PHYSIOLOGICALLY-BASED PHARMACOKINETICS AND THE DERMAL ABSORPTION OF 2-BUTOXYETHANOL VAPOR BY HUMANS

It has generally been assumed that the skin contributes only minor amo unts to the total uptake of solvent vapors, relative to the respirator y tract. Contrary to this assumption, the widely used glycol ether sol vent, 2-butoxyethanol (BE), has been reported to be more effectively a bsorbed through the skin (75% of the total uptake) than through the lu ngs of humans (Johanson and Boman, 1991, Br. J. Ind. Med. 48, 788). Th e possibility that the finger prick blood sampling technique used in t he Johanson and Boman study was confounded by locally high concentrati ons of BE at the site of absorption was suggested using a previously d eveloped PBPK model (Corley et al., 1994, Toxicol. Appl. Pharmacol. 12 9, 61). The current study was conducted to verify the PBPK analysis an d to determine whether or not the skin was the major site for absorpti on of BE vapor by exposing one arm from each of six human volunteers t o 50 ppm C-13(2)-BE vapor for 2 hr. To evaluate the potential conseque nces of blood sampling techniques, samples were taken from both the un exposed arm (catheter; during and after exposure) and the exposed arm (finger prick; end of the exposure only) for analysis of both BE and i ts major metabolite, butoxyacetic acid (BAA). Butoxyacetic acid is res ponsible for the hemolysis observed in toxicity studies with laborator y animals. Humans, however, are significantly less sensitive to this e ffect. The concentration of BE in the finger prick blood samples avera ged 1500 times higher than the corresponding concentration in venous b lood sampled from a catheter installed in the unexposed arm at the end of the exposure. Blood BAA levels were generally within a factor of 4 of each other for the two techniques and, therefore, was considered a better indicator of systemic absorption. Urine was collected for 24 h r and analyzed for the following metabolites found in rat metabolism s tudies: free and conjugated BE, BAA, ethylene glycol (EG), and glycoli c acid (GA), with only BAA detected in the human urine. More important ly, urinary BAA was found to be extensively conjugated (similar to 67% ) with glutamine, confirming recent reports. These results, coupled wi th PBPK modeling of worst-case exposure scenarios (no clothing, 100% o f the body was exposed), demonstrated that no more than 15-27% (low-to -high relative temperatures and humidities), not 75%, of the total upt ake of BE could be attributed to the skin of humans during simulated 8 -hr exposures to the ACGIH TLV concentration of 25 ppm. Even less of t he total uptake was attributed to the skin during simulations of exerc ise with whole-body exposures (5-9%) or by more realistic exposures of only the arms and head (1-8%). As a result, humans are unlikely to re ach hemolytic concentrations of the metabolite BAA in blood following vapor exposures to BE. (C) 1997 Society of Toxicology.