2.2.3. TOX Risk
The TOX_Risk model consists of seven rules, including one based on MUT_Risk. Each has an associated weight of one:
|
hERG: |
hERG_FILTER = Yes AND hERG_pIC50 > [5.5,6.0] (potential hERG liability) |
|---|---|
|
rat: |
Rat_ Acute < [200,300] (acute toxicity in rats) |
|
Xr: |
Rat_TD50 < [2.5,5] (carcinogenicity in chronic rat studies) |
|
Xm: |
Mouse_TD50 < [25,40] (carcinogenicity in chronic mouse studies) |
|
HEPX: |
Ser_AST = Elevated AND Ser_ALT = Elevated AND
|
|
MUT: |
MUT_Risk > 1 |
The rat and mouse toxicity thresholds are based on the distribution of in-scope values in the focused WDI, as is the mutagenicity threshold. The hepatotoxicity rule “HEPX” reflects the way actual blood test results are interpreted – e.g., hepatotoxicity is indicated if aspartic acid transaminase (Ser_AST) and alanine transaminase (Ser_ALT) are both elevated in serum. Liver injury also usually elevates serum levels of lactate dehydrogenase, and including Ser_LDH in the rule reduces the number of false positives. Concomitant elevation of the other serum enzyme model predictions - Ser_AlkPhos or Ser_GGT - is indicative of even more severe liver injury.
The MUT_Risk component of TOX_Risk and ADMET_Risk integrates the 10 test predictions from our [in silico Ames tests] for mutagenicity. Details are provided under Mutagenicity section. It exceeds 1.0 for 15% of the focused WDI subset and exceeds 1.2 for 9% of it.
Most of the individual TOX_Risk rules are rather conservative, with each individual rule being violated to some extent by 7-16% of in-scope predictions for our WDI reference set. TOX_Risk is greater than 2.0 for 6% of the focused WDI after default out-of-scope Risk penalties have been factored in; it is equal to 2.0 for 10% of it.