Toxicokinetics of inhaled trimethylbenzenes in man

Abstract: In the toxicological risk assessment, data on the uptake and disposition (toxicokinetics) of the chemical is important. The three isomeric trimethylbenzenes (TMBs) are widely used as components in solvent mixtures and motor fuels. The aim of the present investigation was to study the human toxicokinetics of inhaled TMB vapours and in particular of 1,2,4-TMB. Liquid/air partition coefficients of the TMBs were determined in vitro by the vial equilibration method. The results indicate a pronounced affinity for blood and adipose tissue whereas partitioning to water was low. Inhalation chamber exposures of male healthy volunteers were performed for 2 h during light physical exercise. The exposure level for each TMB-isomer was 25 ppm. In addition, an exposure to 2 ppm of 1,2,4-TMB was performed. Furthermore, the same men were exposed to 2 ppm of 1,2,4-TMB in white spirit. A method for determination of dimethylhippuric acids (DMHAs), specific metabolites of TMBs, was developed and the excretion of DMHAs in urine after TMB exposure was measured. The relative respiratory uptake was high (56-64%) and exhalation of unmetabolised TMBs amounted to 20-37% of the absorbed amount. The results from the different exposure conditions indicate a tendency towards a deviation from first order kinetics for 1,2,4-TMB at the present Swedish occupational exposure limit (25 ppm), This suggests partial metabolic saturation. In addition, 1,2,4-TMB kinetics was affected by other components in white spirit. The recovery of DMHAs within 24 h varied between the TMBs isomers in the range 3-22% of the absorbed amount Half-times of the DMHAs were in the range 4-8 h. The data suggests that the importance of the metabolic route yielding 3,4-DMHA from 1,2,4-TMB increases with increasing air levels and after exposure to white spirit. A physiologically based toxicokinetic model was developed for 1,2,4-TMB using blood and exhaled air levels of 1,2,4-TMB as well as urinary excretion rates of 3,4-DMHA from the two exposures to 1,2,4-TMB. The model was used to expand from a 2 h exposure to exposure for 8 h at different work loads and different air levels as well as exposure during a working week. Simulations indicated that work load has a pronounced influence on 1,2,4-TMB levels in blood and exhaled air as well as the excretion of 3,4-DMHA. Thus, for certain work tasks internal exposure may be incorrectly estimated by air monitoring. 1,2,4-TMB in venous blood or 3,4-DMHA in urine seem suitable as biological markers of 1,2,4-TMB exposure. Sampling at the end of the working shift gives an indication of the same day's exposure whereas sampling prior to shift towards the end of the week or after the weekend reflects the exposure during the entire week.