Norton Nelson

Tumors of the Respiratory Tract Induced by Inhalation of Bis(Chloromethyl)Ether

Squamous ceil carcinomas of the lung and esthesioneuroepitheliomas of the olfactory epithelium were produced in high incidence in rats following inhalation of 0.1 ppm of bis(chloromethyl)ether. These findings imply a significant potential occupational hazard.

Inhalation carcinogenicity of alpha halo ethers. III. Lifetime and limited period inhalation studies with bis(chloromethyl)ether at 0.1 ppm.

Rats and hamsters were exposed to 0.1 ppm bis(chloromethyl)ether (BCME) six hours per day, five days per week throughout their lifetime. Additional groups of rats were given 10, 20, 40, 60, 80, and 100 exposures to 0.1 ppm BCME and then held until death. Forty cancers originating in the respiratory tract were found in the 200 rats involved in these studies. These included 14 cancers of the lung and 26 cancers of the nasal cavity. They occurred in dose-related fashion. A single undifferentiated carcinoma of the lung was seen in a hamster.

DEPOSITION OF AEROSOLS IN THE HUMAN RESPIRATORY TRACT DURING BREATH HOLDING

Abstract The anatomical character of both the conducting airways and of the functional gas exchange region exerts an important influence on rates of deposition of inhaled aerosol. In the present studies an attempt is made to use the rate of deposition of aerosol particles in the respiratory tract during breath-holding as an index of the effective lumen diameters of the respiratory branches. During breath-holding for periods up to about 30 sec, the ratio of exhaled to inhaled aerosol decreases exponentially with time; this was observed for all subjects at particle sizes from about 0×15 to 1×0 micron. Calculations of lumen diameter based on these observations yielded estimates which are consistent with those obtained by microscopic measurements on human lungs.

Inhalation carcinogenicity of alpha halo ethers. I. The acute inhalation toxicity of chloromethyl methyl ether and bis(chloromethyl) ether.

A range of acute studies were performed with chloromethyl methyl either (CMME) and bis(chloromethyl)ether (BCME), including 14-day LC50s following single seven-hour inhalation exposures. The LC50s for CMME were 55 ppm for rats and 65 ppm for hamsters. The LC50s for BCME were 7 ppm for both species. All animals showed characteristic changes of acute irritation of the respiratory tract manifested by congestion, edema, and hemorrhage. Severe shortening of life span was seen in 30-day exposures of rats to CMME and in all studies with BCME. Incidences of mucosal changes, including atypia, were generally increased in a dose-related manner in both species. The carcinogenicity of BCME in these range finding experiments was demonstrated by a skin cancer in a rat after three exposures and a nasal tumor in a hamster after one exposure to 1 ppm BCME.

The deposition and clearance of radioactive particles in the human lung.

Volunteers inhaled monodisperse iron oxide particles tagged with /sup 198/Au or /sup 51/Cr. Clearance was determined by external monitoring. Rapid clearance in first day (50% of initial) was followed by an additional 10% lost the first week with slower rates after that. During the first day, there was rapid clearance in the first 2 to 4 hr followed by a second, slower phase lasting 10 to 18 hr. Larger particles (e.g., 5 ..mu..m) deposited higher in bronchial tree and were cleared more rapidly than smaller (e.g., 3 ..mu..m) particles. Total first day clearance is from bronchi, as increase in abdomen radioactivity indicates swallowing of cleared particles.

Inhalation carcinogenicity of alpha halo ethers. II. Chronic inhalation studies with chloromethyl methyl ether.

Rats and hamsters were exposed to 1 ppm of chloromethyl methyl ether six hours per day, five days per week, throughout their lifetime. Mortality and weight gain of the exposed animals paralleled that of the control animals. Malignant tumors of the respiratory tract were found in two rats. These were a squamous cell carcinoma of the lung with blood vessel invasion and an esthesloneuroepithelioma originating in the olfactory epithelium and invading the forebrain. One hamster was found to have an adenocarcinoma of the lung and another, a squamous papilloma of the trachea. A single exposed rat had a pituitary tumor of primitive cell type that may well have been coincidental.

Myelogenous leukemia in rodents inhaling benzene

Studies during the past five decades have failed to demonstrate myelogenous leukemia in laboratory animals exposed to benzene despite epidemiologic evidence linking such exposure to myelogenous leukemia in man. We report four cases of myeloproliferative disease among rodents exposed to benzene, 6 h a day, 5 days weekly, for life. There was one case of chronic myelogenous leukemia, one of acute myeloblastic leukemia, and one of granulocytic hyperplasia among 40 CD-1 mice exposed to 300 ppm benzene; and one case of chronic myelogenous leukemia among 40 rats exposed to 100 ppm benzene. Although not statistically significant as compared to the respective control groups, the fact that myelogenous leukemia has not been reported in control animals of these two strains is suggestive of a causative role for benzene.

REGIONAL AEROSOL DEPOSITION IN THE HUMAN RESPIRATORY TRACT

Abstract Regional deposition of aerosol in the human respiratory tract is estimated from experiments in which aerosol concentration and respiratory flow were measured continuously during individual breaths and from a theoretical analogy with a tubular continuous filter bed model of the respiratory tract. Since the volume of anatomic dead space is uncertain, regional distinction is made by selected boundary volumes which separate the upper tract of the selected volume from the more distal lower tract. The central feature of the estimation procedure is the determination of a combined upper tract penetration, for inspiration, pause, and expiration, derived from expired aerosol concentration corrected for aerosol mixing. The estimations indicate the particle size for maximum alveolar deposition is greater than 2 μ, equivalent diameter of a unit density sphere. This result is consistent with the calculations of Findeisen, Landahl, and Beeckmans and higher than the 1 μ value of Brown et al.

Skin irritation and skin tumor production by beta propiolactone (BPL).

Abstract Skin irritation and skin tumors were produced by application of beta propiolactone to mouse skin. Short term application of undiluted BPL or of its solutions in acetone or corn oil produced reactions varying from erythema to hair loss and scarring with one to six applications of 0.8 to 100 mg BPL. Lifetime painting of acetone and corn oil solutions ranging from 0.25 to 5 per cent BPL produced both papilloma and cancer on mouse skim. Tumor production was concentration related; this relationship was more sharply defined when adjustment for mortality was made by a life-table technique. Tumorigenesis by benzpyrene and BPL applied successively appeared additive.

Carcinogenicity of Halo Ethers

The report by Figueroa et al. in this issue concerning the occurrence of lung cancer in workers exposed to chloromethyl methyl ether (CMME) represents another step in apparently parallel efforts th...