INHALATION EXPERIMENTS WITH MIXTURES OF HYDROCARBONS - EXPERIMENTAL-DESIGN, STATISTICS AND INTERPRETATION OF KINETICS AND POSSIBLE INTERACTIONS

The paper describes experimental and statistical methods for toxicokin etic evaluation of mixtures in inhalation experiments. Synthetic mixtu res of three C9 n-paraffinic. naphthenic and aromatic hydrocarbons (n- nonane, trimethylcyclohexane and trimethylbenzene, respectively) were studied in the rat after inhalation for 12 h. The hydrocarbons were mi xed according to principles for statistical experimental design using mixture design at four vapour levels (75, 150, 300 and 450 ppm) to sup port an empirical model with linear, interaction and quadratic terms ( Taylor polynome). Immediately after exposure, concentrations of hydroc arbons were measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat. Multivariate data analysis and mode lling were performed with PLS (projections to latent structures). The best models were obtained after removing all interaction terms, sugges ting that there were no interactions between the hydrocarbons with res pect to absorption and distribution. Uptake of paraffins and particula rly aromatics is best described by quadratic models, whereas the uptak e of the naphthenic hydrocarbons is nearly linear. All models are good , with high correlation (r(2)) and prediction properties (Q(2)), the l atter after cross validation. The concentrations of aromates in blood were high compared to the other hydrocarbons. At concentrations below 250 ppm, the naphthene reached higher concentrations in the brain comp ared to the paraffin and the aromate. Statistical experimental design, multivariate data analysis and modelling have proved useful for the e valuation of synthetic mixtures. The principles may also be used in th e design of liquid mixtures, which may be evaporated partially or comp letely.