Dose-response relationships genotoxic effects

An additional assessment factor, of up to 10, has been apphed in some cases where the NOAEL has been derived for a critical effect, which is considered as a severe and irreversible effect, such as teratogenicity or non-genotoxic carcinogenicity, especially if associated with a shallow dose-response relationship. The principal rationale for an additional factor for nature of toxicity has been to provide a greater margin between the exposure of any particularly susceptible humans and the dose-response curve for such toxicity in experimental animals. 

However, some of the studies were limited by using 2,3,7,8-TCDD concentrations in excess of its solubility in water. Only two early studies reported positive results (Hussain et al. 1972 Seiler 1973). However, the results were limited by failure to demonstrate a dose-response relationship and by low bacterial survival rates. In addition, 2,3,7,8-TCDD exposure induced reverse mutations in Escherichia coli (Hussain et al. 1972) and in Saccharomyces cerevisiae (Bronzetti et al. 1983). The conflicting data obtained in the above studies may result from technical difficulties in testing 2,3,7,8-TCDD rather than from a lack of biological activity. Testing difficulties arise from an extreme insolubility of this compound and a high toxicity observed in some test systems, which would be anticipated to result in a very narrow window for effective genotoxic doses. 

Additional studies in workers with known levels of chromium exposure that control for confounding factors would be useful for defining levels at which chromosomal aberrations occur in humans exposed to chromium(VI) in the workplace. Also, better dose-response relationships would be useful for the various genotoxic and regulatory effects observed with chromium to better determine which end points are the most sensitive and dominant at exposures near environmental levels. 

Tamoxifen, 4-hydroxytamoxifen, nafoxidine, 1 P-oestradiol and ICI 164,384 were all found to protect rat liver nuclei against Fe(III)-ascorbate-dependent lipid peroxidation (Wiseman and Halliwell 1994). The order of effectiveness of these compounds was 4-hydroxytamoxifen >17P-oestradiol > nafoxidine > tamoxifen > ICI 164,384. The idea of a protection by tamoxifen against the formation of the genotoxic reactive intermediates and products of lipid peroxidation in the nuclear membrane and thus of an anticarcinogenic benefit was later questioned Carthew etal. (2001) found a clear dose-response relationship of tamoxifen-induced DNA adducts in the rat liver and the subsequent increase in the development of liver cancer, with and without phenobarbital promotion. In the absence of phenobarbital promotion there was a threshold value for of tamoxifen-induced DNA adducts (180 adducts/10 nucleotides) and the subsequent induction of liver cancer. 

Genotoxicity. Studies of miners and other populations exposed to radon and radon daughters showed an increased occurrence of chromosomal abnormalities. However, because exposure-effect relationships have not yet been established and the biological significance of these chromosomal effects is uncertain, further studies should be performed. In vitro studies using human cell lines could help determine a dose-response for exposure to radon and radon daughters and increased chromosomal abnormalities. Such relationships may be difficult to establish because of possible interactions with other substances, i.e., uranium ore dust. There are no in vivo animal data to support the observed increase in chromosomal abnormalities in human populations. Further observations in laboratory animals are needed to explain these effects. 

The database for HFC-134a is extensive it contains studies with both human subjects and animal models. Potentially sensitive populations, including patients with COPD and adult and pediatric asthmatic patients, were tested with direct inhalation of HFC-134a from metered-dose inhalers. The response of these groups was no different than that of healthy adults. The animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The metabolism of HFC-134a is well understood, and the relationship of exposure con... 

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