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Toxic Reactions: Overview01:26

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Developing an internal threshold of toxicological concern (iTTC).

Jon A Arnot1,2,3, Liisa Toose4, James M Armitage4

  • 1ARC Arnot Research and Consulting Inc., Toronto, ON, Canada. jon@arnotresearch.com.

Journal of Exposure Science & Environmental Epidemiology
|November 8, 2022
PubMed
Summary
This summary is machine-generated.

New internal Threshold of Toxicological Concern (iTTC) values enable chemical safety assessments for multiple exposure routes and aggregate exposures. These iTTCs provide a more versatile approach for risk-based priority setting for data-poor chemicals.

Keywords:
Exposure modeling, Dermal exposure, Dietary exposure, Inhalation exposure, New approach methodologies (NAMs), PBPK modeling

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Area of Science:

  • Toxicology and Chemical Safety Assessment
  • Risk Assessment and Management
  • Environmental Health and Safety

Background:

  • Traditional Threshold of Toxicological Concern (TTC) approaches rely on single-route exposure data (e.g., oral intake).
  • Existing TTCs are insufficient for evaluating aggregate exposures or scenarios involving multiple exposure routes (oral, dermal, inhalation).
  • This limitation hinders comprehensive chemical safety assessment for complex exposure patterns.

Purpose of the Study:

  • To develop and validate a novel method for deriving internal TTCs (iTTCs).
  • To enable chemical safety assessments across various exposure routes and aggregate exposure scenarios.
  • To enhance risk-based priority setting for chemicals with limited toxicological data.

Main Methods:

  • Utilized chemical-specific toxicokinetic (TK) data and models to convert oral dose No Observed Effect Levels (NOELs) into internal concentrations (whole-body and blood).
  • Calculated new iTTCs based on the 5th percentile of internal NOEL distributions, applying a standard uncertainty factor of 100.
  • Established iTTC values for whole-body (0.5 nmol/kg) and blood (0.1 nmol/L).

Main Results:

  • Derived new internal TTC (iTTC) values for whole-body and blood exposure assessments.
  • Reported iTTCs are 0.5 nmol/kg (whole-body) and 0.1 nmol/L (blood), applicable to many organic chemicals.
  • iTTCs can be converted to mass-based units and are suitable for comparison with measured or estimated exposure concentrations.

Conclusions:

  • Developed internal TTCs (iTTCs) offer a significant advancement over traditional TTCs for chemical safety assessment.
  • iTTCs provide a unified framework for evaluating risks from single, multiple, and aggregate chemical exposures.
  • This approach enhances the ability to prioritize chemicals for further safety evaluation, particularly for data-poor substances.