TABLE 4.
Comparison of human EADs predicted from different assays and PBPK models
| EBA | MPA | MHA | EHA | VPA | |
|---|---|---|---|---|---|
| EAD_Httk.PBTK a | 484.7 (404.5) | 541.2 (440.6) | 285.5 (176.0) | 47.0 (22.4) | 10.4 (4.5) |
| EAD_Gp.preg.PBTK a maternal | 153.2 (127.8) | 166.9 (135.8) | 59.12 (36.5) | 14.1 (6.7) | 6.4 (2.7) |
| Range of all human OEDs reported (OECD, 2020) b | 34.4–826.6 | 35.2–1,353.3 | 2.3–928.4 | 0.74–901.3 | 0.11–51.9 |
| Range of human OEDs estimated from most sensitive endpoints | 35.8–357.8 | 37.3–261.1 | 2.3–286.3 | 2.6–10 | 0.11–3.2 |
| OEDs from the most sensitive endpoints in each in vitro model category (OECD, 2020) | |||||
| ZET assay: Pericardial and/or yolk edema, Total embryo EC10 | 53.3 | 84.5 | 55.1 | 4.8 | 2.8 |
| ZET CHA reporter assay: Scoliosis/lordosis, Total embryo EC10 | 124.9 | 44.5 | NA | 0.74 | 0.1 |
| mEST assay: HDAC inhibition, day10, medium‐unbound EC10 | 357.8 | 261.1 | 286.3 | 10 | 2 |
| UKN1 assay: HDAC inhibition, medium‐unbound EC10 | 161.4 | 186.6 | 254.8 | 6 | 3 |
| CALUX reporter assay: Minimum cell‐total EC10 | 35.8 | 37.3 | 2.3 | 2.6 | 3.2 |
Abbreviations: CALUX, Chemically Activated LUciferase eXpression reporter gene assays; CHA, ceratohyal angle assay that assesses the morphological appearance of the ceratohyal; D3, ES cells; EAD, equivalent administered dose; EBA, 2‐ethylbutyric acid or 2‐ethylbutanoic acid (IUPAC name); EC10, effect concentration at which 10% effect is observed compared to the control; EHA, 2‐ethylhexanoic acid; HDAC, histone deacetylase; mEST, mouse embryonic stem cell test; MHA, 2‐methylhexanoic acid; MPA, 2‐methylpentanoic acid; OED, oral equivalent dose; PBPK, physiologically based pharmacokinetic; PBTK, physiologically based toxicokinetic; UKN1, iPSC‐based neurodevelopmental model; VPA, valproic acid; ZET, zebrafish embryo test.
EADs corresponding to nominal (outside of parenthesis) or free medium (inside of parenthesis) dTP concentrations. EAD values in boldface indicate those values that were within the range of human OEDs corresponding to the most sensitive endpoints in each in vitro model category (OECD, 2020).
The individual human oral equivalent dose extracted from literature are contained in Table S6.