You are here:
ARSENIC MODEL DEVELOPMENT FOR IMPROVED RISK ASSESSMENT
Impact/Purpose:
The arsenic PBPK model can (with appropriate scaling) be used to estimate the dose of active metabolites to various target tissues (e.g., lung, skin, liver) in humans. This is particularly important for a chemical with multiple active metabolites such as arsenic. The impact of both varying exposure scenarios and differences in metabolism (due to age, nutritional status, ethnicity, etc.) on cumulative tissue dose and body burden can also be examined and ultimately correlated this with health outcomes observed in epidemiological studies. This reduces the uncertainty inherent in simply using exposure level (e.g., arsenic levels in drinking water) and cancer or noncancer health effects as model input for quantitative risk assessment.
Description:
This project integrates research on the kinetic behavior and metabolism of arsenic at both the cellular and whole organism levels using a physiologically based pharmacokinetic (PBPK) modeling approach. The ultimate goal is development of a robust human PBPK model for arsenic metabolism accessible to modelers and risk assessors via a standardized modeling platform. This project incorporates three major areas: (1) development of kinetic models to describe hepatic methylation of arsenic in rats and humans, (2) development of a whole organism PBPK model initially in the mouse with extrapolation to humans, and (3) implementation of the whole organism model with a more physiological description of the kidney in a platform readily accessible to other modelers.
Our previous work in the area of hepatic methylation models has identified inhibition of the formation of the dimethyl arsenic from monomethyl arsenic by arsenite as an essential mechanism to include in the whole organism models. Both previous and on-going studies of arsenic disposition in mice have been used to develop and parameterize our mouse PBPK model that will ultimately be scaled to humans. Metabolic rate constants for the human model will be estimated from metabolism studies conducted using human hepatocytes in collaboration with Miroslav Styblo at the University of North Carolina.
In the course of PBPK model development, we identified the need for a more complex, physiologically realistic description of the kidney and urinary bladder than has been traditionally incorporated in PBPK models. This has resulted in a subproject to develop a mathematical description of the kidney that incorporates the major excretory processes of glomerular filtration, passive tubular excretion, and active tubular secretion. This model description will also incorporate urine flow with the bladder as a urine storage organ. The advantage of a physiological compared to an empirical approach is the model is more readily scaled to other species, i.e. it has broader extrapolation capability. The model will initially be written in advanced continuous simulation language (ACSL) and then implemented in NERLs Exposure Related Dose Estimating Model (ERDEM) platform. This work is being done in collaboration with NERL. This approach was selected because the generalized model code produced will be applicable to a variety of chemicals and readily accessible to other modelers via the ERDEM platform.