Prechronic Inhalation Toxicity Studies of 2-Mercaptobenzimidazole (2-MBI)in F344/N Rats

2-Mercaptobenzimidazole (2-MBI), used in rubber processing,is a suspect carcinogen structurally related to ethylene thiourea.The inhalation toxicity of 2-MBI was evaluated in male and femaleF344/N rats exposed 6 hr/day, 5 days/week to respirable aerosolsgenerated by spray atomization of aqueous suspensions of the2-MBI powder and subsequent drying of the resulting aerosols.Twelve exposures at target concentrations of 0, 6.3, 12.5, 25.0,50.0, or 100 mg/m³ of 2-MBI produced a dose-related reductionin body weight gains, thyroid follicular cell hyperplasia, adrenalcortex fatty change, and pituitary atrophy. Sub-chronic exposureswere conducted at target concentrations of 0, 3.1, 6.2, 12.5,25.0, and 50.0 mg/m³ of 2-MBI. Rats at 25 mg/m³ displayed hunchedposture, hypoactivity, and reduced body weight gain, with compoundrelated mortality at the highest exposure level. Anemia; increasedSGPT, SGOT, alkaline phosphatase, sorbitol dehydrogenase, BUN,and cholesterol; and reduced free fatty acid were seen in ratsat 25 mg/m³. Increased thyroid weight and thyroid follicularcell hyperplasia were noted in both sexes at 6.2 mg/m³, withreduced triiodothyronine and thyroxine levels in both sexesat > 12.5 mg/m³. Thyroid follicular cell hyperplasia wasalso seen in rats at 3.1 mg/m³. Thymus weights were significantlyreduced in both sexes at all exposure levels with liver weightincreases at 6.2 mg/m³. Exposure-related histopathologic changesincluded pituitary cytoplasmic vacuolization, adrenal cortexnecrosis, lymphoid depletion, thymic atrophy, liver cell hypertrophy,renal mineralization and tubular atrophy, and hypocellularityof the bone marrow.     

Prechronic Inhalation Toxicity Studies of Isobutyl Nitrite

Isobutyl nitrite (IBN) is a volatile liquid that has becomeincreasingly popular as an inhaled recreational drug. To investigateshort-term toxic effects and establish exposure parameters forchronic inhalation studies, F344/N rats and B6C3F1 mice wereexposed to IBN vapors on a 6 hr/day + t90, 5 days/week schedule.Twelve exposures were administered at concentrations of 0, 100,200, 400, 600, and 800 ppm IBN. This exposure series resultedmortality in rats exposed to 600 ppm and mice exposed to 800ppm. Animals exposed at the lower concentrations developed hyperplasiaof the bronchiolar and nasal turbinate epithelium (rats andmice) and lymphocytic atrophy in the spleen and thymus (mice).Longer term, 13-week, subchronic exposures were conducted atconcentrations of 0, 10, 25, 75, 150, and 300 ppm IBN. Exposureto 300 ppm IBN reduced the body weight gains in both sexes ofrats and in female mice. IBN-related clinical pathology changesincluded reduced RBC counts accompanied by moderate increasesin mean corpuscular volume and reticulocyte counts, increasedWBC counts, and mildly increased methemoglobin concentration.Bone marrow hyperplasia was observed in all groups of IBN-exposedrats, while in mice only females at l50 ppm IBN displayed thischange. Excessive splenic pulp hematopoiesis was noted in miceat all IBN exposure levels. Respiratory system changes includedincreased lung weights in rats and female mice at 300 ppm, hyperplasiaof the nasal mucosa (male rats at 75 ppm and female rats at150 ppm), and hyperplasia of the lung epithelium (male miceat 150 ppm and female mice at 75 ppm). The results suggestedthat a concentration of 150 ppm could be used as the highestexposure level for subsequent chronic inhalation tests.     

Local versus Systemic Immunotoxicity of Isobutyl Nitrite Following Subchronic Inhalation Exposure of Female B6C3F1 Mice

Female B6C3F1 mice were exposed to isobutyl nitrite (IBN) byinhalation at 0, 37.5, 75, or 150 ppm for 6 hr per day, 5 daysper week for 15 weeks. The potential of this compound to induceimmunotoxicity was assessed during the 3rd, 13th, 14th, and15th week of exposure and after 2 weeks of recovery followingthe 15 weeks of exposure. Both systemic and lung immune functionswere examined, including body and lymphoid organ weights, pulmonarymacrophage function and host defense, expression of spleniclymphocyte cell-surface markers, natural killer cell function,mixed lymphocyte reaction, and induction of specific antibodyto a T-cell-dependent antigen. There was a dose-related suppressionof T-cell-dependent antibody-forming cell responses in the spleenfollowing IBN exposure; however, other measures of T-cell andnonspecific immunity were not significantly affected. A dose-relatedincrease of H₂O₂ production by alveolar macrophages was presentafter 12 but not after 68 exposures to IBN. In contrast, pulmonaryhost defense mechanisms against Klebsiella pneumoniae were unaffected.These results suggest that in the absence of changes in hostresistance, IBN may have selective and partially reversibleeffects on the immune system.     

A 90-Day Vapor Inhalation Toxicity Study of Decalin

A 90-Day Vapor Inhalation Toxicity Study of Decalin. GAWORSKI,C. L., HAUN, C. C, MACEWEN, J. D., VERNOT, E. H., BRUNER, R.H., AMSTER, R. L., AND COWAN, M. J., JR. (1985). Fundam. Appl.Toxicol. 5, 785–793. A subchronic 90-day inhalation studywas conducted to determine the toxic effects of decalin, a commonlyused industrial solvent. Experimental groups consisting of maleand female beagle dogs, male and female Fischer-344 rats, andfemale C57BL/6 mice were continuously exposed to decalin concentrationsof 5 or 50 ppm. An unexposed control group was also maintained.All dogs and a portion of each rodent group were sacrificedand examined at exposure termination, while the remaining rodentswere held for observation up to 21 months postexposure. No distinctexposure-related lesions were noted in dogs. Dog body weights,organ weights, and blood clinical pathology were also normal.At exposure termination hepatocellular cytoplasmic vacuolizationwas noted in female mice exposed to both concentrations. Thisliver tissue change was reversible and was not a significantfinding in female mice examined during the 21-month postexposureobservation period. In male rats, decalin exposure producednephropathy characterized by hyaline droplets, necrosis, andintratubular casts. Accentuated tubular degeneration and medullarymineralization were noted in exposed rats held for long-termpostexposure observation. There was no associated abnormal increasein mortality nor alterations in serum, blood urea nitrogen,or creatinine levels. Female rats were free of decalin-inducedrenal damage. There was a slightly greater incidence of commonlyoccurring pituitary tumors in both mice and rats; however, thetumor incidence was not dose related. The results of this studysuggest that the toxic effects of decalin are similar to thosepreviously described for other hydrocarbon solvents and fuels.