Tests for urethane induction of germ-cell mutations and germ-cell killing in the mouse.

Urethane, a chemical that has given varied results in mutagenesis assays, was tested in the mouse specific-locus test, and its effect on germ-cell survival was explored. Altogether 32,828 offspring were observed from successive weekly matings of males exposed to the maximum tolerated i.p. dose of 1750 mg urethane/kg. The combined data rule out (at the 5% significance level) an induced mutation rate greater than 1.7 times the historical control rate. For spermatogonial stem cells alone, the multiple ruled out is 3.2, and for poststem-cell stages, 3.5. Litter sizes from successive conceptions made in any of the first 7 weeks give no indication of induced dominant lethality, confirming results of past dominant-lethal assays. That urethane (or an active metabolite) reaches germ cells is indicated by SCE induction in spermatogonia demonstrated by other investigators. Cytotoxic effects in spermatogonia are suggested by our finding of a slight reduction in numbers of certain types of spermatogonia in seminiferous tubule cross-sections and of a borderline decrease in the number of litters conceived during the 8th and 9th posttreatment weeks. The negative results for induction of gene mutations as well as clastogenic damage are at variance with Nomura's reports of dominant effects (F1 cancers and malformations) produced by urethane.

Potentiation of butylated-hydroxytoluene-induced acute lung damage by oxygen. Effects of prednisolone and indomethacin.

We have previously shown that administration of the antioxidant butylated hydroxytoluene (BHT) to mice produces lung damage that can be markedly potentiated by hyperoxia resulting in pulmonary fibrosis. In the present studies using this model, we show that: (1) in animals treated with BHT-O2, prednisolone given for 12 successive days does prevent excessive collagen accumulation provided lung collagen is measured immediately after terminating steroid therapy, whereas a rebound effect occurs later on; (2) limitation of steroid treatment to the first 6 days after acute lung injury enhances accumulation of collagen, whereas steroids given later, on Days 7 through 12, have an alleviating effect; (3) indomethacin under the conditions described is not an effective treatment.

Structure activity relationships of selected naphthalene derivatives.

Twenty-two derivatives of naphthalene were assayed under an acute static regime with biological activity being monitored as population growth of Tetrahymena pyriformis. Activity varied over one log unit. Substituent constant structure-activity analyses revealed the model, log BR = 0.282Ha + 0.352 pi + 0.692F + 0.3341Xvsub - 0.326R + 0.027, to be best and to account for 85% of the variation in log BR (BR, biological response; Ha, hydrogen acceptance; pi, hydrophobic substituent constant; F, polar electronic substituent constant, 1Xvsub, substituent molar connectivity index; R, resonance electronic substituent constant). The Ha and pi parameters are the most important, accounting for 71% of the log BR variability.

Baseline and mitomycin-C-induced sister chromatic exchanges ina melanoma and a colon tumor cell line.

Baseline and mitomycin C (MMC)-induced sister chromatid exchanges (SCEs) in two human tumor cell lines (a colon tumor and a melanoma) and in a normal fibroblast cell line were analyzed and compared. The tumor cells showed numerical and structural chromosomal abnormalities. Their baseline SCE rate was slightly, but not significantly, higher than that of the control. Each tumor cell line showed a dose-dependent increase in SCE frequency above the spontaneous level in its own specific manner. The response in the malanoma cell was consistently below that of the control, but only the response to the highest dose of MMC (10(-9) M) was significantly lower than that of the control. The response of the colon tumor cells varied with respect to that of the control. Thus, it appears that karyotypic instability in tumor cells is not necessarily associated with elevated baseline or induced SCE/chromosome rates. In addition, within each cell line dose group, the SCE frequency was proportional to the number of chromosomes. thus, the SCE/chromosome is a better expression of genetic damage than SCE/metaphase in analyses involving heteroploid cells.