Summary of the toolbox performance for chemicals with high-risk exposure scenarios and investigation of the ability of the toolbox to make protective decisions irrespective of detection of the mode of action.
| Toolbox is not protective . | Toolbox is protective but MOA is not detected . | Toolbox is protective and MOA detected . |
|---|---|---|
| Trimellitic Anhydride—serum IgE increase as a result of respiratory sensitization | Azathioprine—purine mimic inhibiting DNA synthesis (potentially metabolism limited) | Cetirizine Hydrochloride—histamine H1 receptor inhibition |
| Warfarin—VKORC1 inhibition and anticoagulation effects | Benzocaine—methaemoglobin formation | Dexamethasone—Glucocorticoid receptor binding |
| Chlorpyrifos—AChE inhibition (metabolism driven) | Fenbuconazole—interference with steroid biosynthesis (Aromatase) | |
| Cyclophosphamide—DNA binding/damage (metabolism driven) | Furosemide—primary mode of action is Na-k-Cl transporter binding (not detected). Secondary mode of action is increase in prostaglandin synthesis (COX1+COX2) (detected) | |
| Digoxin—Na+/K+-ATPase inhibition | Ibuprofen—COX 1 and COX 2 inhibition | |
| Glibenclamide—K+ channel inhibition | Ketoconazole (oral)—prevention of ergosterol synthesis (Aromatase) | |
| Hydralazine hydrochloride—Ca2+ flux interference | Metoclopramide—D2 antagonism | |
| Metformin—gluconeogenesis inhibition (cellular energy measures respond but at concentrations>exposure) | Paracetamol—COX 1 and COX 2 inhibition (although no metabolic competency in the assay) | |
| Topiramate—GABA receptor binding (subunit specificity) | Verapamil Hydrochloride—calcium channel blockage |
| Toolbox is not protective . | Toolbox is protective but MOA is not detected . | Toolbox is protective and MOA detected . |
|---|---|---|
| Trimellitic Anhydride—serum IgE increase as a result of respiratory sensitization | Azathioprine—purine mimic inhibiting DNA synthesis (potentially metabolism limited) | Cetirizine Hydrochloride—histamine H1 receptor inhibition |
| Warfarin—VKORC1 inhibition and anticoagulation effects | Benzocaine—methaemoglobin formation | Dexamethasone—Glucocorticoid receptor binding |
| Chlorpyrifos—AChE inhibition (metabolism driven) | Fenbuconazole—interference with steroid biosynthesis (Aromatase) | |
| Cyclophosphamide—DNA binding/damage (metabolism driven) | Furosemide—primary mode of action is Na-k-Cl transporter binding (not detected). Secondary mode of action is increase in prostaglandin synthesis (COX1+COX2) (detected) | |
| Digoxin—Na+/K+-ATPase inhibition | Ibuprofen—COX 1 and COX 2 inhibition | |
| Glibenclamide—K+ channel inhibition | Ketoconazole (oral)—prevention of ergosterol synthesis (Aromatase) | |
| Hydralazine hydrochloride—Ca2+ flux interference | Metoclopramide—D2 antagonism | |
| Metformin—gluconeogenesis inhibition (cellular energy measures respond but at concentrations>exposure) | Paracetamol—COX 1 and COX 2 inhibition (although no metabolic competency in the assay) | |
| Topiramate—GABA receptor binding (subunit specificity) | Verapamil Hydrochloride—calcium channel blockage |
Full details can be found in Table S4.
Summary of the toolbox performance for chemicals with high-risk exposure scenarios and investigation of the ability of the toolbox to make protective decisions irrespective of detection of the mode of action.
| Toolbox is not protective . | Toolbox is protective but MOA is not detected . | Toolbox is protective and MOA detected . |
|---|---|---|
| Trimellitic Anhydride—serum IgE increase as a result of respiratory sensitization | Azathioprine—purine mimic inhibiting DNA synthesis (potentially metabolism limited) | Cetirizine Hydrochloride—histamine H1 receptor inhibition |
| Warfarin—VKORC1 inhibition and anticoagulation effects | Benzocaine—methaemoglobin formation | Dexamethasone—Glucocorticoid receptor binding |
| Chlorpyrifos—AChE inhibition (metabolism driven) | Fenbuconazole—interference with steroid biosynthesis (Aromatase) | |
| Cyclophosphamide—DNA binding/damage (metabolism driven) | Furosemide—primary mode of action is Na-k-Cl transporter binding (not detected). Secondary mode of action is increase in prostaglandin synthesis (COX1+COX2) (detected) | |
| Digoxin—Na+/K+-ATPase inhibition | Ibuprofen—COX 1 and COX 2 inhibition | |
| Glibenclamide—K+ channel inhibition | Ketoconazole (oral)—prevention of ergosterol synthesis (Aromatase) | |
| Hydralazine hydrochloride—Ca2+ flux interference | Metoclopramide—D2 antagonism | |
| Metformin—gluconeogenesis inhibition (cellular energy measures respond but at concentrations>exposure) | Paracetamol—COX 1 and COX 2 inhibition (although no metabolic competency in the assay) | |
| Topiramate—GABA receptor binding (subunit specificity) | Verapamil Hydrochloride—calcium channel blockage |
| Toolbox is not protective . | Toolbox is protective but MOA is not detected . | Toolbox is protective and MOA detected . |
|---|---|---|
| Trimellitic Anhydride—serum IgE increase as a result of respiratory sensitization | Azathioprine—purine mimic inhibiting DNA synthesis (potentially metabolism limited) | Cetirizine Hydrochloride—histamine H1 receptor inhibition |
| Warfarin—VKORC1 inhibition and anticoagulation effects | Benzocaine—methaemoglobin formation | Dexamethasone—Glucocorticoid receptor binding |
| Chlorpyrifos—AChE inhibition (metabolism driven) | Fenbuconazole—interference with steroid biosynthesis (Aromatase) | |
| Cyclophosphamide—DNA binding/damage (metabolism driven) | Furosemide—primary mode of action is Na-k-Cl transporter binding (not detected). Secondary mode of action is increase in prostaglandin synthesis (COX1+COX2) (detected) | |
| Digoxin—Na+/K+-ATPase inhibition | Ibuprofen—COX 1 and COX 2 inhibition | |
| Glibenclamide—K+ channel inhibition | Ketoconazole (oral)—prevention of ergosterol synthesis (Aromatase) | |
| Hydralazine hydrochloride—Ca2+ flux interference | Metoclopramide—D2 antagonism | |
| Metformin—gluconeogenesis inhibition (cellular energy measures respond but at concentrations>exposure) | Paracetamol—COX 1 and COX 2 inhibition (although no metabolic competency in the assay) | |
| Topiramate—GABA receptor binding (subunit specificity) | Verapamil Hydrochloride—calcium channel blockage |
Full details can be found in Table S4.
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