I. Eide et K. Zahlsen, INHALATION EXPERIMENTS WITH MIXTURES OF HYDROCARBONS - EXPERIMENTAL-DESIGN, STATISTICS AND INTERPRETATION OF KINETICS AND POSSIBLE INTERACTIONS, Archives of toxicology, 70(7), 1996, pp. 397-404
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.