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Harvey Clewell
Principal Consultant at Ramboll

Dr. Harvey J. Clewell is a research scientist with over forty-five years of experience in environmental quality and toxicology research, chemical risk assessment and hazardous materials management.  He is currently a Principal Consultant with Ramboll US Consulting, Inc.  He has gained an international reputation for his work on the incorporation of mechanistic data and mode of action information into chemical risk assessments, having played a seminal role in the use of physiologically based pharmacokinetic modeling in cancer and non-cancer risk assessments.  In 2007 the Society of Toxicology recognized Dr. Clewell with the Arnold J. Lehman Award for major contributions to chemical safety and risk assessment.  He also served as a member of the ECVAM Scientific Advisory Panel from 2012 to 2016. 

OpenTox Summer School 2022 

Open-Source Toxicokinetic Modeling Resources

Harvey Clewell and Matt Linakis, Ramboll US Consulting, Inc.

It is becoming increasingly evident that there is a need for accessible open-source tools for Physiologically Based Kinetic (PBK) modeling that are fit for the purpose of specific modeling requirements (e.g., pharmaceutical, cosmetic, agrochemical, academic) and user types (i.e., developer, regulator, student).  In this session, we will present the results of a comprehensive evaluation of open-source PBK modeling platforms to provide a basis for determining which of the platforms are most suitable for applications of interest to different communities of users and developers.  Demonstrations will then be presented using three popular open-source platforms: the USEPA httk package, Magnolia and PK-Sim/MoBi. For those interested in getting a jump start, Magnolia can be downloaded here:  The download includes PBPK models for butadiene (under parameter estimation) and perchloroethylene (under Monte Carlo analysis) as examples.

OpenTox 2022 Virtual Conferecne 

PBPK and Toxicokinetic Modeling

The field of toxicology is currently undergoing a global paradigm shift to the use of in vitro approaches for assessing the risks of chemicals and drugs in a more mechanistic and higher throughput manner. However, reliance on in vitro data entails a number of new challenges associated with translating the in vitro results to corresponding in vivo exposures. Physiologically based kinetic (PBK) modeling provides an effective framework for conducting quantitative in vitro to in vivo extrapolation (IVIVE). The combination of in silico- and in vitro parameter estimation with PBPK modeling can be used to predict the in vivo exposure conditions that would produce chemical concentrations in the target tissue equivalent to the concentrations at which effects were observed with in vitro assays of tissue/organ toxicity.  This session will focus on recent progress in the development and application of open source PBK tools for IVIVE, with an emphasis on efforts to increase regulatory acceptance of NAMS.

Application of Open Source, Next Generation Physiologically Based Kinetic (NG-PBK) Models for In Vitro to In Vivo Extrapolation (IVIVE) of Toxicity Assays

The application of NG-PBK models in regulatory risk assessment has often been challenging due to limitations in available open-source modelling tools.  Some regulatory agencies have required that PBK models be submitted only as open-source code and refuse to consider modeling conducted with proprietary platforms.  As a result, there has been an increasing use of unstructured programming languages such as R for model submissions.  However, regulatory review and evaluation of such models has often been hampered by the difficulty of recruiting peer reviewers possessing the necessary programming expertise and the willingness to invest the significant time and effort required, particularly when the model being reviewed is complex.  To increase the accessibility of PBPK modelling to both regulators and stakeholders, there is a pressing need for further development of open-source PBK modelling tools that are more user-friendly, flexible and transparent.  This presentation will provide examples of the application of a simple, generic PBK model to support risk assessments for oral and dermal exposures to cosmetics.   The model, which runs in the open-source tool, Magnolia, takes advantage of the self-documenting features of Magnolia to greatly simplify the process of regulatory evaluation.