Richard G. Cuddihy

A simulation model describing the metabolism of inhaled and ingested selenium compounds

Abstract Organ distribution and retention of the trace element selenium were studied in rats after inhalation of selenious acid and elemental selenium aerosols. A simulation model of selenium metabolism was developed from data obtained. Although the rate of absorption of these two compounds into blood was different, once absorbed both chemical forms behaved identically. This indicates that both compounds joined the same selenium metabolic pool. The simulation model was extended to estimate the levels of selenium in people inhaling selenium compounds normally found in urban atmospheres and in individuals exposed to selenium compounds in the workplace. Predictions of the model for uptake and organ retention of selenium from the environment were compared to measured organ burdens in humans. Inhalation of selenium compounds at levels normally present in urban atmospheres does not contribute significantly to human body burdens of selenium. The most probable source of selenium in human tissues is due to ingestion of selenium in food. However, selenium present in the workplace, in concentrations at the timeweighted threshold limit value, may pose an inhalation hazard to at least some of the workers.

Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance.

Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people.

Systemic absorption of selenious acid and elemental selenium aerosols in rats

Absorption of Se from the nasal passages, lungs, gastrointestinal tract, and skin was studied in Fischer-344 rats. Radiolabeled selenious acid and elemental Se particles were administered by inhalation, gavage, nasal instillation, and iv injection. Selenious acid was always absorbed into the general circulation more rapidly and to a greater extent than elemental Se. By 4 h after inhalation of selenious acid and elemental Se aerosols, 94% of the selenious acid and 57% of the elemental Se deposited in lungs was absorbed into blood. Of the selenious acid instilled into nasal passages, 18% was absorbed into blood; 16% of the elemental Se was absorbed. Gastrointestinal absorption was 87% for selenious acid and 50% for elemental Se. Selenious acid solutions were also painted onto the pelts of rats. From 10 to 30% of the selenious acid was absorbed through the skin. Following inhalation or injection of either Se compound, most of the Se was excreted in the urine. Significantly more Se appeared in feces of animals receiving elemental Se by gavage than animals receiving selenious acid. Results indicate that if people were to absorb inhaled Se from the upper respiratory tract in a manner similar to that of rats, one-third more selenious acid would be absorbed into the general circulation than elemental Se. All Se deposited in the lungs would be absorbed into blood. However, selenious acid would be absorbed more rapidly than elemental Se.

Pulmonary collagen metabolism after lung injury from inhaled 90Y in fused clay particles.

Abstract Pulmonary fibrosis was studied in Syrian hamsters exposed by inhalation to an aerosol of 90 Y in fused montmorillonite clay particles. Control hamsters were exposed to an aerosol of fused clay containing stable zirconium. Animals with cumulative radiation doses to lung of 2000 to 14,000 rad were sacrificed between 14 and 169 days after exposure. Controls were sacrificed at similar times. One day before sacrifice, the animals were injected with [ 14 C]-proline to label pulmonary collagen. When compared with controls, fractional incorporation of [ 14 C]-proline into native collagen increased as early as 14 days after 90 Y exposure. This collagen synthesis continued to increase until about 126 days after exposure when fractional incorporation in irradiated animals was 175% of the mean control values. It remained at this level through 169 days. Collagen degradation, measured by ultrafilterable hydroxyproline peptides, increased similarly by 14 days after exposure, but later returned to values similar to those for control animals. By 55 days after exposure, when fibrosis was observed histologically, pulmonary native collagen was increased in irradiated animals as compared to control animals. Static lung compliance in irradiated hamsters, a measure of expansibility of the lung, was decreased 14 through 55 days after exposure. Later, compliance became indistinguishable from that of control animals when this parameter increased in both groups. This study demonstrated that pulmonary injury from beta irradiation delivered within a 2-week period stimulated both synthesis and degradation of collagen which led to collagen accumulation and scarring by 2 months after exposure. Continued radiation was not necessary to sustain this particular response of the lung to injury.

Absorption, distribution, and retention of inhaled selenious acid and selenium metal aerosols in Beagle dogs☆☆☆

We studied the distribution and retention of inhaled selenious acid and selenium metal aerosols which were similar in size and chemical form to selenium aerosols that may be produced during fossil fuel combustion. Beagle dogs were given 10 to 61 micrograms Se/kg of body weight by inhalation. Aerosols generated for the inhalation exposures were also collected and instilled into the upper respiratory tracts or stomachs of additional dogs to measure systemic absorption at these sites. Selenium-75, incorporated into the aerosols, was used to determine the Se content in the whole animal, excreta, and individual tissues as a function of time. Virtually all of the inhaled selenious acid aerosol was rapidly absorbed into the blood from the lungs, gastrointestinal tract, and the nasal membranes. Selenium metal aerosols were less rapidly absorbed. Selenium that was absorbed into the blood was translocated to the liver, kidney, spleen, and heart. Selenium-75 in these organs had a biological half-life of 30 to 40 days. Approximately 50% of the deposited Se was eliminated with a biological T1/2 of 1.2 days. Urine was the major route of excretion, accounting for 70 to 80% of the excreted Se. The long-term component of the whole-body retention function for both inhaled aerosols had a half-life of about 34 days and accounted for about 20% of the initial Se dose. The data suggested that although absorption of selenious acid into blood following inhalation was more rapid than absorption of selenium metal, once absorbed the disposition of both compounds was similar.

Health effects of diesel exhaust. A contemporary air pollution issue.

Extracts of diesel exhaust particles are mutagenic in bacterial and mammalian cell assays; they contain hundreds of identifiable organic compounds, some of which are known mutagens and carcinogens. The particles are readily respired and about 20% to 30% of them are deposited in the pulmonary region, where they are retained for long periods. At low diesel exhaust concentrations, typical of those likely for human exposure, particle deposition and clearance rates are essentially normal and particle concentrations in the pulmonary region are expected to remain quite low. At very high concentrations of diesel exhaust, clearance processes may be overwhelmed and lung burdens of particles may continue to increase over long periods. Evidence from laboratory animals suggests that pulmonary injury and reduced respiratory function would occur in humans at these high concentrations. Epidemiologic data and laboratory studies appear to indicate that the human lung cancer risk from exposure to diesel exhaust would be quite low, even if use of diesel vehicles increased substantially.

Absorption of diethylenetriaminepentaacetic acid (DTPA) from the respiratory tracts of beagle dogs

Absorption of diethylenetriaminepentaacetic acid (DTPA) from the nasopharyngeal (NP), tracheobronchial (TB) and pulmonary (P) regions of beagle dogs was determined because of the current interest in aerosolized DTPA as a method for the removal of radionuclides deposited in the respiratory tract. Radiolabled DTPA was instilled into the NP, TB and P regions of dogs and its subsequent translocation was followed for 48 hours. Results revealed that 16, 48 and 90% of the instilled DTPA was absorbed into the circulatory system from the NP, TB and P regions, respectively. A comparison was also made between NP absorption of aerosolized as opposed to instilled DTPA. Nasopharyngeal absorption (23%) of aerosolized DTPA was slightly higher than that of instilled DTPA. Further, DTPA deposited in the respiratory tract remained in the body longer than intravenously injected DTPA. These findings indicate that a substantial quantity of DTPA is absorbed from all regions of the respiratory tract and that DTPA need not be deposited within the deep lung to produce systemic absorption of DTPA for the removal of internally deposited radioactive isotopes.

Deposition and retention of inhaled niobium in beagle dogs.

AbstractThe deposition and retention of inhaled 95Nb(V) oxalate and 95Nb(V) oxide aerosols were studied in beagle dogs. The aerosols were polydisperse in particle sizes with activity median aerodynamic diameters (AMAD) between 1.6 and 2.5 μm. About 60% of the inhaled aerosols deposited in the dogs,

Bioassay model for estimating body burdens of 241Am from excretion analyses.

A simple bioassay model for predicting the organ burdens of 241Am from excretion rates is presented for inhalation exposures. The model uses three compartments representing lung, liver and skeleton. The model was developed using data from studies in laboratory animals of inhaled or injected 241Am and was validated for people by comparison to cases of accidental inhalation exposures to 241Am. The data for people have a large amount of variability but indicate that the retention half-time of 241Am in liver is approximately 2 yr and in skeleton is approximately 30 yr. These parameters can be used in the model to estimate body and organ burdens from excretion rates after inhalation of 241Am or the model can be fitted to an individuals measured excretion rates.