Role of kinetics in acute lethality of nonreactive volatile organic compounds (VOCs).
The role of kinetics in the acute inhalation toxicity of nonreactive, volatile organic compounds (VOCs), including lipophilic and hydrophilic compounds, was analyzed with a physiologically based pharmacokinetic (PB-PK) model for the rat. For 15 VOCs, a total of 23 LC50 values were retrieved from the literature. It was observed that the external exposure parameter (LC50.exposure length; in ppm.h), varied approximately 60-fold. Concentrations of compounds in the lipoid brain fraction were simulated using a kinetic model. This lead to a more than 10-fold reduction in the toxic range of the 15 VOCs. The average value for this simulated dose surrogate was 70 +/- 31 mM for all VOCs. These observations support the presumption that nonspecific, acute narcotic lethality is directly related to the extent of VOC distribution into lipoid brain constituents. The present results can be used for estimation of the acute lethality of nonreactive VOCs on the basis of kinetic simulations. In addition, the presently calculated dose surrogate for VOC lethality in rats is found to be very similar to the reported internal lethal concentrations of so-called "baseline toxicity compounds" in fish. This indicates a common mechanism of acute VOC toxicity among mammalian and aquatic species.
DeJongh
J
J
Research Institute of Toxicology (RITOX), Utrecht, The Netherlands. J.DEJONGH@RITOX.DGK.RUU.NL
Verhaar
H J
HJ
Hermens
J L
JL
D000473:Alkanes / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D006841:Hydrocarbons, Aromatic / Q000493:pharmacokinetics* / Q000633:toxicity*; D006843:Hydrocarbons, Chlorinated / Q000493:pharmacokinetics* / Q000633:toxicity*; D019570:Inhalation Exposure; D007928:Lethal Dose 50; D008954:Models, Biological; D051381:Rats
D000473:Alkanes; D006841:Hydrocarbons, Aromatic; D006843:Hydrocarbons, Chlorinated