Compound-based toxicity

Toxicological Information. The toxicity of the higher olefins is considered to be virtually the same as that of the homologous paraffin compounds. Based on this analogy, the suggested maximum allowable concentration in air is 500 ppm. Animal toxicity studies for hexene, octene, decene, and dodecene have shown Httle or no toxic effect except under severe inhalation conditions. The inhalation LD q for 1-hexene is 33,400 ppm for these olefins both LD q (oral) and LD q (dermal) are >10 g/kg. 

Although many of the aromatic compounds based on benzene have pleasant odors, they are usually toxic, and some are carcinogenic. Volatile aromatic hydrocarbons are highly flammable and burn with a luminous, sooty flame. The effects of molecular size (in simple arenes as well as in substituted aromatics) and of molecular symmetry (e.g., xylene isomers) are noticeable in physical properties [48, p. 212 49, p. 375 50, p. 41]. Since the hybrid bonds of benzene rings are as stable as the single bonds in alkanes, aromatic compounds can participate in chemical reactions without disrupting the ring structure. 

The impetus for this flurry of activity has been the recognized need for cost-effective tools, based on sound scientific principles (i.e., state-of-the-art), to assist in the performance of exposure assessments for new and existing chemical compounds and toxic wastes. 

In Figs. 8-10 one can see that the distribution of average potency, selectivity, and average efficacy/toxicity ratio is exactly as one would desire. One can conclude that list 1, the highest priority list, contains the most efficacious compounds based on the degree of testing performed so far. 

Abraham, V.C., Towne, D.L., Waring, J.F., Warrior, U. and Burns, D.J. (2008) Application of a high-content multiparameter cytotoxidty assay to prioritize compounds based on toxicity potential in humans. Journal of Biomolecular Screening, 13, 527-537. 

For most of these compounds more toxicity information is included in the Registry of Toxic Effects of Chemical Substances (RTECS) data base.8 also for a large number of compounds in other tables. Further acid derivatives have been described.107 h Unless otherwise stated. ipr. Oral. 

The search for relationships among the dynamic and equilibrium properties of related series of compounds has been a paradigm of chemists for many years. The discovery of such unifying principles and predictive relationships has practical benefits. Numerous relationships exist among the structural characteristics, physicochemical properties, and/or biological qualities of classes of related compounds. Perhaps the best-known attribute relationships are the correlations between reaction rate constants and equilibrium constants for related reactions commonly known as linear tree-energy relationships (LFERs). The LFER concept led to the broader concepts of QSARs, which seek to predict the environmental fate of related compounds based on correlations between their bioactivity or physicochemical properties and structural features. For example, therapeutic response, environmental fate, and toxicity of organic compounds have been correlated with... 

Cyclization reactions of GGPP mediated by car-bocation formation, plus the potential for Wagner -Meerwein rearrangements, will allow many structural variants of diterpenoids to be produced. The toxic principle taxine from common yew (Taxus baccata Taxaceae) has been shown to be a mixture of at least eleven compounds based on the taxadiene skeleton which can be readily rationalized as in Figure 5.43, employing the same mechanistic principles as seen with mono- and sesqui-terpenes. 

A toxicity screening in late 1985 compared six compounds, including BY 319 and pantoprazole. The results for pantoprazole were very promising. In a four-week toxicity study in early 1986, pantoprazole displayed the most promising data from the series of dimethoxy pyridine compounds. Based on the various animal models, pantoprazole was found to be approximately equipotent to omeprazole [37b], much more stable at neutral and weakly acidic pH, and displayed higher selectivity in enzyme models (pantoprazole is more selective to the H+/K+- as opposed to the Na+/K+-ATPase than omeprazole). Pantoprazole was not the only possible candidate compound at this time. Smith Kline French also had a potential candidate compound, SK F95601 (see Fig. 3.7), which was a 4-amino-3-chloropyridine compound [38]. 

Common unspecific mode of action of all organic compounds has been taken up in quantitative structure-activity relationships (QSARs see Chapter 5) as the concept of baseline toxicity and in toxicokinetics as the body burden concept (see Chapter 2). Baseline toxicity refers to the idea that a minimum toxicity expectation may be formulated for any given organic compound based on considerations of a compound s partition properties between hydrophilic and lipophilic chemicals (e.g., between water and octanol). Commonly, this is expressed in terms of the octanol-water partition coefficient (K0,J of a chemical. The partition coefficient allows estimations of a local concentration or body burden for each individual chemical in the mixture. Assuming that this produces the same toxic effect (disturbances of cell membranes), it is then possible to anticipate joint narcotic action by adding together the respective local concentrations or body burdens for each individual mixture component. 

Whole mixture approach for common mixtures. This is an option if dealing with a common, and often complex, mixture with more or less constant concentration ratios between the mixture components, for example, coke oven emissions. A reference value (e.g., PNEC) or dose-response relationship can be established for the mixture as if it were 1 (complex) compound, and a safe level can be determined like for single compounds based on toxicity data on the mixture itself or a sufficiently similar mixture. The effect data can subsequently be used in future assessments of mixtures that are identical (e.g., originating from the same source) or sufficiently similar. 

Finally, ASKA mice should provide crucial information regarding the therapeutic index. ASKA-based in-vivo studies will be able to establish mechanism and target-based efficacy and toxicity for most protein kinases. Such information should prove useful in the preclinical testing of development candidates, because it will allow distinction between mechanism (target)-based and compound (off-target)-based toxicities [35], At this point, we would like to challenge the scientific community and express our interest in the development of p38-ASKA mice, to either promote or discourage the numerous clinical trials of p38 for various indications and to clarify the associated liver toxicity upon treatment of patients with p38 inhibitors. 

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