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Inhal Toxicol

Title:		Comparing respiratory-tract and hepatic exposure-dose relationships for metabolized inhaled vapors: a pharmacokinetic analysis
Author(s):		Sarangapani R; Clewell HJ; Cruzan G; Andersen ME;
Address:		"ICF Consulting, The K.S. Crump Group, Inc., Research Triangle Park, North Carolina, USA"
Journal Title:		Inhal Toxicol
Year:		2002
Volume:		14
Issue:		8
Page Number:		835 - 854
DOI:		10.1080/08958370290084656
ISSN/ISBN:		0895-8378 (Print) 0895-8378 (Linking)
Abstract:		"Inhaled vapors that are metabolized locally in the respiratory-tract tissues and systemically in the liver and other organs have different dose-response relationships at the portal of entry compared to systemic target organs. For instance, inhaled chloroform and styrene cause cytotoxicity in the nasal cavity at concentrations much lower that those causing hepatic or renal toxicity. Here, we develop a physiologically based pharmacokinetic (PBPK) model that incorporates a multicompartment, unidirectional flow description of the respiratory tract within a whole-body model in order to estimate both respiratory tract and hepatic metabolism. We then use this model to study the difference in exposure-dose relationship between the respiratory-tract tissues and the liver. The integrated PBPK model confirms that for soluble vapors the exposure-dose curve for metabolism in respiratory-tract tissue will be shifted dramatically to lower concentrations compared to the exposure-dose relationship in systemic organs. This behavior is the result of direct air to tissue equilibration at the portal of entry while other systemic tissues only respond to concentrations in the blood. For cases where metabolism/metabolites of inhaled vapors produce local toxicity, portal of entry effects are expected at lower concentrations and, in general, will be the limiting response for setting reference concentrations (RfCs) for many compounds. The difference in dose-response relationships for metabolism in the respiratory tract versus systemic organs depends on blood/air and blood/tissue partition coefficients and on the degree of systemic extraction of the metabolized vapors"
Keywords:		"Animals Dose-Response Relationship, Drug Hydrocarbons/adverse effects/*pharmacokinetics *Inhalation Exposure Liver/chemistry/drug effects/*pathology Male *Models, Biological Organic Chemicals/adverse effects/*pharmacokinetics Rats Rats, Inbred F344 Respir;"
Notes:		"MedlineSarangapani, Ramesh Clewell, Harvey J Cruzan, George Andersen, Melvin E eng Comparative Study England 2002/07/18 Inhal Toxicol. 2002 Aug; 14(8):835-54. doi: 10.1080/08958370290084656"