Sister chromatid exchange / editor, Avery A. Sandberg.

Date:
[1982], ©1982
Catalogue details

Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Credit: Sister chromatid exchange / editor, Avery A. Sandberg. Source: Wellcome Collection.

    77/736 (page 55)
    Induction of Micronuclei / 55 significantly weaker than expected when hnear interpolation was performed between high doses and the control values. Supported by linear alkylation data [21] and data from combined treatments with caffeine, we have suggested [20,21] that a non-linear dose response induced by MMS or ethyl methanesul- phonate (EMS) is due to error-free repair at low doses. At higher doses this function is saturated or lost, switching to a more error-prone repair process. It is quite obvious that studies on non-linear dose réponse at low doses will play an important role when it comes to risk estimates of environmental chemicals. The error-free removal of different alkyl products from DNA has been shown to differ both between different cell lines in vitro [42,43] and cell types in vivo [44,45]. This implies that different organs in the intact body may be exposed to different risks of genetic damage leading to cancer. THE DOSE RELATION WITH COMBINED TREATMENTS Environmental exposure of chemicals is most often in the form of complex mixtures or a combination of several single chemicals. Therefore, studies with combined treatments are most important. In this context, synergistic, antago¬ nistic, and co-mutagenic effects could be studied with great advantage in vivo using micronucleus induction. For instance, we recorded an antagonistic action of phénobarbital (PB) on the clastogenic effect of MMS, which was due to an enhanced metabolic excre¬ tion [21]. In most cases, enzyme inducers hke PB are connected with enhance¬ ment of chemical mutagenicity, but in this case the inducing effect in vivo resulted in a deactivation of the mutagenic agent. In the same connection [21], we also found that the combination of caf¬ feine and MMS gave rise to an enhanced response with micronuclei at a high dose of MMS but not at a low dose. Since caffeine has been shown to interact with DNA during replication repair [47], it was suggested that the enhanced re¬ sponse in micronuclei at high doses but not at low doses could be due to a co- mutagenic action of caffeine, which was not found in combination with X-rays [20]. The alkylation of the bone marrow was not influenced by the caf¬ feine treatment, indicating that the metabolism of MMS was unaffected by caffeine (Fig. 3). The enhancing effect of caffeine was also seen in combina¬ tion with the pro-mutagen dimethylnitrosamine (DMN), but in this case also at low doses (Fig. 3). Seiler demonstrated in vivo nitrosation of ethylenethiourea (ETU) by intra¬ peritoneal injection of mice with ETU and simultaneous feeding with sodium nitrite. He found [46] that the number of micronucleated erythrocytes in the bone marrow was enhanced as compared to treatment with ETU alone.