Toxic Responses Induced at High Doses May Affect Benchmark Doses

Area of Science:

• Toxicology
• Risk Assessment
• Pharmacokinetics

Background:

• The benchmark dose (BMD) approach is replacing the no-observed-adverse-effect level (NOAEL) for deriving health-based guidance values.
• The BMD approach utilizes benchmark dose lower confidence bounds (BMDLs) from dose-response models across the entire tested dose range.
• This method assumes high-dose responses are relevant for modeling low-dose effects, crucial for establishing reference points (RPs).

Purpose of the Study:

• To investigate the impact of high-dose specific mechanisms of action (MOAs) on BMDLs.
• To determine if high-dose responses, potentially unrelated to low-dose effects, distort low-dose modeling.
• To assess the sensitivity of BMDLs to high-dose specific responses.

Main Methods:

• Simulated quantal response data based on a low-dose and a high-dose MOA.
• Applied the benchmark dose (BMD) approach to model the simulated data.
• Analyzed the resulting BMDLs to assess their distribution and sensitivity.

Main Results:

• Modeled BMDLs exhibited wide scattering, often overlapping with the toxic dose range.
• BMDLs were found to be sensitive to high-dose responses, even those irrelevant to low-dose effects.
• The presence of a high-dose specific MOA significantly influenced the resulting BMDLs.

Conclusions:

• High-dose specific responses can unduly influence BMDLs derived from low-dose data.
• Careful consideration of potential high-dose MOAs is necessary when applying the BMD approach.
• Ensuring the relevance of high-dose data for low-dose modeling is critical for accurate risk assessment.