Development,Characterization and Application of Predictive-Toxicology Models

Abstract

The adoption of SAR techniques for risk assessment purposes requires that the predictive performance of models be characterized and optimized. The development of such methods with respect to CASE/MULTICASE are described. Moreover the effects of size, informational content, ratio of actives/inactives in the model on predictivity must be determined.

Characterized models can provide mechanistic insights: nature of toxicophore, reactivity, receptor binding. Comparison of toxicophores among SAR models allows a determination of mechanistic overlaps (e.g., mutagenicity, toxicity, inhibition of gap junctional intercellular communication vs. carcinogenicity).

Methods have been developed to combine SAR submodels and thereby improve predictive performance.

Now that predictive toxicology methods are gaining acceptance, the development of Good Laboratory Practices is a further priority, as is the development of graduate programs in Computational Toxicology to adequately train the needed professional.     

Course of the terpolymerization of ethylene,propylene, and dicyclopentadiene. I. Single initial addition of dicyclopentadiene

Detailed studies were made of the course of the terpolymerization of ethylene, propylene, and dicyclopentadiene to form unsaturated elastomers. All the dicyclopentadiene was added at the start of a polymerization, but the monoolefins were added continuously throughout the run. Under these conditions, unsaturation of the initial polymer is fairly high but decreases steadily as the reaction progresses. From analyses of the initial samples from each run, the catalyst of VCl₄ (with Al₂Et₃Cl₃ cocatalyst), with heptane as the polymerization solvent, was most efficient for introducing unsaturation into terpolymer. This system also produces gel in the terpolymer in the latter stages of reaction, however. Catalysts of VCl₄, VOCl₃, or V(C₅H₇O₂)₃, with Al₂Et₃Cl₃ cocatalyst, in benzene solvent gave terpolymers of quite similar unsaturations. With all systems, terpolymer yield increases very rapidly in the first few minutes of reaction, then very slowly for the remainder of the 30-min. reaction time, reflecting the rapid loss of activity of the vanadium catalysts. Molecular weight growth of the terpolymer prepared in heptane was extremely rapid, reaching a high value in a few minutes. When prepared in benzene, the terpolymers showed a steady increase in molecular weight throughout the reaction but reached only a moderate final value (as expressed by inherent viscosity).     

Achieving high conversions in nitroxide-mediated living styrene miniemulsion polymerization

Nitroxide-mediated living radical polymerizations of styrene were run in miniemulsion. Using a modified miniemulsion process that does not require the use of a volatile costabilizer, near complete conversions could be achieved in 2-3 hours while preserving narrow molecular weight distributions and a high degree of chain livingness. Increased rates and final conversions were achieved by semi-batch addition of the nitroxide scavenger ascorbic acid.     

Electrochemical and spectroscopic characterisation of structural reorganisation in N,N′–dialkylpyridinium cation radical deposits

The electrochemical reduction to form a deposit of the radical cation salt for a series of n-alkyl asymmetrically substituted viologens and the corresponding anodic oxidation processes have been investigated using electrochemical methods in in situ uv-visible reflectance spectroscopy. Particular attention was focussed on the nature of the restructuring involved in the ageing of the deposit. The use of both p- and s-polarised radiation clearly showed that initially the viologen units were deposited with the major molecular axis parallel to the electrode and on ageing they reorganised into a preferred orientation perpendicular to the electrode. The viologens with the larger substituents were initially deposited as aggregates of mixed micelles containing both cation radical and dication units. The latter were reduced at a well defined potential, the process being seen as a highly-reversible sharp current spike on the linear sweep voltammograms.     

Interfacial Mass Transfer in Nitroxide‐Mediated Miniemulsion Polymerization

A mathematical model has been developed to describe the interfacial mass transfer of TEMPO in a nitroxide‐mediated miniemulsion polymerization (NMMP) system in the absence of chemical reactions. The model is used to examine how the diffusivity of TEMPO in the aqueous and organic droplet phases, the average droplet diameter and the nitroxide partition coefficient influences the time required for the nitroxide to reach phase equilibrium under non‐steady state conditions. Our model predicts that phase equilibrium is achieved quickly (< 1 × 10⁻⁴ s) in NMMP systems under typical polymerization conditions and even at high monomer conversions when there is significant resistance to molecular diffusion. The characteristic time for reversible radical deactivation by TEMPO was found to be more than ten times greater than the predicted equilibration times, indicating that phase equilibrium will be achieved before TEMPO has an opportunity to react with active polymer radicals. However, significantly longer equilibration times are predicted, when average droplet diameters are as large as those typically found in emulsion and suspension polymerization systems, indicating that the aqueous and organic phase concentrations of nitroxide may not always be at phase equilibrium during polymerization in these systems.

Influence of droplet phase TEMPO diffusivity, D_TEMPO,drop, on the predicted organic phase concentration of TEMPO.     

Model Studies of Nitroxide‐Mediated Styrene Miniemulsion Polymerization – Opportunities for Process Improvement

Modeling studies were performed to investigate how persulfate‐initiated nitroxide‐mediated styrene miniemulsion polymerizations are influenced by changes to the polymerization recipe. By manipulating the initial concentrations of potassium persulfate and nitroxide, and the aqueous phase volume, trends in the predicted polymerization time, number average molecular weight, polydispersity and degree of polymer livingness were identified that indicate operating conditions for improved process performance. Specifically, our model predicts the existence of experimental conditions that simultaneously minimize polymer polydispersity and maximize the livingness of the polymer. The mechanisms responsible for the predicted trends were identified from the predicted molecular weight distributions of the living and dead polymer chains.

Predicted number MWDs at 20% monomer conversion for styrene NMMP systems employing various levels of [KPS]_aq,0. Dormant KPS‐initiated polymer radicals.