Soaps, detergents and agrochemicals: Agrochemicals: classes, modes of action and discovery

4.1 Pesticides are grouped by target, by route into the pest and by the enzyme they block

A pesticide active ingredient is a chemical designed to harm a target pest (Kent). The three big groups are Insecticides, Herbicides and Fungicides; the wider family includes nematicides for soil worms, acaricides for mites, rodenticides and plant growth regulators.

Each group is subdivided by how the chemical reaches the pest. An insecticide may be a contact poison, a stomach poison, a fumigant gas, or systemic, meaning it is taken up by the plant and carried in its sap so that any insect feeding on it is poisoned. A herbicide may be contact, killing only the leaves it lands on, or systemic, moving down to the roots, which is what kills established perennial weeds.

The most telling classification is by mode of action, the biochemical target, because it governs resistance. Kent reproduces the industry schemes (IRAC, HRAC and FRAC). Organophosphates and carbamates both block acetylcholinesterase, the enzyme that switches off nerve signals, so the insect's nerves keep firing. Pyrethroids and DDT hold nerve sodium channels open. Neonicotinoids act on the receptor for acetylcholine. Herbicides target processes in plants: glyphosate blocks EPSP synthase in amino acid synthesis, triazines such as atrazine block photosynthesis, sulfonylureas block the ALS enzyme, and phenoxy acids such as 2,4-D mimic the plant hormone auxin, causing lethal, disordered growth. Shreve notes that most herbicides attack functions absent in animals.

Two molecules with the same target count as one weapon. Pests evolve resistance by mutation and selection: Kent counts more than 550 insect and mite species, 150 plant pathogens and 270 weed biotypes with recorded resistance. Rotating modes of action, pre-mixes and integrated pest management are the defences, so each genuinely new mode of action has scarcity value.

• Kent (2012), Ch 17 The Agrochemical Industry · pdf pp. 652-664, 670
• Shreve (1984), Ch 26 Agrichemical Industries · pdf pp. 482-483, 485, 492
• Dryden (1997), IVG Pesticides · pdf p. 553

4.2 From DDT to diamides: each generation fixed the last one's flaw

The earliest insecticides were inorganic poisons such as Paris green, lead arsenate and Bordeaux mixture (copper sulphate and lime). Shreve notes they were toxic to mammals and accumulated in soils. Plant extracts followed, such as nicotine, rotenone and pyrethrins from chrysanthemum flowers.

The synthetic era began with organochlorines. DDT was the first chemical with enough residual action to be useful: an insect could die by walking over a surface sprayed days before. Shreve credits it with saving at least 5 million lives from malaria. Persistence was also its flaw. DDT is stored in body fat and concentrates up the food chain, and insects developed resistance. Dryden records that BHC, made in India from about 1953, was the country's first organic insecticide, and that persistent chlorinated pesticides, phased out in the West, were still made where disease control mattered.

Organophosphates such as parathion, malathion and monocrotophos break down far faster in the environment and seemed less prone to resistance, but Dryden warns that many are very toxic in concentrated form and are chemically close to nerve gases. Carbamates such as carbaryl combined low mammalian toxicity with breakdown so rapid that, Shreve says, they can be used within a day of harvest.

Synthetic pyrethroids copied the natural pyrethrins but added sunlight stability while keeping low mammalian toxicity. They also show the importance of stereochemistry, the three-dimensional shape of a molecule. Kent explains that cypermethrin has three chiral centres and so eight stereoisomers, of which one is the most active; alpha-cypermethrin, a mixture of the best pair, is two to three times as effective. Up to 25% of pesticide actives are chiral, and producing only the active form reduces the load of inactive material released.

Kent's list of molecules launched in the 1990s and 2000s shows the newer classes: neonicotinoids, fiproles, spinosyns and diamides such as chlorantraniliprole, launched in 2007. Each brought a new target and, typically, lower doses.

• Shreve (1984), Ch 26 Agrichemical Industries · pdf pp. 483-487
• Dryden (1997), IVG Pesticides · pdf pp. 553-556
• Kent (2012), Ch 17 The Agrochemical Industry · pdf pp. 667-668, 678-685

4.3 Discovery and registration: a decade and $250 million per molecule

A new active starts as a molecule with a defined biological effect. Kent describes two ways to find one. Random screening tests large collections of historical compounds against insects, weeds and fungi in greenhouses. Rational design modifies a lead molecule step by step to bind a known target enzyme better, helped by structure-activity models. The molecule must also dissolve enough in water to move in sap and enough in fat to cross waxy leaf surfaces, a balance tracked by the octanol-water partition coefficient.

The hit rate is tiny. Shreve notes that several hundred thousand compounds had been tested to arrive at 179 approved US insecticides, that new approvals were slowing because testing and approval had become so costly, and that one new pesticide took an estimated 1,080 employee-years in 1982. Kent brings the numbers up to date: 10-12 years on average from discovery to launch, and a discovery and development cost of about $150 million in 1995, rising to more than $250 million by 2010 as data requirements grow.

Registration is the gate. A company submits a data package to each national authority covering chemistry, toxicology, residues, environmental fate and efficacy. Kent puts the cost of preparing the application for a new active substance at $15-20 million. Approvals are reviewed periodically, and carcinogens, endocrine disruptors and persistent pollutants are being phased out. Each country sets its own requirements, though OECD regulators aimed to harmonise them by 2014.

The economics follow from this shape. Spending is large, fixed and early; the protected selling window after launch is limited; and resistance or a regulatory review can end a product's life early. Only companies selling across many crops and countries can spread such costs, which is why discovery is concentrated in a few multinationals.

• Kent (2012), Ch 17 The Agrochemical Industry · pdf pp. 665-668, 675-676
• Shreve (1984), Ch 26 Agrichemical Industries · pdf p. 486

See it in the table

Check your understanding

Why do industry bodies classify pesticides by mode of action as well as chemical family?

Organophosphates and carbamates are different chemical families. What do they share?

Using Kent's figures, by how much did the cost of discovering and developing a new crop protection product rise between 1995 and 2010?