Arthur Sellakumar

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.

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.

The carcinogenicity of discontinuous inhaled benzene exposures in CD-1 and C57Bl/6 mice

Groups of male C57Bl and CD-1 mice were exposed to benzene via inhalation using two different exposure protocols. One protocol consisted of repetitive week-long exposures to 300 ppm benzene (6 h/d×5 d/wk) interrupted by 2 weeks of non-exposure. The exposure pattern (1 week of exposure followed by 2 weeks of non-exposure) was continued until the death of the last exposed animal. The second protocol consisted of exposures to 1200 ppm benzene (6 h/d×5 d/wk) for 10 weeks. Exposures were then terminated and the animals allowed to live out their lives. For each protocol, appropriate age-matched control mice received comparable exposures to filtered, conditioned air. The discontinuous exposure patterns mimic the patterns of exposure often encountered in the workplace and, in addition, prolong the survival of exposed animals so as to maximize potential tumorigenic responses. Both exposure protocols were markedly hematotoxic to both mouse strains as measured by peripheral blood counts. Both strains of mice responded to the intermittent 300 ppm benzene exposures with elevated incidences of malignant tumors. Particularly noteworthy was a 35% incidence of zymbal gland tumors in the C57Bl mice. In contrast, only the CD−1 mice responded to the 1200 ppm benzene exposures delivered over 10 weeks with elevated tumor incidences. A 46% incidence of lung adenoma was particularly striking in these mice. Neither of the benzene exposure protocols induced elevated incidences of leukemia/lymphoma in either strain. These studies demonstrate that discontinuous exposures to benzene are tumorigenic and that a lifetime exposure to benzene, even if delivered at a lower concentration and in an intermittent exposure pattern, is more tumorigenic than a short-term exposure to benzene.

The hematotoxic effects of inhaled benzene on peripheral blood, bone marrow, and spleen cells are increased by ingested ethanol☆☆☆

Abstract For 13 weeks, groups of C57Bl 6J male mice were exposed to 300 ppm benzene by inhalation, 6 hr/day, 5 days/week, and to 5 or 15% ethanol in the drinking water, 4 days/week. The number and type of blood cells in the peripheral blood, marrow, and spleen were determined at regular intervals. Anemia and lymphocytopenia were observed in the peripheral blood of all benzene and benzene/ethanol-treated groups. These cytopenias, however, were more severe in the benzene/ethanol-treated mice. In addition, there was a transient increase of normoblasts in the peripheral blood of benzene/ethanol-treated mice which was not observed in mice treated with benzene alone or in control mice. Groups exposed to benzene or benzene/ethanol displayed reduced marrow and splenic cellularities but the reductions were more severe in mice exposed to benzene/ethanol. Specifically, these reduced cellularities were characterized by decreased numbers of lymphocytes in both marrow and spleen and decreased numbers of granulocytes and normoblasts in the marrow. In benzene/ethanol-treated mice a transient increase in the numbers of splenic normoblasts was observed which coincided with the transient appearance of normoblasts in the peripheral blood of these animals. This condition was not observed in mice treated with only benzene or only ethanol. Mice exposed to benzene/ethanol presented a greater degree of atypical cellular morphology than mice treated with benzene alone. These data suggest that the ingestion of ethanol increases the hematotoxicity of inhaled benzene.

Distribution, metabolism and toxicity of inhaled sulfur dioxide and endogenously generated sulfite in the respiratory tract of normal and sulfite oxidase-deficient rats.

We report on the distribution, metabolism, and toxicity of sulfite in the respiratory tract and other tissues of rats exposed to endogenously generated sulfite or to inhaled sulfur dioxide (SO2). Graded sulfite oxidase deficiency was induced in several groups of rats by manipulating their tungsten to molybdenum intake ratio. Endogenously generated sulfite and S-sulfonate compounds (a class of sulfite metabolite) accumulated in the respiratory tract tissues and in the plasma of these rats in inverse proportion to hepatic sulfite oxidase activity. In contrast to this systemic mode of exposure, sulfite exposure of normal, sulfite oxidase-competent rats via inhaled SO2 (10 and 30 ppm) was restricted to the airways. Minor pathological changes consisting of epithelial hyperplasia, mucoid degeneration, and desquamation of epithelium were observed only in the tracheas and bronchi of the rats inhaling SO2, even though the concentration of sulfite plus S-sulfonates in the tracheas and bronchi of these rats was considerably lower than that in the endogenously exposed rats. We attribute this histological damage to hydrogen ions stemming from inhaled SO2, not to the sulfite/bisulfite ions that are also a product of inhaled SO2. In addition to the lungs and trachea, all other tissues examined, except the testes, appeared to be refractory to high concentrations of endogenously generated sulfite. The testes of grossly sulfite oxidase-deficient rats were severely atrophied and devoid of spermatogenic cells.

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)

Tumur induction by 7H‐dibenzo[c,g] carbazole in the respiratory tract of Syrian hamsters

The respiratory tract of male and female Syrian golden hamsters was treated intratracheally with 7H-dibenzo[c,g]carbazole (DBC), a tobacco smoke component. The carcinogen was given by multiple instillations at two dose levels. At the lower dose (9 mg), 35 of 46 hamsters (72%) developed respiratory tract tumors. The group receiving treatment at the higher dose level (30 mg) died earlier because of the toxicity of the compound. In this group, 15 of 45 animals (33%) had respiratory tract tumors. These occurred in the larynx, trachea, bronchi, and lungs, but predominated in the trachea and bronchi. Morphologically, most tumors were papillomas and squamous cell carcinomas. This study indicates the highly potent carcinogenic effect of DBC and that respiratory tumors can be induced in this model system without any carrier dust.

Effects of different dusts on respiratory carcinogenesis in hamsters induced by benzo(a)pyrene and diethylnitrosamine

Abstract The modes of interaction between (a) subcutaneously injected diethylnitrosamine (DEN) and intratracheally instilled ferric oxide (Fe 2 O 3 ); and (b) benzo(a)pyrene (B(a)P) and dusts; namely, Fe 2 O 3 , aluminium oxide (Al 2 O 3 ) or carbon (C) intratracheally instilled, were studied in Syrian golden hamsters. The objective was to determine whether or not an initiation-promotion type relationship existed. DEN alone induced laryngeal and tracheal papillomas and, when followed by Fe 2 O 3 , elicited lung tumors. These tumors may be auto-tranplanted tumors. Fe 2 O 3 followed by DEN treatment, and simultaneous DEN/Fe 2 O 3 treatment produced tumors of the larynx and trachea in the same way as DEN alone. Single applications of DEN and of Fe 2 O 3 induced 1 tracheal papilloma. A number of forestomach papillomas, as well as other tumors, such as adrenal cortex adenomas, were seen in treated groups and in similar numbers in the untreated controls. Repeated applications of B(a)P alone and Fe 2 O 3 given before or after B(a)P failed to induce more than a few laryngeal and tracheal tumors. A significant number of tumors occurred only when both agents, B(a)P and dust, were administered simultaneously. Thus, no significant initiating-promoting action by dusts on DEN or B(a)P-induced lung tumorigenesis in the respiratory tract of Syrian golden hamsters was observed. It is concluded that Fe 2 O 3 acts as a carrier agent, enhancing the effects of B(a)P.

Squamous metaplasia and respiratory tumors induced by intratracheal installations of 7, 12-dimethylbenz(a)-anthracene in Syrian golden hamsters

Abstract Repeated intratracheal installations of 7,12 -dimethylbenz(a)anthracene in the respiratory tract of Syrian golden hamsters induced papillomas, carcinoma in situ and squamous cell carcinomas of the larynx and trachea. The neoplastic progression was characterized by pronounced and extensive squamous metaplasia showing evidence of hyperortho- and hyper-parakeratosis, without secondary changes, inflammation and fibrosis in the lung. The total number of tumors seen, 20 and 13 respectively, the short latent period ( 20 or 21 weeks) and the low doses, 0·85 mg and 1·2 mg in total respectively, show that DMBA is also a potent carcinogen in the respiratory system.

An assessment of the tumorigenic properties of a Hudson County soil sample heavily contaminated with hexavalent chromium.

During much of this century, Hudson County, New Jersey, was a major center for the processing of chromium ore. Some of the residue from this processing was used in landfills and in construction materials throughout the county and, in some cases, in highly populated areas. Given that it is widely accepted that exposure to hexavalent chromium compounds poses a risk for the development of respiratory-tract cancer, concerns were raised that individuals who worked or resided in chromium-contaminated areas might be at increased risk for the development of respiratory cancer. To address these concerns, we evaluated a Hudson County soil sample-heavily contaminated with chromium ore residue (Cr(+6) concentration at 5 895 mg/kg)-with respect to its carcinogenic potential to the respiratory tract of Sprague-Dawley rats. Groups of animals were given repeated intratracheal exposures to one of four materials: (1) Hudson County chromium-contaminated soil (CCS), (2) CCS augmented with calcium chromate (CaCrO4), (3) CaCrO4 alone, or (4) control soil. Nominal total doses of Cr(+6) for each respective group were 324 microg/kg, 7,975 microg/kg, 8,700 microg/kg, and 0.02 microg/kg. Incidences of malignant tumors and nephritis were not elevated in any group. Four primary lung tumors appeared in animals that received CCS + CaCrO4, and one primary lung tumor appeared in the group treated with CaCrO4 alone. These incidences were not significant statistically, but the rare spontaneous occurrence of these tumors in Sprague-Dawley rats suggested that they were treatment related. No primary lung tumors appeared in the control or CCS-treated groups.