Examining the risks and benefits of considering both the traditional dose--response and hormesis in arriving at an acceptable exposure level.

In examining traditional dose-response and hormesis, we have considered the case examples of pulmonary hyperplasia following inhalation of carbon black and pulmonary hyperplasia after methyleneindolenine (3MEIN) exposures, development of irreversible pulmonary fibrosis, effect of continuous exercise and low-level lead exposures, and colorectal cancer. Adaptation can be used to estimate conventional dose responses. All cases discussed provided increased information about the reactions if hormetic features were included. In only the shigatoxin case was there clear irrefutable evidence that beneficial hormetic properties exist and must be considered; however, the one-in-six advantage is too great to ignore the potential benefits of hormesis. We recommend such hormetic properties be considered together with conventional dose responses to improve estimates of chemical risk.

Invited response to definition of hormesis (EJ Calabrese and LA Baldwin).

Calabrese and Baldwin have proposed the Theory of Hormesis to explain a variety of disparate data. We evaluated the explanation using examples of pulmonary injury, radiation injury to white blood cells and selenium as an essential element, reducer of carcinogenesis and a potential toxicant. Calabrese and Baldwin have fulfilled many of the criteria allowing generalizability of their theory. They have gathered data extensively. These data were logically consistent with their experiences. They needed to examine critically the theory and any theories competing with it. At this point, each theory must be proved, disproved or its limitations clearly stated. It is in this phase that most work is still being accomplished. This examination is important because it provides referents for vigorous outside criticism, the final phase. Calabrese and Baldwin are to be complimented on seeking outside comment. Considerable refinement of the theory has taken place with time.

Pulmonary diseases caused by airborne contaminants in swine confinement buildings.

Exposure to toxic gases and particles or dusts while working or living in confinement animal systems pose a pulmonary health hazard. The severity of lung impairment from exposure to such environment is investigated using intratracheal instillation, intratracheal nebulization, and inhalation procedures. Ability to deliver particles with intratracheal instillation that are evenly distributed throughout the lung depends on the material used for injection. Pulmonary histopathology reflects anatomic changes following inhalation or instillation of chemicals or particles. Endobronchial saline washings of bronchioles and alveoli allow measurement of markers of pulmonary inflammation such as total nucleated cell (leukocyte) counts and those of macrophages, neutrophils and lymphocytes; TNF-alpha, and collagen concentration are used to further evaluate pulmonary response to endotoxin or dust exposure. Alveolar epithelial cells have an important role in clearing pulmonary fluid and maintaining the structure of lung tissue. After repeated exposure, damage to epithelial cells may result in their death, causing edema and collagen deposition that may lead to fibrosis.

An analysis of the chronic oral toxicity of polyether ionophore antibiotics in animals.

Feeding well-mixed ionophores to adapted cattle improves ruminal fermentation and growth rates. In nonruminants, growth is improved by reducing competing gastrointestinal microorganisms. Interactions of monensin with other drugs may be beneficial or toxic. Tiamulin and furazolidone potentiate monensin's negative effects. For example, monensin produces positive inotropy and cardiomyopathy dependent on calcium and extracellular sodium. Based on available toxicity data and derived no observable effect levels (NOEL) in the same species and across species, monensin was more toxic than salinomycin, lasalocid or narasin. Lasalocid was 5- to 10-fold less toxic to horses than is monensin. Based on available toxicity data and derived NOEL, lasalocid was less toxic than all ionophores except salinomycin. Very high levels of narasin caused death in sows, leg muscle weakness in turkeys, and cardiopulmonary clinical signs in 15% of the rabbits from Brazilian rabbit farms. Only salinomycin and lasalocid were less toxic than narasin. Salinomycin was the least toxic of all the ionophores. Maduramicin was the most toxic of all the ionophores. Nearly all maduramicin fed to poultry persists in litter (manure), making this poultry litter toxic if fed to cattle as a nitrogen source. While ionophore comparative toxicity was difficult to estimate, most cross-comparisons utilized NOEL within and across species. The relative toxicities of the ionophores from lowest to highest were salinomycin < lasalocid < or = narasin < or = monensin (but lasalocid < monensin) < maduramicin.

Pulmonary toxicity of nickel subsulfide in F344/N rats exposed for 1-22 days.

Repeated inhalation of nickel subsulfide (Ni3S2) by F344/N rats for 3 months results in chronic active inflammation in the lung and atrophy of the olfactory epithelium. The primary purpose of this study was to determine early responses of the respiratory tract to inhaled Ni3S2 in rats and to track the course of development of such lesions in rats exposed for up to 22 days. A secondary purpose was to obtain an improved estimate of the half-time for clearance of Ni from Ni3S2-exposed lungs. Groups of F344/N rats were exposed to 0, 0.6 or 2.5 mg Ni3S2/m3, 6 h/day for 1-22 days. Histopathological changes in nose and lung, as well as biochemical and cytological changes in lung, as measured in bronchoalveolar lavage fluid (BALF) and lung tissue, alveolar macrophage (AM) viability and Ni concentration in lung were evaluated. Inflammatory lung lesions in rats exposed to 2.5 mg Ni3S2/m3 peaked in intensity after 4 days of exposure. Minimal degeneration of the olfactory epithelium was noted in the 2.5 mg Ni3S2/m3-exposed rats after day 4 of exposure, with atrophy of the olfactory epithelium occurring in rats killed at 22 days. Lactate dehydrogenase, beta-glucuronidase and total protein in BALF were significantly elevated within 7 days of exposure while alkaline phosphatase activity was significantly depressed. AM viability was significantly reduced after 2 days of exposure. Concentrations of Ni in lung increased rapidly during the first 7 days of exposure, but more slowly thereafter. Lung burden data from this and a previous study suggest a clearance half-time for Ni of 3.5-8 days. Results indicate that Ni3S2 is relatively soluble in lung and inhalation of concentrations near the current Threshold Limit Value of 1 mg Ni/m3 can produce detrimental changes in the respiratory tract of rats after only a few days of exposure.

Total and respirable dust in swine confinement buildings: the benefit of respiratory protective masks and effect of recirculated air.

Caretakers and pigs in dusty environments inhale particles and toxic gases which can cause subclinical illness. We determined the reduction in sampled dust elicited by respiratory masks mounted on glass funnels. Open-faced filters or British cyclones were sampled to measure quantities of dust which the masks had trapped. Respiratory masks reduced the sampled total suspended particulates (open-faced filters) by > or = 75% with NIOSH/MSHA certified protectant (2-tie) masks and > or = 50% with NIOSH/MSHA non-certified comfort (1-tie) masks. Respirable particulates (British cyclones) were reduced by > or = 45% with NIOSH/MSHA certified protectant (2-tie) masks. These data suggest properly worn respiratory protective masks afford significant protection against both total suspended and respirable particulates in swine confinement facilities. Penetration of 3-25% of total aerosol mass through masks allowing only 1% penetration of a silica aerosol with an aerodynamic diameter of 0.6-1.0 microns suggested that measurable portions of the aerosol mass in these confinement houses behaved as if they were less than 1 micron in diameter. Because of the small size of the aerosol, NIOSH/MSHA certified respiratory protective masks should be worn when working in those facilities. We also studied concentrations of ammonia, endotoxin and total and respirable dust particles to determine effects of a recirculation fan which increased the nominal air flow capacity of the building by 10%. Recirculated air had minimal effects on ammonia, total airborne endotoxin or total particulate mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Propellant-driven aerosols for delivery of proteins in the respiratory tract.

Metered-dose propellant-driven aerosols of an antigenically reactive protein were produced by combining bovine gammaglobulin (BGG) with one of several surfactants soluble in Freon or dimethylether propellants. Small-particle protein aerosols were most effectively produced by lyophilizing surfactants and proteins prior to the addition of propellants. Up to 26% of the total aerosolized protein was of respirable size. Aerosol metering valves delivering small volumes were most effective in producing respirable-sized (< or = 4 micron median mass aerodynamic diameter) protein aerosols. Proteins were suspended in liquified propellants as both propellant-soluble molecules and visible sedimenting clusters which both contributed to making respirable-sized protein aerosol particles. Electron microscopy showed that respirable-sized protein particles were composed of variable-sized chain aggregates of spherical subunits. Proteins were antigenic after suspension in liquified propellant and release as aerosols, but antigenicity diminished with extended propellant exposure. Local immunity in the respiratory tract is a key factor in resistance to respiratory infections. Metered-dose propellant-driven aerosols offer a potentially attractive method for delivering small-particle aerosols of immunizing antigens or other therapeutic proteins to the respiratory tract.

Perinatal hypocuprosis affects synthesis and composition of neonatal lung collagen, elastin, and surfactant.

To investigate the role of iron, ascorbate, and fructose on copper depletion and the effect of copper depletion on neonatal lung collagen, elastin, and surfactant, female rabbits were fed a control diet [10 parts per million (ppm) copper], a basal marginal copper diet (1.5 ppm), or a basal diet containing a high concentration of iron (1,750 ppm), ascorbic acid (1%, wt/wt), or fructose (20% of carbohydrates, wt/wt) or a combination of iron, ascorbic acid, and fructose throughout gestation. Whereas 10% of neonates in the control group died in the first 24 h, 27-67% of the offspring of rabbits fed the marginal copper diet died. Birth weight was also lower for the pups of the females fed the marginal copper diets. Lungs of neonates born to females fed iron or ascorbate and marginal copper diets had low levels of copper, high proportions of acid-extractable, high-molecular-weight collagen, and low lysyl-oxidase activities, consistent with incomplete maturation of collagen. The bronchoalveolar lavage fluids of newborns whose mothers were fed marginal copper diets alone or in combination with iron and/or ascorbate had lower levels of total surfactant phospholipids than the fluids from lungs of control newborns. The lower surfactant phospholipid content of these groups could be attributed mainly to lower phosphatidylcholine and, in particular, dipalmitoylphosphatidylcholine levels. These results suggest that high maternal intakes of iron, ascorbate, or their combination in pregnancy deplete biologically available copper, which in turn induces neonatal lung abnormalities.

Chamber for testing metered-dose propellant-driven aerosols of immunologically relevant proteins.

A small aerosol chamber was developed for testing and delivery of aerosols of immunologically important proteins to the respiratory tracts of rodents. The chamber was designed to accommodate the small aerosol volumes produced by metered-dose propellant-driven aerosol canisters. Metered bursts of protein aerosols released into the chamber could be sampled for their particle sizes or used to expose the noses of up to six mice to the aerosols. The chamber consisted of a polyethylene tank with two removable plexiglass end plates. One end plate accommodated the propellant-driven, metered-dose, aerosol vial. The other end of the tank was fitted with a plate accepting aerosol sampling devices or a plate containing mouse restrainers. Uniform concentrations of aerosolized proteins were obtained at different positions in the chamber when sampled for particles of respirable size. Respirable-sized protein particles produced by propellant-driven aerosols ranged from 5 to 50% of total aerosolized protein. Propellant-driven aerosols of proteins released in the chamber produced aerosol particles equivalent to 15-26 micrograms of total protein exposure to the respiratory tract of each mouse. The chamber permitted aerosol releases without risk of operator exposure. This aerosol chamber will permit the testing of protein aerosols for their immunologic consequences to the respiratory tract. Potential proteins for testing in this device include immunizing vaccine antigens, immunomodulating cytokine proteins, and passive antibody aerosol therapies against respiratory infections.

Characterization of particles, ammonia and endotoxin in swine confinement operations.

To define the atmospheres swine confinement operations, we measured concentrations of total and respirable dust particles, ammonia and endotoxin in the nursery and grower areas of 4 swine confinement houses. Increased ventilation in spring-summer relative to that in winter reduced concentrations of large dust particles more rapidly than it did smaller particles or ammonia. The greater decrease in large particles correlating to increased room air velocity may reflect larger particles' momentum causing impaction on surfaces. There was significant spatial variation in the concentration of airborne endotoxin within individual swine rooms and pens reflecting different mixing of large feed and smaller manure particles. Smaller particles had 4-fold higher concentrations of endotoxin than did larger particles, suggesting they had higher fecal material concentrations. Total airborne endotoxin and total suspended particulates correlated to the fraction of functional endotoxin contained in large particles, suggesting that small particles (0.5-2.0 micrometers) collide with large particles (50 micrometers). These data suggest that large non-respirable particles remove smaller respirable particles from indoor atmospheres due to kinematic coagulation.

Ototoxicity in dogs and cats.

Ears are special sense organs whose principal functions are hearing and maintaining equilibrium. Aminoglycoside antibiotics, erythromycin, polymyxin B, and cisplatin can affect either or both of these functions by binding with, injuring, and/or destroying special receptor cells associated with these functions. Severe hearing loss manifests itself as deafness, whereas loss of equilibrium will present as abnormal righting reflexes, nausea, and vomiting. Damage is proportional to levels of these ototoxins in the endolymphatic fluids. Evidence suggests that toxicity may be influenced by endolymphatic calcium concentrations, and levels of cAMP and cGMP are altered in specialized cochlear cells during ototoxicity, suggesting an additional mechanism for ototoxicity. The administration of salicylates and loop diuretics may potentiate the action of ototoxins, especially aminoglycoside antibiotics, probably by increasing the levels of these toxins in the endolymphatic fluid. Although many of these assessments have been made in laboratory animals, applicability may also be expected in small domestic animals, and extreme care should be taken in prescribing potentially ototoxic drugs to small animals. Cochlear damage from ototoxic compounds occurs initially in the cells detecting high-frequency sounds located at the lower basal region. In aging dogs and humans, this sensitivity of receptors in the lower basal region is enhanced. Early auditory damage is detectable by BAER and cochlear microphonic potentials. Vestibular responses can also be detected early as vestibular ocular reflexes and visual-vestibulo-ocular reflexes. Early detection is especially important because early changes can sometimes be reversible. Cavinton (apovincaminic acid) and fosfomycin represent examples of experimental agents being evaluated in laboratory animals for application as potential treatments to limit the ototoxicity associated with various drugs.

Drought increases forage nitrate and cyanide.

To investigate drought-associated increases in concentrations of nitrate and cyanide in animal forage, we compared forage nitrate and cyanide in 1986-87 (annual rainfall 33 in) to nitrate and cyanide in a drought (1988 and 1989; annual rainfall 20 and 27 in, respectively). Fifteen to 20% of the nitrate and cyanide samples from 1986-1987 had sufficiently high concentrations to be of concern (3000 ppm nitrate, 20 ppm cyanide as submitted). Only 4-6% of the 1986-1987 samples had concentrations sufficiently high to produce acute respiratory distress (13,000 ppm nitrate, 50 ppm cyanide as submitted). During 1988 sample numbers had more than doubled, suggesting increased concern for the possibility of nitrate or cyanide intoxication and yielding parallel increases in the number of samples with elevated nitrates or cyanides. By 1989, 25-33% of the samples had concentrations of health concern with respect to either nitrate or cyanide, while 14-19% had concentrations sufficiently high to produce acute respiratory signs. Shortages of forage caused by a 2-y drought were further exacerbated by nitrate and cyanide increases in that feed. Future efforts should concentrate on controlling groundwater nitrate and delivery of nitrate to the plant root-systems.

89Strontium-induced bone marrow depression suppresses the early inflammatory response and fibrosis caused by intratracheal bleomycin.

To investigate the effect of bone marrow depression on the development of bleomycin-induced lung injury, F-344/Crl rats were given an intraperitoneal (IP) injection of 89SrCl2 (2 mCi/kg body weight) 7 days prior to the intratracheal (IT) instillation of 7.0 U/kg body weight bleomycin (Sr-bleomycin group). A second group of rats was given an IP injection of saline followed 7 days later by IT bleomycin (bleomycin group). Additional rats were given 89Sr IP and saline IT (Sr group) or saline IP and saline IT (saline group). Rats were sacrificed at 0, 3, 10, 21, and 30 days after the intratracheal instillations. 89Sr administration resulted in significantly lower numbers of circulating blood neutrophils and monocytes in the Sr-bleomycin group compared with the bleomycin group through at least the first 21 days following the IT instillations. Lymphocyte numbers were also depressed in the Sr-bleomycin group at days 3 and 21. Analysis of bronchoalveolar lavage fluid (BALF) revealed significantly reduced protein and lymphocyte numbers in the BALF from the 89Sr-bleomycin group compared with the bleomycin group at day 3, but not at later time points. Neutrophils in BALF were also lower (though not significantly) in the 89Sr-Bleomycin group at day 3. There was no difference in the number of BALF macrophages between the Sr-bleomycin and bleomycin groups at any time point throughout the study. Histology and morphometry showed the same trends as the BALF data with much less severe lesions in the 89SR-Bleomycin group compared with the bleomycin group at day 3, but not at later time points. At day 10, hydroxyproline values were significantly higher in the bleomycin group (47% increase above saline group) than the Sr-bleomycin group (only 18% increase above Sr group), but by day 21, there was no longer a significant difference between these two groups. These results demonstrate that bone marrow depression significantly suppresses the early inflammatory response and collagen deposition caused by a single IT dose of bleomycin, but has little effect on the resolution of bleomycin-induced injury.

Effect of inhaled azodicarbonamide on F344/N rats and B6C3F1 mice with 2-week and 13-week inhalation exposures.

Azodicarbonamide (ADA), a compound used in the baking and plastics industries, has been reported to cause pulmonary sensitization and dermatitis in people. Two-week repeated and 13-week subchronic inhalation exposures of F344/N rats and B6C3F1 mice to ADA were conducted to determine the toxicity of inhaled ADA. The mean air concentrations of ADA in the 2-week studies were 207, 102, 52, 9.4, or 2.0 mg/m3. No exposure-related mortality nor abnormal clinical signs were observed in rats or mice during or after exposure. The terminal body weights were slightly depressed in the highest exposure group. Liver weights were lower in male rats exposed to 200 mg ADA/m3. No significant lesions were noted on either gross or histologic evaluation of rats or mice. In the 13-week subchronic study, the mean air concentrations of ADA were 204, 100, or 50 mg/m3. No mortality or clinical signs related to exposure were observed. The terminal body weights of exposed rats were not significantly different from those of control rats but were significantly depressed in mice exposed to 100 or 200 mg ADA/m3. No histopathological lesions were noted in mice. Lung weights were increased and enlarged mediastinal and/or tracheobronchial lymph nodes were noted in rats exposed to 50 mg ADA/m3. No exposure-related lesions were observed microscopically in rats exposed to 100 or 200 mg ADA/m3. All rats in the 50 mg ADA/m3 exposure group only had lung lesions that consisted of perivascular cuffing with lymphocytes and a multifocal type II cell hyperplasia, suggesting a possible immune reaction to an antigen in the lung. Viral titers for rats exposed to 50 mg ADA/m3 were negative for Sendai virus and pneumonia virus of mice, which produce similar lesions. The possibility of an unknown viral antigen causing this lesion cannot be eliminated. Lung tissue from male rats was analyzed for ADA and biurea, the major metabolite of ADA. No ADA was detected. The amount of biurea in the lungs increased nonlinearly with increasing exposure concentration, suggesting that clearance was somewhat impaired with repeated exposures. However, even at the highest exposure concentration, this amount of biurea was less than 1% of the estimated total ADA deposited over the exposure period. In summary, ADA is rapidly cleared from the lungs, even when inhaled at concentrations up to 200 mg/m3. Exposure to ADA for up to 13 weeks did not appear to be toxic to rodents.

Influence of preexisting pulmonary emphysema on susceptibility of rats to inhaled diesel exhaust.

The susceptibilities of normal rats and rats with preexisting pulmonary emphysema to chronically inhaled diesel exhaust were compared. Rats were exposed 7 h/day, 5 days/wk for 24 months to diesel exhaust at 3.5 mg soot/m3, or to clean air as controls. Emphysema was induced in one-half of the rats by intratracheal instillation of elastase 6 wk before exhaust exposure. Measurements included lung burdens of diesel soot, respiratory function, bronchoalveolar lavage, clearance of radiolabeled particles, pulmonary immune responses, lung collagen, excised lung weight and volume, histopathology, and mean linear intercept of terminal air spaces. Parameters indicated by analysis of variance to exhibit significant interactions between the influences of emphysema and exhaust were examined to determine if the effects were more than additive (indicating increased susceptibility). Although 14 of 63 parameters demonstrated emphysema-exhaust interactions, none indicated increased susceptibility. Less soot accumulated in lungs of emphysematous rats than in those of nonemphysematous rats, and the reduced accumulation had a sparing effect in the emphysematous rats. The results did not support the hypothesis that emphysematous lungs are more susceptible than are normal lungs to chronic exposure to high levels of diesel exhaust. The superimposition of effects of emphysema and exhaust, however, might still warrant special concern for heavy exposures of emphysematous subjects.

Influence of experimental pulmonary emphysema on the toxicological effects from inhaled nitrogen dioxide and diesel exhaust.

This project examined the influence of preexisting, experimentally induced pulmonary emphysema on the adverse health effects in rats of chronic inhalation exposure to either nitrogen dioxide or automotive diesel-engine exhaust. Previous reports indicated that humans with chronic lung disease were among those most severely affected by episodic exposures to high concentrations of airborne toxicants. There were no previous reports comparing the effects of chronic inhalation exposure to components of automotive emissions in emphysematous and normal animals. The hypothesis tested in this project was that rats with preexisting pulmonary emphysema were more susceptible than rats with normal lungs to the adverse effects of the toxicant exposures. Young adult rats were housed continuously in inhalation exposure chambers and exposed seven hours per day, five days per week, for 24 months to nitrogen dioxide at 9.5 parts per million (ppm)2, or to diesel exhaust at 3.5 mg soot/m3, or to clean air as control animals. These concentrations were selected to produce mild, but distinct, effects in rats with normal lungs. Pulmonary emphysema was induced in one-half of the rats by intratracheal instillation of the proteolytic enzyme elastase six weeks before the toxicant exposures began. Health effects were evaluated after 12, 18, and 24 months of exposure. The measurements included respiratory function, clearance of inhaled radiolabeled particles, pulmonary immune responses to instilled antigen, biochemistry and cytology of airway fluid, total lung collagen, histopathology, lung morphometry, and lung burdens of diesel soot. The significance of influences of emphysema and toxicant exposure, and interactions between influences of the two treatments, were evaluated by analysis of variance. The elastase treatment resulted in pulmonary emphysema that was manifested by enlarged alveoli and alveolar ducts, and by ruptured alveolar septa. There was no accompanying inflammation and no alterations of bronchioles. The emphysema persisted throughout the study period, with little evidence of progression. Lung weight was increased, physiological lung volumes were enlarged, lung compliance was increased, and airflow was obstructed. Nitrogen dioxide exposure of normal rats caused mild epithelial hyperplasia and a thickening of the walls of terminal bronchioles, an extension of bronchiolar epithelium into proximal alveoli, and inflammation in proximal alveoli. Lung volume and weight and the lung collagen content were increased. Airway fluid indicators of cell damage and oxidant protective mechanisms were increased. Similar effects of nitrogen dioxide exposure were superimposed over the effects of emphysema in emphysematous nitrogen dioxide-exposed rats. Several parameters were affected similarly by nitrogen dioxide exposure and emphysema (for example, increased lung volume), and the combined effects tended to be additive.(ABSTRACT TRUNCATED AT 400 WORDS)

Talc deposition and effects after 20 days of repeated inhalation exposure of rats and mice to talc.

The relationship between the inhalation exposure concentration of talc and the resulting lung burdens and histologic lesions was studied using groups of 20 F344/Crl rats and 20 B6C3F mice (10 male and 10 female) exposed to one of three concentrations of asbestos-free talc for 6 hr/day, 5 days/week for 4 weeks. Controls were exposed to filtered air using the same schedule. The pulmonary retention of talc and the development of pulmonary pathology were evaluated. The mass median aerodynamic diameter (MMAD) of the talc aerosol was 3.0 microns with a geometric standard deviation (sigma g) of 1.9. The mean exposure concentrations for rats were 0, 2.3, 4.3, and 17 mg talc/m3. Lung burdens in rats averaged 0, 0.07, 0.17, and 0.72 mg talc/g lung after the 20-day inhalation exposure; thus, the amount retained in the lung per unit of exposure concentration increased with increasing concentration. Mean exposure concentrations for the mice were 0, 2.2, 5.7, and 20.4 mg of talc/m3, which resulted in lung burdens of 0, 0.10, 0.29, and 1.0 mg talc/g lung; thus, the relationship between exposure concentration and the amount retained in the lung was approximately constant. Lung burdens from this study were used to project lung burdens that would result from longer exposures of rodents and man. No clinical signs were observed in the rats or mice prior to sacrifice 24 hr after the last exposure day. Histologic alterations in lung tissue consisted of only a modest, diffuse increase of talc-containing, free macrophages within alveolar spaces in both rat and mouse groups exposed to the highest level of talc for 20 days. A model simulating chronic talc inhalation exposure of rats and mice predicted lung burdens of 2-3 mg talc/g lung (wet wt) if animals were exposed to 17 mg talc/m3 for 2 years, and deposition and clearance of talc were unchanged by continued exposure. A potential limitation in this modeling is that if clearance of talc is delayed by continued exposure, the accumulated talc lung burdens would be higher than those projected by the simulation model. Humans exposed to aerosols of respirable talc are projected to accumulate much higher lung burdens than would occur in rodents exposed to the same aerosol, because humans have a higher estimated deposition fraction and slower estimated clearance of the deposited talc dust. Equilibrium lung burdens of greater than or equal to 2 mg talc/g lung were predicted for human exposures at or near the TLV for talc.

Biochemical responses of rat and mouse lung to inhaled nickel compounds.

Nickel subsulfide (Ni3S2), nickel sulfate (NiSO4), and nickel oxide (NiO) are encountered occupationally in the nickel refining and electroplating industries, with inhalation being a common route of exposure. The purposes of this study were to evaluate the biochemical responses of lungs of rats and mice exposed for 13 weeks to occupationally relevant aerosol concentrations of Ni3S2, NiSO4, and NiO, to correlate biochemical responses with histopathologic changes, and to rank the compounds by toxicity. Biochemical responses were measured in bronchoalveolar lavage fluid (BALF) recovered from lungs of exposed animals. Parameters evaluated in BALF were lactate dehydrogenase (LDH), beta-glucuronidase (BG), and total protein (TP). Total and differential cell counts were performed on cells recovered in BALF. All compounds produced an increase in LDH, BG, TP, and total nucleated cells, and an influx of neutrophils, indicating the presence of a cytotoxic and inflammatory response in the lungs of exposed rats and mice. Increases in BG were greater than increases in LDH and TP for both rats and mice. Chronic active inflammation, macrophage hyperplasia, and interstitial phagocytic cell infiltrates were observed histologically in rats and mice exposed to all compounds. Statistically significant increases in BG, TP, neutrophils, and macrophages correlated well with the degree of chronic active inflammation. Results indicated a toxicity ranking of NiSO4 greater than Ni3S2 greater than NiO, based on toxicities of the compounds at equivalent mg Ni/m3 exposure concentrations.

A model for scaling the results of U excretion rate studies in beagle dogs to man.

A biokinetic model was used to simulate retention and excretion of two forms of U: ammonium diuranate (ADU), a relatively soluble form, and U3O8, a relatively insoluble form. These two U forms represent those most likely to be encountered in the U milling industry. The simulation model was compared with results from a study of aerosols of commercial refined U ore inhaled by laboratory animals. Beagle dogs were exposed by inhalation to ADU aerosols to achieve a median initial body burden of 0.058 mg U kg-1 body weight (within a range of 0.016 to 0.64 mg U kg-1), or to U3O8 aerosols to achieve a median retained body burden of 0.28 mg U kg-1 (0.030-0.81 mg U kg-1). The simulation model accurately described the accumulation of nephrotoxic concentrations of U in kidneys of animals exposed to ADU. Very small fractions of the initial body burden of U3O8 were translocated to kidney, and these fractions were overestimated by the model. The model showed general agreement with results of other laboratory animal studies and with available information from human exposures to ADU, UF6, or U3O8.

Effects of buthionine sulfoximine on the development of ozone-induced pulmonary fibrosis.

The capacity of reduced glutathione (GSH) to protect lung tissue against ozone-induced pulmonary fibrosis was investigated. Male B6C3F1 mice were exposed to 0, 0.2, 0.5, and 1.0 ppm ozone for 23 hr/day for 14 days. During exposures and/or for a period of 90 days after exposures, subgroups of mice at each exposure level were given drinking water containing 30 mM L-buthionine-S,R-sulfoximine (BSO) to lower in vivo levels of GSH. These BSO treatments reduced blood glutamylcysteine synthetase (GCS) activity (regulatory enzyme for GSH biosynthesis) and lung nonprotein sulfhydryl (NPSH) levels in nonexposed animals by approximately half. In contrast, ozone exposures increased blood GCS activity and lung NPSH levels in a concentration-dependent manner, with smaller increases in the BSO-treated mice. Immediately after exposures, an ozone-related inflammatory response was seen in lungs, but no histopathological signs of developing fibrosis were evident. Ninety days later, mice exposed to 1 ppm ozone and not treated with BSO had modest evidence of pulmonary fibrosis. Mice exposed to 1 ppm ozone and treated with BSO during this post-exposure period (regardless of BSO treatment during exposures) showed histopathological evidence of exacerbated pulmonary fibrosis, compared to similarly exposed mice not treated with BSO postexposure. These results indicated that interference with the body's normal defense mechanisms against oxidant damage, including suppression of GSH biosynthesis, exacerbates the subsequent development of pulmonary fibrosis.