Joseph W. Illing

Influence of ozone on pentobarbital-induced sleeping time in mice, rats, and hamsters

Abstract Studies were conducted to investigate the effect of ozone (O 3 ) in prolonging pentobarbital (PEN)-induced sleeping time (S.T.). Since O 3 is a common air pollutant, an O 3 -induced alteration of mechanisms of drug action could have public health implications. It was shown that a 5-hr exposure to 1960 μg O 3 /m 3 (1 ppm) caused an increased PEN-induced S.T. in female mice (three strains), rats, and hamsters. This response was not observed in male rats or in male mice even when the latter were exposed for 5 hr/day for 3 days. Male hamsters were affected, but less so than females. Ozone concentration and time relationships were investigated in female mice. Concentrations from 196 to 9800 μg O 3 /m 3 (0.1 to 5 ppm) increased PEN-induced S.T. However, as the concentration was decreased, an increasing number of daily 3-hr exposures were needed to cause an effect. Once the maximal effect was observed, further daily exposures resulted in a dissipation or a disappearance of the effect. Also, recovery occurred within 24 hr after exposure ceased. Other experiments were performed in which mice received a continuous exposure to a C × T (concentration × time) of 5, ranging from 196 μg/m 3 (0.1 ppm) × 50 hr to 1960 μg/m 3 (1 ppm) × 5 hr. For most of the concentrations, the magnitudes of the O 3 effects were roughly equivalent. These data are interpreted as a systemic effect of O 3 on mechanisms of the termination of action of pentobarbital.

Effects of Phosgene Exposure on Bacterial, Viral, and Neoplastic Lung Disease Susceptibility in Mice

AbstractIn this study the effects of phosgene inhalation on host resistance models representative of bacterial, viral, and neoplastic lung diseases were assessed. A single Ch exposure to concentrations of phosgene of 0.025 ppm and above significantly enhanced mortality due to laboratory-induced aerosol infection with Streptococcus zooepidimi-cus (group C). Bacteria recovered from lavage fluid of mice exposed to 0.05 ppm for 4 h increased dramatically between 3 and 48 h post infection, while bacteria recovered from lavage fluid of air exposed mice declined to nearly undetectable levels over the same time period. Concentrations of phosgene 10-fold higher than the lowest observable effect concentration for streptococcus susceptibility had little or no effect on alveolar macrophage phagocytic activity and little or no effect on total cells recovered, viability, or differential cell counts in lavage fluid obtained shortly after exposure. A single 4-h exposure to as little as 0.025 ppm phosgene also caused a si...

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.

Decreased resistance to infection in exercised mice exposed to NO2 and O3

A mechanized wheel was constructed for use in evaluating the interaction of exercise and gaseous pollutants such as O3 and NO2. Immediately after the pollutant exposure, both exercised and nonexercised female mice (CD-1) were combined with controls, challenged with an aerosol of viable Streptococcus pyogenes (group C), and then observed over a 15-d period for incidence of mortality. Exposure to O3 at 196 micrograms/m3 (0.1 ppm) or 590 micrograms/m3 (0.3 ppm) while exercising yielded mortality rates that were significantly higher than those observed in the O3 groups that were not exercised. With exposure to NO2 at 5640 micrograms/m3 (3 ppm), exercise produced a significant enhancement in mortality over the other treatment groups. These studies show that exercise can affect the mortality observed in this model system and indicate the need for establishing safe exposure levels of pollutants as a function of the activity level of the exposed population.

Effect of ozone on drug-induced sleeping time in mice pretreated with mixed-function oxidase inducers and inhibitors.

Abstract Prior studies have shown that ozone (O 3 ) increases pentobarbital (PEN)-induced sleeping time (S.T.) in female mice, rats, and hamsters. To investigate some potential mechanisms producing these effects, we measured zoxazolamine-induced paralysis time and thiopental- and hexobarbital-induced S.T., all of which were prolonged significantly in mice following a 5-hr exposure to 1960 μg O 3 /m 3 (1 ppm). To probe the effect of O 3 exposure on the drug metabolism microsomal monooxygenase system, CD-1 mice were pretreated with mixed-function oxidase inducers [PEN, phenobarbital, pregnenolone-16α-carbonitrile, and β-naphthoflavone (BNF)] or inhibitors (SKF 525A and piperonyl butoxide) prior to a 5-hr exposure to 1960 μg O 3 /m 3 (1 ppm). In CD-1 mice, pretreatment with PEN caused no effects on PEN-induced S.T. For all other compounds, the PEN-induced S.T. of CD-1 mice was significantly decreased, irrespective of whether the animals were exposed to air or O 3 . Ozone exposure significantly increased PEN-induced S.T. equivalently in the vehicle- and inducer-pretreated animals. Similar studies were conducted in DBA and C57BL mice pretreated with BNF. DBA mice responded similarly to CD-1 mice. However, with C57BL mice, O 3 significantly increased PEN-induced S.T. in the vehicle, but not in the BNF group. When CD-1 mice were pretreated with inhibitors, a generally increased magnitude of the O 3 effect was observed with increasing doses of inhibitor. These data suggest that O 3 exposure may affect several aspects of drug metabolism and distribution.

Pulmonary host defense responses to inhalation of sulfuric acid and ozone

The effects of simultaneous exposure to ozone (O3) and sulfuric acid [H2SO4, 0.23 microns volume median diameter (VMD)] and a single exposure to ultrafine (less than 0.1 micron VMD) H2SO4 under various conditions were studied using the infectivity/mortality and the ciliary beating frequency model systems. A 3-h exposure to a combined aerosol of 196 micrograms O3/m3 and 483 or 241 micrograms H2SO4/m3 significantly increased the susceptibility of mice to a laboratory-induced respiratory infection. However, exposure to 543 micrograms ultrafine H2SO4/m3 for 2 h or 365 micrograms/m3 2 h/d for 5 d did not significantly affect this parameter. Upper airway response, as measured by changes in hamster tracheal ciliary beating frequency, was not affected by either a 3-h combined exposure to 196 micrograms O3/m3 and 847 micrograms H2SO4/m3 or a 2-h exposure to 458 micrograms ultrafine H2SO4/m3.

Increased susceptibility to parathion poisoning following murine cytomegalovirus infection

In mice treated with ordinarily sublethal doses of parathion 2 to 5 days postinfection with murine cytomegalovirus (MCMV) 50 to 100% mortality was observed. These mortalities appeared to be due to a decrease in the ability of infected mice to detoxify parathion. Pentobarbital-induced sleeping time was also enhanced 3 and 6 days postinfection and cytochrome P-450 concentrations were markedly depressed in mice tested 3 days after infection. MCMV-induced effects on sensitivity to parathion and pentobarbital did not appear to be directly attributable to liver infection since concentrations of virus in the liver persisted at maximum concentrations well beyond the time when sensitivity to these compounds returned to normal. The time frame during which enhanced sensitivity to parathion and pentobarbital was observed suggests that this sensitivity may have been caused by viral-induced interferon-mediated depression of cytochrome P-450.

Extrapulmonary effects of NO2 as reflected by pentobarbital-induced sleeping time in mice

The influence of nitrogen dioxide (NO2) on pentobarbital (PEN)-induced sleeping time (S.T.) was investigated in mice. Acute exposure to concentractions as low as 470 microgram NO2/m3 (0.25 ppm) caused a significant increase in PEN-induced S.T. No significant effects on PEN-induced S.T. were detected after 1 or 2 days (3 h/day) exposure to 235 microgram NO2/m3 (0.125 ppm). None of the exposure regimens affected the time required for the drug to induce sleep. When the effects of repeated daily exposures (3 h/day) to 9400 microgram NO2/m3 (5 ppm) were compared in male and female mice, the females had a significantly increased PEN-induced S.T. after 1 and 2 days of exposure. However, an increase in PEN-induced S.T. was not observed in males until the 3rd day of exposure. Since the duration of PEN-induced S.T. is primarily determined by hepatic mixed function oxidase activity, it is possible that NO2 may alter some aspects of xenobiotic metabolism.

Inhalation studies of Mt. St. Helens volcanic ash in animals. III. Host defense mechanisms.

The effects of inhalation exposure of mice or rats to 9.4 mg/m3 volcanic ash, 2.5 mg/m3 SO2, or both on host defense mechanisms were assessed. Cytologic changes in pulmonary lavage fluid included an increase in percentage polymorphonuclear leukocytes due to SO2 exposure and an increase in eosinophils due to ash. SO2 and ash also produced decreases in percentage alveolar macrophages. In the case of ash-exposed animals, this decrease was offset by an increase in lymphocytes. Total cell counts and viability were not affected by any of the exposures. Pulmonary clearance mechanisms were affected in that there were both decreased alveolar macrophage phagocytic capability following ash and ash + SO2 exposures and depressed ciliary beat frequency attributable to ash exposure. None of the inhalation exposures caused increases in susceptibility to an immediate or 24 hr postexposure aerosol challenge with Streptococcus. However, intratracheal instillation of both fine- and coarse-mode volcanic ash caused slight but significant increases in mortality due to bacterial challenge 24 hr after the instillation. The phytohemagglutinin-induced blastogenic response of splenic lymphocytes from exposed animals did not differ significantly from that of control lymphocytes, although the lipopolysaccharide-induced blastogenic response was enhanced. Ash exposure had no effect on susceptibility to murine cytomegalovirus. In summary, volcanic ash alone or in combination with SO2 had only minimal effects on certain host defense mechanisms.

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.