Modeling of toxicological effects

Hartzell, G.E. Grand, A.F. Switzer, W.G. "Modeling of Toxicological Effects of Fire Gases VII. Studies on Evaluation of Animal Models in Combustion Toxicology," J. Fire Sciences 1988, 6(6), 411-431. 

Hartzell, G.E., H.W.Stacy, W.G.Swiztzer, D.N.Priest, and S.C.Packham. 1985. Modeling of toxicological effects of fire gases 4. Intoxication of rats by carbon monoxide in the presence of an irritant. J. Fire Science. 3 263—279. 

Modelling of toxicological effects of fire gases. VI. Further studies on the toxicity of smoke-containing hydrogen chloride. J. Fire Sci. 5(6) 368-91. 

An HI 1 indicates that the mixture exceeds the TLV. A separate HI is calculated for each set of xenobiotics in a mixture that causes the same type of toxicological effect. For example, an HI would be calculated for all liver toxicants in the mixture, a separate HI would be calculated for xenobiotics that cause kidney damage, etc. Further refinement of the additivity model or development of an alternative model will require more extensive research. 

Molecular toxicology (5) fundamental understanding of microbes/metabolic pathways— Perry s Handbook for Bugs (4) models of exposure effects... 

Successful predictive models in toxicology exist - however, they are of a rather local nature. Effects considered in toxicology can be caused by different mechanisms. Efforts to get away from a class perspective to one that is more consistent regarding modes of toxic action are still a subject of ongoing research. 

Studies in rats have shown effects of lead on bone mineralization and bone growth. The effects observed in rats may be relevant to our understanding of the mechanisms for the growth deficits that have been associated with low-level in utero and childhood lead exposures. Additional studies of the effects of lead on bone metabolism in humans and in animal models would improve our understanding of the toxicological significance of lead in bone. 

USEtox calculates characterization factors for human toxicity and freshwater ecotoxicity. Assessing the toxicological effects of a chemical emitted into the environment implies a cause-effect chain that links emissions to impacts through three steps environmental fate, exposure, and effects. Linking these steps, a systematic framework for toxic impacts modeling based on matrix algebra was developed to some extent within the OMNIITOX project [10]. USEtox covers two spatial scales, the continental and the global scales. 

Models for determining the dose-response relationship vary based upon the type of toxicological hazard. In the dose-response for chemical carcinogens, it is frequently assumed that no threshold level of exposure (an exposure below which no effects would occur) exists, and, therefore, any level of exposure leads to some finite level of risk. As a practical matter, cancer risks of below one excess cancer per million members of the population exposed (1 x 10 ), when calculated using conservative (risk exaggerating) methods, are considered to represent a reasonable certainty of no harm (Winter and Francis, 1997). 

Investigational New Drug (IND) application. The IND petition requires full disclosure of where and how the NME is manufactured and controlled for quality and stability. It also contains proposed analytical methods, pharmacology and toxicology data, and evidence of desired effects in disease models. The application lists proposed chnical investigators and contains complete human subject protocols. Under current regulations the FDA must provide a written response to the sponsor within 30 days after submission. The lack of a timely response is tacit approval for the sponsor to proceed to the clinic. 

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