IPM 452/552 – Lecture 5 Notes (Pesticide Classes – Insecticides & Acaricides)

Pesticide Naming & Regulatory Basics

• Three common “names” for every pesticide:

  • Chemical name (IUPAC chemical name): precise structural description.

  • Common name: internationally accepted short form (e.g., carbaryl, glyphosate).

  • Product/brand name: formulation-specific; contains active ingredient (AI) + solvents, adjuvants, emulsifiers, etc. EPA risk-assesses the AI but legally registers each formulated product.

  • Example 1:

    • IUPAC: 1-naphthyl methyl carbamate

    • Common name: carbaryl

    • Product name: Sevin

  • Example 2:

    • IUPAC: N-(Phosphonomethyl) glycine

    • Common name: glyphosate

    • Round up

• EPA conducts risk assessments on the active ingredient but registers individual procucts (formulation of active ingredients)

• Average efficacy of pest control practices worldwide in reducing yield loss potential of pathogens, viruses, animals (mostly insects) and weeds is a surrogate for impact of pest damage on crop production

• Mammalian toxicity data appear on labels per formulation.

• Example (lambda-cyhalothrin product “Karate”):

  • Oral LD50 = 93 mg/kg (females)

  • Dermal LD50 = >2000 mg/kg

  • This indicates that the oral exposure is significantly more toxic compared to dermal exposure, highlighting the importance of handling precautions.

• Active Ingredient (AI): Lambda-cyhalothrin is a synthetic pyrethroid that targets the nervous system of insects.

  • Oral LD50 = 56 mg/kg (females)$LD_{50}\,(♀)=56\;\text{mg·kg}^{-1}

  • Dermal LD50 = 632 mg/kg (males)$LD_{50}\,(♂)=632\;\

Global Yield Losses & Use Statistics

• Average untreated (“do-nothing”) pest loss ≈ 17\%$(all pests) in major crops; treating insects alone reduces loss to$\sim 10\% (Oerke 2005).

• U.S. pesticide market trends (1964-2010):

  • Total pounds a.i. peaked late 1970s; insecticides represent shrinking share compared with herbicides.

  • “Other” class = fumigants, desiccants, growth regulators, harvest aids.

• Insecticide use 2009-2010 (USDA-NASS):

  • Highest pounds: corn > cotton > soybean > potatoes; apples treat 99\%$of acreage yet pounds declined by$\sim1.5\times10^{6} lb over 30 yr.

• Neonicotinoid ("neonic") expansion (1995-2011):

  • Acreage mainly through seed treatments; corn + soybean dominate.

  • Invasive soybean aphid outbreak → spike then gradual decline in foliar neonics; host-plant resistance affects use curves.

Social vs. Biochemical Classification

• “Social” categories – how regulators/industry group products:

  • Conventional insecticides (older, often broad spectrum).

  • Reduced-risk insecticides.

  • Biopesticides / PIPs (plant-incorporated protectants).

• Mode-of-action (MOA) divisions (IRAC numbering):

  • Neurotoxins (sodium, acetylcholinesterase, nicotinic, GABA, glutamate/Cl⁻, ryanodine).

  • Respiratory (mitochondrial) inhibitors.

  • Endocrine mimics (ecdysone, juvenile hormone).

  • Metabolic inhibitors (chitin, lipid synthesis, etc.).

  • Sensory agonists (feeding blockers, repellents).

  • Microbial agents / PIPs.

Market & Chemistry Evolution

• Organochlorines (DDT & cyclodienes) nearly abandoned → Organophosphates (OPs) dominated 1970-1990 → Pyrethroids, carbamates, neonics, diamides, spinosyns, METIs expand post-1990.

• 2013 global sales by MOA (Sparks & Nauen 2015): diamides, neonics, and spinosyns comprise fastest-growing segments.

• \$13.9\,\text{billion}$= total insecticide market (2010); neonics alone$\$8.8\,\text{billion}.

IRAC & Resistance Management

• IRAC website supplies searchable MOA tables, wall posters, phone apps.

• Each MOA assigned a number now printed on labels—facilitates rotation for resistance management.

Reduced-Risk Concept (EPA, 1993 → updated post-FQPA 1996)

• Qualifying criteria (ideally all):

  • Low human toxicity; minimal non-target effects; low water contamination potential; low use rates; lower resistance risk; IPM compatibility.

• Incentives: accelerated review & registration (first 22 AIs approved by 1997).

• Comparative mammalian toxicology table shows OPs (red) vs. reduced-risk AIs (green) – log orders safer.

• Vertebrate Selectivity Ratio SR=\frac{LD{50}\,\text{rat}}{LD{50}\,\text{insect}}$increasing over decades while field use-rate (lb/acre) decreases (Sparks 2013).</p></li></ul><h3 id="0ea0a95b-b36a-4e6f-af30-02424902d167" data-toc-id="0ea0a95b-b36a-4e6f-af30-02424902d167" collapsed="false" seolevelmigrated="true">Insect Nervous System Primer (necessary for MOA understanding)</h3><ul><li><p>Neuron parts: dendrites (receptors) – soma – axon; synapse ≈$20\,\text{nm}$gap.</p></li><li><p>Resting potential ≈$-70\,\text{mV}$created by selective Na⁺/K⁺ permeability.</p></li><li><p>Action potential (AP): Na⁺ influx then K⁺ efflux; all-or-none spike to$\sim+40\,\text{mV} propagating unidirectionally.

• Chemical transmission: ACh released into synapse, binds nicotinic receptor (nAChR) → new AP; AChE quickly hydrolyzes ACh.

• Inhibitory neurotransmitter GABA opens Cl⁻ channels → hyperpolarization.

• Two chief vulnerable sites:

  1. Axonal ion channels (Na⁺).

  2. Synapse (AChE, nAChR, GABA receptors).

Neurotoxic Insecticides

Sodium Channel Modulators (delay closing)

Pyrethrins & Pyrethroids (and DDT)

• Natural pyrethrum (6 esters, \sim1!–!2\% in dried flowers) unstable to sunlight (t½ water < 1 h, soil < 24 h).

• Piperonyl butoxide (PBO) discovered 1949—synergist inhibiting P450s, lowers cost & dose; human dermal absorption \approx1.7\%$.</p></li><li><p>Michael Elliot 1960s: synthetic pyrethroids (e.g., permethrin, bifenthrin, cyhalothrin) 10-100× more stable; use rate$0.1!–!0.2\,\text{lb·A}^{-1}$.</p></li><li><p>Isomerism critical—only$1S$-trans permethrin is bioactive.</p></li><li><p>Negative temperature coefficient: red flour beetle survival ↑ as temp ↑ (cyfluthrin residues).</p></li><li><p>Selectivity factors (Narahashi 2001): temperature dependence (×5), intrinsic sensitivity (×10), rapid mammalian detox (esterases), skin penetration low, small body size, etc.</p></li><li><p>Mammalian PK: cyfluthrin half-life$\sim5!–!7\,\text{h}; poor skin absorption (Hughes & Edwards 2010).

Sodium Channel Blocker – Indoxacarb

• Pro-insecticide bio-activated in Lepidoptera to decarbomethoxylated metabolite that blocks Na⁺ current leading to sub-threshold APs.

• Highly selective: fall armyworm oral LD_{50}=0.01\,\text{ng·mg}^{-1}$vs. rat$1277\,\text{ng·mg}^{-1}.

• Uses: lepidopteran control in crops, ant/cockroach baits.

Acetylcholinesterase (AChE) Inhibitors

• Organophosphates (OPs) & Carbamates (CBs).

  • OP pro-insecticides (phosphorothioates) require P450 oxidation to oxon; only oxon binds AChE.

  • Examples: chlorpyrifos, malathion, azinphos-methyl (cancelled), aldicarb, carbaryl, formetanate.

  • High acute toxicity; broad spectrum; OP phase-outs ongoing, still limited use.

Nicotinic ACh Receptor Modulators

Neonicotinoids (IRAC 4A) & Sulfoximines (4C)

• Mimic ACh but bind insect nAChR with far > affinity than vertebrate (Tomizawa & Casida 2005). Selectivity ratios up to >10^{3}$.</p></li><li><p>Main AIs: imidacloprid, clothianidin, thiamethoxam, acetamiprid, thiacloprid, dinotefuran; sulfoxaflor (4C).</p></li><li><p>Low mammalian acute toxicity (oral$LD_{50}>2000\,\text{mg·kg}^{-1}$for most) and high NOAELs (clothianidin$>9\,\text{mg·kg}^{-1}\text{/d} Feeding).

• Field rates < 0.5\,\text{lb·A}^{-1}; seed-treatment dominates corn/soy (USA) & canola (UK).

Spinosyns (IRAC 5)

• Fermentation metabolites of Saccharopolyspora spinosa; spinosad = A + D; spinetoram semi-synthetic (higher potency).

• Bind distinct site on nAChR (not neonic site) → excitation; excellent selectivity; oral/dermal LD_{50}>5000\,\text{mg·kg}^{-1}$; fast environmental degradation; organic formulations (Entrust) available.</p></li><li><p>Caveat: High bee toxicity.</p></li></ul><h4 id="d4cc449c-6c44-4748-8af2-fbcee3030eab" data-toc-id="d4cc449c-6c44-4748-8af2-fbcee3030eab" collapsed="false" seolevelmigrated="true">GABAergic Modulators</h4><ul><li><p><strong>Cyclodienes, endosulfan, lindane</strong> (historical): non-competitive GABA antagonists, high persistence; many cancelled.</p></li><li><p><strong>Fipronil (IRAC 2B)</strong> phenylpyrazole—blocks GABA receptor; IC50 insect$\sim7\,\text{nM}$vs. human$\sim942\,\text{nM}$→ selective. Products: Termidor (termites), Frontline (pets), Regent.</p></li></ul><h4 id="537b00f8-ee4f-4263-bb4a-cf5cfa5b5b09" data-toc-id="537b00f8-ee4f-4263-bb4a-cf5cfa5b5b09" collapsed="false" seolevelmigrated="true">Glutamate-Gated Cl⁻ Channel Agonists – Avermectins (IRAC 6)</h4><ul><li><p>Abamectin, emamectin, ivermectin: open GluCl channels causing paralysis; powerful acaricide/nematicide; very low application rates$0.025!–!0.05\,\text{lb·A}^{-1}$; moderate intrinsic mammalian toxicity mitigated by low exposure.</p></li></ul><h4 id="49371cfe-51e0-419e-acc6-7ef42db4796b" data-toc-id="49371cfe-51e0-419e-acc6-7ef42db4796b" collapsed="false" seolevelmigrated="true">Ryanodine Receptor Activators – Diamides (IRAC 28)</h4><ul><li><p>Chlorantraniliprole (Rynaxapyr/Altacor), cyantraniliprole, flubendiamide.</p></li><li><p>Prolong Ca²⁺ release from SR, depleting stores → muscle paralysis; vertebrate RyR insensitive.</p></li><li><p>Mammalian$LD_{50}>5000\,\text{mg·kg}^{-1}$; rates$0.02!–!0.09\,\text{lb·A}^{-1}; excellent codling moth control.

Feeding Blocker – Pymetrozine (IRAC 9B)

• Agonist of TRPV chordotonal organ channels → stops stylet insertion & feeding; aphid-specific; formulations Fulfill, Endeavor; harmless to most natural enemies.

Respiratory / Mitochondrial Electron Transport Inhibitors (METIs)

• Target Complex I (NADH-CoQ reductase) in mites.

• Key acaricides: pyridaben, fenpyroximate, bifenazate (pro-acaricide via ester hydrolysis).

• METIs show fast mite knockdown, \text{LD}_{50}\,\text{oral} > 245\,\text{mg·kg}^{-1}, dermal usually >2000\,\text{mg·kg}^{-1}$; selective due to rapid vertebrate metabolism.</p></li></ul><h3 id="6c629d73-e914-437a-af5c-8d87952f2583" data-toc-id="6c629d73-e914-437a-af5c-8d87952f2583" collapsed="false" seolevelmigrated="true">Endocrine/Developmental Disruptors (Insect Growth Regulators – IGRs)</h3><h4 id="48755d98-4f51-4ffb-a4f9-aa96abe630a3" data-toc-id="48755d98-4f51-4ffb-a4f9-aa96abe630a3" collapsed="false" seolevelmigrated="true">Ecdysone Receptor Agonists (Diacylhydrazines, IRAC 18)</h4><ul><li><p>Tebufenozide (Confirm), methoxyfenozide (Intrepid).</p></li><li><p>Non-steroidal mimic → premature molt, feeding stops, death by starvation within$\sim48\,\text{h}$.</p></li></ul><h4 id="45719bb2-eef9-4496-8e1b-120c995770c6" data-toc-id="45719bb2-eef9-4496-8e1b-120c995770c6" collapsed="false" seolevelmigrated="true">Juvenile Hormone Mimics (IRAC 7A)</h4><ul><li><p>Methoprene, hydroprene, pyriproxyfen (Esteem).</p></li><li><p>Maintain juvenile state → arrest development / sterilize eggs; early codling moth suppression.</p></li></ul><h4 id="3824fe81-6e9f-4bab-b70e-07cecd30077c" data-toc-id="3824fe81-6e9f-4bab-b70e-07cecd30077c" collapsed="false" seolevelmigrated="true">Chitin Synthesis Inhibitors (Benzoylureas, IRAC 15)</h4><ul><li><p>Diflubenzuron (Dimilin), novaluron (Rimon), hexaflumuron (Recruit), lufenuron (Program).</p></li><li><p>Block chitin synthase during cuticle formation → failed molt; extremely low mammalian toxicity (oral$LD_{50}>4500 mg·kg⁻¹).

• Termite baits (hexaflumuron, noviflumuron) & flea control (lufenuron) highlight urban IPM.

Lipid Synthesis Inhibitors – ACCase Blockers (IRAC 23)

• Inhibit acetyl-CoA carboxylase (first step fatty acid synthesis) → incomplete molt + desiccation; oral LD_{50}>2000\,\text{mg·kg}^{-1}.

Comparative Toxicology & Application Rates

• OPs: oral LD50 often <$5\,\text{mg·kg}^{-1}$; neonics, diamides, spinosyns generally >2000\,\text{mg·kg}^{-1}$.</p></li><li><p>Neonic application$<1.5$lb a.i./acre vs. chlorpyrifos often$>1$lb a.i./acre.</p></li><li><p>NOAELs: neonics$>1$mg·kg⁻¹·day⁻¹; nicotine$0.002$$ mg·kg⁻¹·day⁻¹ (far more toxic).

Environmental & IPM Implications

• Ideal insecticide: selective, low persistence, low non-target toxicity.

• Post-1990 chemistries meet many criteria → favored in IPM; yet legacy OP/CB still used where cost/resistance drive.

• Resistance management relies on rotating IRAC groups, integrating biological/ cultural tactics.

• Biotech PIPs and host-plant resistance can sharply alter insecticide use trends (e.g., Bt crops, aphid-resistant soybean).

Bottom Line

• Overall U.S. insecticide pounds continue downward owing to higher potency AIs and IPM adoption.

• Majority of new products exploit subtle biochemical differences (receptor binding, metabolic activation) to gain mammal safety and pest specificity.

• Understanding nerve physiology, endocrine regulation, and mitochondrial respiration is essential for both discovery and responsible stewardship of modern insecticides.