Data derived Extrapolation Factors for developmental toxicity: A preliminary research case study with...

Area of Science:

• Environmental toxicology and risk assessment
• Developmental toxicology and chemical exposure
• Pharmacokinetics and interspecies extrapolation

Background:

• Regulatory guidelines from EPA and IPCS offer differing default approaches for dosimetric extrapolation in toxicity assessments.
• EPA (1991) suggests peak concentration (Cmax), while IPCS (2005) recommends area under the curve (AUC) when critical effect dosimetry is unknown.
• Accurate dose metrics are crucial for developing Chemical Specific Adjustment Factors (CSAFs) and Data-Derived Extrapolation Factors (DDEFs).

Purpose of the Study:

• To derive a DDEF for developmental toxicity of perfluorooctanoic acid (PFOA).
• To identify the appropriate dosimetric adjustment for PFOA developmental effects by comparing animal and human kinetic data.
• To evaluate the influence of different dosimetric approaches (Cmax vs. AUC) on risk assessment for PFOA.

Main Methods:

• Reviewed developmental effects of PFOA identified by EPA (2016) to determine relevant dosimetric parameters.
• Compared PFOA pharmacokinetic data from mouse studies with newly available human data from a Phase 1 clinical trial (Elcombe et al., 2013).
• Calculated DDEF for PFOA using average concentration during critical developmental exposure windows.

Main Results:

• Most PFOA developmental effects appear related to average concentration or AUC during specific developmental windows, rather than Cmax.
• Derived DDEF values for PFOA were 1.3 or 14, differing significantly from other assessments based on interspecies half-life differences.
• The derived DDEFs align with current EPA (2014) and IPCS (2005) guidelines for risk assessment.

Conclusions:

• Average concentration during critical exposure windows is a more appropriate dose metric than Cmax for PFOA developmental toxicity extrapolation.
• The derived DDEF provides a refined approach to interspecies dosimetric adjustment for PFOA risk assessment.
• This research supports the use of exposure-window-specific average concentrations for developing robust DDEFs in toxicological evaluations.