Thymomas induced by simple alkylating agents in C57BL/Cbi mice: kinetics of the dose response

Specific-pathogen-free inbred C57BL/Cbi mice (adult virgin females) were given single sublethal doses of N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea and were studied for a lifetime for the development of thymomas. A fatal lymphocytic lymphoma with a "starry sky" pattern due to the presence of macrophages was induced in the thymuses of treated mice within 250 days of treatment. Control and low-dose treatment groups had up to 70% incidence of a histiocytic lymphoma that was usually primary in mesenteric lymph nodes and nearly always occurred later than 250 days after treatment. A "one-hit" linear relationship existed between the time of appearance of induced thymic lymphomas and the log fraction of non-tumor-bearing mice. The absolute latency period of these tumors was constant and independent of dose. The effect of dose was an exponential increase of the total incidence of induced thymic lymphomas. By mathematical analysis, the best estimate of the exponent from the results was 2 or 3, indicating that the development of these induced tumors may be produced by 2 or 3 "events" in the target cell. Possible candidates for these events are premutagenic alkylation of DNA, inactivation of DNA repair, oncovirus activation, regenerative hyperplasia, development of trisomy No 15, and inhibited immunosurveillance.