SAR Models for Estimating the Percutaneous Absorption of Polynuclear Aromatic Hydrocarbons

Abstract

A structure-activity relationship (SAR) of the in vitro percutaneous absorption of polycyclic aromatic hydrocarbons (PAH) is described. The data set consisted of 60 three to seven ring PAH. Over 50 numeric descriptors were generated from the modeled molecular structures. Computer aided methods were used to evaluate descriptors and develop linear expressions relating the percent of dermally applied PAH dose absorbed through skin (PADA) to PAH structure. Three regression models with one and two variables were developed. The log octanol/water partition coefficient (log P) was the most important variable in determining percutaneous absorption. An inverse relationship between log P and the skin penetration properties of the PAH was observed. Nearly 40 of 60 PAH tested had PADA-values within a factor of two of benzo[a]pyrene (BaP); well over 50 of 60 had PADA-values within a factor of three. The results lend support to the use of isotopically labeled BaP as a surrogate for measuring the dermal flux (in vivo and in vitro) and estimating the dermal bioavailability of PAH from complex mineral oil and coal-tar derived mixtures.

A review of the current state of the art of physiologically-based tests for measuring human dermal in vitro bioavailability of polycyclic aromatic hydrocarbons (PAH) in soil

“…The in vivo animal studies which relate specifically to PAH dermal bioavailability from soils have used monkeys, rats and guinea pigs (Yang et al, 1989;Wester et al, 1990;Turkall et al, 1994;Kadry et al, 1995;Moody et al, 1995;Roy et al, 1998a). These tests take the general form of applying the test chemical to a designated area of skin in an appropriate vehicle (for the purposes of this review this is soil).…”

“…Human skin is, however, not always easily available and a number of studies have used alternative animal skins. In studies where PAH dermal bioavailability, with and without soil have been studied (Wester et al,, 1990;Moody et al, 1995;Roy et al,, 1998b;Roy and Singh, 2001;Moody et al, 2007;Moody et al, 2009;Moody et al, 2011), pig (Jacques et al, 2010), rat (Yang et al, 1989;Moody et al, 1995;Roy et al, 1998a) and guinea pig skin (Moody et al, 1995) have been used.…”

“…Key dermal bioavailability studies for PAH in soil are discussed with key points summarised in Table 1 ( Yang et al,, 1989;Wester et al, 1990;Moody et al, 1995;Roy et al, 1998a;Roy et al, 1998b;Riviere et al, 1999;Roy and Singh, 2001;Abdel-Rahman et al, 2002;Moody et al, 2007;Moody et al, 2009;Jacques et al, 2010;Moody et al, 2011). .…”

“…Roy et al,, 1998a) and Kp (Potts and Guy, 1992) with physico-chemical properties of multiple compounds (Table 2). A large amount of work on QSAR is driven by the need to help characterise the risk to human health under relevant state regulations (e.g.…”

“…QSAR are usually completed for multiple compounds modelled in a pure form and infinite dose conditions. For example, Roy et al, (1998a) modelled in vivo PADA data for 60 PAH individual compounds whilst Flynn (1990) modelled K p for 97 organic chemicals. Studies have since been completed that have used Roy's and Flynn's data (e.g.…”