Toxic ratio definition

From a purely pragmatic perspective, it is clear that reactive metabolites are linked with toxicity and that a circumstantial link can be made to idiosyncratic toxicides. Consequently, even though the mechanism of this toxicity is not fully understood, since assays are available to measure the potential for bioactivation in an ideal world one would not carry this liability forward. Conversely, it is not an ideal world, all drug molecules have challenges and the definition of therapeutic index (i.e., the ratio between the toxic exposure and the therapeutic exposure) is critical. Covalent binding of reactive metabolites to macromolecules is a crude measure and not a full predictor of toxicity and it is well known that toxicity can be ameliorated by a lower dose. Furthermore, the so-called definitive assays require radiolabeled drug material which is expensive and generally slow to produce. 

Toxicology studies are conducted to define the safety profile of a candidate and include definition of the no-toxic-effect dose, MTD, potential organs of toxicity, and potential biochemical markers to detect and track toxic events. Most developmental compounds that do not become therapeutic products have unacceptable toxicity in animals or humans. Before the definitive toxicology studies needed to support an IND submission are initiated, a number of animal experiments can be conducted to characterize the potential toxicity of the candidate. These early toxicology evaluations are usually conducted in the same species as used in pharmacology evaluations. As mentioned earlier, the lowest dose that has no toxicity or an acceptable level of toxicity is compared with the dose that gives the desired pharmacologic response in the same animal species to obtain a therapeutic ratio or index for that species. 

The definition of the acute to chronic ratio (ACR) has been one of the methods used to predict the threshold concentration at which a toxicant does not produce noticeable effects during a chronic exposure. This ratio is based on the same concept as the application factors, but its numerical value is the inverse (Stephan, 1982). The ACR is the ratio between chemical concentrations exerting a lethal versus sublethal toxic effect and describes the ratio of a lethal to sublethal end-point ... 

Recall from Chapter 2 the definition of atom economy, the ratio of the mass of the species in the desired product relative to the mass of all of the reactants. In all of these reactions the atoms present in the reactants are also present in the products. In this case it is implied that these reactions are 100% atom economical. Remember from Chapter 2 that atom economy is a mass utilization number only it does not take into account the energy usage, the toxicity of the products, or whether the feedstocks are derived from renewable materials. 

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