In this step, the assessor focuses on the chemicals and groups of chemicals that drive toxicity.
MoA data are only necessary for chemicals that drive toxicity, as the remaining chemicals can be conservatively assumed to follow additive models and not change the predicted HI values [26].
In compounds from these two series there was a 30- to 50-fold decrease in activity going from TbNMT enzyme to T. brucei cell efficacy, which further narrowed selectivity over mammalian NMT inhibition; this may have the potential to drive toxicity.
In sum, there are good hypothetical explanations why transmembrane and disordered proteins are especially likely to be overloaded or driven into toxicity when overexpressed.
However, other mechanisms of oxidative stress may play a role in PAH-driven toxicity.
A potential way to decouple the toxicity from efficacy is to determine if the pharmacokinetic parameters that drive toxicity differ from those driving efficacy, as has been the case with several other antibacterial agents (5 – 12).
In terms of testing requirements, Helinor Johnston (Heriot-Watt University Edinburgh, UK) emphasized the necessity for extensive characterization of the nanomaterial in a given test medium, since physiochemical properties that drive toxicity may vary dramatically depending on the test system applied.
The objectives of all of these approaches is to identify and characterize the mechanisms that drive toxicity, and to define a set of comprehensive assays that improve early safety screening.
A recent large scale study performed by the ACTG, suggested that overall success may be higher with an integrase inhibitor, when compared with a ritonavir boosted protease inhibitor, but closer examination of these results shows that this was mostly driven by toxicities associated with the protease inhibitors and a switch from these drugs was not associated with a lower rate of long-term success.
MCR values for exposures in Group IIIB give an indication of how many chemicals will drive the toxicity associated with the exposures.
The combined exposures that are subject to higher tier assessments also focus on the chemicals that drive the toxicity of the combined exposures.
