title: Translational research to develop a human PBPK models tool kit-volatile organic compounds (VOCs).
abstract: Toxicity and exposure evaluations remain the two of the key components of human health assessment. While improvement in exposure assessment relies on a better understanding of human behavior patterns, toxicity assessment still relies to a great extent on animal toxicity testing and human epidemiological studies. Recent advances in computer modeling of the dose-response relationship and distribution of xenobiotics in humans to important target tissues have advanced our abilities to assess toxicity. In particular, physiologically based pharmacokinetic (PBPK) models are among the tools than can enhance toxicity assessment accuracy. Many PBPK models are available to the health assessor, but most are so difficult to use that health assessors rarely use them. To encourage their use these models need to have transparent and user-friendly formats. To this end the Agency for Toxic Substances and Disease Registry (ATSDR) is using translational research to increase PBPK model accessibility, understandability, and use in the site-specific health assessment arena. The agency has initiated development of a human PBPK tool-kit for certain high priority pollutants. The tool kit comprises a series of suitable models. The models are recoded in a single computer simulation language and evaluated for use by health assessors. While not necessarily being state-of-the-art code for each chemical, the models will be sufficiently accurate to use for screening purposes. This article presents a generic, seven-compartment PBPK model for six priority volatile organic compounds (VOCs): benzene (BEN), carbon tetrachloride (CCl(4)), dichloromethane (DCM), perchloroethylene (PCE), trichloroethylene (TCE), and vinyl chloride (VC). Limited comparisons of the generic and original model predictions to published kinetic data were conducted. A goodness of fit was determined by calculating the means of the sum of the squared differences (MSSDs) for simulation vs. experimental kinetic data using the generic and original models. Using simplified solvent exposure assumptions for oral ingestion and inhalation, steady-state blood concentrations of each solvent were simulated for exposures equivalent to the ATSDR Minimal Risk Levels (MRLs). The predicted blood levels were then compared to those reported in the National Health and Nutrition Examination Survey (NHANES). With the notable exception of BEN, simulations of combined oral and inhalation MRLs using our generic VOC model yielded blood concentrations well above those reported for the 95th percentile blood concentrations for the U.S. populations, suggesting no health concerns. When the PBPK tool kit is fully developed, risk assessors will have a readily accessible tool for evaluating human exposure to a variety of environmental pollutants.
authors: Division of Toxicology and Environmental Medicine, Agency for Toxic Substances and Disease Registry, Atlanta, Georgia 30333, USA. mgm4@cdc.gov
authors: M Moiz
authors: MM
authors: Mumtaz
authors: Meredith
authors: M
authors: Ray
authors: Susan R
authors: SR
authors: Crowell
authors: Deborah
authors: D
authors: Keys
authors: Jeffrey
authors: J
authors: Fisher
authors: Patricia
authors: P
authors: Ruiz
mesh_terms: D003198:Computer Simulation; D004784:Environmental Monitoring / Q000379:methods*; D004785:Environmental Pollutants / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D016021:Epidemiologic Studies; D006801:Humans; D008954:Models, Biological; D011634:Public Health / Q000379:methods; D012107:Research Design; D018570:Risk Assessment / Q000379:methods; D014481:United States; D055549:Volatile Organic Compounds / Q000145:classification / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D004785:Environmental Pollutants; D055549:Volatile Organic Compounds