Sidney Laskin

The inhalation toxicology of benzene: Incidence of hematopoietic neoplasms and hematotoxicity in AKRJ and C57BL6J mice

Abstract AKR J mice and C57BL 6J mice were given lifetime exposures to 100 and 300 ppm benzene, respectively. Peripheral blood cell counts were obtained biweekly throughout the exposures. Anemia and lymphocytopenia were produced in benzene-exposed AKR mice. Twenty percent of the exposed AKR mice developed bone marrow hypoplasia, compared to 2% for the controls. The benzene exposures did not alter the incidence or induction time of the viral-induced lymphomas commonly seen in AKR mice. In C57BL mice, exposure to benzene produced anemia, lymphocytopenia, and neutrophilia accompanied by a left shift. Thirteen (33%) of the exposed C57BL mice developed bone marrow hyperplasia and in four of these mice, hyperplasia was essentially limited to granulopoietic elements. None of the control C57BL mice developed bone marrow hyperplasia. In benzene-exposed C57BL mice there was a significant increase in the incidence of hematopoietic neoplasms including six cases (15%) of thymic lymphoma. Although two control mice (5%) died with lymphoma neither of these tumors involved the thymus. Thymic lymphoma is rare in C57BL mice but can be produced by ionizing radiation and chemical carcinogens.

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.

Hematotoxicity of inhaled benzene to sprague- dawley rats and akr mice at 300 ppm.

Sprague-Dawley rats and AKR/J mice were exposed to 300 ppm benzene vapor for 6 h/d, 5 d/wk, for life. Rats exhibited lymphocytopenia, mild anemia, and moderately decreased survival. Mice showed severe lymphocytopenia and anemia accompanied by granulocytosis and reticulocytosis. Treated mice also showed significantly decreased survival and weight gain. No indications of a leukemic or preleukemic response were observed in either species.

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.

Inhaled benzene fetotoxicity in rats

Abstract Groups of pregnant Sprague-Dawley rats were exposed to 100, 300, and 2200 ppm of benzene vapor in air for 6 hr daily on Days 6 to 15 of gestation. The mean maternal body weight gain of the 2200-ppm group was significantly depressed. However, the incidence of resorption was not affected. The mean fetal body weight and crown-rump length were significantly lower than the corresponding control groups only at the highest exposure level. Soft tissue examination revealed no significant increase in the incidence of anomalies among the exposed animals. Skeletal examinations showed a significant increase in the number of fetuses with delayed ossofication of sternebrae in the 300- and 2200-ppm groups. The female offspring appeared to be affected to a greater extent than male fetuses with respect to the incidence of delayed ossification of sternebrae. The litter incidence of missing sternebrae was significantly increased in the 100- and 2200-ppm exposure groups. The incidence of missing sternebrae was significantly increased in female but not in male offspring at 2200 ppm of benzene.

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.

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.

Toxicity of chronic benzene inhalation: CD-1 mice exposed to 300 ppm

Male, six-week old mice were exposed to benzene in an inhalation chamber for 6 hr/day, 5 days/wk. Red cell, white cell and white cell differential counts were performed. Tissues routinely sectioned at autopsy included lung, liver, spleen, bone marrow and kidney, as well as abnormally appearing organs. Hemototoxic responses observed include immediate depression of peripheral lymphocytes and red blood cells, and an increase in circulating granulocytes. Exposed animals dying with bone hypoplasia survived about 75 fewer days than mice dying with bone hyperplasia. The appearance of hemosiderin pigments in the spleens is evidence for benzene-induced hemolysis. (JMT)

The Laskin aerosol generator

This paper describes construction details and operating characteristics of a nebulizer developed by Sidney Laskin and used over a period of 30 yr in various laboratories to generate respirable aerosols for whole-animal inhalation exposure studies. Under the proper operating conditions, the device is capable of producing nearly monodisperse aerosols in the respirable size range (1.5 micron volume median diameter with a geometric standard deviation of 1.1) for long periods of time