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Evaluation of a rapid, generic human gestational dose model.
Dustin F Kapraun1, Mark Sfeir2, Robert G Pearce2
1Center for Public Health and Environmental Assessment, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Reproductive Toxicology (Elmsford, N.Y.)
|September 19, 2022
Summary
A new generic physiologically based toxicokinetic (PBTK) model estimates chemical exposure in pregnant women and fetuses. This tool aids reproductive toxicity risk assessment by simulating chemical transfer and prioritizing high-risk substances.
Area of Science:
- Environmental Health
- Toxicology
- Pharmacokinetics
Background:
- Chemical risk assessment must consider susceptible populations like pregnant women and fetuses.
- Limited toxicokinetic (TK) data exists for most environmental chemicals.
- Physiologically based TK (PBTK) models are crucial for estimating chemical exposure and tissue concentrations.
Purpose of the Study:
- To develop and evaluate a generic PBTK model for human pregnancy.
- To estimate chemical concentrations in maternal and fetal compartments.
- To prioritize chemicals based on predicted fetal exposure.
Main Methods:
- Augmented the High-Throughput Toxicokinetics (httk) software with pregnancy-specific physiological formulas.
- Simulated maternal-fetal plasma concentration ratios.
- Validated the model using in vivo measurements of maternal plasma concentrations.
- Prioritized chemicals based on predicted fetal brain concentrations.
Main Results:
- The generic PBTK model successfully simulated maternal-fetal chemical concentration ratios.
- Model predictions aligned with literature in vivo data for maternal plasma concentrations.
- The model can simulate 859 chemicals with existing in vitro TK data.
Conclusions:
- A generic PBTK model for pregnancy is a valuable tool for risk assessment.
- This model facilitates in vitro to in vivo extrapolation for reproductive and developmental toxicity.
- It enables efficient prioritization of chemicals for further safety evaluation.
