Workshop on In Vitro to In Vivo Extrapolation

In Vitro to In Vivo Extrapolation for High Throughput Prioritization and Decision Making

February 17-18, 2016
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina, USA

Data from high throughput in vitro tests are being generated for many chemicals of environmental and commercial interest, with the expectation that in vitro assay data could ultimately be used to predict adverse effects of chemical exposures in vivo. Translating values obtained from in vitro assays into estimates of in vivo outcomes is a complex process involving the use of mathematical modeling and increasingly complex test systems. This series of four webinars culminating in an in-person workshop addressed the capabilities and the limitations of in vitro to in vivo extrapolation (IVIVE) within the context of risk decision making.

During the workshop participants (1) reviewed the state of the science to form recommendations on the best practices for using IVIVE in chemical screening and risk decision making, (2) identified areas that require additional data and/or research, and (3) highlighted examples of how best to apply IVIVE in a tiered risk decision-making strategy.

The workshop built on information presented in an October 2015-January 2016 webinar series. Slides from the webinars are available below under "Webinar Materials."

Workshop Materials

Workshop Presentations

Opening Session


The EURL ECVAM Toxicokinetics Report and EURL ECVAM Strategy
Alicia Paini, European Union Reference Laboratory for Alternatives to Animal Testing

Workshop Background and Summaries of Webinars
John Wambaugh, U.S. Environmental Protection Agency (EPA)

Session 1: Application in Risk Assessment: What Do We Need for Decision-making and Prioritization?

Using In Vitro Data in Quantitative Risk Assessments (QRAs)
Paul Price, EPA

Interindividual Variability in High Throughput Risk Prioritization of Environmental Chemicals
Caroline Ring, EPA

Quantitative Considerations of Dose-Response for IVIVE
Ted Simon, Ted Simon LLC

Toxicokinetics in Risk Assessment: From Predictive Evaluations to Regulatory Testing
Mike Bartels, The Dow Chemical Company

Development and Application of Biologically Based Dose-Response Modeling for Pregnancy Conditions: Evaluation of Thyroid Active Chemical Exposure During Sensitive Life Stages
Annie Lumen, U.S. Food and Drug Administration

Session 2: Metabolism and Excretion

Strength and Limitations of In Vitro Xenobiotic Metabolism Assays and In Silico Models
Stephen Ferguson, NIEHS

In Silico Screening of Primary Clearance Mechanisms
John Troutman, The Procter & Gamble Company

In Vitro Models for Quantitative Prediction of Hepatobiliary Clearance
Kim Brouwer, University of North Carolina at Chapel Hill

Session 3: In Silico Modeling

Predictive Power of PBPK Modeling and In Silico/In Vitro-In Vivo Extrapolation Using GastroPlus™ and ADMET Predictor™ Software Tools
Grazyna Fraczkiewicz, Simulations Plus, Inc.

In Vitro In Vivo Extrapolation and its Applications in Predicting Pharmacokinetic Population Variability
Alice Ke, SimCyp, a Certara Company

Summary Presentations

Day 1 Wrap-up
Barbara Wetmore, ScitoVation, LLC

Breakout Group Summary

Webinar Materials

October 7: Setting the Stage: Purpose, Definitions, Scope, and Assumptions

Barbara Wetmore, Ph.D., The Hamner Institutes for Health Sciences

November 4: Building Fit-for-purpose Pharmacokinetic Models

John Wambaugh, Ph.D., National Center for Computational Toxicology, U.S. Environmental Protection Agency

December 3: The Role of Pharmacokinetic Model Evaluation

Lisa Sweeney, Ph.D., Naval Medical Research Unit Dayton and Jackson Foundation for the Advancement of Military Medicine

January 6: Framework for Establishing an Internal Threshold of Toxicological Concern

Corie Ellison, Ph.D., Sharon Woods Innovation Center, The Procter & Gamble Company