Quantitative extrapolation of in vitro whole embryo culture embryotoxicity data to developmental toxicity in vivo using the benchmark dose approach.
If in vitro data are to be used as a basis for hazard characterization, a translation of an in vitro concentration toward an in vivo dose must be made. In this study we examined the correlation between dose descriptors from the in vitro Whole Embryo Culture (WEC) test and in vivo developmental toxicity tests. We applied the Benchmark Dose (BMD) approach to estimate equipotent in vitro concentrations (Benchmark Concentrations [BMCs]) and equipotent in vivo doses (BMDs). Using the data generated in an European Center for the Validation of Alternative Methods validation study we found that the BMCs were highly reproducible among laboratories. The three endpoints analyzed (head length, crown-rump length, and total morphological score) were strongly correlated. A clear in vitro-in vivo correlation was found between BMCs and BMDs. However, a considerable uncertainty would remain if the BMDs were estimated from the BMC using this correlation: the confidence interval of such an in vivo dose estimate would span various orders of magnitude. Differences in toxicokinetic properties among the compounds explained at least part of the scatter of the in vitro-in vivo correlation. But also heterogeneity in the design of the available in vivo studies underlies much of the scatter, and this puts a limit on validating in vitro data as predictors of in vivo data. Further analysis of the in vitro-in vivo correlation would therefore require high-quality in vivo data, generated by appropriate (and similar) study designs.
Piersma
Aldert H
AH
National Institute of Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands. ah.piersma@rivm.nl
Janer
Gemma
G
Wolterink
Gerrit
G
Bessems
Jos G M
JG
Hakkert
Betty C
BC
Slob
Wout
W
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D046149:Embryo Culture Techniques; D023381:Endpoint Determination; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D010599:Pharmacokinetics; D011247:Pregnancy; D051381:Rats; D012015:Reference Standards; D013723:Teratogens / Q000633:toxicity*; D014116:Toxicology / Q000379:methods*; D054928:Validation Studies as Topic
D013723:Teratogens