Society For Risk Analysis Annual Meeting 2013

Session Schedule & Abstracts


* Disclaimer: All presentations represent the views of the authors, and not the organizations that support their research. Please apply the standard disclaimer that any opinions, findings, and conclusions or recommendations in abstracts, posters, and presentations at the meeting are those of the authors and do not necessarily reflect the views of any other organization or agency. Meeting attendees and authors should be aware that this disclaimer is intended to apply to all abstracts contained in this document. Authors who wish to emphasize this disclaimer should do so in their presentation or poster. In an effort to make the abstracts as concise as possible and easy for meeting participants to read, the abstracts have been formatted such that they exclude references to papers, affiliations, and/or funding sources. Authors who wish to provide attendees with this information should do so in their presentation or poster.

Common abbreviations

M2-D
Modeling for Chemical Risk Assessment (PBPK, Cumulative)

Room: Key Ballroom 4   10:30 AM- 12:00 PM

Chair(s): Audrey Turley   audrey.turley@icfi.com



M2-D.1  10:30  A harmonized PBPK model of hexavalent chromium in rats and mice . Sasso AF*, Schlosser PM; US Environmental Protection Agency   sasso.alan@epa.gov

Abstract: Hexavalent chromium (Cr(VI)) is an environmental and occupational contaminant, and is present in both soil and drinking water in the United States. In 2-year drinking water bioassays, the National Toxicology Program found clear evidence of carcinogenic activity in male and female rats and mice. Because reduction of Cr(VI) to Cr(III) is an important detoxifying step that can occur in the gastrointestinal (GI) tract prior to systemic absorption, numerous physiologically-based pharmacokinetic (PBPK) models have been developed over the past two decades to estimate inter-species differences in toxicity. While the currently available models adequately simulate the available dietary and drinking water datasets available for Cr(VI) and Cr(III), intravenous and gavage data were typically not evaluated. Due to uncertainties related to the kinetics and absorption of Cr(VI) in the GI tract, data for other routes of exposure provide valuable toxicokinetic information. Furthermore, all previous kinetic models for GI reduction assume a single pathway is responsible for the reduction of Cr(VI) to Cr(III), which does not capture the underlying complexities of GI reduction kinetics. The current work attempts to 1) harmonize assumptions between alternate prior PBPK models, 2) adequately simulate data for different routes of exposure and study designs, and 3) incorporate a revised model for GI reduction kinetics (which assumes multiple parallel reduction reactions). The potential impacts on future human health risk assessments will be discussed. The views expressed are those of the authors, and do not necessarily represent the views or policies of the U.S. EPA.

M2-D.2  10:50  Multiscale mechanistic modeling of the respiratory toxicodynamics of engineered nanoparticles. Mukherjee D*, Botelho D, Sarkar S, Gow AJ, Schwander SS, Chung KF, Tetley TT, Zhang J, Georgopoulos PG; Chemical Engineering, Rutgers University   dwaipayan.chem@gmail.com

Abstract: Engineered Nanoparticles (ENPs) are increasingly becoming constituents of consumer and industrial products. A major exposure route for ENPs is inhalation and as a result, the respiratory system is the first biological target. The aim of this work is to develop a multiscale computational model for the physiologically and biochemically based simulation of toxicodynamic processes associated with ENP inhalation. Computational modules for different biological effects have been developed as components of a dose-response risk information analysis system, which provides a mechanistic framework that utilizes data from both in vitro and in vivo studies designed specifically for this purpose. Modules are developed for multiple biological scales (from cell to tissue to organ) within the respiratory system, providing explicit characterization of processes such as surfactant dynamics and uptake and elimination of ENP by cells. The respiratory system was decomposed into functional modules with alveolar surfactant dynamics, cellular dynamics, cellular inflammation and ENP-surfactant interactions being considered separately. The model first developed and parameterized for mice, was extended to rats using additional species-specific data and will be ultimately extrapolated to humans. The model also considers the mechanistic pathways involved in pulmonary cellular inflammation utilizing parameters estimated using in vitro measurements involving each cell type and ENPs. Surfactant levels and composition and the resultant changes in alveolar surface tension were linked to lung function using a pulmonary mechanics model. The model predictions were successfully compared with lung function measurements following forced oscillatory breathing maneuvers and with in vivo measurements of cell counts, cytokines and surfactants in the lung lavage fluid of ENP exposed rodents. Ongoing work focusses on adaption of the mechanistic modules to support risk analysis of human exposures to ENPs.

M2-D.3  11:10  Development of a PBPK Model for ETBE and TBA in Rats and Its Application to Discern Relative Contributions to Liver and Kidney Effects. Brinkerhoff CJ*, Salazar KD, Lee JS, Chiu WA; Oak Ridge Institute for Science & Education, Oak Ridge, TN; ORD/NCEA-IRIS, US EPA, Washington DC; ORD/NCEA-IRIS, US EPA, Research Triangle Park, NC   brinkerhoff.chris@epa.gov

Abstract: Ethyl tert-butyl ether (ETBE) is an oxygenated gasoline additive. ETBE is rapidly absorbed and metabolized to acetaldehyde and tert-butyl alcohol (TBA). Published studies for both ETBE and TBA in rats have reported liver and kidney effects including increased organ weights, and nephropathy. The magnitudes of these effects vary by chemical and route of exposure. Additionally, exposure to ETBE by inhalation produced an increased incidence of liver adenomas in male rats, but ETBE delivered in drinking water or TBA in drinking water did not. This difference could be due to the higher internal dose of ETBE in the inhalation study compared to the ETBE and TBA drinking water studies. A physiologically-based pharmacokinetic (PBPK) model could estimate internal doses to aid in interpreting these differences in effect however there are no existing models of ETBE in rats or of direct administration of TBA. We have developed and applied a PBPK model of ETBE and TBA in rats. The PBPK model was parameterized with toxicokinetic data in rats from iv and inhalation studies of TBA and from oral and inhalation studies of ETBE. The PBPK model was used to make quantitative comparisons of the internal blood concentrations of ETBE and TBA associated with kidney and liver effects. The dose-response relationships for ETBE blood concentration and liver adenoma incidence across inhalation and oral routes support the hypothesis that the differences in the incidence of liver adenomas are due to differences in internal dose of ETBE. The model is also being used to evaluate differences between administered and metabolized TBA in dose-response relationships for nephropathy and kidney and liver weight changes. The views expressed in this abstract are those of the authors and do not necessarily represent the views or policies of the U.S. Environmental Protection Agency or other affiliations.

M2-D.4  11:30  Considering Buffers in Cumulative Risk Assessments. Evans AM*, Rice GE, Teuschler LK, Wright JM; AME-Oak Ridge Institute of Science and Education; GER, LKT, JMW-U.S. Environmental Protection Agency   evans.amandam@epa.gov

Abstract: Cumulative risk assessments (CRAs) quantitatively or qualitatively evaluate the risks of combined exposures to chemical and nonchemical stressors. CRAs also examine vulnerabilities (e.g., pre-existing health condition, genetic predisposition, poverty) as these may lead to variability in response to stressors. Resilience, the ability to adapt and/or recover from certain stressors (i.e., reduced risk), has rarely been considered in CRAs. Buffers (e.g., good nutrition, physical activity, healthy weight) may increase resilience. Existing CRA methods (e.g., the hazard index approach) may not work or may need to be altered for some buffers (e.g., due to U-shaped curves). Here, we examine the contribution of buffers in CRAs using fish consumption as a case study. Fish consumption is associated with exposure to multiple chemical stressors including methyl mercury (MeHg) and polychlorinated biphenyls (PCBs) associated with adverse neurodevelopment, as well as increased exposure to polyunsaturated fatty acids (PUFAs). PUFA exposures are potential buffers of adverse neurodevelopment, as they are associated with improved cognitive development. To characterize the joint neurodevelopmental hazard to MeHg, PCBs, and PUFAs, quantitative and qualitative approaches for CRA will be examined and general recommendations regarding the integration of buffers and resilience factors will be discussed. Case studies comparing the use of current and proposed methodologies will be important for the future incorporation of buffers and resilience factors in CRAs. The views expressed in this abstract are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA.



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