US EPA

This White Paper describes current U.S. EPA practices associated with dose additive methods for human health risk assessments of chemical mixtures. It discusses challenges associated with the use of toxicological information and individual chemical dose response information when applying dose additive methods and considers the potential for future applications of dose addition that take advantage of kinetic and dynamic data generated from New Approach Methodologies (NAMs). In particular, it:

1. addresses challenges associated with the use of toxicological information and individual chemical dose response information when applying such methods,
2. considers the potential for future applications of dose addition that use toxicokinetic and toxicodynamic data generated from New Approach Methodologies (NAMs), and
3. discusses uncertainties in conducting risk and hazard assessments using dose-additive mixture methods.

Dose addition provides a simple mathematical approach for estimating joint toxicity associated with complex interactions among biological systems and combinations of chemicals encountered in the environment. The use of dose additive models is the default approach of U.S. EPA for assessing the noncancer health hazards from mixtures of toxicologically similar chemicals because it has been shown to be, for similar chemicals, reasonably predictive of combined effects. These dose additive methods follow U.S. EPA’s 1986 Guidelines for the Health Risk Assessment of Chemical Mixtures and U.S. EPA’s 2000 Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures. These two documents describe several dose additive methods that were available for use by U.S. EPA to assess health risks from chemical mixtures, and also stress the feasibility, practicality, and usefulness of these methods.

This document was prepared by a Risk Assessment Forum (RAF) Cumulative Risk Assessment Technical Panel composed of senior risk assessors and toxicologists from across the U.S. EPA and through an interagency agreement with Argonne National Laboratories and an U.S. EPA contract. The RAF is a standing committee of senior U.S. EPA scientists that was established to promote Agency-wide consensus on risk assessment issues and to ensure that this consensus is incorporated into appropriate U.S. EPA risk assessment guidance.

The purpose of this White Paper is to explain methods currently in use by the U.S. EPA and to stimulate development of improved methods for assessing health risks from environmental chemical mixtures by discussing advances in practices for evaluating chemical mixtures and considerations when applying new sources of toxicological data.

U.S. EPA. Advances in Dose Addition for Chemical Mixtures: A White Paper. U.S. Environmental Protection Agency, Washington, DC, EPA/100/R-23/001, 2023.