Gene-silencing pesticides pose test for EU regulators

European regulators may need specific guidance before farmers can use a new generation of precision pesticides that kill crop pests by switching off essential genes, researchers have said.

Scientists in Germany examined the US approval of Calantha, a sprayable biopesticide used to control Colorado potato beetle in potato crops, to assess how a similar product might be regulated in the EU.

Calantha was the first agricultural pesticide based on RNA interference, or RNAi, to be approved anywhere in the world when it was authorised by the US Environmental Protection Agency in 2023.

Aline Koch, from the University of Regensburg, and Gabi Krczal, from agricultural research company RLP AgroScience, reviewed the evidence submitted for that approval and compared it with European pesticide legislation.

Writing in the journal Pest Management Science, they concluded that existing EU rules could potentially accommodate RNA-based pesticides. However, specific guidance may be needed to determine what evidence manufacturers must provide, as well as how risks to people, wildlife and the wider environment should be assessed.

Targeting a single pest

RNA interference is a natural process that prevents genes from producing particular proteins.

Calantha’s active ingredient, Ledprona, consists of double-stranded RNA designed to match part of an essential gene in Colorado potato beetles.

When beetle larvae eat treated potato leaves, the RNA prevents the gene from producing a protein involved in clearing defective proteins from cells. These defective proteins accumulate, eventually killing the larvae.

The targeted approach means the pesticide can affect Colorado potato beetles and some closely related species without harming many of the beneficial insects and other organisms exposed to conventional broad-spectrum insecticides.

Calantha is sprayed onto potato foliage using conventional application equipment. Unlike some other uses of RNAi in crop protection, it does not require the crop itself to be genetically modified.

Greenhouse trials found Ledprona restricted leaf damage to less than 5% and produced control comparable with the conventional insecticide spinosad.

In US field trials conducted in 2019 and 2020, three weekly applications limited leaf loss to an average of 6.81%. Mortality among larger larvae exceeded 99%, although it took 7 to 8 days for the full effect to become apparent. Feeding declined before the larvae died, reducing crop damage during that period.

The maximum Ledprona application rate was 9.9 g of active ingredient per hectare, compared with 88 g/ha for spinosad and 73 g/ha for chlorantraniliprole in the trials.

Evidence from the US assessment

The researchers used the US assessment to explore the types of evidence European regulators could consider if an RNA-based pesticide were submitted for approval.

US regulators concluded that Ledprona presented no relevant risk to organisms outside the beetle order. Testing found no treatment-related effects in honey bees, earthworms or ladybirds, although potential effects were found in two beetle species closely related to the target pest.

The RNA also degraded relatively quickly in the environment. More than 90% disappeared within 4 days in soil, while its reported half-life ranged from 0.5 to 2.92 days.

Ledprona was classified as practically non-toxic and non-irritating in oral, inhalation and skin-exposure tests. It was completely degraded within 10 minutes in simulated gastric fluid.

However, the formulated Calantha product was classified as a weak skin sensitiser, and protective equipment is recommended when it is handled and applied.

Adapting EU assessments

Current EU legislation does provide routes for approving active substances and low-risk plant-protection products, but it was not developed specifically for pesticides that work by matching genetic sequences.

Assessing those products may require regulators to place greater emphasis on bioinformatics, which can compare the pesticide’s RNA sequence with genetic information from humans and non-target organisms to identify possible unintended effects.

That approach has limitations because genetic information for many species remains incomplete or incorrectly annotated. Computer analysis could therefore miss a genuine risk or predict an effect that doesn’t occur.

Koch and Krczal said bioinformatic predictions would need to be supported by biological testing. European authorities would also need to decide how to assess residues in food and drinking water, environmental exposure, long-term effects and possible risks to sensitive groups, they said. 

While the US approval provides a useful model for Europe, dedicated guidance would help ensure RNA-based pesticides are assessed consistently across the EU before they become available to farmers, they added.

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