Gil Lostes, J.; (2010) A study of chemosensory effects of volatile organic compounds on humans. Doctoral thesis , UCL (University College London).

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Abstract

Indoor air quality is closely associated with human health since most people spend approximately ninety per cent of their time indoors. Environmental tobacco smoke, which is a very complex mixture, is one of the most important contributors to indoor air pollution, especially significant is its contribution to indoor concentrations of volatile organic compounds (VOCs). Evaluation of chemosensory irritation (eye irritation and nasal irritation) caused by VOCs uses human subjects as panelists, and is very time consuming and costly. Thus prediction of chemosensory irritation, e.g. by quantitative structure-activity relationships (QSARs) involving the use of VOC physicochemical parameters (descriptors), is highly desirable. The prediction of sensory responses on humans by QSARs requires the use of experimentally determined descriptors in the QSARs, at least for the most successful methods to date. In this work descriptors for more than 100 VOCs have been determined, using experimental gas chromatographic data, gas-liquid and liquid-liquid partition coefficients. A number of gas chromatographic columns were characterized in this work; these columns cover a large range of polarities. VOC descriptors were then introduced into QSARs to fit and then to predict eye irritation thresholds (EITs) and nasal irritation thresholds (NPTs). Furthermore, this project established a general connection between EITs and other chemosensory responses in humans. If there were a connection between those values, this would enable inter-conversion to be made, and would provide a method of estimating one threshold from the other. An attempt was made to demonstrate the suitability of using experimental Draize eye test scores and NPT values to calculate EIT values. A new equation to predict EIT values was proposed that includes a very much larger set of experimental values from other biological endpoints than just EIT, and hence should be statistically more sound than an equation based on a limited number of EIT values only. Psychometric functions are used in chemosensory studies to describe the probability of chemosensory detection as a function of concentration. These functions are experimentally determined, again using human subjects, so function prediction is desirable. Psychometric functions have been predicted for several VOCs for odour, eye and nasal irritation, and nasal lateralization. A physicochemical model for delivery of VOCs to eye receptor neurons has been developed based on the two-stage model. In this model the complexity of the VOC delivery to the cornea throughout the different layers of the pre-corneal tear film leading to a succession of equilibrium processes is reduced to a much more simple overall equilibrium process. Finally, it is known that there is a critical molecular dimension along a given homologous series, e.g. n-alkylbenzenes and 2-ketones, beyond which eye irritation is not evoked (at the cut-off point). This work has been continued by investigating several homologous series of compounds that are found in tobacco smoke, and it seems possible to predict the ‘cut-off’ point by using energy minimization of the system and molecular dynamics in aqueous phase. Software packages such as Molecular Operating Environment 2007.09 (Chemical Computing Group) and Hyperchem version 7.5 (Hypercube Inc.) were used to perform molecular dynamics and energy minimization.

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