Internal threshold of toxicological concern values: enabling route-to-route extrapolation

Area of Science:

• Toxicology
• Risk Assessment
• Computational Chemistry

Background:

• The Threshold of Toxicological Concern (TTC) concept uses generic human exposure thresholds derived from animal testing to assess chemical safety.
• Current TTC values are based on external oral exposure, limiting their application for substances with low absorption.
• Internal exposure is more relevant for risk assessment of chemicals with low oral or dermal absorption.

Purpose of the Study:

• To derive internal TTC values for a more accurate risk assessment of substances with low internal exposure.
• To adapt the TTC concept for scenarios involving negligible absorption and low internal exposure.

Main Methods:

• External no-observed-adverse-effect levels (NOAELs) from three databases were multiplied by individual chemical bioavailability.
• Oral bioavailability was predicted using the in silico ACD Percepta tool.
• Internal TTC values were calculated using a reduced uncertainty factor of 25.

Main Results:

• Internal TTC values were derived for different chemical categories (Cramer classes).
• For Cramer class I, the internal TTC is 6.9 μg/kg bw/d (90% CI: 3.8-11.5 mg/kg bw/d).
• For Cramer classes II/III, the internal TTC is 0.1 μg/kg bw/d (90% CI: 0.08-0.14 μg/kg bw/d).

Conclusions:

• The derived internal TTC values enable the application of the TTC concept to low internal exposure situations.
• This advancement supports regulatory risk assessment for chemicals with limited absorption.
• The study provides a refined approach to chemical safety evaluation by considering internal exposure metrics.