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Differential Toxicity Characterization of Green Alternative Chemicals
Citation:
JUDSON, R. Differential Toxicity Characterization of Green Alternative Chemicals. Chapter 2, Paul T. Anastas, Robert S. Boethling, Adelina Voutchkova (ed.), Handbook of Green Chemistry: Set III; Green Processes - Designing Safer Chemicals. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 9:21-46, (2012).
Impact/Purpose:
The aim of this chapter was to describe briefly a series of modern methods for analyzing the potential for toxicity of chemicals, and to illustrate how information coming from these methods could be used to analyze the potential benefits of substitution of one chemical for another. These methods range from structure-based QSAR models to in vitro bioassays to systems models. They cover all of the important aspects of chemical toxicity, including bioavailability, bioaccumulation, pharmacokinetics, and target-based molecular toxicity. The goal of this collection of techniques is partially to replace whole animal testing for chemical toxicity, because that approach is so expensive and time consuming that it is not practical for use during the design phase of possible green replacement chemicals. On the other hand, these modeling and high-throughput in vitro methods are ideally suited to this use, which is analogous to the lead development process in the pharmaceutical industry, which was a major driver for the development of these techniques in the first place. Finally, as already mentioned, there may often not be a clear tradeoff between one chemical and a possible replacement, because of the complexities of chemicals interacting with different biological targets. One of the most surprising findings of the ToxCast program was how many biological targets were hit by each of the environmental chemicals being studied. One related finding is that the lowest in vivo dose at which a chemical causes toxicity is correlated with the number of in vitro targets the chemical hits, that is, there is a tendency for more "promiscuous" chemicals to cause toxicity at lower doses. This promiscuity for environmental chemicals appears to be different than for pharmaceuticals, which are designed to be "clean" and to have a minimum of off-target effects. However, we have tested chemicals across a wider range of targets than typically occurs in pharmaceutical development, and see much of the activity at relatively high concentrations (low potency). Over the next year, we will be including a number of marketed drugs in our program, and will then have a direct basis of comparison.
Description:
Assessing the toxicity of a chemical across all possible disease domains and understanding its dose- response behavior cost millions to tens of millions of dollars per chemical, and can take years to decades to evaluate fully. This expense and the lack of regulatory requirements for complete toxicity testing has resulted in the widespread manufacture and use of thousands of industrial chemicals for which complete toxicity testing has never been carried out. Lack of data significantly complicates the problem of evaluating whether a green alternative is less toxic than the existing chemical that it is meant to replace. However, despite the intractable appearance of this problem, there are promising new approaches to the evaluation of chemical toxicity that may be well suited to predict differential toxicity between a pair of chemicals and to help evaluate the environmental profile of an alternative. To approach this problem, we need to think about what ultimately leads to toxicity. The remainder of the chapter is organized into sections dealing with each of the five components (bioavailability, bioaccumulation, reactivity, clearance, and interaction potency and efficacy) required to assess differential toxicity. The first four are subjects of recent reviews so they are treated only briefly, to the level required for understanding how to perform a final integrated differential toxicity assessment. The final component of specific chemical-target interactions is treated in more depth. Final sections deal with integration of these different streams of information.
