Structure-activity relationship (SAR) models are recognized as powerful tools to predict the toxicologic potential of new or untested chemicals and also provide insight into possible mechanisms of toxicity. Models have been based on physicochemical attributes and structural features of chemicals. We describe herein the development of a new SAR modeling algorithm called cat-SAR that is capable of analyzing and predicting chemical activity from divergent biological response data. The cat-SAR program develops chemical fragment-based SAR models from categorical biological response data (e.g. toxicologically active and inactive compounds). The database selected for model development was a published set of chemicals documented to cause respiratory hypersensitivity in humans. Two models were generated that differed only in that one model included explicate hydrogen containing fragments. The predictive abilities of the models were tested using leave-one-out cross-validation tests. One model had a sensitivity of 0.94 and specificity of 0.87 yielding an overall correct prediction of 91%. The second model had a sensitivity of 0.89, specificity of 0.95 and overall correct prediction of 92%. The demonstrated predictive capabilities of the cat-SAR approach, together with its modeling flexibility and design transparency, suggest the potential for its widespread applicability to toxicity prediction and for deriving mechanistic insight into toxicologic effects.

Structure-activity relationship (SAR) models are powerful tools to investigate the mechanisms of action of chemical carcinogens and to predict the potential carcinogenicity of untested compounds. We describe here the application of the cat-SAR (categorical-SAR) program to two learning sets of rat mammary carcinogens. One set of developed models was based on a comparison of rat mammary carcinogens to rat noncarcinogens (MC-NC), and the second set compared rat mammary carcinogens to rat nonmammary carcinogens (MC-NMC). On the basis of a leave-one-out validation, the best rat MC-NC model achieved a concordance between experimental and predicted values of 84%, a sensitivity of 79%, and a specificity of 89%. Likewise, the best rat MC-MNC model achieved a concordance of 78%, a sensitivity of 82%, and a specificity of 74%. The MC-NMC model was based on a learning set that contained carcinogens in both the active (i.e., mammary carcinogens) and the inactive (i.e., carcinogens to sites other than the mammary gland) categories and was able to distinguish between these different types of carcinogens (i.e., tissue specific), not simply between carcinogens and noncarcinogens. On the basis of a structural comparison between this model and one for Salmonella mutagens, there was, as expected, a significant relationship between the two phenomena since a high proportion of breast carcinogens are Salmonella mutagens. However, when analyzing the specific structural features derived from the MC-NC learning set, a dichotomy was observed between fragments associated with mammary carcinogenesis and mutagenicity and others that were associated with estrogenic activity. Overall, these findings suggest that the MC-NC and MC-NMC models are able to identify structural attributes that may in part address the question of "why do some carcinogens cause breast cancer", which is a different question than "why do some chemicals cause cancer".

An automated gas‐chromatographic measurement of carbon dioxide is described and its application to a biodegradation screening test procedure is demonstrated. The biodegradation test system consists of 20‐ml glass vials containing aqueous solutions of a test chemical and an acclimated microbial inoculum. The vials and their contents are sealed with rubber septa. At specified time intervals, the contents of selected vials are acidified. Subsequent automated headspace determination of carbon dioxide provides a measure of cumulative biological degradation. To demonstrate the validity of the overall test procedure, the biodegradabilities of eight organic compounds were measured: aniline, benzaldehyde, ethylenediaminetetraacetic acid, ethylene glycol, linear alkylbenzene sulfonate, nitrilotriacetic acid, p‐nitrophenol and N‐methylaniline. Biological degradation was also monitored by measuring residual test chemical concentrations. There was excellent internal consistency of results by comparison of carbon dioxide evolution values with specific chemical analyses. Both the results of carbon dioxide measurements and specific chemical analyses are discussed in relation to literature values derived from similar screening test procedures. It is concluded from this study that automated headspace determination of carbon dioxide has several advantages over existing test methods. It is further concluded that application of this headspace procedure in the screening test described provides an accurate, albeit conservative, estimate of biodegradability, with positive results indicating a low potential for environmental persistence.

Results from biochemical analyses for a series of 20 butitaxel analogues, paclitaxel and docetaxel were used to build two- and three-dimensional quantitative structure-activity relationship (QSAR) models in order to investigate the properties associated with microtubule assembly and stabilization. A comparative molecular field analysis (CoMFA) model was built using steric and electrostatic fields. The CoMFA model yielded an r2 of 0.943 and a cross-validated r2 (i.e. q2) of 0.376. Hologram quantitative structure-activity relationship (HQSAR) modeling of these same data generated an r2 of 0.919 and a q2 of 0.471. Contour maps used to visualize the steric and electrostatic contributions associated with activity or lack thereof were, as expected, localized to the varied position of the taxane system. Each analogue was docked successfully into a model of beta-tubulin derived from previously determined cryoelectron microscopy analyses of the tubulin alpha/beta heterodimer. All analogues superimposed well with paclitaxel bound to the protein, as well as with each other. Defining the variable region of each structure as the ligand and docking it separately into the paclitaxel site revealed a modest correlation (r2 = 0.53) between activity and docking energy of all the compounds in the dataset. When only the butitaxel derivatives were considered, the correlation increased to 0.61. The mathematical models derived here provide information for the future development of taxanes.