Journal Article Review: PBTK Modeling Demonstrates Contribution of Dermal and Inhalation Exposure Components to End-Exhaled Breath Concentrations of Naphthalene(D. Kim, M. Andersen, Y. Chao, P. Egeghy, S. Rappaport, L. Nylander-French, Environmental Health Perspectives, 2007)Luanne JeramKim McDonaldThursday, December 3, 2009Introduction The single largest source of chemical exposure on NATO military based is jet propulsion fuel 8 (JP-8) JP-8 contains many aromatic hydrocarbons: benzene and naphthalene aliphatic hydrocarbons (nonane and decane)  Exposures to JP-8 can occur during:  spills transportation and storage fueling general maintenance and operation of aircraft and military vehicles fueling military tent heaters cleaning and degreasing parts with the fuelExposure Routes Dermal Inhalation Sampling Personal – inhalation but not dermal Skin – dermal but not inhalation Exhaled air – integrated estimate of both inhalation & dermal but not relative contributions of the exposure routes to the internal dose. Both inhalation and dermal exposure contribute to internal dose What are the relative contributions?Physiologically based toxicokinetic (PBTK) modelingEffective tool for quantifying absorption, distribution, metabolism, and elimination of chemicals.  Five compartments Lungs Liver Fat Rapidly perfused tissues Slowly perfused tissues Model predicts time course of naphthalene in tissue and blood from low-level exposures to naphtalene vapor Need - PBTK model that included both inhalation and dermal routes of exposure.  Objective – Develop an optimal PBTK model, combined with exposure and biomarker data from field studies used to quantify the relative contributions of dermal and inhalation exposures to end-exhaled breath concentrations of naphthalene among U.S. Air Force personnel.Physiologically Based Toxicokinetic (PBTK) models for the study of naphthalene toxicokinetics. AbbreviationsKuptake, input rate constant for dermal exposure; Kpv, permeability coefficient for the viable epidermis; Aexp, exposed surface area; Psc:ve, stratum corneum:viable epidermis partition coefficient; QE, blood flow rate to skin; Pve:b, viable epidermis:blood partition coefficient; QP, pulmonary ventilation rate; Pb: a, blood:air partition coefficient; QF, blood flow rate to fat; Pf:b, fat:blood partition coefficient; O, blood flow rate to other tissue; Po:b, other tissue:blood partition coefficient; EL, extraction ratio.Inhalation ExposureDermal ExposureExposure Routes modeled: dermal and inhalation.  Pulmonary uptake = QP x CPBZ.  QP: Pulmonary ventilation rate CPBZ: Concentration of naphthalene in the personal breathing-zone  This calculations assumes rapid equilibrium of the naphthalene across the alveolar linings and neither storage nor metabolism in the lungs appreciably affects the uptake of naphthalene into the systemic circulation.  Dermal absorption and penetration is modeled as a one directional diffusive process according to Fick’s first law of diffusion. Through the stratum corneum (SC) to the viable epidermis (VE).MBDE for SC MBDE for VEElimination of Naphthalene by exhalation and metabolism The concentration of naphthalene in exhaled air is equal to the blood concentration divided by the blood:air partition coefficeint Pb:a.  Pulmonary clearance is QP (pulmonary ventilation rate) divided by Pb:a Naphthalene metabolism occurs in the liver by a single metabolic pathway (following first order kinetics). Liver clearance (CL)is: The ratio of liver clearance to liver blood flow is the extraction ratio (EL)Dermal exposure toxicokinetics The PBTK model was optimized for dermal exposure using data from 10 individuals who were exposed to JP-8 on the skin under laboratory conditions  Large variability was detected between individuals The rate of input from dermal exposure is equivalent to the product of the permeability coefficient for the SC (Kps), the exposed surface area (Aexp) and the concentration of the naphthalene in the JP-8.Predictions of end-exhaled breath concentrations The authors used the PBTK model to predict the end-exhaled breath concentration of naphthalene for 53 US Air Force personnel who did not have dermal contact with jet fuel and had end-exhaled breath concentrations > 0.0 µg/m3Comparison of dermal and inhalation exposure routes Simulations were conducted to compare the contribution of dermal exposure with the end-exhaled breathe concentrations relative to inhalation exposure.  The area under the end-exhaled breath concentration time curve (AUCex) was calculated for dermal exposures where Cexis the concentration of naphthalene in the end-exhaled breath and tiis the time at the end of the exposure: Sensitivity analysis indicated that the end-exhaled breath concentration was most sensitive to the estimated air concentration of naphthalene during work but not sensitive to the variables DERMDOSE and Aexpsince dermal route accounts for only a small percentage of total exposurePBTK model was used to predict: End-exhaled breath measurements for the U.S. Air Force personnel exposed to JP-8 by the inhalation route. The predicted concentration at the end of the work shift was the same as the measured value Dermal and inhalation exposures to three U.S. Air Force personnel selected to represent 10th, 50th, and 90thpercentiles base on their end-exhaled breath concentrations. The predicted concentrations of naphthalene were well above what was expected in end-exhaled breath.  Discrepancy due to the wearing of respiratory protection, therefore the personal breathing zone samples were not representative of the actual inhalation exposure.Conclusions The contribution of dermal exposure to end-exhaled breath was relatively small (4% for 50thpercentile) however as end-exhaled breath concentration increased the relative contribution of dermal exposure also increased (11% for 90thpercentile).  The optimized PBTK model has reduced the uncertainty in modeling JP-8 exposure because fewer parameters where required to predict the time course of naphthalene than the previous models.  Further study of inter- and intra-individual variations in exposure assessment is required to better characterize the toxicokinetic behavior of JP-8 components after occupational and/or environmental exposures.Conclusions This modeling approach