Genotoxicity chemistry

ACD/Tox Suite is a collection of software modules that predict probabilities for basic toxicity endpoints. Predictions are made from chemical structure and based upon large validated databases and QSAR models, in combination with expert knowledge of organic chemistry and toxicology. ToxSuite modules for Acute Toxicity, Genotoxicity, Skin Irritation, and Aquatic Toxicity have been used. 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. 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 values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

The data base for HCFC-141b is extensive and contains studies with human subjects as well as several mammalian species. The study with human subjects was well conducted and addressed clinical symptoms, respiratory effects, cardiotoxicity, hematology and clinical chemistry effects, and pharmacokinetics. The study with humans established a no-effect level (AEGL-1) that may be conservative, because a lowest-observed-effect level was not attained. The AEGL-1 of 1,000 ppm is supported by the animal data, which show an absence of effects at concentrations that are higher by a factor of 10. Animal studies addressed both acute and chronic exposure durations as well as neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitiza... 

Jiigerstad, M., Skog, K., Arvidsson, P. and Solyakov, A. (1998). Chemistry, formation and occurrence of genotoxic heterocyclic amines identified in model systems and cooked foods, Z. Lebensm. Unters. Forsch A, 207, 419—427. 

While coordination chemistry of hydroxamic acids has been studied extensively (particularly with Cu(II), Zn(n), Fe(III), Co(III), and Cr(III) ions) there have been only few reports in the literature on the formation of Cr(V) complexes of these ligands. The current interest in coordination chemistry of Cr(V) arises mainly from the proposed crucial role of reactive Cr(V) intermediates in Cr(VI)-induced genotoxicity and carcinogenicity . ... 

Hartmann A., A.C. Alder, T. Roller, and R.W. Widmer (1998a). Identification of fluoroquinolone antibiotics as the main soruce of umuc genotoxicity in native hospital wastewater. Environmental Toxicology and Chemistry 17 383-393. 

It is now well established that surface defects and imperfections determine the chemical reactivity of solid surfaces, making defect engineering an important branch of modern solid state chemistry and physics. However, this reactivity can in turn be responsible for the toxicity of different silicate dusts. A number of interesting studies have appeared which correlate the surface properties of different silicates to their genotoxicity and potential health hazards.190 192 In particular the potential of a surface to generate and release free radicals via the... 

Richeson CE, Mulder P, Bowry VW, Ingold KU (1998) The complex chemistry of peroxynitrite decomposition new insights. J Am Chem Soc 120 7211-7219 Rodrigues GS, MadkourSA, Weinstein LH (1996) Genotoxic activity of ozone in tradescantia. Environ Exp Bot 36 45-50... 

Bianchi V, Levis AG. 1985. Mechanisms of chromium genotoxicity. In Merian E, Frei RW, Hardi W et al., eds. Carcinogenic and mutagenic metal compounds Environmental and analytical chemistry and biological effects. London Gordon and Breach Science Publishers, 269-294. 

De Flora S, Wetterhahn KE. 1989. Mechanisms of chromium metabolism and genotoxicity. Life Chemistry Reports. 7 169-244. 

Z. E. Gagnon, C. Newkirk, S. Hicks, Impact of platinum group metals on the environment A toxicological, genotoxic and analytical chemistry study, J. Environ. Sci. Health Part A, 41 (2006), 397D414. 

Snyder RD, Pearl GS, Mandakas G, Choy WN, Goodsaid F, Rosenblum IY (2004) Assessment of the sensitivity of the computational programs DEREK, TOPKAT and MCASE in the prediction of the genotoxicity of pharmaceutical molecules. Environ Mol Mutagen 43 143-158 Todeschini R, Consonni V (2000) Handbook of Molecular Descriptors. In the series of Methods and Principles in Medicinal Chemistry, Vol. 11. Wiley VCH Weinheim... 

To assess the success of bioremediation, the stability of PAH residues bound to soil particles must also be determined (Eschenbach et al., 1998). Changes in the solution chemistry of the humic fraction of the soil (Jones Tiller, 1999) may release PAHs either as the free hydrocarbons or as metabolites. Little is known about the impact of bioremediation on the mutagenicity and genotoxicity of most PAHs (Malachova, 1999). 

Atienzar, F.A., Conradi, M., Evenden, A.J., Jha, A.N. and Depledge, M.H. (1999) Qualitative assessment of genotoxicity using random amplified polymorphic DNA comparison of genomic template stability with key fitness parameters in Daphnia magna exposed to benzo[a]pyrene. Environmental Toxicology and Chemistry, 18, 2275-2282. 

However, what is true for a carcinogenicity study may be wrong for an analytical chemistry study what can be applied to an in vitro genotoxicity study could be completely out of question for a field study. Therefore, it would seem to be important to interpret these definitions flexibly and with well considered regard to the study type and the experimental activities connected with it. Thus, it would seem that in order to arrive at a clear situation, the Standard Operating Procedures for the conduct of the various study types, or at least the study plan, should address these issues and define the dates in a concrete way. 

I The synthesis of often complex chemical structures that bear in themselves sufficient specificity and selectivity for a pharmacological action is only manageable via reactive steps of chemistry. Such reactions often involve or result in electrophilic intermediates, which may possess genotoxic activity. It is a dream of every chemist to create reaction conditions that fully create a product from its educts. This dream can hardly be put into reality. 

The pressures on Process Chemistry are mounting rapidly Industry seeks rapid entry into the clinic, postponing development spend until proof of concept, then rapid conunerciaUzation once benefit is established. External and internal trends look for more complete data, deep process understanding, absolute control of genotoxic impurities, establishing of design space and quality by design, and real time control of the process via on line sensors. 

O Hagan, S., and A. Menzel. 2003. A subchronic rat toxicity study and in vitro genotoxicity studies with a conjugated hnoleic product. Food Chemistry and Toxicology 41 1749-1760. 

---