Influence of Matrix Formulation on Dermal Percutaneous Absorption of Triazole Fungicides Using QSAR and PBPK/PD Models
D Chang, Peter Paul Egeghy, James B. Knaak, Rogelio Tornero‐Velez, Miles S. Okino, Fred W. Power, Mike Dellarco, C Mazur, John F. Kenneke, Curtis C. Dary · Epidemiology · 2006
P-629 Abstract: The successful use of the Exposure Related Dose Estimating Model (ERDEM) for assessment of human exposure to the triazole fungicides requires the accurate determination of representative and comparable input parameters. In the specific case of dermal exposure, the formulation matrix plays an important role in the absorption and distribution of specific chemicals. Addition of the matrix formulation (vehicle and additives) into a comprehensive physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model is crucial to understanding the effects of triazole fungicides for human risk assessment. Quantitative structure activity relationships (QSAR) were developed and used to obtain kp values (cm/h) for percutaneous dermal absorption, skin/water and tissue/blood partition coefficients, and metabolic parameter values (Vmax and Km) for several triazole fungicides (diniconazole, hexaconazole, cyproconazole, propiconazole, fenbuconazole, uniconazole and triadimefon). Recently, Riviere and Brooks (2005) have developed a hybrid linear free energy relationship (LFER) method to describe the dermal absorption rate, kp, in the presence of complex chemical mixtures utilizing the following baseline model, where MF is a mixture factor that accounts for the properties of the formulation matrix; ΣαH2, ΣβH2 and πH2 are the usual solvatochromatic parameters describing hydrogen bonding acidity, basicity and dipolarity/polarizability; R2 represents the excess molar refractivity; and Vx is the standard McGowan volume of the chemical penetrants. The linear regression coefficients c, m, a, b, s, r, and v couple these descriptors to kp. Utilizing the above equation, we have included additional matrix formulation information via a hybrid LFER method to describe the effects of complex mixtures in the prediction of kp within the framework of a PBPK/PD model. Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy.