Potential for genotoxicity

Ennever, F.K., Rosenkranz, H.S. (1987). Evaluating the potential for genotoxic carcinogenicity of methyl isocyanate. Toxicol. Appl. Pharmacol. 91 502-5. 

Because uranium is a predominantly alpha-emitting radionuclide, current theories on gene mutation and chromosomal aberrations by high-LET alpha radiation suggest a potential for genotoxicity from uranium s radioactivity (BEIR 1980,1988,1990 Leach et al. 1970 Morris et al. 1990 Muller et al. 1967 Otake and Schull 1984 Sanders 1986 Stokinger et al. 1953 UNSCEAR 1982,1986,1988) (see Appendix D for a review of the hazards associated with radionuclide exposure). Other genotoxicity studies are discussed in Section 2.5. 

Muller, L., et al., A rationale for determiiung, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regulatory Toxicology and Pharmacology 44, 198-211, 2006. 

The potential for genotoxicity may also be evaluated in the mouse micronucleus test and in a host-mediated assay in the mouse. The former procedure is a measure of the clastogenic activity of the compound in erythrocyte stem cells (Heddle, 1973 Jenssen et al., 1974), and the latter is similar to the in vitro Ames test, except that exposure of the tester organisms occurs in an animal that has been dosed with the compound to be tested. Etretinate is negative in both tests (Hummler and Schiipbach, 1981). 

Disulfoton has been tested for genotoxicity in a variety of assays with mostly negative results however, the few positive results indicate genotoxic potential. Carcinogenicity was not observed in Beagle dogs, rats, or mice fed disulfoton for 2-years. 

While many of the studies on genotoxicity of disulfoton were negative, the positive results indicate a potential for mutagenic and clastogenic effects in humans exposed to disulfoton. 

Humans are susceptible to the acute toxic effects of 1,2-dibromoethane from various routes of exposure. Except for adverse reproductive effects in men after occupational exposure, chronic effects of 1,2-dibromoethane exposure have not been documented in humans. Based on data derived from animal studies, mechanisms of action of 1,2-dibromoethane at a cellular level, toxicokinetics, and genotoxicity tests, there is a potential for certain adverse health effects in humans exposed chronically to low environmental levels of 1,2-dibromoethane that could exist near hazardous waste sites or areas of former agricultural use. 

Genotoxicity. A limited number of in vitro assays with bacteria and mammalian cells and an in vivo assay with mice indicate that 1, 2-diphenylhydrazine is genotoxic. Replicate assays have not been conducted with the exception of assays with Salmonella, and mutation in mammalian systems and genotoxicity in human cells have not been evaluated. Additional studies, particularly involving mammalian systems and providing information on the potential for heritable mutations, would add to the database on genotoxicity and validate available information. 

The UDS assay is used to measure the repair that follows DNA damage. However, the relevance of UDS to human health is not known. While results were positive in two assay in animals, sufficient data are not available from more predictive indicator assays to adequately characterize the genotoxic potential for 3,3 -dichlorobenzidine in humans. Other genotoxicity studies are discussed in Section 2.5. 

The term genotoxicity is a broader term and refers to potentially harmful effects on genetic material, which are not necessarily associated with mutagenicity. Thus, tests for genotoxicity include tests, which provide an indication of induced damage to DNA (but not direct evidence of mutation) via effects such as unscheduled DNA synthesis (UDS), sister chromatid exchange (SCE), DNA strand breaks, DNA adduct formation or mitotic recombination, as well as tests for mutagenicity. ... 

The aims of testing for genotoxicity are, therefore, to assess the potential of a substance to be a genotoxic carcinogen, or to cause heritable damage in humans, which can be manifested as impaired male and/or female fertility, or adverse effects on fetal or postnatal development. 

There were no indications of genotoxic potential for 2,4-D acid, or any of its derivatives, in bacterial assays, in unscheduled DNA synthesis assay, or in mouse bone marrow micronucleus tests. ... 

In one animal study, a significant increase in lung tumors was observed in female mice exposed by inhalation. Available data indicate a genotoxic potential for sulfur dioxide. Increases in chromosome aberrations and sister chromatid exchanges have been detected in occupationally exposed workers. The lARC has determined that there is limited evidence for the carcinogenicity of sulfur dioxide in experimental animals and inadequate evidence in humans. 

---