Symposium Webinar

Opportunities and Challenges in Using the Kinetically Derived Maximum Dose Concept to Refine Risk Assessment

September 30, 2020

Two publications developed following this symposium are now available in Regulatory Toxicology and Pharmacology:

Questions and Answers directed to all participants

Questions and Answers for specific participants are linked below with the speakers' slides

Symposium Presentations

Welcome and Introductions 
Nicole Kleinstreuer, Ph.D., NICEATM


Use and Evaluation of KMD Data at USEPA's Office of Pesticide Programs
Anna Lowit, Ph.D., EPA

Q&A for Dr. Lowit


Current State-of-play: OECD Discussions on Doses Selection in Chronic Toxicity Studies
Anne Gourmelon, OECD

Q&A for Ms. Gourmelon


Problem Formulation: Background, Motivation, and Expected Outcomes
Michelle Embry, Ph.D., Health and Environmental Sciences Institute


Maximum Tolerated Dose: Concepts and Background
Chad Blystone, Ph.D., DABT, NTP

Q&A for Dr. Blystone


Concepts of Non-linear Pharmacokinetics and KMD
Alan Boobis, Ph.D., Imperial College London

Q&A for Dr. Boobis


Implications of Non-linear PK in Toxicity Testing and Interpretation of Dose-response Data
Salil Pendse, Nuventra, Inc.

Q&A for Mr. Pendse


Determining an Inflection Point from External-internal Dose Data
Philip Villanueva, EPA

Q&A for Mr. Villanueva


Estimating Human Exposures and Comparison to Doses Used in Testing
Jeff Dawson, EPA

Q&A for Mr. Dawson


Dose Setting and Considerations for the 3Rs
Fiona Sewell, Ph.D., National Centre for the Replacement Refinement & Reduction of Animals in Research

Q&A for Dr. Sewell


Integration of TK into Toxicity Studies and Dose Level Setting
Jean Domoradzki, Ph.D., DABT, Corteva Agriscience

Q&A for Dr. Domoradzki


Integrating KMD/TK Data with MoA and Other Information in a Weight of Evidence Approach
Harvey Clewell, Ph.D., Ramboll

Q&A for Dr. Clewell


Brief Summary
Cecelia Tan, Ph.D., EPA


Q&A and Additional Discussion
Moderator: Michelle Embry, Ph.D., Health and Environmental Sciences Institute


The kinetically derived maximum dose (KMD) refers to the dose at which a departure from dose proportionality or linear pharmacokinetics (PK) is observed. Non-linear PK can be caused by saturation or limitation of various factors related to absorption, distribution, metabolism, and excretion (ADME). In preclinical studies on new drugs conducted in animals, the KMD is routinely considered to provide perspective on the relevance of these studies to human safety assessment. Specifically, toxicity findings at doses above a KMD may not be relevant to human health risks when potential exposure levels are orders of magnitude lower.

In contrast to its routine use in pharmaceutical development, consideration of the KMD in the design or interpretation of animal toxicity studies for environmental chemicals is rare. Interest is growing in use of the KMD to interpret animal dose-response data or set top dose in chronic toxicity studies of these chemicals, but many technical and scientific issues hinder its proper use. The purpose of this symposium was to highlight these commonly raised issues and provide the background information needed to develop more consistent, transparent approaches to support broader KMD application in risk assessment.  

The presentations in this symposium reviewed the application of the KMD in toxicity testing. They summarized commonly raised technical and scientific issues related to the use of KMD as an approach to select doses in toxicology testing studies or to interpret dose-response study results. Examples of these issues include:

  • Appropriate use of PK data to determine dose non-linearity.
  • The possibility of human exposure levels close to KMD.
  • Determination of KMD from sparse blood or tissue concentration data.
  • Use of in silico models to predict systemic dose and key ADME parameters.
  • Use of KMD to set the top dose in toxicity studies.

The symposium was organized by NICEATM, the U.S. Environmental Protection Agency Office of Pesticide Programs, and the Health and Environmental Sciences Institute.