Chronic Inhalation Toxicity Research Articles

Evaluation of the chronic inhalation toxicity of a manganese oxide aerosol--I. Introduction, experimental design, and aerosol generation methods.

A brief literature review on manganese toxicity is presented; as related to designing a chronic inhalation study for evaluating methylcyclopentadienyl manganese tricarbonyl when utilized as a motor fuel additive. The experimental design of this study is described. The generation system utilized to simulate the manganese aerosol produced by an internal combustion engine is described in detail. This generation system operated twenty-four hours per day, seven days per week producing aerosols at 11.6, 112.5, and 1152 micrograms Mn/m3 with an aerodynamic diameter of approximately 0.11 micron.

Chronic marihuana inhalation toxicity in rats

Exposure of rats to marihuana or placebo smoke for periods of up to 87 days was performed with an automatic inhalator. Δ 9-Tetrahydrocannabinol ( Δ 9-THC) concentrations in the marihuana smoke were similar to those inhaled by man and were presented to rats in a 50-ml puff volume of 2-sec duration and a 30-sec exposure interval followed by a 30-sec period of fresh air each minute. By varying the number of puffs from three simultaneously smoked marihuana cigarettes (2.1% Δ 9-THC), 8–10 Fischer rats simultaneously received a single daily Δ 9-THC dose of 0.7, 2, or 4 mg/kg, 6 consecutive days per week for 27, 57, or 87 days. Lethal cumulative toxicity in male rats began in the first week, which eventually resulted in 60% deaths, at two peak intervals, in weeks 3 and 8. During the first week, some dose-related CNS inhibition, hypothermia, and hypopnea occurred to which tolerance developed at different rates. In the second and third weeks, CNS stimulation was prevalent at lower doses. Neurotoxicity (“popcorn” reaction) occurred in 70% of both sexes on the high dose and reached a peak in weeks 3 and 8. Tolerance to these manifestations developed in subsequent weeks. Generally, growth rates and food intake decreased in males treated with the high dose but, in the other treated groups, food and water consumption were evaluated throughout the study. Increased organ to body weight ratios for the brain, lungs, and heart of males reflected decreases in final body weight. No convulsive episodes were noted. In weight-decreased rats, congestion in major organs and pulmonary edema suggested circulatory failure. In the treated animals, which were sacrificed, a dose-related moderate focal pneumonitis, characterized by the accumulation of aggregates of yellow-brown, sudanophilic alveolar macrophages, polymorphonuclear leukocytes, and lymphocytes, was observed. Female rats evoked as yet unknown protective mechanisms more efficiently than males in the face of neurotoxicity and morphological changes.

Subacute and chronic toxicity studies of fluorocarbon propellants in mice, rats and dogs

Six subacute and chronic inhalation toxicity studies were conducted in rats, mice and dogs treated with fluorocarbon propellants. The studies varied in length from 2 weeks to 23 months and the dose of propellant varied from 164 mg/kg/day to 2240 mg/kg/day. The only signs of toxicity observed were sedation, ataxia and mild depression which occurred in the 2 studies in which the propellant doses were the highest. These effects, observed during and immediately after exposure, disappeared rapidly and were attributed to mild anesthetic properties of the fluorocarbon propellants. Abnormal values were not found in the hematologic, blood chemistry or urinalysis values in any of the 6 toxicity studies. Gross and microscopic examination of tissues of the respiratory tract, including lung, did not reveal any evidence of propellant toxicity, irritation or carcinogenicity. In the 3- and 12-month toxicity studies, EKG changes were not observed in dogs which had received large daily doses of the propellants.

2506. A breath of dust: Davis, J. M. G. (1972). The fibrogenic effects of mineral dusts injected into the pleural cavity of mice. Br. J. exp. Path.53, 190

This review substantiates kinetically and pathologically the differences between chrysotile and amphiboles. The serpentine chrysotile is a thin walled sheet silicate while the amphiboles are double-chain silicates. These different chemistries result in chrysotile clearing very rapidly from the lung (T1/2 = 0.3 to 11 days) while amphiboles are among the slowest clearing fibers known (T1/2 = 500 days to ∞). Across the range of mineral fiber solubilities chrysotile lies towards the soluble end of the scale. Chronic inhalation toxicity studies with chrysotile in animals have unfortunately been performed at very high exposure concentrations resulting in lung overload. Consequently their relevance to human exposures is extremely limited. Chrysotile following subchronic inhalation at a mean exposure of 76 fibers L > 20 μm/cm3 (3413 total fibers/cm3) resulted in no fibrosis (Wagner score 1.8–2.6), at any time point and no difference with controls in BrdU response or biochemical and cellular parameters. The long chrysotile fibers were observed to break apart into small particles and smaller fibers. Toxicologically, chrysotile which rapidly falls apart in the lung behaves more like non-fibrous mineral dusts while response to amphibole asbestos reflects its insoluble fibrous structure. Recent quantitative reviews of epidemiological studies of mineral fibers have determined the potency of chrysotile and amphibole asbestos for causing lung cancer and mesothelioma in relation to fiber type have also differentiated between these two minerals. The most recent analyses also concluded that it is the longer, thinner fibers that have the greatest potency as has been reported in animal inhalation toxicology studies. However, one of the major difficulties in interpreting these studies is that the original exposure estimates rarely differentiated between chrysotile and amphiboles. Not unlike some other respirable particulates, to which humans are, or have been heavily occupationally exposed, there is evidence that heavy and prolonged exposure to chrysotile can produce lung cancer. The value of the present and other similar studies is that they show that low exposures to pure chrysotile do not present a detectable risk to health. Since total dose over time decides the likelihood of disease occurrence and progression, they also suggest that the risk of an adverse outcome may be low if even any high exposures experienced were of short duration.

Comparative chronic inhalation toxicity of beryllium ores, bertrandite and beryl, with production of pulmonary tumors by beryl

Intermittent daily exposure of monkeys, rats, and hamsters for periods up to 23 months to 15 mg/m 3 of bertrandite or beryl ore dust resulted in the appearance of pulmonary tumors in 18 of the 19 rats that survived 17 months of exposure to beryl. Corresponding lesions were not observed in any of the other animals exposed to beryl or in those exposed to bertrandite. Bertrandite-exposed rats, however, exhibited granulomas and atypical proliferation of the lung. Monkeys from both ore exposures deviated from the unexposed control group only by a nonspecific phagocytic dust reaction around the respiratory bronchioles and small blood vessels. Beryl and bertrandite-exposed hamsters showed pulmonary atypical proliferation and the bertrandite animal lungs contained a few granulomatous lesions. Body-weight gains, except for the ore-exposed rats, corresponded with those of the control-unexposed animals. Mortalities in the ore-exposed animals exceeded those of the controls. Hematologic parameters of ore-exposed and control monkeys and rats were within accepted ranges. Alkaline phosphatase activities in lung, kidney, spleen, and serum samples from serially sacrificed animals of all species yielded equivocal data. Collagenous silicotic nodules did not develop in any ore-exposed animal despite an approximately 20% free-silica content of the ores sufficient to result in such a response.