.6+/-4%) and patients (87.7+/-10%) was found to be extremely significant (P<0.005). The LRIs of active (92.85+/-12%) and inactive (83.65+/-5%) states of BD were significantly different (P<0.05) from each other. There was no significant difference between the H/M ratios of controls (2.4+/-0.27) and patients (2.39+/-0.31) or between patients in active and inactive disease states. Our study revealed prolonged lung retention of 123I-MIBG in BD, probably reflecting the severity of the disease. In conclusion, 123I-MIBG lung retention is a valuable finding in the evaluation of pulmonary vascular status and may be a potential marker of prognosis in BD.

Fiberoptic Bronchoscopic Balloon Dilatation in Malignant Tracheobronchial Disease: Indications and Results

Bronchoscopic balloon dilatation (BBD) has become a valuable tool in the treatment of benign tracheobronchial stenoses. The objective of this study was to assess indications for and results of fiberoptic BBD in treating malignant lesions. One hundred twenty-six balloon dilatation procedures were performed in 78 patients with predominantly bronchial carcinoma. BBD was only performed when alternative modes of local treatment (eg, laser therapy or stent implantation) were not indicated or were inappropriate. Indications were symptomatic stenoses of the tracheobronchial tree: dyspnea or stridor (52%), retention pneumonia (15%), atelectasis (10%), retention of secretions (21%), or lung abscess (2%). Fifty-five percent of all procedures consisted of dilatations of tracheal or bronchial lesions (group 1). In 22% of procedures, a stent was dilated (group 2). In 13%, BBD was used to facilitate stent placement (group 3), and in 10% to enable the correct positioning of irradiation probes for brachytherapy (group 4). In group 1 and group 2, 2 of 2 lung abscesses resolved, 5 of 8 atelectases resolved, and 11 of 12 retention pneumonias resolved. Dyspnea improved in only 12 of 32 patients. No abscess recurred. Two pneumonias and two atelectases reappeared due to restenosis. Stent implantation and brachytherapy procedures were facilitated in 90% of cases. In 52% of cases, BBD was supported by high-frequency jet ventilation. Complications consisted of one fatal hemoptysis caused by a lacerated pulmonary artery, and minor bleeding not necessitating specific therapy. Fiberoptic BBD is useful in the management of airway stents prior to and postimplantation, as well as in the placement of brachytherapy catheters. BBD is also successful in the resolution of poststenotic lung abscesses, retention pneumonias, and atelectases.

Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats.

The perioperative period is characterized by a state of immunosuppression, which was shown in animal studies to underlie the promotion of tumor metastasis by surgery. As this immunosuppression is partly ascribed to the neuroendocrine stress response, the authors hypothesized that spinal blockade, known to attenuate this response, may reduce the tumor-promoting effect of surgery. Fischer-344 rats were subjected to a laparotomy during general halothane anesthesia alone or combined with either systemic morphine (10 mg/kg) or spinal block using bupivacaine (50 microg) with morphine (10 microg). Control groups were either anesthetized or undisturbed. Blood was drawn 5 h after surgery to assess number and activity of natural killer cells, or rats were inoculated intravenously with MADB106 adenocarcinoma cells, which metastasize only to the lungs. Metastatic development was assessed by quantifying lung retention of tumor cells 24 h after inoculation or by counting pulmonary metastases 3 weeks later. Laparotomy conducted during general anesthesia alone increased lung tumor retention up to 17-fold. The addition of spinal block reduced this effect by 70%. The number of metastases increased from 16.7 +/- 10.5 (mean +/- SD) in the control group to 37.2 +/- 24.4 after surgery and was reduced to 10.5 +/- 4.7 during spinal block. Systemic morphine also reduced the effects of surgery, but to a lesser degree. Natural killer cell activity was suppressed to a similar extent by surgery and by anesthesia alone. The addition of spinal blockade to general halothane anesthesia markedly attenuates the promotion of metastasis by surgery.

Methodology for the measurement of mucociliary function in the mouse by scintigraphy.

The objective of the study was to develop a scintigraphic method for measurement of airway mucociliary clearance in small laboratory rodents such as the mouse. Previous investigations have characterized the secretory cell types present in the mouse airway, but analysis of the mucus transport system has been limited to in vitro examination of tissue explants or invasive in vivo measures of a single airway, the trachea. Three methods were used to deposit insoluble, radioisotopic colloidal particles: oropharyngeal aspiration, intratracheal instillation, and nose-only aerosol inhalation. The initial distribution of particles within the lower respiratory tract was visualized by gamma-camera, and clearance of particles was followed intermittently over 6 h and at the conclusion, 24 h postdelivery. Subsets of mice underwent lavage for evidence of tissue inflammation, and others were restudied for reproducibility of the methods. The aspiration and instillation methods of delivery led to greater distributions of deposited activity within the lungs, i.e., approximately 60--80% of the total respiratory tract radioactivity, whereas the nose-only aerosol technique attained a distribution of 32% to the lungs. However, the aerosol technique maximized the fraction of particles that cleared the airway over a 24-h period, i.e, deposited onto airway epithelial surfaces and cleared by mucociliary function such that lung retention at 24 h averaged 57% for delivery by aerosol inhalation and > or =80% for the aspiration or intratracheal instillation techniques. Particle delivery methods did not cause lung inflammation/injury with use of inflammatory cells and chemoattractant cytokines as criteria. Scintigraphy can discern particle deposition and clearance from the lower respiratory tract in the mouse, is noninvasive and reproducible, and includes the capability for restudy and lung lavage when time course or chronic treatments are being considered.

Effects of gadolinium on the retention and translocation of 239Pu-hydroxide.

The effect of gadolinium on the lung retention, excretion, and translocation of plutonium was studied in rats instilled intratracheally with plutonium hydroxide with and without gadolinium. Three types of plutonium hydroxide were prepared: pure 239Pu-hydroxide colloid, that containing a high concentration of gadolinium, and that containing a low concentration of gadolinium. The lung retention of 239Pu was higher and the fecal excretion was lower in the rats administered 239Pu-hydroxide containing a high concentration of gadolinium than those administered pure 239Pu-hydroxide colloid. The translocation of 239Pu from lung to other organs including the liver, spleen, femur, and kidney was not affected by gadolinium. The cytological examination of bronchoalveolar lavage cells showed that the administration of 239Pu-hydroxide containing a high concentration of gadolinium induced the inflammatory reactions in the lung. The delayed alveolar clearance of plutonium in the rats administered 239Pu-hydroxide colloid containing a high concentration of gadolinium may be attributable to the change in physicochemical characteristics of colloid and the inflammation induced in the lung by gadolinium.

Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats

We have previously shown in rats that the provision of analgesic doses of morphine significantly reduces the tumor-promoting effects of undergoing and recovering from surgery. Because morphine had no effect in non-operated animals, and because a single preoperative dose given hours before tumor inoculation was effective, we have suggested that it is the pain-relieving effects of the drug that underlies its beneficial impact. To support and strengthen this suggestion, two different regimens of analgesia were employed, the systemic administration of the more selective μ-agonist, fentanyl, and the intrathecal (i.t.) administration of bupivacaine plus morphine. To assess host resistance against metastasis, we used a lung clearance assay of the MADB106 mammary adenocarcinoma, a natural killer (NK)-sensitive syngeneic cell line that metastasizes only to the lungs. Female and male Fischer 344 rats were randomly assigned to one of four groups using a 2×2 experimental design: experimental laparotomy under halothane anesthesia versus anesthesia alone, by drug treatment versus vehicle. In the first in vivo experiment, fentanyl was administered 20 min before surgery (40 μg/kg subcutaneously (s.c.)), and at the end of surgery in a slow-release suspension (20 μg/kg s.c.). In the second in vivo experiment, bupivacaine (10 μg) plus morphine (20 μg) in 50 μl was administered i.t. before surgery. Surgery resulted in a 3- to 4-fold increase in the lung retention of MADB106 cells in both males and females, and the observed surgery-induced increase in lung tumor retention was reduced by more than 65% in the fentanyl-treated animals and more than 45% in the animals receiving i.t. bupivacaine plus morphine. Neither drug regimen exerted effects in the anesthesia only animals. Surgery also resulted in a significant suppression of whole blood NK activity assessed at 5 h postoperatively, the same time point at which MADB106 tumor cells were inoculated in the in vivo studies. Unlike the in vivo study, fentanyl suppressed NK activity at this time point in non-operated rats, but had no effect in operated rats. Taken together, these findings strengthen the suggestion that the management of perioperative pain is a critical factor in preventing surgery-induced decreases in host resistance against metastasis. If similar relationships between pain and metastasis occur in humans, then pain control must become a priority in the postoperative care of individuals with cancer.

LUNG CLEARANCE IN CHILDREN WITH DUCHENNE MUSCULAR DYSTROPHY OR SPINAL MUSCULAR ATROPHY WITH AND WITHOUT CPAP (CONTINUOUS POSITIVE AIRWAY PRESSURE)

Bronchiolar clearance was studied in 7 boys in the age range of8 to 17 years, 6 with Duchenne muscular dystrophy (DMD)and 1 with spinal muscular atrophy type II (SMA-II). These boys had healthy lungs but a severely reduced muscular strength (wheelchair dependent). In 6 of the boys, clearance was studied twice, at one occasion as a control and at the other occasion following treatment with continuous positive airway pressure (CPAP). A control group of healthy adults was used. In the clearance examinations, 6- μ m Teflon particles, labeled with 111 In was inhaled extremely slowly, 0.05 L/s. This gives a deposition mainly in the bronchioles. Lung retention was measured after 0, 24, 48, and 72 hours. A model for deposition of particles in the adult lung was scaled down to represent the children in this study. Deposition in various airway generations was calculated to be similar in children and adults. Also the measured retentions were similar in the boys and the adults. In the clearance experiments during CPAP treatment, there was a significantly lower retention after 72 hours (but not after 24 and 48 hours)than in the control experiments. The results indicate that a severe reduction of muscular strength, and thereby a reduction of mechanical movement of the lung, does not affect clearance from large and small airways. However, some effect of clearance from small airways cannot be excluded due to the short measuring period. The small but significant effect of the CPAP treatment might have potential clinical importance and suggest that bronchiolar clearance can be affected by some form of mechanical force.

Evaluation of respiratory and cutaneous doses and urinary excretion of alkylphosphates by workers in greenhouses treated with omethoate, fenitrothion, and tolclofos-methyl.

This research evaluated exposure pathways across work tasks for three organophosphate pesticides in a group of greenhouse workers. During reentry in ornamental plant greenhouses, five male workers were monitored for five consecutive days. Skin contamination (excluding hands) was evaluated with nine pads of filter paper placed on the skin. Hand contamination was assessed by washing with 95% ethanol. Respiratory exposure was evaluated by personal air sampling. The respiratory dose was based on a lung ventilation of 20 L/min. The doses absorbed were estimated assuming 10% skin penetration and 100% lung retention. Urinary alkylphosphates were assayed in the 24-hour urine samples of the days on which exposure was evaluated. Respiratory exposure was usually less than skin contamination, being 4.5 +/- 8.4%, 9.9 +/- 10.0%, and 49.5 +/- 26.6% (mean +/- standard deviation) of total exposure for omethoate, tolclofos-methyl, and fenitrothion, respectively. Multiple regression analysis showed that urinary alkylphosphate (nmol/24 hours) (y) was significantly correlated (r = 0.716, p < 0.001) with the respiratory doses of the three active ingredients absorbed the same day (x1) and with the cutaneous dose absorbed the previous day (x2). The relationship was expressed by the equation y = 0.592x2 + 0.117x, + 156.364. The doses of omethoate absorbed by one worker were more than 45 times the acceptable daily intake (ADI) of 1.41 nmol/kg body weight (b.w.) The ADI for fenitrothion and tolclofos-methyl (10.8 and 212.6 nmol/kg body weight, respectively) were never exceeded. High absorption by one worker underlines the importance of correct use of protective clothing. In this study the hands were always a source of contact with the pesticides. Greater precautions should be taken to reduce contamination (clean gloves, constant use of gloves).