Indirect genotoxic effects

As many metal compounds exert a rather weak mutagenic effect, their carcinogenic action cannot be explained by this effect alone. However, in several cases, indirect genotoxic effects - namely synergism with known mutagens - may be one reason for their tumorigenicity. 

There is indirect evidence that 3,3 -dichlorobenzidine or metabolites can cross the placenta. A study that examined the potential genotoxic effects of 3,3 -dichlorobenzidine found that oral administration of 3,3 -dichlorobenzidine to pregnant rats induced micronuclei in the liver of fetuses (Cihak and Vontorkova 1967). There is no information regarding accumulation of 3,3 -dichlorobenzidine or metabolites in breast milk or its potential transfer to offspring via breast milk. 

The available data indicate that creosote is an indirect mutagen and induces gene mutation in bacteria and mouse lymphoma cells. However, a substantial database exists on the genotoxic effects of the PAHs found in the creosote mixture. More in vivo assays using human tissues with coal tar creosote, coal tar, coal tar pitch, and coal tar pitch volatiles, or specific components of these mixtures, would be useful to more completely characterize the genotoxic potential of these mixtures. 

This theory most directly applies to carcinogenesis induced by Ni(ll), since Ni(ll) binds preferentially to histones (proteins of the cell nucleus) rather than to DNA (354—373). The Ni -protein complexes can then catalyze oxidative DNA damage by ROS (149). Catalytic rather than stoichiometric action of Ni(ll) complexes in oxidative DNA damage is consistent with significant genotoxic effects caused by small concentrations of the metal ion (350-368). Indirect (i.e., ROS mediated) oxidative mechanisms are also considered among the major causes of Cd(ll) and Cr(Vl) induced carcinogenicity (351, 353). 

Zebrafish Brachydanio/Danio rerio) embryos can be produced in large numbers and carry sufficient nutrients within the egg sack to allow development within micro plate volumes [52, 53]. Mutation frequency has been estimated indirectly using transgenic fish [54[ and UDS, comet, MNT and alkaline filter elution methods have been used effectively [55]. At present, there has been insufficient study of the model to understand predictivity of mammalian genotoxicity, and none of the methods has been demonstrated at throughputs sufficient for hit and lead screening. 

When DNA damage occurs, a number of repair systems can increase the cell s probability of survival. Several assays for genotoxicity rely on indirect measurement of the effects of these repair systems. TWo assays (the B. subtilis rec assay and the E. ooli DNA polymerase assay) measure reduction in the survival of chemically treated cells that lack at least one DNA-repair enzyme, compared with cells that have an intact repair system.198 373... 

Due to experimental data, an indirect rather than direct genotoxic carcinogenic effect of lead has been indicated (Silbergeld et al. 2000). Thus, there may be a threshold for the carcinogenic effects in man that would argue in favor of setting health-based occupational exposure limits for lead. 

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