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This essay is in response to: How can innovations in technology and research reduce exposures to toxic chemicals?
For the past 12 years, The 12 Principles of Green Chemistry by Anastas and Warner have provided a cohesive set of design guidelines for integrating sustainability in the chemical industry. The principles call on chemists to recognize inherent hazard (whether physical, toxicological, or global) as a design flaw and develop products that minimize hazard across all stages of a chemical lifecycle from raw materials to manufacturing and end-of-life. Since the 1990s the field of green chemistry has flourished and the creativity of researchers worldwide has led to success in pollution prevention through advances in catalysis, benign solvents, and renewable chemical feedstocks.
Despite this progress, the principle of green chemistry that deals with molecular design for reduced toxicity has not yet been addressed in any systematic fashion. This has led to situations where putative alternatives to high-profile toxins are as hazardous, or more so, than the products they are meant to replace. There is irony in the fact that chemicals like polybrominated diphenyl ethers (PBDEs), bisphenol A (BPA), and dioctyl phthalate have been much better characterized in terms of persistence, bioaccumulation, and toxicity than have any of their replacement candidates.
Extensive pre-market testing in late stages of product development is possible and has been successful in some cases, for example the development of the non-phthalate plasticizer DINCH by BASF. However it has been widely reported that BASF invested 5 million euros into toxicity testing alone. A recent editorial in Nature suggested that compliance with REACH, the European chemicals regulation overhaul adopted in 2006, will also have high costs; it was estimated that for each chemical to be used in commerce, an expenditure of nearly US $200,000 and 800 vertebrate animals will be necessary. Such costs may not be feasible for academic laboratories, small companies, or manufacturers who wish to evaluate large numbers of chemicals. Testing burdens could be mitigated by development of predictive tools that could be applied in early stages of product conception. For these tools to be realized there is a need for better understanding of the relationship between toxic effects and basic physicochemical properties of substances.
This approach would be analogous to the drug discovery process in medicinal chemistry, in which the Lipinski rules for drug-likeness have been formulated to predict what molecular features will lead to pharmaceutically active compounds. The Lipinski rules are easy for chemists to understand: limits on molecular weight, hydrophilicity, and number of nitrogen and oxygen atoms, for example. For non-pharmaceutical chemicals, a complementary set of guidelines would be extremely useful—plasticizers, flame retardants, dyes, and many other commodity chemicals should not be biologically active, so what are the properties that chemists should use as a simple pre-screen when designing new molecules? The goal would be to provide ranges of values associated with particular toxic endpoints or toxic mechanisms of action.
Research at Yale has shown that this approach is feasible: based on a statistical analysis of animal studies compiled in the EPA ACToR database, it can be seen that just a few chemical properties can distinguish chemicals listed on the EPA Toxic Release Inventory from “safe” (i.e., high-lethal dose) chemicals or random samples of chemicals. This work will be extended in the future to include better molecular property prediction software and encompass a wider variety of hazardous endpoints. It is not expected to replace conventional toxicity testing, but could help reduce costs and animal burdens by red-flagging problem chemicals before significant resources are invested. Easier alternative assessment will provide scientists with easier choices in designing sustainable chemical enterprise for the 21st century.
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