Masters Theses

Date of Award

12-1981

Degree Type

Thesis

Degree Name

Master of Science

Major Professor

Robert L. Ullrich

Committee Members

Hanspeter Witschi, John Storer

Abstract

This study was designed to investigate the carcinogenic effects of combinations of chemical and/or physical agents, particularly at low doses. The animal model chosen for this investigation was lung tumor development in the Swiss Webster mouse.

The treatment combination of a known carcinogen and the non-carcinogenic chemical butylated hydroxytoluene (BHT) was evaluated in two series of experiments. One study evaluated the combination of urethan with BHT, while the other investigated fission neutron radiation plus BHT. An additional study looked at the effects of a combination of low doses of two carcinogenic agents, urethan and fission neutrons, in this animal system. Finally, a study of the BHT enhancement of lung tumorigenesis was done by investigating the related action of BHT to induce extensive cell proliferation in the murine lung.

A treatment sequence of a single high dose (1000 mg/kg) of urethan followed by eight weekly administrations of BHT (300 mg/kg) resulted in a significantly increased mean number of pulmonary tumors per mouse compared to urethan treatment only. A low dose of urethan (100 mg/kg) plus eight weekly BHT treatments, however, did not produce a significantly enhanced lung tumor multiplicity compared to low dose urethan treatment alone. No increase in tumor multiplicity was found in animals treated with fission neutrons ( <50 rads) alone or fission neutrons followed by weekly BHT treatment. Mice given urethan (100 mg/kg) followed two weeks later by fission neutron irradiation developed a significantly increased pulmonary tumorigenesis over untreated controls. This increase, however, was apparently due to urethan, as the tumor multiplicity of the combined treatment groups was similar to urethan treatment alone.

Following the first of a series of weekly BHT treatments significant cell proliferation, indirectly detected by the incorporation of radioactive thymidine into pulmonary DNA, occurred in both BALB/c and Swiss Webster mice. Significant cell proliferation, however, did not occur following further weekly BHT administration, but did again following BHT treatment when an interval of at least two weeks elapsed between injections of the chemical.

This thesis, therefore, showed that BHT significantly enhanced the lung tumorigenic effects of high doses of urethan, but not of low doses of the same chemical or of another carcinogen, namely fission Neutrons. Second, a treatment combination of two carcinogens revealed that fission neutrons at low doses did not influence the tumorigenic effects of urethan. Finally, the lack of significant cell proliferation in the murine lung reported in this study following further weekly BHT administrations suggests that BHT enhancement of murine pulmonary tumor development is not entirely related to its induction of lung cell proliferation.

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