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4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms
4.1 Toxicokinetics 4.1.1 Absorption, distribution, metabolism and excretion (a) Overview This section provides an overview of the toxicokinetics of polycyclic aromatic hydrocarbons (PAHs). Other more comprehensive reviews of the toxicokinetics of PAHs include those by the Environmental Protection Agency (1991), the Agency for Toxic Substances and Disease Registry (ATSDR, 1995) and the International Programme on Chemical Safety (IPCS, 1998), as well as reviews on the metabolism and bioactivation of PAHs by Conney (1982), Cooper et al . (1983), Shaw and Connell (1994), Penning et al . (1999), Joint FAO/WHO Expert Committee on Food Additives (JECFA, 2005) and Xue and Warshawsky (2005). Little is known about the toxicokinetics of mixtures of or individual PAHs in humans. Multiple studies have been conducted to monitor urinary metabolites of PAHs and PAH–DNA adducts in the lymphocytes of workers exposed to mixtures of PAHs. However, most of the available data on toxicokinetic parameters for PAHs derive from studies of benzo[ a]pyrene in animals. Because of their lipophilicity, PAHs dissolve into and are transported by diffusion across lipid/lipoprotein membranes of mammalian cells, thus facilitating their absorption by the respiratory tract, gastrointestinal tract and skin. PAHs with two or three rings can be absorbed more rapidly and extensively than those with five or six rings. Once absorbed, PAHs are widely distributed throughout the body, with some preferential distribution to or retention in fatty tissues. They are rapidly metabolized to more soluble metabolites (epoxides, phenols, dihydrodiols, phenol dihydrodiols, dihydrodiol epoxides, quinones and tetrols), and conjugates of these metabolites are formed with sulfate, glutathione (GSH) or glucuronic acid. The covalent binding of reactive PAH metabolites to form DNA adducts may represent a key molecular event in the formation of mutations and the initiation of cancer. The structures of the DNA adducts that are formed provide an inference of the precursor metabolites. PAHs are eliminated from the body principally as conjugated metabolites in the faeces, via biliary excretion, and in the urine. Most PAHs with potential biological activity range in size from two to six fused aromatic rings. Because of this vast range in molecular weight, several of the physicochemical properties that are critical to their biological activity vary greatly. Five properties in particular have a decisive influence on the biological activity of PAHs: their vapour pressure, their adsorption onto surfaces of solid carrier particles, their absorption into liquid carriers, their lipid/aqueous partition coefficient in tissues and their limits of solubility in the lipid and aqueous phases of tissues.
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These properties are intrinsically linked with the metabolic activation of the most toxic PAHs, and an understanding of the nature of this interaction may facilitate the interpretation of studies on their deposition and disposition that are occasionally conflicting. Transporters may play a role in the biological activity of PAHs. Adenosine triphosphate (ATP) binding cassette (ABC) transporters (49 genes characterized in humans) transport specific molecules across lipid membranes including hydrophobic compounds and metabolites (Schinkel & Jonker, 2003). P Glycoprotein transports mainly non metabolized compounds and multidrug resistance associated protein