Designing safer molecules: Onus on synthetic chemists

That task has traditionally been left to toxicologists further down the production line. But synthetic chemists can and should take earlier responsibility for the safety of their molecules, urges a group led by Julie Zimmerman at Yale University in New Haven, Conn.

In a paper published in Green Chemistry, the researchers show how obeying two key rules of thumb greatly reduces the chances of a molecule being acutely toxic to fish and other aquatic organisms. They plan to follow this up with similar design guidelines to avoid other types of damage, such as toxicity to birds.

The research demonstrates to synthetic chemists how our growing understanding of toxicity puts the onus on them to deliberately avoid making molecules that fall in the danger zone, argues co-author Paul Anastas, who is currently on leave from Yale as science adviser to the US Environmental Protection Agency (EPA).

Decades of safety tests have generated enough data for researchers to learn how chemicals produce toxic effects, and computer models are picking out the molecular properties that underlie this activity. “Rather than measuring how bad something is after it’s made, and then going back to the drawing board, you can start to design molecules in what is likely to be a safer chemical space,” says Anastas.

Zimmerman’s team analysed data on hundreds of chemicals that have already been tested by the EPA and the Japanese environment ministry for their acute toxicity to three aquatic species – the fathead minnow (Pimephales promelas), the tiny Japanese medaka fish (Oryzias latipes) and the water flea Daphnia magna.

Following established toxicology research, the team was not surprised to find that the most toxic chemicals tended to be quite soluble in fat relative to water, because this makes it easier for a molecule to pass through a cell’s membrane – the first hurdle for a chemical to overcome in order to have a biological effect.

The group also found, as expected, that the toxic chemicals are adept at ripping electrons from other molecules, a property that makes it more likely they will cause damage once inside a cell.

Combining the data on all species, the team quantified a range of values for variables relating to these two properties, within which fell 77 per cent of the “desirable” chemicals; those with low or no toxicity.