Toxicokinetics percutaneous

Zhang and Wu (1987) chose the small pig (male and female, black, 4.2-13.0 kg) because of the aforementioned resemblance of its skin to that of humans. They chose this model to study the percutaneous toxicokinetics of occluded liquid sulfur mustard, and studied the iv route in this species as the reference route, as well as the toxicokinetics after subcutaneous (sc) exposure. 

J. P. Langenberg and H. C. Trap, Inhalation and Percutaneous Toxicokinetics of Sulfur Mustard and Its Adducts in Hairless Guinea Pigs and Marmosets. Efficacy of Nasal Scavengers, Final report for USAMRMC contract DAMD17-03-1-0613, ADA441282, 2005. 

Toxicokinetic studies in humans have demonstrated that coumarin is rapidly absorbed from the gastrointestinal tract after oral administration and extensively metabolized by the liver in the first pass, with only 2-6% reaching the systemic circulation intact (Ritschel etal., 1977, 1979 Ritschel Hofimann, 1981).The elimination of coumarin from the systemic circulation is rapid, the half-lives following intravenous doses of 0.125, 0.2 and 0.25 mg/kg bw being 1.82, 1.46 and 1.49 h [109, 88 and 89 min], respectively (Ritschel et a/., 1976). Coumarin is also extensively absorbed after dermal application. In one study with human subjects, some 60% of a 2.0-mg dose applied for 6 h was absorbed (reviewed in Lake, 1999). The percutaneous absorption of coumarin has also been demonstrated in vitro with human skin (Beckley-Kartey et al, 1997 Yourick Bronaugh, 1997). 

Van der Schans, M.J., Lander, B.J., Van der Wiel, H., Langenberg, J.P., Benschop, H.P. (2003). Toxicokinetics of nerve agent ( )-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration. Toxicol. Appl. Pharmacol. 191 48-62. 

Toxicokinetics of the nerve agent (+/-)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration. Toxicol Appl Pharmacol, 191, 48-62. 

It should be expected that further quantitative measurements on elimination routes of nerve agents, in combination with the wealth of available toxicokinetic data, will enable further development of physiologically-based modeling of toxicokinetics. Further model developments are needed, in particular for the respiratory and percutaneous exposure routes. Ultimately, this modeling will enable reliable interspecies extrapolation of toxicokinetic results, including extrapolation to man, which is the ultimate goal. 

The toxicokinetics of OP/nerve agents including stereoisomers at the inhalation and percutaneous routes of administration should be expanded. 

Payan, J.P., Boudry, 1., Beydon, D., Fabry, J.P, Grandclaude, M.C., Ferrari, E., and Andre, J.C. (2003). Toxicokinetics and metabolism of W-[(14)C]W-methyl-2-pyrrolidone in male Spraque-Dawley rats in vivo and in vitro percutaneous absorption. Drug Metabolism and Disposition, 31, 659-669. 

Occupational disease, caused by skin contact with toxic substances, represents a major health problem In the United States (1). Dermal exposure of agricultural workers to pesticide agents, of course. Is a particularly pertinent example of this problem. Prediction of the detrimental toxic effects of hazardous chemical exposure Is difficult, however, because of the complexity of the percutaneous absorption process in man and a lack of any consistently Identifiable relatlonshlp(s) between transport rate and chemical properties. In addition, the very diverse approaches, which have been used to measure skin penetration, further complicate the situation since the extrapolation of results to man In his workplace may Involve questionable, non-valldated assumptions. Our specific aim Is to predict accurately the toxicokinetics of occupationally-encountered molecules (e.g., pesticides) absorbed across human skin In vivo. We present... 

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