Chronic Morpholine Exposure of Rats

Chronic Morpholine Exposure of Rats. HARBISON, R. D., MARINO,D. J., CONAWAY, C. C., RUBIN, L. F., AND GANDY, J. (1989). FundamAppl. Toxicol. 12,491–507. The chronic toxicity and carcinogenicpotential of morpholine were evaluated in 60 Sprague-Dawleyrats/sex/group receiving morpholine at mean inhalation exposureconcentrations of 0, 10, 50 and 150 ppm for 6 hr/day, 5 days/week,for 104 weeks. Survival, body weight gains, organ weights, hematology,and clinical chemistries were normal in exposed groups and comparableto those of the control animals. The incidences of palpabletissue masses and of histologically confirmed neoplasia werecomparable among all groups, including the control groups, andwere typical of the strain and age of the rats tested. In-lifeclinical examinations revealed increased incidences of irritationaround the eyes and nares, chromadacryorrhea, and urine stainson the fur, predominately in high-dose animals. Morpholine exposurewas associated with corneal irritation seen by ophthalmoscopicexamination and confirmed microscopically as keratitis limitedto the highest exposure group. Irritation of the maxillary andnasoturbinates as indicated by infiltration of neutrophils,focal squamous metaplasia of the turbinate epithelium, and necrosisof the turbinate bone was observed in high-dose animals. Therefore,chronic exposure of rats to morpholine for 2 years at concentrationsof 150 ppm or less revealed no carcinogenic potential or chronicsystemic toxicity. Consistent with its known irritating properties,morpholine produced only local irritation, which was limitedalmost exclusively to high-dose animals.     

Subchronic and Chronic Inhalation Toxicity of Antimony Trioxide in the Rat

Fischer 344 rats were exposed by inhalation to Sb₂O₃ (antimonytrioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and23.46 mg/m³ for 6 hr/day, 5 days/week for 13 weeks followedby a 27-week observation period. Subsequently, an inhalationon-cogenicity study was conducted at exposure levels of 0, 0.06,0.51, and 4.50 mg/m³ for 12 months followed by a 12-month observationperiod. The Sb₂O₃ in the subchronic study had a mass medianaerodynamic diameter (MMAD) of 3.05 ± 0.21 microns (mean± SD) with a geometric standard deviation (GSD) of 1.57± 0.06. In the chronic study, the MMAD was 3.76 ±0.84 and the GSD was 1.79 ± 0.32. Except for the eyes,no adverse clinical observations were attributed to Sb₂O₃ ineither study. In the subchronic study, corneal irregularitieswere seen after about 2 weeks of exposure and did not abateduring the observation period. In the chronic study, ophthalmoscopicevaluation at 24 months revealed a dose-related increase incataracts of 11, 24, 28, and 32% (both sexes combined) for eachgroup, respectively. Body weights were significantly lower (6%)than the control group's weights in the 23.46 mg/m³ males inthe subchronic study. These rats did not recover this weightduring the 27-week observation period. Body weights of the femalesin both studies and males in the chronic study were unaffected.There were no Sb₂O₃ effects on clinical chemistry or he-matologyin either study. Mean absolute and relative lung weights weresignificantly increased in the 4.92 and 23.46 mg/m³ groups inthe subchronic study. The 23.46 mg/m³ group's lung weights didnot recover to control levels during the 27-week observationperiod. Lung weights for rats in the chronic study were unaffected.Microscopic changes in the lungs in the subchronic and chronicstudy were limited to subacute-chronic interstitial inflammation,increased numbers of alveolar-in-traalveolar macrophages, foreignmaterial in the alveolar-in-traalveolar macrophages in the peribronchialand perivascular (chronic study only) lymphoid aggregates andin the peribronchial lymph nodes, granulomatous inflammation/granulomas,and fibrosis. In the chronic study, any observed neoplasms occurredwith comparable incidence among all groups and were within thehistorical range for controls. Clearance of Sb₂O₃ from the lungwas burden dependent and was reduced by 80/ in the 4.50 mg/m³group in the chronic study. The previously reported studies,which found Sb₂O₃ to be a carcinogen, were run at higher lungburdens. Under the exposure conditions of the current study,Sb₂O₃ was not a carcinogen.     

Cellular and Molecular Characteristics of Transformed T Cells from an Antigen-Specific T-Cell Line

An antigen-specific T-cell line which transforms into T-lymphoma cells in vitro but apparently not in vivo is described. Membrane markers, tumorigenicity and T-cell receptor (TcR) V alpha and V beta-gene usage of the in vitro transformed T-cell line were analysed to investigate whether the transformation event was poly-, oligo-, or monoclonal. The results indicate that the T lymphoma has no chromosome abnormalities, contains no tumour-inducing virus, can induce clone-specific immunity, and is oligoclonal with respect to TcR V alpha and V beta expression. The nature of the transformation event and clinical application of vaccination against T lymphomas is discussed. In addition, the expressed TcR V alpha and V beta repertoire of Con A T blasts was apparently not affected by the Igh-l or the MHC haplotype, as investigated in Igh-l and MHC congeneic C57Bl mice.