Journal Article

Testing for Additivity in Chemical Mixtures Using a Fixed-Ratio Ray Design and Statistical Equivalence Testing Methods

Stork, LeAnna G., Gennings, Chris, Carter, Walter H., Wagner, Elizabeth D., Simmons, Jane Ellen, Johnson, Robert E., Plewa, Michael J., Mays, Darcy P.

2007

Overview

Fixed-ratio ray designs have been used for detecting and characterizing interactions of large numbers of chemicals in combination. Single-chemical dose—response data are used to predict an \"additivity curve\" along an environmentally relevant ray. A \"mixture curve\" is estimated from the mixture dose—response data along the ray. A test of additivity is equivalent to a test of these two curves, which is based on the traditional hypothesis testing framework that assumes additivity in the null hypothesis and rejects with evidence of interaction. However, failure to reject may be due to lack of statistical power, making the claim of additivity problematic. As a solution we have developed rigorous methodology to test for additivity using statistical equivalence testing logic in which additivity is claimed based on pre-specified biologically important additivity margins, if the data support such a claim. Using the principle of confidence interval inclusion, a confidence region about the difference of meaningful functions of model parameters from the mixture model and that predicted under additivity is computed. When the confidence region is completely contained within the additivity margins then additivity is claimed with a Type I error rate chosen a priori to be some acceptably small value. The method is illustrated using an environmentally relevant fixed-ratio mixture of nine haloacetic acids where cytotoxic response is measured.

• Publisher: American Statistical Association and the International Biometric Society,American Statistical Association,International Biometric Society
• Subject: Additivity / Agronomy. Soil science and plant productions / Animal, plant and microbial ecology / Applied ecology / Biological and medical sciences / Biometrics, statistics, experimental designs, modeling, agricultural computer applications / Chemical mixtures / Confidence interval / Disinfection / Dose response relationship / Ecotoxicology, biological effects of pollution / Equivalence relation / Fundamental and applied biological sciences. Psychology / Generalities. Biometrics, experimentation. Remote sensing / Modeling / Parametric models / Risk analysis / Toxicology