Initiation and promotion at different ages and doses in 2200 mice. III. Linear extrapolation from high doses may underestimate low-dose tumour risks.

The dose-response relationships from the data described in Paper I were analysed. Among unpromoted animals, only doses sufficient to cause ulceration with subsequent promotion due to wound healing caused a rapid crop of tumours, so the dose-response curve exhibited strong upward curvature. Among promoted animals, the response of the skin to initiation appeared to have been nearly saturated by all DMBA doses tested, so that a 30-fold decrease in dose produced only a 3-fold decrease in effect. The dose-response relationship thus exhibited strong downward curvature. Among promoted animals, estimation of the risks associated with very low doses of carcinogen by linear extrapolation through the origin from the effects of larger doses (which is often assumed to be conservative) would under-estimate the true risks by 10-fold or more. Our results emphasize that whereas linear interpolation from the results of high doses may be reasonable for data on the effects of continuous treatment with non-toxic dose levels of carcinogen, it may be misleading when extrapolating, as here, from the effects of single large doses

Initiation and promotion at different ages and doses in 2200 mice. II. Decrease in promotion by TPA with ageing.

Using the data described in Paper I, we compare the effects of the same treatment timings and doses given at different ages. Initiation with DMBA at 68 weeks of age, followed 3 weeks later by TPA, has a significantly (P less than 0.0001) less rapid effect on subsequent tumour incidence than does initiation at 8 or at 48 weeks of age, followed 3 weeks later by TPA. We suggested that this is chiefly due not to changes in the numbers of cells initiated by DMBA, but rather to a decrease in the promotional efficacy of TPA in ageing mice

Morphological, immunohistochemical and ultrastrucmturaclh anges in dimenthylnimtrosamine induced liver injury. Effect of malotilate

Summary. Dimethylnitrosarnine (DMN) induced liver injurq in rats with cell necrosis, inflammation, hemorrhages, increased collagen type 111 synthesis and basement membrane component laminin and collagen IV localization in perisinusoidal sites. Malotilate ingestion during DMN treatment abolished inflammation and decreased interstitial collagen deposits and vascularization. 1 t affected clearly less DMN-caused hemorrhage. When malotilate treatment was started subsequently to development of DMN-injury, it also caused decrease in inflammation, though less, as well as in collagen 111, BM and fibronectin deposits. We suggest that the mode of the malotilate effect on reducing the DMN-induced fibrosis of the liver is via inhibiting the inflammation. decreased fibronectin deposition possibly also playing a role