Model toxicant effects

To acquire an overview of methods and examples of some pitfalls in modeling log P, log S, and the toxic effects of compounds... 

Gas dispersion models provided the toxic effects of chemical releases, fire, or unconfined vapor cloud explosion. 

In five pilot plants that can be used to simulate the route of anionic surfactants from the consumer via the effluent purification plant to the receiving water, possible toxic effects of residual surfactant content and breakdown products of the secondary alkanesulfonates were investigated [102]. As indicators of the effects on living organisms of the effluent in the receiving water, flora and fauna that are frequently encountered in the p-mesosaprobic zone were used as models. The embryo-larval test was also employed as an additional method for the detection of toxic compounds in the water. 

Two main hazards associated with chemicals are toxicity and flammability. Toxicity measurements in model species and their interpretation are largely the province of life scientists. Chemical engineers can provide assistance in helping life scientists extrapolate their resrrlts in the assessment of chemical hazards. Chemical engineers have the theoretical tools to make important contributions to modehng the transport and transformation of chemical species in the body—from the entry of species into the body to their action at the rrltimate site where they exert their toxic effect. Chemical engineers are also more likely than life scientists to appreciate... 

Some OPs are prime examples of pollutants that are highly toxic but of low persistence, and serve as useful models for other compounds of that ilk that have been less well investigated. Because of their limited persistence, toxic effects are expected to be localized and of limited duration. As the compounds degrade quickly in tissues. 

In summary, preliminary results from two animal models (rabbit and mouse) indicate that poly(N-palmitoylhydroxyproline ester) elicits a very mild, local tissue response that compares favorably with the responses observed for established biomaterials such as medical grade stainless steel or poly(lactic acid)/poly(glycolic acid) implants. At this point, additional assays need to be performed to evaluate possible allergic responses, as well as systemic toxic effects, carcinogenic, teratogenic, or mutagenic activity, and adaptive responses. 

For a number of liposome preparations—both injectables and locally administered products—the therapeutic advantages over existing formulations have been proven in animal models clinical trials with liposome preparations are now under way. So far, clinical studies showed no significant toxic effects which could be ascribed to the lipid components of the liposomes used. 

Once candidate molecules have been selected, there is an increased possibility for more in-depth in silico studies for toxic effects. These could, for instance, take the form of attempts to design out toxicities from a fundamental point of view, or may involve de novo modeling efforts. For instance, just as drug activity is optimized by QSAR, toxicity could also be minimized. 

A QSAR for which the standard error of each descriptor is given concerns the bradycardic effect of a series of tetraalkylbispidines [47]. The QSAR models the selectivity between the desired bradycardic effect and the adverse contractile effect. It is important, in assessing and modeling drug toxicity, that the toxic effect is assessed relative to the desired effect as described above. The QSAR developed for the selectivity of the tetraalkylbispidines was ... 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Hoffer BJ, Olson L, Palmer MR. 1987. Toxic effects of lead in the developing nervous system Inoculo experimental models. Environ Health Perspect 74 169-175. 

Systemic targeting of pDNA and siRNA polyplexes has been demonstrated in several animal models. In continuation of the work with localized antiproliferative and immunostimulatory poly(I C) RNA, intravenous systemic delivery of EGER-targeted PEG-modified polyplexes were successfully used for human carcinoma treatment in mice [225]. The therapeutic effect was most pronounced when intravenous delivery of poly(I C) polyplexes was followed by intraperitoneal injection of peripheral blood mononuclear cells [226]. This induced the complete cure of SCID mice with pre-established disseminated EGFR-overexpressing tumors, without adverse toxic effects. Due to the chemokines produced by the internalized poly (I C) in the tumor cells, the immune cells home to the tumors of the treated animal and contribute to the tumor destruction. 

The toxic effects model uses concentration-time profiles from the respiratory and skin protection models as input to estimate casualty probabilities. Two approaches are available a simple linear dose-effect model as incorporated in RAP and a more elaborate non-linear response model, based on the Toxic Load approach. The latter provides a better description of toxic effects for agents that show significant deviations of simple Haber s law behaviour (i.e. toxic responses only depend on the concentration-time product and not on each quantity separately). 

Toxic effects of expositions are calculated for a variety of exposures and effect combinations, assuming a probabilistic dose-effect relationship. Lethal and incapacitating responses (e.g. respiratory effects, topical skin effects or incapacitating eye effects) of varying degrees of severity are addressed. The model also distinguishes between effects resulting from vapour exposure and from exposures to liquid droplets. These primary effect probabilities are subsequently combined to afford overall casualty probabilities for lethality, severe incapacitation and incapacitation due to topical eye effects. 

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