Challenges in Designing Non-Toxic Molecules: Using medicinal chemistry frameworks to help design non-toxic commercial chemicals

By Shira Joudan, Education Committee Coordinator for the GCI

Throughout the past 20 years, there have been numerous reports on the state of the science of designing non-toxic molecules, including three in this year alone.1–3 The idea of safe chemicals has been around for much longer than the green chemistry movement, however it is an important pillar in what it means for a chemical to be green. In fact, many scientists agree that the synthesis of safer chemicals is likely the least developed area of Green Chemistry, with lots of room for improvement.2 For more information, see our post and video on Green Chemistry Principle #4.

One expert on designing non-toxic molecules is Stephen C. DeVishira-blog-picto of the United States Environmental Protection Agency (US EPA). In a recent paper DeVito highlights some major challenges creating safer molecules, and discusses how we can approach this challenge.1 We require a societal change about how we think of toxicity, and this shift must begin with specific education.

How can we agree upon definition of a “safe” chemical?

We need to decide and agree upon parameters that deem a molecule safe, or non-toxic. Generally, most chemists agree that an ideal chemical will have no (or minimal) toxicity to humans or other species in the environment. It should also not bioaccumulate or biomagnify in food chains, meaning it should not build up in biota, or increase in concentration with increased trophic levels in a food chain. After its desired usage, an ideal chemical should break down to innocuous substances in the environment. Potency and efficacy are also important, as well as the “greenness” of its synthesis. Setting quantitative thresholds to these parameters and enforcing them is the largest challenge.

How do we tackle the over 90,000 current use chemicals?

Although not all of these chemicals are actually in use, they are all registered under the US EPA’s Toxic Substances Control Act (TCSA), which contains both toxic and non-toxic chemicals. Many chemicals that are being used should be replaced with safer alternatives, but there are so many that it seems terrifying to know where to begin. Another replacement option is designing new technologies that don’t require the function that these chemicals provide. About two-thirds of the chemicals registered in TCSA or Environment and Climate Change Canada’s Chemicals Management Plan were in use before registration was required. Unlike pharmaceuticals and pesticides which are heavily regulated by Health Canada, commercial chemicals do not require stringent toxicity tests. But things are changing in the US and in Canada. For example, Canada has just listed 1550 priority chemicals that will be addressed by 2020. When considering replacement for chemicals of concern, the most common barrier to reducing the use is currently “no known substitutes or alternative technologies”.

How do we ensure sufficient training on the concepts of safer chemical design?

Many people making new chemicals are unfamiliar with green chemistry and basic toxicology principles. Without the proper toolbox of knowledge designing safer chemicals is challenging. [The Green Chemistry Commitment is a great place to start!] DeVito discusses the need for “toxicological chemists” which would be analogous to medicinal chemists, but instead produce non-toxic commercial chemicals. Medicinal chemists have the training to design appropriate pharmaceuticals, however commercial chemicals do not receive the same attention in terms of designing safe and efficacious products. Since humans are exposed to the commercial chemicals as well, often in intimate settings, the same attention to detail should be used during the synthetic process in order to produce safe chemicals.

Synthetic organic chemists are the ones designing the new chemicals, and we can no longer keep traditional chemists and toxicologists an arm’s length apart. Instead, there is a need for a new type of scientist that considers the function of the chemical for its desired usage and its toxicity potential to humans and the environment. Similar to the training of medicinal chemists, these chemists should receive training in biochemistry, pharmacology and toxicology, and also in environmental fate processes. DeVito suggests adding topics into an undergraduate curriculum, some of which are highlighted here:

  • Limit bioavailability: A common way to prevent toxicity has been to reduce the bioavailability of molecules. Essentially, the idea is that if the chemical cannot be absorbed into the bloodstream of humans or other species, it will not be able to cause significant toxic effects. A common predictor for bioavailability is the “Rule of 5”, where a molecule will have poor absorption if it contains more than five hydrogen bond donors or 10 hydrogen bond acceptors, a molecular weight of more than 500 amu, and a logP (or log Kow) of greater than 5.4 More sophisticated prediction methods also exist based on linear free energy relationships. A good example of low bioavailability is the artificial sweetener sucralose, where only 15% of the chemical is absorbed through the gastrointestinal tract into the bloodstream.5
  • Isosteric substitutions of molecular substituents: By removing parts of the molecule and replacing it with another functional group with similar physical and chemical properties (isosteric) toxicity can be reduced. This is common in medicinal chemistry, where it is referred to as bioisosterism, and is used to reduce toxicity, alter bioavailability and metabolism. A simple substitution can be replacing a hydrogen atom for a fluorine atom, but there can also be much larger isosteric substitutions.
  • Designing for degradation: A toxic molecule that persists in the environment can lead to global long term exposure. Understanding common environmental breakdown mechanisms can allow us to design molecules that will break down to innocuous products after their desired usage. A good starting point is understanding aerobic microbial degradation, since most of our waste ends up at a wastewater treatment plant. An important thing to keep in mind is that if a non-toxic molecule degrades to a toxic molecule, the starting material will still be of concern.

Toxicity is complicated. The best way to arm the next generation of chemists with the skills needed to design smart, safe chemicals is to tailor the undergraduate education to our new goals.

Numerous institutions, including the University of Toronto, are working towards this by signing onto the Green Chemistry Commitment!

(1)         DeVito, S. C. On the design of safer chemicals: a path forward. Green Chem. 2016, 18 (16), 4332–4347.

(2)         Coish, P.; Brooks, B. W.; Gallagher, E. P.; Kavanagh, T. J.; Voutchkova-Kostal, A.; Zimmerman, J. B.; Anastas, P. T. Current Status and Future Challenges in Molecular Design for Reduced Hazard. ACS Sustain. Chem. Eng. 2016, 4, 5900–5906.

(3)         Jackson, W. R.; Campi, E. M.; Hearn, M. T. W.; Collins, T. J.; Voutchkova-Kostal, A. M.; Kostal, J.; Connors, K. A.; Brooks, B. W.; Anastas, P. T.; Zimmerman, J. B.; et al. Closing Pandora’s box: chemical products should be designed to preserve efficacy of function while reducing toxicity. Green Chem. 2016, 18 (15), 4140–4144.

(4)         Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development setting. Adv. Drug Deliv. Rev. 2001, 46, 3–26.

(5)         Roberts, A.; Renwick, A. G.; Sims, J.; Snodin, D. J. Sucralose metabolism and pharmacokinetics in man. Food Chem. Toxicol. 2000, 38, 31–41.

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