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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Toxicol Appl Pharmacol. 2019 Dec 30;389:114876. doi: 10.1016/j.taap.2019.114876

Figure 7. Comparison of HTPP Assay Results to In Vivo Effect Values and published NAM Results.

Figure 7.

(A) Comparison of different alternative approaches to the PODtrad. HTPP PODs were used to extrapolate an administered equivalent dose (HTPP AED) that would correspond to a plasma concentration equivalent to the HTPP POD in a human population. The median HTPP AED (HTPP AED 50th) was then compared to the 5th percentile (PODtrad) derived from a collection of in vivo mammalian effect values from a variety of study types and test species that used an oral route of administration. Similarly, PODs from the ToxCast assay suite were calculated from published literature (Paul-Friedman et al., 2019), extrapolated to AEDs and compared to PODtrad. For comparison, TTCs from the same study were added as well. Vertical dotted lines and numbers below indicate the median of the distribution for each NAM. The vertical dashed line indicates the unity line. The histogram comprises only chemicals that had available HTTK and in vivo data (ToxCast n=426, TTC n=413, HTPP n=420 (only HTPP hits)).

(B) IVIVE results for exemplary chemicals. The PODtrad values (lightblue squares) are compared to HTPP AED results. Monte Carlo simulation was used during reverse dosimetry analysis to account for physiological diversity in an average human population. The median and 5th to 95th confidence interval are shown for HTPP AED (purple circle and error bars). For ToxCast, only the median AED is displayed (darkblue diamonds). Chemicals were sorted according to the difference between the HTPP AED distribution and the PODtrad and grouped into “below”, “within” and “above” categories as described in Methods.

(C) Tally of the number of chemicals grouped in the “above”, “within” and “below” categories. Chemicals in the former group had AEDs that overpredicted the dose associated with in vivo effects. Chemicals in the two latter groups provided either a comparable or conservative surrogate for the PODtrad, respectively. Since no dose range exists for the TTC approach, the chemicals were grouped into “above” and “below” only.