Post-exposure Day Research Articles

Respiratory Tract Changes in Guinea Pigs, Rats, and Mice Following a Single Six-Hour Exposure to Methyl Isocyanate Vapor

Groups of male and female Fischer 344 rats, B6C3F1 mice, and Hartley guinea pigs were exposed once for 6 hr to mean concentrations of 10.5, 5.4, 2.4, 1.0, or 0 (control) ppm of methyl isocyanate (MIC) vapor. Rats and mice were also exposed to 20.4 ppm of MIC. The majority of deaths occurred during postexposure days 1 through 3. The 6-hr LC50 values (with 95% confidence limits) were 6.1 (4.6 to 8.2) ppm for rats, 12.2 (8.4 to 17.5) ppm for mice, and 5.4 (4.4 to 6.7) ppm for guinea pigs. Notable clinical observations during and immediately following MIC exposure were lacrimation, perinasal/perioral wetness, respiratory difficulty (e.g., mouth breathing), decreased activity, ataxia, and hypothermia. Body weight losses were common in all species following MIC exposures of 2.4 ppm or greater. Microscopic lesions included acute necrosis of the epithelial lining throughout the respiratory tract in animals that died shortly after exposure, coupled with congestion, edema, and inflammation. A microscopic lesion that appeared unique to guinea pigs was bronchiolitis obliterans (where the products of necrosis and inflammation completely closed the bronchioles). Additional microscopic lesions observed in some animals that died or were sacrificed at the end of the study (postexposure day 14) consisted of squamous metaplasia of respiratory epithelium in the nasal cavity, which extended into the larynx, trachea, and in some cases, the bronchi.(ABSTRACT TRUNCATED AT 250 WORDS)

Eighty-Five Day Postexposure Follow-Up Study in Fischer 344 Rats after Repeated Exposures to Methyl Isocyanate Vapor

The objectives of this study were to describe the microscopic lesions in the respiratory tract of Fischer 344 rats as a result of 4- or 8-days exposure (6 hr/day) of 3 ppm MIC and to characterize the postexposure development of these lesions up to day 85. All rats survived the exposure regimen, although significant decreases in body weight and encrustation of the eyes, nose, or mouth were observed. During the first 15 days of postexposure, the rats were hypoactive and had increased respiratory rates. Male mortality was as high as 63%; only 5% of the MIC-exposed females died. The cause of death was interpreted to be respiratory compromise complicated by anorexia and probably dehydration as well. During the next 28 postexposure days, 48% of the male survivors died, while only 3% of the female survivors died. Throughout the 85-day postexposure period, body weight gains in the MIC-treated groups were consistently below control values. Inflammatory and squamous metaplastic lesions of the respiratory tract, observed the day following completion of either the 4- or 8-day exposure regimen, decreased in both frequency and/or severity in survivors of the 85-day postexposure period, indicating recovery from the cytotoxic and irritating effects of MIC vapor. The squamous metaplastic epithelium was replaced by regenerative epithelium beginning in the deeper portion of the respiratory tract.(ABSTRACT TRUNCATED AT 250 WORDS)

Methyl isocyanate subchronic vapor inhalation studies with Fischer 344 rats

Groups of Fischer 344 rats were exposed to 3.1, 0.6, 0.15, or 0.0 (control) ppm of methyl isocyanate (MIC) vapor 6 hr per day for two 4-day sessions separated by a 2-day rest. There were no deaths during the study. The rats were killed the morning following the last exposure day. The 3.1-ppm-exposed rats had decreased body weight, food consumption, and blood oxygen saturation (males only). Increased hemoglobin concentration (males only) and lung weights were also observed in this group of rats. Multiple histologic lesions, limited to the respiratory tract, were observed in rats of the 3.1-ppm group only. The lesions consisted of necrosis, suppurative inflammation, squamous metaplasia, and intraluminal and submucosal fibroplasia (bronchi and bronchioles only) which extended from the anterior nasal cavity to the terminal bronchioles. In a second study, rats were exposed to 3.0 ppm MIC, 6 hr per day, for either one or two 4-day sessions and sacrificed on postexposure Days 1, 15, 43, and 85. All rats survived the 4- or 8-day exposure regimen, although significant decreases in body weight and encrustation of the eyes, nose, or mouth area were observed. During the first 15 days postexposure, male mortality was 63%; only 6% of the MIC-exposed females died. The cause of death was interpreted to be a combination of pulmonary vascular and inflammatory changes coupled with anorexia. For survivors, recovery from the necrotizing and irritating effects of MIC vapor was observed. Squamous metaplasia of respiratory epithelium, observed in rats sacrificed at the end of the exposure period, was replaced by tall pseudostratified columnar (regenerative) epithelium beginning in the bronchi and bronchioles as well as the distal trachea. Collagen maturation and condensation of the intraluminal and submucosal fibroplasia occurred during the postexposure period. The results of these investigations support the current threshold limit value for MIC of 0.02 ppm.

Acute inhalation studies with methyl isocyanate vapor: I. Methodology and LC50 determinations in guinea pigs, rats, and mice

Groups of male and female Fischer 344 rats, B6C3F1 mice, and Hartley guinea pigs were exposed once for 6 hr to mean concentrations of 10.5, 5.4, 2.4, 1.0, or 0 (control) ppm of methyl isocyanate (MIC) vapor. Rats and mice were also exposed to 20.4 ppm of MIC. No deaths occurred in animals exposed to 2.4 or 1.0 ppm. The majority of deaths for the 20.4- and 10.5-ppm groups occurred during postexposure Days 1 through 3, while at 5.4 ppm deaths were observed throughout the 14-day postexposure period. The 6-hr LC50 values (with 95% confidence limits) were 6.1 (4.6 to 8.2) ppm for rats, 12.2 (8.4 to 17.5) ppm for mice, and 5.4 (4.4 to 6.7) ppm for guinea pigs. Notable clinical observations during and immediately following MIC exposure were lacrimation, perinasal/perioral wetness, respiratory difficulty (e.g., mouth breathing), decreased activity, ataxia, and hypothermia. The frequency of clinical signs decreased during the second postexposure week. Body weight losses were common in all species following MIC exposures of 2.4 ppm or greater. At 1.0 ppm, only female mice had body weight depression. Recovery of body weight loss was observed in the 5.4- (guinea pigs only), 2.4-, and 1.0-ppm concentration groups. The lungs of all animals that died were discolored. Following microscopic examination of the respiratory tract, deaths were attributed to pulmonary edema and congestion. In a separate study, Fischer 344 rats and Hartley guinea pigs were exposed once for 4 hr to mean concentrations of 36.1, 25.6, 15.2, or 5.2 ppm of MIC vapor. In general, the results were similar to those of the single 6-hr exposure study.

Acute inhalation studies with methyl isocyanate vapor: II. Respiratory tract changes in guinea pigs, rats, and mice

Hartley guinea pigs, Fischer-344 rats, and B6C3F1 mice of both sexes were exposed to varying concentrations of methyl isocyanate (MIC) vapor with the highest concentration being 20.4 ppm for rats and mice and 10.5 ppm for guinea pigs. A control group for each species was exposed to air only. All animals were exposed for a duration of 6 hr, and survivors were sacrificed 14 days following exposure. The respiratory tract was removed and examined microscopically from all animals. Guinea pigs were more sensitive to the MIC vapor than were rats which were in turn more sensitive than mice. Gross lesions encountered in many of the animals that died consisted of nasal discharge, often blood tinged, and discoloration of the lungs. Microscopic lesions included acute necrosis of epithelial lining throughout the respiratory tract in animals that died shortly after exposure coupled with congestion, edema, and inflammation. A microscopic lesion which appeared unique to guinea pigs was bronchiolitis obliterans where the necrosis and inflammation had completely closed the bronchioles. Additional microscopic lesions observed in some animals that died or were sacrificed at the end of the study (postexposure Day 14) consisted of squamous metaplasia of respiratory epithelium in the nasal cavity, which extended into the larynx, trachea, and, in some cases, the bronchi. In addition, epithelial regeneration throughout the tract and submucosal fibroplasia in the trachea, bronchi, and bronchioles were observed, the latter lesion being primarily confined to rodents. No animals exposed to 2.4 or 1.0 ppm of MIC vapor died following exposure. There were minimal microscopic lesions at sacrifice in the 2.4 ppm-exposed animals from all three species. Only in guinea pigs were there lesions in the 1.0-ppm group attributed to MIC vapor exposure.

Acute Inhalation Studies with Methyl Isocyanate Vapor. II. Respiratory Tract Changes in Guinea Pigs, Rats, and Mice

Acute Inhalation Studies with Methyl Isocyanate Vapor. II. Respiratory Tract Changes in Guinea Pigs, Rats, and Mice. FOWLER, E. H., AND DODD, D. E. (1986). Fundam. Appl. Toxicol. 6, 756–771. Hartley guinea pigs, Fischer-344 rats, and B6C3F1 mice of both sexes were exposed to varying concentrations of methyl isocyanate (MIC) vapor with the highest concentration being 20.4 ppm for rats and mice and 10.5 ppm for guinea pigs. A control group for each species was exposed to air only. All animals were exposed for a duration of 6 hr, and survivors were sacrificed14 days following exposure. The respiratory tract was removed and examined microscopically from all animals. Guinea pigs were more sensitive to the MIC vapor than were rats which were in turn more sensitive than mice. Gross lesions encountered in many of the animals that diedconsisted of nasal discharge, often blood tinged, and discoloration of the lungs. Microscopic lesions included acute necrosis of epithelial lining throughout the respiratory tract in animals that died shortly after exposure coupled with congestion, edema, and inflammation. A microscopic lesion which appeared unique to guinea pigs was bronchiolitis obliterans where the necrosis and inflammation had completely closed the bronchioles. Additional microscopic lesions observed in some animals that died or were sacrificed at the end of the study (postexposure Day 14) consisted of squamous metaplasia of respiratory epithelium in the nasal cavity, which extended into the larynx, trachea, and, in some cases, the bronchi. In addition, epithelial regeneration throughout the tract and submucosal fibroplasia in the trachea, bronchi, and bronchioles were observed, the latter lesion being primarily confined to rodents. No animals exposed to 2.4 or 1.0 ppm of MIC vapor died following exposure. There were minimal microscopic lesions at sacrifice in the 2.4ppm-exposed animals from all three species. Only in guinea pigs were there lesions in the 1.0-ppm group attributed to MIC vapor exposure.

Recovery of absolute threshold with UVA-induced retinal damage

A within-trial psychophysical procedure tracked the initial loss and subsequent recovery of visual thresholds in albino rats exposed to ultraviolet light at 350 nanometers and 0.4 milliwatts per square centimeter. Absolute thresholds increased up to 5 log units immediately following the 15 hour ultraviolet exposure, with a daily recovery of 1–2 log to asymptotic thresholds over a 7-day post-exposure period. The corresponding retinal damage on Day 1 included extensive vesiculation of the photoreceptor outer segments, vacuolation of the inner segments, and pyknosis of cell nuclei. The total number of photoreceptor nuclei and outer segments was unchanged relative to control eyes through post-exposure Day 3. Both nuclei and outer segment counts then consistently decreased 15–20 percent between Days 3–7. The two-stage loss of photoreceptors but daily recovery of absolute thresholds again suggests a significant dissociation of retinal structure and psychophysical function in light-induced ocular pathology.

Effects of acute nitrogen dioxide exposure on swimming performance of mice.

To evaluate the acute effects of NO2 on the physical performance of experimental animals, male mice 15-16 wk old were exposed to 5, 10, 20, or 40 ppm NO2 for 24 h, and forced swimming endurance time (FSET), the changes in FSET during the postexposure days, lung wet weight, lung water content, and blood lactate level were examined. FSET of mice exposed to NO2 at 10, 20, and 40 ppm decreased immediately after exposure, FSET of mice exposed to 5 ppm NO2 did not change immediately after exposure, but a significant decrease was observed from d 1 to d 4 after exposure. FSET recovered to the initial control level after 5-6 d, 7-8 d, and over 9 d in mice exposed to NO2 at 5, 10, and 20 ppm, respectively. Lung wet weight of mice exposed to 20 and 40 ppm NO2 and lung water content of mice exposed to 10, 20, and 40 ppm NO2 increased with dose. A negative relation was demonstrated between FSET and lung wet weight and between FSET and lung water content. Without forced swimming exercise, the blood lactate level of mice exposed to 5 ppm NO2 was almost equivalent to that of control mice, but the blood lactate level of the exposed mice significantly increased immediately and 24 h after forced swimming exercise for 4 min.

Cardiac function in goats exposed to carbon monoxide.

To investigate the possibility that prolonged carbon monoxide (CO) exposure would depress myocardial function, six chronically instrumented, unsedated goats were exposed to 160--200 ppm CO for 2 wk, resulting in a mean carboxyhemoglobin saturation of 20%. Cardiac index and stroke volume remained unchanged during and after exposure. Hematocrit and hemoglobin concentration started increasing on the 10th day of exposure, this increase reached statistical significance (P less than 0.05) on the 6th postexposure day. Contractility (Vmax) of the left ventricular myocardium and heart rate were unchanged during exposure to CO, but both were significantly (P less than 0.05) decreased at some time during the 1st wk after removal from CO. If there was a decrease in intrinsic myocardial function during CO exposure, it may have been masked by increased sympathetic activity. The mechanism(s) that might produce the decrease in heart rate and contractility after removal from CO are not obvious. Possible explanations are discussed.

Effects of subclinical hydrogen sulfide intoxication on mouse brain protein metabolism

Exposure of adult female mice to 100 ppm hydrogen sulfide for 2 h resulted in a marked decrease in incorporation of labeled leucine in cerebral protein and myelin 24 and 48 h after the exposure. The reduced incorporation was accompanied by decreased lysosomal acid proteinase activity at the same time. The incorporation increased to the control level 72 h after the exposure whereas the lysosomal enzyme activity remained below the control range at the end of the follow-up period. The changes were distinct from carbon monoxide-induced changes and might have resulted from the inhibition of cerebral cytochrome oxidase activity. The delay of maximal effects to the third postexposure day might pose a potential toxicological hazard in repeated exposure to higher hydrogen sulfide concentrations.

Interactions between Viscerotropic Velogenic Newcastle Disease Virus and Pet Birds of Six Species. I. Clinical and Serologic Responses, and Viral Excretion

Clinical and serologic responses to a psittacine isolate of viscerotropic velogenic Newcastle disease virus (VVNDV) were evaluated in pet birds of six species: budgerigar, yellow-headed Amazon parrot, halfmoon conure, lesser hill mynah, black-headed nun, canary. The clinical response was most marked in the budgerigars, parrots, and conures, and only minimal in the nuns. Between post-exposure days (PED) 3 and 5 some birds developed ruffled plumage, conjunctivitis, and central nervous system dysfunction: ataxia, wing tremors, paralysis of the extremities, and tremors of the head accompanied by nodding and jerking. Mortality by PED 203 was 55% (29/52) in the halfmoon conures, 22% (23/105) in budgerigars, 29% (12/42) in parrots, and 21% (15/71) in nuns. The only clinical signs in canaries and mynahs were progressive death losses, respectively 25% (33/132) and 21% (10/48). The visceral lesions common in chickens with VVNDV were not observed in these six species. Canaries rapidly eliminated Newcastle disease virus (NDV), whereas it was detected for protracted periods in the oral and cloacal secretions of the other five species (for more than a year in parrots). Serologic evaluation by the hemagglutination-inhibition and neutralization tests also indicated prolonged NDV infections in 5 of the 6 species. The seroconversion rate observed in canaries was minimal (13%).

The Effect of 2 MHz Ultrasound Irradiation on Pisum sativum Roots

The effect of 2 MHz ultrasound at intensity levels from 2.5 to $22 {\rm W}/{\rm cm}^{2}$ on the growth rate and mitotic index of Pisum sativum roots was studied. The ultrasound produced an immediate reduction in the growth rate on the first postexposure day, followed by a gradual recovery to the control value. Ultrasound reduced the root meristem mitotic index. Intensity- and time-dependent relations were found for the growth rate and mitotic index reductions.

Induction of immunity to feline caliciviral disease.

Six specific-pathogen-free cats were exposed by aerosol to a feline calicivirus of low virulence (F-9 virus). Homotypic (anti-F-9) seroconversion occurred in all cats by postexposure day 14. The serum of one cat on postexposure day 14 and four of six cats on postexposure day 35 neutralized feline picornavirus isolate no. 225 (FPV-255), a virulent feline calicivirus. Homologous antiviral activity was detected before the appearance of heterologous (anti-FPV-255) activity and always was present in higher titer. Protective immunity was evaluated on postexposure day 35 by aerosol challenge with FPV-255. The pyrexia, depression, dyspnea, oral ulcers, and severe pneumonia produced in two susceptible specific-pathogen-free cats by exposure to FPV-255 did not occur in the cats that had been infected previously with F-9 vir. The study demonstrates that heterotypic protective immunity to feline calicivirus disease can be induced by prior infection with feline calicivirus of low virulence.

The hematological effects of chronic, low level exposures to carbon monoxide in rats.

Chronic, intermittent exposures to low levels of carbon monoxide (23% COHb) produce statistically significant elevations in red blood cell count, hematocrit, hemoglobin content, and reticulocyte percentage in rats. However, during ten postexposure days the elevations show significant reversibility. Because no significant change in plasma volumes appears to occur, the mild polycythemia is evidently due to increased erythropoiesis. The degree of polycythemis obtained is probably not critical in respect to increases in blood viscosity.

Non-thermal effects of 2 MHz ultrasound on the growth and cytology of Vicia faba roots.

Abstract The effect of 2 MHz ultrasound at intensity levels from 1 to 20 W/cm2 on growth rate, lateral root formation, mitotic index and chromosome morphology was studied. The ultrasound produced an immediate reduction in growth rate on the first post-exposure day followed by recovery to control value after ten days. Ultrasound reduced lateral root formation and mitotic index. Intensity and time dependent relations were found for growth rate reduction and lateral root formation. No “classical” chromosome aberrations were found but chromosomal anomalies—bridged prophases and metaphases and agglomerated metaphases—of another nature were observed after sonication: these anomalies were quantitated into a damage index.

Susceptibility of cattle to an isolate of Dictyocaulus viviparus from black-tailed deer.

Patent infections did not develop in calves after inoculation with Dictyocaulus viviparus infective larvae isolated from black-tailed deer (Odocoileus hemionus columbianus). One calf died of bacterial pneumonia on postinoculation day 21. Two calves coughed and had elevated respiratory rates and dyspnea between days 14 and 21. Respiration was normal for these calves on day 25. A calf and a susceptible black-tailed deer were placed on contaminated grass pasture with eight deer infected naturally with D. viviparus. Patent infection did not develop in the calf but larvae of D. viviparus were recovered in feces from the deer on post-exposure day 30.

Bone Marrow Regeneration in Germfree NO-2 Mice after 700 Rad Whole Body Irradiation

The purpose of this experiment was to compare the pattern of hemopoietic regeneration following bone marrow aplasia in conventional and germfree ${\rm ND}_{2}$ mice after 700 rads whole body x-ray exposure. All conventional mice died of the consequences of pancytopenia, i.e., bleeding and infection, within 10-12 days postirradiation. In these animals, no sign of bone marrow restoration could be detected; however a limited amount of hemopoietic recovery was seen in the spleen. In contrast, about 40% of the germfree mice survived the first 12 days of postexposure. Quantitative cyto- and histomorphological studies of the blood, bone marrow and spleen provided evidence of a progressive hemopoietic recovery which could be followed in some of the animals for more than 20 days postirradiation. The first evidence of erythro- and megakaryocytopoietic regeneration in the bone marrow was observed at days 10 and 16, respectively, postirradiation. Blood erythrocyte and platelet counts began to rise between days 15 and...

EFFECT OF CS AEROSOL UPON LUNG GAS TRANSFER AND ALVEOLAR VOLUME IN HEALTHY MEN

Measurements of transfer factor (Tl'), alveolar volume (VA') and KCO (transfer co‐efficient for carbon monoxide; Tl' ÷ VA') have been made by the single breath carbon monoxide method with a single breath determination of alveolar volume before and after exposure to CS aerosol on 11 volunteer servicemen. For each subject the study occupied 3 days of which the first and third were control and post exposure days respectively. The exposure to CS was on the morning of the second day for approximately 1 hr to a concentration which was increased progressively from about 0·6 to 2·0 mg m−3. During the study no changes were observed in the alveolar volume or its subdivisions, vital capacity and residual volume. The transfer factor and KCO were rather higher on the first control day before exposure than on the post exposure day, with the day of exposure intermnediate. Exposure to CS aerosol was followed immediately by an increase in transfer factor and subsequently by a transient decrease to below the initial value. The changes were of small magnitude and quite insufficient to exert any material effect upon gas exchange; they were probably due to variations in vasomotor tone asociated with the procedure affecting the distribution of body blood volume, including the volume of blood in the lung capillaries.

A Fluorescent Erythrocyte Test for Lead Poisoning in Waterfowl

Forty-five mallards (Arlas platyrhynchos) and 12 Canada geese (Branta canadensis) were experimentally poisoned with lead shot. Blood samples collected from poisoned and unexposed birds were subjected to blue-ultraviolet light of approximately 400 m,t4 and examined microscopically for the presence of fluorescent erythrocytes. Some red fluorescence of erythrocytes was observed in all 64 blood samples drawn between 10 hours and 10 days postexposure from 27 of the poisoned mallards. Similarly, all 23 blood samples drawn between postexposure days 1 and 14, from the 12 poisoned Canada geese, contained unequivocally fluorescent erythrocytes. In general, after the first 3 to 9 days postexposure, the strength of the fluorescence progressively decreased, but still remained diagnostic at death for 19 of 20 mallards and for all 7 Canada geese that succumbed to lead poisoning. By com- parison, 19 mallards that had recovered from lead toxicosis, 20 unexposed mallards, and 11 of 12 unexposed geese had no erythrocytes that fluoresced. The fluorescence probably resulted from in- creased erythrocyte protoporphyrin caused by elevated blood lead concentrations. The fluorescent erythrocyte test is a quick, simple test for lead poisoning in waterfowl and appears to be as reliable as some conventional techniques previously used. In addition, blood from live birds can be tested for the presence of fluorescent erythrocytes. This test can therefore be used in conjunction with banding programs to investigate the incidence of lead intoxication in waterfowl populations.

Some heterocyclic nitrogenous compounds as radioprotectants for hematological levels in x-irradiated mice.

In normal controls, the levels of hemoglobin concentration and hematocrit values remained almost unchanged throughout the experimentation period. Intraperitoneal administration of imidazole and benzimidazole affected rapid pharmacodynamic incidences which were not detected with cysteamine. Administration of imidazole did not induce detectable change in the level of hemoglobin concentration but slightly decreased the hematocrit value. Benzimidazole created slight depression in hemoglobin concentration and exerted no effect on hematocrit value. Cysteamine caused slight depression of both hemoglobin concentration and hematocrit value. Those changes were readily restorable with imidazole and benzimidazole while those with cysteamine lasted for more than three days. Irradiation caused progressive decrease in hemoglobin concentration and hematocrit values which continued till the death of the animals. A significant increase in the sedimentation rate of red blood cells was recorded. Irradiation of chemically protected animals caused initial decrease in hemoglobin concentration and hematocrit values which lasted till the fifths post-exposure day. Later, gradual restoration of normal levels of hematological values was recorded. Restoration was more rapid with benzimidazole than with imidazole, while cysteamine lied half way in its action. The increase in sedimentation rate of red blood cells was less pronounced and gradual restoration of the normal sedimentation rate was maintained during the post-irradiation time. It seems likely that the radioprotectants act on cellular and subcellular levels in the protected tissues but the actual role played by such compounds still awaits further investigation. Imidazole and benzimidazole proved to be effective radioprotectants of the hematopoietic tissue. Benzimidazole proved to exert the best radioprotective characters amongst the tested compounds in this concern.