Derivation of New Threshold of Toxicological Concern Values for Exposure via Inhalation for Environmentally-Relevant Chemicals.

Mark D Nelms,Grace Patlewicz

doi:10.3389/ftox.2020.580347

Abstract

The requirements of amended Toxic Substances Control Act (TSCA) stipulates that the US Environmental Protection Agency (US EPA) evaluate existing chemicals and make risk based assessments. There are ~33,000 substances that are active in commerce on the TSCA public non-confidential inventory, many of which lack available toxicity and exposure information to inform risk-based decision making. One approach to facilitate the assessment of these substances being considered is the Threshold of Toxicological Concern (TTC). TTC values are intended to identify safe levels of exposure for data poor substances. TTC values derived based on non-cancer data notably by Munro et al. (1996) are well-established and are in routine use for food additive applications however far less attention has been focused on developing TTC values where inhalation is the route of exposure. Here, an effort was made to derive new inhalation TTC values using the EPA's Toxicity Values database, ToxValDB. A total of 4,703 substances captured in ToxValDB were assigned into their respective TTC categories using the Kroes module within the Toxtree software tool and custom profilers developed in Nelms et al. (2019) and Patlewicz et al. (2018). For the substances assigned into the 3 Cramer classes, the 5th percentiles were calculated from the empirical cumulative distributions of No observed (adverse) effect level (concentration) values. The 5th percentiles were converted to their respective TTC values and compared with published values reported by Escher et al. (2010) and Carthew et al. (2009). The TTC values derived from ToxValDB were orders of magnitude more conservative, further, Cramer classification was not found to be effective at discriminating potencies. Instead, use of aquatic toxicity modes of action such as Verhaar et al. (1992) were found to be effective at separating substances in terms of their potencies and new TTC thresholds were derived.

Highlights

The basis of the Threshold of Toxicological Concern (TTC) approach relies on setting a level of human intake or exposure that is considered to be of negligible risk, despite the absence of chemical-specific toxicity data
Three sources of toxicity data were utilized in this study: (1) the US Environmental Protection Agency (US EPA)’s Toxicity Values database, referred to as ToxValDB; (2) the inhalation TTC dataset from Appendix A of the Escher et al (2010) manuscript, referred to as the “Escher dataset”; and (3) the inhalation TTC dataset from Appendix A of the Carthew et al (2009) manuscript, referred to as the “Carthew dataset.”
It comprises point of departure (POD) values such as NO(A)EC and lowest-observed effect concentration (LO(A)EC) data. These data have been aggregated from over 40 publicly available sources including US Federal and State agencies [e.g., US EPA, US Food and Drug Administration (FDA), and California EPA], alongside international organizations [e.g., World Health Organization (WHO)], as well as data submitted under regulatory frameworks, such as the European Union’s REACH regulation [e.g., non-confidential registration data submitted to the European Chemicals Agency (ECHA) by industry registrants]

Summary

Introduction

The basis of the Threshold of Toxicological Concern (TTC) approach relies on setting a level of human intake or exposure that is considered to be of negligible risk, despite the absence of chemical-specific toxicity data. The workflow in practice starts with a consideration of whether a substance should be excluded from the TTC approach, that it is to say, it is inorganic, bioaccumulative (dioxin like), a protein, a polymer etc. If substance is not excluded from consideration for TTC, the step in the workflow considers whether the substance presents any structural alerts that raise concern for potential genotoxicity. If a substance presents no alerts for genotoxicity, the step in the TTC workflow considers whether the substance is an organophosphate or carbamate—if yes, a TTC value of 18 ug/day (0.3 ug/kg-day) is assigned. The Cramer class decision tree and the Kroes et al (2004) workflow has been implemented in software tools such as Toxtree (Patlewicz et al, 2008) and the OECD Toolbox (Schultz et al, 2018)

Methods

Results

Conclusion