Defining embryonic developmental effects of chemical mixtures using the embryonic stem cell test

Area of Science:

• Developmental toxicology
• Risk assessment

Background:

• Cumulative risk assessment requires understanding combined effects of teratogenic compounds.
• The EU-H2020 project "EuroMix" investigated craniofacial malformations as a case study.

Purpose of the Study:

• To evaluate dose addition using the embryonic stem cell test (EST) for combined exposures of teratogenic compounds.
• To assess the applicability of dose addition in cumulative risk assessment for craniofacial malformations.

Main Methods:

• Applied the embryonic stem cell test (EST) to binary mixtures of teratogenic compounds.
• Selected compounds based on rodent studies, covering diverse chemical families and modes of action (MOA).
• Designed mixtures as equipotent concentrations of two compounds with similar or dissimilar MOA.

Main Results:

• The EST demonstrated dose addition for all studied binary mixtures, regardless of MOA.
• Overlapping dose-response curves were observed between single compounds and mixtures.
• EST was effective in evaluating differentiation-inhibiting effects on early craniofacial development.

Conclusions:

• Dose addition is a valid principle for assessing combined exposures of teratogenic compounds in the EST.
• Supports the use of dose addition as a default approach in cumulative risk assessment for craniofacial malformations.