Evaluation of the Interaction-Based Hazard Index Formula Using Data on Four Trihalomethanes from U.S. EPA’s Multiple-Purpose Design Study

Author:

Hertzberg Richard C.1,Teuschler Linda K.2,McDonald Anthony3,Sey Yusupha Mahtarr3ORCID,Simmons Jane Ellen3

Affiliation:

1. Biomathematics Consulting, Atlanta, GA 30307, USA

2. LK Teuschler & Associates, St. Petersburg, FL 33707, USA

3. Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA

Abstract

The interaction-based hazard index (HIINT), a mixtures approach to characterizing toxicologic interactions, is demonstrated and evaluated by statistically analyzing data on four regulated trihalomethanes (THMs). These THMs were the subject of a multipurpose toxicology study specifically designed to evaluate the HIINT formula. This HIINT evaluation uses single, binary and quaternary mixture THM data. While this research is considered preliminary, the results provide insights on the application of HIINT when toxicology mixture data are available and on improvements to the method. The results for relative liver weight show the HIINT was generally not conservative but did adjust the additive hazard index (HI) in the correct direction, predicting greater than dose-additivity, as seen in the mixture data. For the liver serum enzyme endpoint alanine aminotransferase, the results were mixed, with some indices giving an estimated effective dose lower than the observed mixture effective dose and others higher; in general, the HIINT adjusted the HI in the correct direction, predicting less than dose-additivity. In addition, a methodological improvement was made in the calculation of maximum interaction magnitude. Suggested refinements to the HIINT included mixture-specific replacements for default parameter values and approaches for supplementing the usual qualitative discussions of uncertainty with numerical descriptions.

Funder

U. S. Environmental Protection Agency

Publisher

MDPI AG

Reference43 articles.

1. U.S. EPA (1986). Guidelines for the Health Risk Assessment of Chemical Mixtures, EPA/630/R-98/002.

2. Regulatory assessment of chemical mixtures: Requirements, current approaches and future perspectives;Kienzler;Regul. Toxicol. Pharmacol.,2016

3. Kortenkamp, A., Backhaus, T., and Faust, M. (2009). State of the Art Report on Mixture Toxicity, University of London.

4. Regulatory assessment and risk management of chemical mixtures: Challenges and ways forward;Bopp;Crit. Rev. Toxicol.,2019

5. U.S. EPA (2000). Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures, EPA/630/R-00/002.

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