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Biomedical subjects

F J Miller

Publications and source records attributed to F J Miller.

At least 91 records · Page 5Linked to original sources
PubMed1989

Inhalation reference dose (RfDi): an application of interspecies dosimetry modeling for risk assessment of insoluble particles.

Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

Aerosols↗
PubMed1989

Efficacy, safety, and tolerability of ioversol in intra-arterial digital subtraction angiography.

Twenty-two women and 18 men undergoing intra-arterial digital subtraction angiography were enrolled in an open-label, noncomparative study to assess the efficacy, safety, and patient tolerance of the contrast medium ioversol. The quality of radiographs generated was excellent in 60.0% of the studies, diagnostic in 37.5%, and nondiagnostic in 2.5%. There were no clinically significant drug-related changes in vital signs or laboratory tests among the patients, and no drug-related adverse effects were reported. Heat and pain related to injection of ioversol were graded on a four-point scale, with 0 indicating none and 3 indicating severe. The average scores were 1.3 for heat and 0.1 for pain. In this study, ioversol was a safe and effective contrast medium for angiography and was associated with a low incidence of patient discomfort.

Adult↗
PubMed1989

Experimental percutaneous gallstone lithotripsy: results in swine.

The Kensey-Nash device is used to fragment gallstones percutaneously. It is inserted into the gallbladder through an 8-F introducer sheath, a cage is expanded to protect the gallbladder, and the impeller is activated. A strong vortex automatically pulls the stones into the basket. The device was tested in 24 pigs in which human gallstones (5-19 mm, bilirubin and cholesterol types) had been implanted and in two control pigs with no gallstones. All pigs except two were killed immediately after the procedure (acute studies); the two were followed up for 36 days and then killed. Fragments (1-3 mm) were similar in size to those seen in current extracorporeal shock wave lithotripsy studies. A complication occurred in one animal, and technical failures occurred in two, causing these three studies to be aborted.

Animals↗
PubMed1989

Exposure to low levels of ozone results in enhanced pulmonary retention of inhaled asbestos fibers.

Health effects associated with exposure to ozone at environmentally relevant concentrations are subject to considerable controversy. Currently, no compelling evidence exists that exposure to low levels of ozone leads to lasting impairment of pulmonary structure or function. One adverse health effect of ozone may be to change lung uptake or clearance functions for other inhaled air pollutants. As a test of this hypothesis, Fischer 344 rats were continuously exposed to 0.06 ppm ozone 7 days a week with a slow rise in ozone to a peak of 0.25 ppm and subsequent decrease to 0.06 ppm over a 9-h period five times each week for 6 wk. Three days after the end of ozone exposure, animals-were exposed to aerosolized asbestos fibers for 5 h and examined immediately after or 30 days after exposure to asbestos. Filtered air control animals were simultaneously exposed to asbestos. Immediately after the end of fiber exposure, lung asbestos fiber burden was similar in both groups. However, 1 month after exposure, fiber mass and fiber number were significantly greater (p less than 0.05) in the lungs of animals exposed to ozone than in the lungs of those exposed to air. These findings suggest that ambient levels of ozone can impair clearance of fibrogenic and carcinogenic materials such as asbestos from the lungs and represent an important adverse effect of prolonged exposure to low levels of this oxidant gas.

Animals↗
PubMed1988

Effects of low levels of NO2 on terminal bronchiolar cells and its relative toxicity compared to O3.

This report describes structural changes occurring in the terminal bronchioles of rats exposed to low levels of NO2 continuously for 6 weeks. In addition, the relative susceptibility of epithelial cells to oxidants and the comparative toxicity of NO2 and O3 are discussed. Terminal bronchioles isolated from rats exposed 5 days/week to 2.0 ppm NO2 (plus two 1-hr daily spikes to 6.0 ppm) were found to have 19% less ciliated cells per unit area of epithelial basement membrane. The remaining ciliated cells had a reduced mean surface area (-29%). The shape of the Clara cell changed with reduced size of the dome protrusions but increased cell contact with the basement membrane. These data indicate that exposure to 2.0 ppm NO2 (+ spikes) for 6 weeks caused injuries to cilia and ciliated cells and possible Clara cell differentiation in the terminal bronchioles of adult rats. Exposures of adult or juvenile rats to 0.5 ppm NO2 (+ two 1-hr daily spikes 5 days/week to 1.5 ppm) did not cause morphologically measurable injuries in the terminal bronchioles. The severity of the concentration-dependent epithelial cell reactions to NO2 and O3 in adult rat terminal bronchioles were compared to those occurring in the proximal alveolar regions (PAR). Epithelial cells in the PAR appeared to be more susceptible to oxidant insult since both 0.5 ppm NO2 and 0.25 ppm O3 were found to cause epithelial injury only in the PAR. Comparison of epithelial reactions to 6-week exposures to either NO2 or O3 indicated that 0.25 ppm O3 caused four times as much increase in the number of type I epithelial cells as did 2 ppm (+spikes) NO2. Therefore, O3 could be 40 times more toxic than NO2 in the PAR on the basis of the inspired concentration and the focal response. On the other hand, there was no loss of ciliated cells following the 0.25 ppm O3 exposure. This suggests that the ratio of O3 to NO2 toxicity in the terminal bronchioles is considerably less than 10. The relative toxicity of the two oxidant gases appears to be site specific.

Animals↗
PubMed1988

Definitive radiation therapy in bile duct carcinoma.

Between 1980 and 1985, 24 patients with primary adenocarcinoma of the bile duct were treated with various combinations of surgery, biliary intubation, external irradiation, and transcatheter brachytherapy. Seventy-five percent of tumors were in the proximal bile ducts. Ten patients received no or only palliative radiation, Group 1, whereas 14 patients received definitive courses of radiation (4 by external beam irradiation, 2 by transcatheter irradiation, and 8 by both modalities), Group 2. Survival in Group 1 and Group 2 was significantly different (p less than 0.005) with median survivals of 2.0 and 12.8 months, respectively. This result may be in part due to differences in treatment and in part due to selection bias because the series is small, uncontrolled, and retrospective. Median survival of the 8 patients treated with combined modalities was 13.2 months (range 7.4-30.3) with 4 patients alive 8.7 to 16.2 months, 3 without cholangiographic evidence of disease. Complications of therapy were common, including bacterial sepsis (58%), cholangitis (38%), gastrointestinal bleeding (46%), intra or extrahepatic abscesses (33%), and recurrent biliary obstruction (25%). Cholangitis, hemorrhage, abscesses, and ulcers appeared more frequently in definitively treated patients, whereas recurrent biliary obstruction was absent in this group and frequent in Group 1. Differences in complication rates between groups were not statistically significant. Early diagnosis and management usually reversed a downhill clinical course in patients with abscess and hemorrhage. Both surgical and percutaneous techniques of biliary decompression, the usual initial form of therapy in bile duct cancer, are associated with frequent and serious complications. Although many of our complications may have derived from biliary decompression, it is possible that definitive treatment may have increased the frequency of serious complications.

Adenoma, Bile Duct↗
PubMed1988

Research needs and advances in inhalation dosimetry identified through the use of mathematical dosimetry models of ozone.

Knowledge of the quantitative relationship between exposure concentration and delivered dose (i.e., dosimetry) is a fundamental starting point in the evaluation of the toxicity of chemicals, not only for intra- and interspecies comparisons but also for designing experiments that elucidate mechanisms of action and that identify issues or research areas for further study. To these ends a mathematical, lower respiratory tract dosimetry model for gases has been developed which, when linked to experimentally determined upper respiratory tract removal of a gas, can be used for dosimetric extrapolations between one test condition to a theoretical condition (e.g., animal-to-man, child-to-adult, high-to-low dose). This paper, using the ozone (O3) dosimetry model as an example, describes (1) the results of sensitivity analyses that have identified variables that can significantly influence the precision of model predicted doses, (2) research progress in improving the precision of those highly sensitive variables, and (3) approaches being used to validate the model. Results from studies of upper respiratory tract removal of O3 in animals and human are used as inputs into the mathematical model of the lower respiratory tract to illustrate applications of dosimetric extrapolations.

Administration, Inhalation↗
PubMed1988

Social and parenting factors affecting criminal-offence rates. Findings from the Newcastle Thousand Family Study (1947-1980).

A rare opportunity to study deprivation and criminality across generations arose from the follow-up of the families who participated in the Newcastle Thousand Family Survey. The data on these families had been preserved and it was possible, using criminal records, to examine longitudinally whether children who grew up in 'deprived' rather than 'non-deprived' families were more at risk of offending during later childhood and beyond. The results of this study suggest that this is indeed so.

Age Factors↗
PubMed1988

CT findings after uncomplicated percutaneous gastrostomy.

CT scans of the upper abdomen were obtained 1 hr to 9 days after percutaneous placement of feeding gastrostomy in 18 patients in order to establish a range of normal postprocedural findings. A majority of patients (56%) had pneumoperitoneum. Additional findings included abdominal wall hematomas in six patients (33%) and gastric hematomas in three patients (17%). Except for one case of mild ascites in an individual with large hepatic metastases, no abdominal fluid collections were discovered. After percutaneous gastrostomy, pneumoperitoneum and abdominal wall or gastric hematomas are commonly present. Presence of subcutaneous emphysema, free peritoneal fluid, or a loculated abdominal fluid collection should alert one to a possible complication.

Aged↗
PubMed1988

Effects of inhalation of 0.25 ppm ozone on the terminal bronchioles of juvenile and adult rats.

Cells of the terminal bronchioles are particularly susceptible to the effects of inhalation of low levels of ozone (O3). One-day-old (juvenile) or 6-week-old (adult) rats were exposed to 0.25 ppm O3 for 12 h/day or to continuous room air for 6 weeks. Morphometric analysis of perpendicular cross sections of terminal bronchioles demonstrated that exposure to O3 produced alterations in the surface characteristics of ciliated and nonciliated (Clara) cells in both groups of rats. There were significant losses (20-30%) of the surface area contributed by cilia and the luminal surface of Clara cells was decreased by 16-25%. O3 exposure also produced significant decreases in the number of brush cells per square millimeter of terminal bronchiolar basement membrane. The results of this study indicate that the normal structure of terminal bronchiolar epithelial cells is significantly altered by inhalation of 0.25 ppm O3. No statistically significant interactions between the effects of O3 and animal age at the beginning of the exposure were found.

Aging↗
PubMed1987

Ozone uptake in awake Sprague-Dawley rats.

Knowledge of ozone (O3) uptake in rats in integral to efforts to quantitatively extrapolate animal data to man. We have measured percentage O3 uptake in 30 adult Sprague-Dawley rats exposed, nose only, for 1 hr to 0.3, 0.6, or 1.0 ppm O3. Tidal volume and breathing rate measurements, obtained by plethysmography, were time-matched with changes in airstream concentrations of O3, oxygen, and carbon dioxide, due to animal breathing, for computation of O3 uptake and respiratory gas exchange values. Ozone uptake was calculated by a fractional deposition technique, i.e. O3 in vs O3 out. Total respiratory system O3 uptake was found to be approximately 40% of that inspired and did not vary with O3 concentration nor during the 1-hr exposure. The quantity of O3 inhaled and retained by the rat increased proportionally with O3 concentration.

Animals↗
PubMed1987

A model of the regional uptake of gaseous pollutants in the lung. II. The sensitivity of ozone uptake in laboratory animal lungs to anatomical and ventilatory parameters.

An O3 dosimetry model is used to simulate the local absorption of O3 in the lower respiratory tract of rats and guinea pigs. The model takes into account lower respiratory tract anatomy, transport in the lumen and air spaces, and transport and chemical reactions in the mucous and surfactant layers and in the underlying tissue and capillaries. For each species two anatomical models were used to investigate their influence in predicting absorption. Results with all four anatomical models and various ventilatory parameters showed a qualitative similarity in the shape of the dose versus airway number curves but significant differences in predicted percentage total and percentage pulmonary uptake. The percentage uptake was also sensitive to breathing frequency and tidal volume. Rat lobe models were used to study absorption in lobes and show that O3 tissue dose in centriacinar regions decreases with increasing distance from the trachea. The effect on results of values used for functional residual capacity and of values used for the chemical rate constants for O3 reactions in mucous were explored. Results differed quantitatively but not qualitatively.

Air Pollutants↗
PubMed1987

Evaluating the toxicity of urban patterns of oxidant gases. I. An automated chronic gaseous animal inhalation exposure facility.

An automated animal inhalation exposure facility was designed to conduct chronic exposures of rodents to gaseous pollutants. The facility consisted of 3 walk-in chambers with modular cages to allow for exposure of up to a maximum of 480 mice or 240 adult rats. Critical parameters of operation, such as relative humidity, pollutant concentration, and temperature, were monitored continuously. Failure of the system to maintain parameters within specified limits activated the alarm system. Distribution of test gases in the chambers was evaluated for homogeneity, and the standard deviation was determined to be within +/- 5% of the target concentrations throughout the chamber. The exposure facility was successfully used to expose 720 rats to diurnal patterns of O3 (baseline of 0.06 ppm for 13 h with an exposure peak to 0.25 ppm over 9 h) and NO2 (baseline of 0.5 ppm for 16 h with an exposure peak to 1.5 ppm over 6 h) for a period of 18 mo.

Administration, Inhalation↗
PubMed1987

Evaluating the toxicity of urban patterns of oxidant gases. II. Effects in mice from chronic exposure to nitrogen dioxide.

The study reported herein evaluates the influence of a chronic exposure to an urban pattern of NO2 (continuous baseline exposure of 0.2 ppm, on which were superimposed two 1-h spikes of 0.8 ppm NO2, 5 d/wk) as compared to the baseline exposure to determine the contribution of the spikes to toxicity. Mice were exposed for up to 52 wk with interim examinations. Multivariate analysis of variance revealed a statistically significant treatment effect on infectivity (p = 0.05) and pulmonary function (p = 0.03) parameters. Infectivity mortality of mice in the spiked exposure regimen was significantly greater than that in either the NO2-background-exposed mice or in control mice. Four of the pulmonary function variables exhibited the greatest differences among the treatment groups: end expiratory volume, vital capacity, respiratory-system compliance, and multiple-breath nitrogen washout. Results from the pulmonary-function analyses indicate that the spiked exposures to 0.8 ppm NO2 may have induced a subtle lesion. The chronic study results indicate that the presence of spikes of NO2 is contributing significantly to effects on antibacterial lung defenses and pulmonary function of mice.

Administration, Inhalation↗
PubMed1987

Influence of exposure patterns of nitrogen dioxide and modifications by ozone on susceptibility to bacterial infectious disease in mice.

The nitrogen dioxide (NO2) diurnal cycle found in urban communities usually consists of a low basal concentration upon which are superimposed higher concentration peaks or spikes of short duration. Various components of this environmental exposure mode were examined to assess effects of urban exposure profiles on susceptibility to infectious pulmonary disease. Mice were exposed to NO2 peaks of 4.5 ppm for 1, 3.5, or 7 h, challenged with Streptococcus sp. either immediately or 18 h postexposure, and then observed for mortality. When the streptococcal challenges were immediately after NO2 exposure, the mortality rate was directly related to the length of peak exposure, whether or not a basal exposure was used, and all peak lengths significantly increased mortality. When the challenge was delayed for 18 h after the peak exposure, spiked exposures of 3.5 and 7 h increased mortality to the same degree. If a 1-h peak exposure to 4.5 ppm was superimposed twice daily upon a continuous basal NO2 concentration of 1.5 ppm, there was a suggestive trend toward increased mortality near the end of the second week of exposure when challenge occurred immediately after the morning spike. Studies were also conducted to examine interactions with ozone (O3) and NO2, since urban air typically contains both of these oxidants. Using various combinations of basal and spiked exposure levels of NO2 and O3, synergistic results were obtained for streptococcal-induced mortality.

Air Pollutants↗
PubMed1987

Pulmonary effects due to short-term exposure to oil fog.

Rats were exposed to an oil fog generated by flash vaporation and subsequent condensation of lightweight lubricating oil. Exposures were for 3.5 h/d, 4 d/wk, for 4 wk, at concentrations of 1.5, 0.5, or 0.0 mg/l and a particle size of approximately 1 micron. Samples of respiratory tissues were taken for histopathologic analyses, lavage fluid samples were collected, and pulmonary function measurements were made the day after the last exposure. An accumulation of macrophages within the alveolar lumen, an increase in lavage fluid protein content, and an increase in total cell content in lavage fluid due to an influx of polymorphonuclear leukocytes was noted in rats exposed at the 1.5-mg level. Also, for this exposure group there was an increase in lung wet and dry weight and an increase in end-expiratory volume, and pneumonitis was observed histopathologically in 4 of 10 male rats exposed. Pneumonitis was not observed among six female rats examined. Oil fog had no effect on total lung capacity, residual volume, vital capacity, lung compliance, or the distribution of ventilated air within the lung. Effects following exposure to 0.5 mg/l were limited to slight accumulation of macrophages in the alveolar lumen and an increase in the total cells in lavage fluid, which could not be attributed to an increase in any particular cell type.

Air Pollutants↗