Direct genotoxic effects

Essential for assessment of the impact of pollutants at population level is the distinction that is made between somatic and germ-line mutations. Mutations in somatic cells may (among other effects) induce neoplasia, but because they do not occur in cells that give rise to gametes the mutation will not be passed on to the next generations. 

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In animal studies, significant increases in adenocarcinomas and squamous cell carcinomas of the lung have occurred in rats after inhalation or intratracheal instillation in rats, but not in hamsters. Increasing in vitro and in vivo evidence suggests that the rat lung tumor response to crystalline silica exposure is a result of marked and persistent inflammation and epithelial proliferation. However, other pathways such as a role for crystalline silica surfacegenerated oxidants or a direct genotoxic effect cannot be ruled out. 

It has been postulated that sulfuric acid may produce tumors by direct genotoxic effects of lowered pH or may promote carcinogenesis by inducing chronic tissue irritation. lARC has determined that there is sufficient evidence that occupational exposure to strong inorganic acid mists containing sulfuric acid is carcinogenic to humans. ... 

Other critical endpoints of lead toxicity include toxicity to the nervous system and the kidneys. Based on experimental findings, it seems plausible that lead has no direct genotoxic effects, which argues for establishing a practical threshold limit value for lead toxicity. Thus, an occupational exposure limit (OEL) based on avoiding functional CNS alterations is expected also to protect versus toxicity to the peripheral nervous system and the kidney, including possibly the development of renal cancer. 

Such low-dose extrapolation is typically only conducted for tumors believed to be caused by a genotoxic effect, which some, but by no means all, scientists believe have no threshold. For other types of tumors and for many nonneoplastic endpoints a threshold cannot be estimated directly from data at a limited number of dose levels a no observed effect level (NOEL) can be estimated by finding the highest dose level at which there is no significant increase in effects. 

Mechanistic information is most relevant for the evaluation and classification of carcinogens. As indicated below, a carcinogenic effect, which is induced by a specific mechanism that does not involve direct genotoxicity, such as hormonal deregulation, immune suppression, cytotoxicity, the detailed search for the underlying... 

A dose-and duration-related decrease in splenic lymphocyte viability (as measured by H-TdR incorporation) and immune response (as measured by IgM secretion) was observed in the absence of S9 activation. Addition of S9 enhanced this effect after acute-duration exposure. However, there was very little formation of benzo[a]pyrene/DNA adducts at benzo[a]pyrene concentrations of 1-200 pmol in the splenic lymphocytes this lack of effect was accompanied by a very low level of benzo[a]pyrene metabolism to DNA-adducting metabolites. Benzo[a]pyrene/DNA adducts were measured in liver and lung however, in the in v/vo experiment. This led the authors to suggest that benzo[a]pyrene-induced immunotoxicity as expressed by splenic lymphocytes was the result of a cytotoxic effect that was mediated, in part, by a genotoxic mechanism involving the formation of benzo[a]pyrene/DNA adducts remote from the spleen and a direct cytotoxic effect not requiring activation of benzo[a]pyrene to the reactive intermediate. 

Direct genotoxic and mitogenic effects of asbestos, as well as of some manmade fiber s, have been detected in in vitro assays [e.g., (Dopp et al. 1997 Osgood 1994 Wang et al. 1999)]. The physical presence of phagocytosized fibers can interfere with chromosome segregation during mitosis and result in aneuploidy and... 

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