Pesticides are substances used to prevent,destroy, repel or mitigate any pest ranging from insects,animals and weeds to microorganisms such as fungi,molds, bacteria and viruses. insect killers(insecticides) mold and fungi killers(fungicides) Toxic Effects of Pesticides weed killers (herbicides) slug pellets(molluscicides) plant growth regulators bird and animal repellents rat and mouse killers(rodenticides) Pesticides help to manage and prevent pests that spread ga6taetpbenaeceuiangs,andotherpropet Pesticides help to manage and prevent pests that spread disease,that da Agricultural production has increased 82%in the past 30 years due to pesticides n.CD.CASARETT ANb DOULL's:The Sask Sdence of Poisens.MeGraw-Hil 200 Medical uses: Suppression of typhus epidemic in Italy,1943-1944 1943-72.8x109 ·Control of blindn fly that car Sales Control of Malaria in Africa,Middle East,and Asia by Herbicides 47.6% eliminating the mosquito populations Insecticides 29.4% Fungicides 17.4% Others 5.5% an,1.Chemical and CRC Press 200
1 Toxic Effects of Pesticides Pesticides are substances used to prevent, destroy, repel or mitigate any pest ranging from insects, animals and weeds to microorganisms such as fungi, molds, bacteria and viruses. • insect killers (insecticides) • mold and fungi killers (fungicides) • weed killers (herbicides) • slug pellets (molluscicides) • plant growth regulators • bird and animal repellents • rat and mouse killers (rodenticides) Pesticides help to manage and prevent pests that spread disease, that damage crops, buildings, and other property, and that are a public nuisance. Medical uses: • Suppression of typhus epidemic in Italy, 1943-1944 • Control of blindness in West Africa by killing the black fly that carried the disease • Control of Malaria in Africa, Middle East, and Asia by eliminating the mosquito populations Pesticides help to manage and prevent pests that spread disease, that damage crops, buildings, and other property, and that are a public nuisance. Agricultural production has increased 82% in the past 30 years due to pesticides Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004 Klaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001 World production (1995): 2.6x109 kg US production (1997): 0.54x109 kg World production of DDT (1943-74): 2.8x109 kg
Regulations(US): eBatae Vulnerability of Children Federal Insecticide,Fungicide, and Rodenticide Act(FIFRA) Greater exposure 2g出S别 On a body-weight:caloric consumption ratio Children are 2.5x adults.Diet less varied (fruit and milk) ·↑Hand to mouth activity montrngrnat nsible for Skin surface area per body weight is double and poultry h that of an adult ·↑Rate of respiration Food Quality Protection Act (1996) specia10-fodaietastconndeoher rnd hirn ☐□□Pesticide6 cycle(USA) Vulnerability of Children -图□口> Greater physiological susceptibility 门回国 Period of rapid development of nerve cells Loss of organ function can be permanently imprinted ·Absorption and↓elimination of pesticides Metabolizing enzymes not fully developed Figure 22-3.A schem Estimated cost to develop new pesticide product:$80 mln(1999)
2 Regulations (US): Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Established in 1947 under USDA Turned over to the EPA in 1972 FDA retains authority over monitoring residues in foods USDA is responsible for monitoring residues in meat and poultry Food Quality Protection Act (1996) Special 10-fold safety factor and other precautions added to consider possible effects in infants and children Klaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001 Vulnerability of Children Greater exposure • On a body-weight: caloric consumption ratio Children are 2.5x adults. Diet less varied (fruit and milk) • ↑ Hand to mouth activity • Skin surface area per body weight is double that of an adult • ↑ Rate of respiration Vulnerability of Children Greater physiological susceptibility • Period of rapid development of nerve cells • Loss of organ function can be permanently imprinted • ↑ Absorption and ↓ elimination of pesticides • Metabolizing enzymes not fully developed Klaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001 Estimated cost to develop new pesticide product: $80 mln (1999)
Complexities of the Nomenclature:Example Modes of action of pesticides: Disturbance in energy production Chemical Name Inhibition of photosynthesis ) Free radical generation SH-group reactivity Interference with cell division Inhibition of nucleic acid synthesis Inhibition of enzymes: Ergosterol synthesis Amino acid synthesis 级4，ENT游 Varies Codes Chitin synthesis Cholinesterase Hormone-like and behavior-modifying agents 1.h des:Mode af Action and Teod ogr.CRE Press 2004 Disturbance in energy production Disturbance in energy production Site of Action Compounds Toic for Most animals C e-al Most animals (o ate) Rotenon Insects,fish B.O ic rgnm Most arganisms Naturally occurring compound ts.fis Highly toxic to fish them to CRC Ps 2004
3 Complexities of the Nomenclature: Example Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004 • Disturbance in energy production • Inhibition of photosynthesis • Free radical generation & SH-group reactivity • Interference with cell division • Inhibition of nucleic acid synthesis • Inhibition of enzymes: Ergosterol synthesis Amino acid synthesis Chitin synthesis Cholinesterase • Hormone-like and behavior-modifying agents Modes of action of pesticides: Disturbance in energy production Naturally occurring compound Blocks electron transfer from NADH to ubiquinone in mitochondria Highly toxic to fish Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004 Disturbance in energy production Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004
Inhibition of photosynthesis Free radical generation SH-reactivity ()H 。d Mercury-containing agents(mercurials): binding to DNA,RNA,proteins and formation of cross-links Herbicide action may be via: SH-group reactive agents: Form protein-compound and protein-compound-protein cross-links inside (umen)pH5 pe8ga9eneaoseg Copper-containing agents: Binding to D1 protein at promote redox cycling and generation of free radicals e binding site derivatives,triazines) Inhibition or destruction of Interference with cell division 8mitoieaCoRir2ng"ts(e.g. Common mode of action:inhibition of tubulin-block microubules thatsparat hromomuing cllv Inhibition of nucleic acid synthesis Inhibition of ergosterol synthesis Sporulation-inhibiting fungicides ehloroacgnti Herbicides inhibitin idine int and ph RNA ides) C-CH,R' CRC Press 2004 and Te slegr.CRC 2004
4 Inhibition of photosynthesis Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004 Herbicide action may be via: •Disruption of H+ ion gradients (weak organic acids) •Free radical generators (e.g., paraquat) •Binding to D1 protein at plastoquinone binding site (D1-blockers: urea derivatives, triazines) •Inhibition or destruction of protective carotenoids (e.g., amitrole, aclonifen) Free radical generation & SH- reactivity • Mercury-containing agents (mercurials): binding to DNA, RNA, proteins and formation of cross-links • SH-group reactive agents: Form protein-compound and protein-compound-protein cross-links • Copper-containing agents: promote redox cycling and generation of free radicals Interference with cell division Common mode of action: inhibition of tubulin – blockage of microtubules that separate chromosomes during cell division Inhibition of nucleic acid synthesis Sporulation-inhibiting fungicides Herbicides inhibiting incorporation of uridine into RNA (chloroacetanilides and phenylamides) Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004 Inhibition of ergosterol synthesis Squalene epoxidase Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004
Inhibition of ergosterol synthesis Inhibition of amino acid synthesis 女竹女层 nvvl-shikin 3-phosphate synthase(EPSP) Demethylase(DMI)-inhibiting fungicides: Azoles and triazoles : 基 Pyridines and pyrimidines Pyperazines bits gluta synthase 三 Morpholines o8a编 1.h des:Mode af Action and Teodedlogr.CRC Press 2004 Inhibition of choline esterase or action potential 。Most chemical insecticides act by 。Organochlorine poisoning the nervous Insecticides system of the target organisms ·Organophosphate Insecticides ·CNS of insects are highly developed and 。Carbamates similar to that of the ·Pyrethroid mammal insecticides ·Chemicals that act on ·Botanical the insect nervous Insecticides system may have similar effects on higher forms of life
5 Inhibition of ergosterol synthesis 14-α-demethylase (CYP51) Demethylase (DMI)-inhibiting fungicides: Azoles and triazoles Pyridines and pyrimidines Pyperazines Amines Morpholines Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004 Inhibition of amino acid synthesis Glyphosate (Roundup®, Vision®): Inhibits 5-enolpyruvyl-shikimate- 3-phosphate synthase (EPSP) Gluphosinate (Basta®, Total®): Inhibits glutamine synthase Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004 Inhibition of choline esterase or action potential • Organochlorine Insecticides • Organophosphate Insecticides • Carbamates • Pyrethroid insecticides • Botanical Insecticides Klaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001 • Most chemical insecticides act by poisoning the nervous system of the target organisms • CNS of insects are highly developed and similar to that of the mammal • Chemicals that act on the insect nervous system may have similar effects on higher forms of life Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004
General Modes of Action Organochlorine Insecticides Pesticides acting on the axon (impulse ngs rCW心界e8gto -DOT .Hexochlorocyclohexanes Lindane ympmion: Pesticides ACh A peic enyme ·Cyclodienes -Dieldrin ic(inhibitory) Aldrin Cholinergic synapses ·Chlordecone 8 on to the rele ase or n 2.C ode of Act n and To HISTORY OF DDT CURRENT STATUS: 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane No US registration,most uses cancelled in 1972,all uses by 1989 N s prod ort,or export ofD)shdpollta (Clea Water Ac) 8enaretegwcehalket later entestwsss market in 1041 Seven years DDT can take more than 15 years to break down Found in animale far from whe vere it is used B8raneandpwso69ynrecosntononewe Bio-accumulates in fish and marine mammals.Found concentrations in these animals are many thousands of times higher than levels in water .DDT can be absorbed by some plants and by animals and humans who WWII-DDT was used by the allies to suppress a eat those plants typhus epidemic in Naples DDT is fat-soluble and is stored in adipose tissues of humans and 1943-1944 DDT was applied directly to the head animals of humans to control lice HUMAN EXPOSURE FROM: Success with DDT hastened the development of Eating contaminated fish and shelfish aldrin,dieldrin,endrin,chlordane,benzene Eating imported hexachloride etc. a th east mi from crops grown in conaminateds
6 General Modes of Action Pesticides acting on the axon (impulse transmission): • Interference with transport of, Na+, K+, Ca2+, or Cl- ions Pesticides acting on synaptic transmission: • Inhibition of specific enzyme activities: GABA-ergic (inhibitory) synapses Cholinergic synapses • Contribution to the release or persistence of chemical transmitters at nerve endings Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004 Organochlorine Insecticides • Dichlorodiphenylethanes – DDT • Hexochlorocyclohexanes – Lindane – Benzene hexachloride • Cyclodienes – Dieldrin – Aldrin • Chlordecone – Kepone – Mirex HISTORY OF DDT 1,1,1-trichloro-2,2-bis-(p-chlorophenyl) ethane • WWII – DDT was used by the allies to suppress a typhus epidemic in Naples • 1943-1944 DDT was applied directly to the head of humans to control lice • Success with DDT hastened the development of aldrin, dieldrin, endrin, chlordane, benzene hexachloride etc. DDT was discovered to be an insecticide in 1939 by Paul Muller. He was a scientist working for Geigy, a Swiss firm that was focused on the chemical development of agricultural insecticides. Products with DDT entered the Swiss market in 1941. Seven years later, in 1948, Muller received the Nobel Prize for medicine and physiology in recognition for the lives DDT saved. DDT • DDT can take more than 15 years to break down • Found in animals far from where they were it is used • Bio-accumulates in fish and marine mammals. Found concentrations in these animals are many thousands of times higher than levels in water • DDT can be absorbed by some plants and by animals and humans who eat those plants • DDT is fat-soluble and is stored in adipose tissues of humans and animals CURRENT STATUS: • No US registration, most uses cancelled in 1972, all uses by 1989 • No US production, import, or export • DDE (metabolite of DDT) is regulated as a hazardous air pollutant (Clear Air Act) • Priority toxic pollutant (Clean Water Act) HUMAN EXPOSURE FROM: • Eating contaminated fish and shellfish • Eating imported food exposed to DDT • Infant exposed through breast milk • Eating products from crops grown in contaminated soil
Insecticide advantages of DDT Low volatility ·Chemical stability Lipid solubility Slow rate of biotransformation and degradation Disadvantages of DDT Biomagnification in food chain Profound effects on wild life ("Silent Spring") Health Effects of DDT Paresthesia of tongue,lips,and Hypertrophy of hepatocytes Hepatic tumors rghgomoeto, No epidemiological evidence linking DDT 10m Lowrate of absorption through the skin Human health effects minor iAP ,CD.亡ASAR T AND DOULLTec bdy:The Baue Sites of DDT poisoning OPIDN 3 Na" Organophosphate-Induced Delayed Neurotoxicity (OPIDN) Pesticides with High Potency Leptophos and Mipofox Pesticides with low Potency -Parathion,chloropyrifos,fenthion,malathion Toxc REsPONses oF THE NERvous SYsTEM ing D 血 sen,CD.CASARETT AND DOULLY T
7 Insecticide advantages of DDT • Low volatility • Chemical stability • Lipid solubility • Slow rate of biotransformation and degradation Disadvantages of DDT • Persistence in the environment • Bioconcentration • Biomagnification in food chain • Profound effects on wild life (“Silent Spring”) Health Effects of DDT • Paresthesia of tongue, lips, and face • Irritability, dizziness, vertigo, tremor, and convulsions • Hypersusceptibility to external stimuli (light, touch, and sound) • Hypertrophy of hepatocytes • Hepatic tumors • No epidemiological evidence linking DDT to carcinogenicity in humans • Low rate of absorption through the skin • Human health effects minor Klaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001 Sites of DDT poisoning Klaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001 OPIDN • Organophosphate-Induced Delayed Neurotoxicity (OPIDN) • Pesticides with High Potency – Leptophos and Mipofox • Pesticides with low Potency – Parathion, chloropyrifos, fenthion, malathion
"Aging"of Acetylcholinesterase OPIDN:Clinical Symptoms ·Flaccidity Recovery begins in the 1s Symptoms occur 14 days reverse order post exposure Recovery is seldom complete Muscle weakness Injury to spinal Cord as well g一g Shuffle gait as lower limbs occur ·Hypertonicity 。Hyper-reflexia Abnormal reflexes ·Paralysis 一。 OPIDN:Testing Requirements All new organophosphate compounds must be tested for OPIDN before they are put on the Market market Tests must be carried out in Chickens an,C.CASA处TAND DOULL MeCraw-Hll 2001 PON1 polymorphism: Pyrethroid Insecticides PON1-human serum paraoxonase envm in metabolism of organophosphate compounds 0要0 PON1R192PON1Q192 Newest class of insecticides lysis of PON1 substrates. New analoas will be (hopefullv) More stable in light and air PON10192/PON1R192 Better persistence PON1R192/PON1R192 -Low mammalian toxicity Fromc Hulla et aL Tare.SoL (1999)
8 “Aging” of Acetylcholinesterase Klaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001 OPIDN: Clinical Symptoms • Flaccidity • 1st Symptoms occur 14 days post exposure • Muscle weakness • Shuffle gait • Hypertonicity • Hyper-reflexia • Abnormal reflexes • Paralysis • Recovery begins in the reverse order • Recovery is seldom complete • Injury to spinal Cord as well as lower limbs occur • All new organophosphate compounds must be tested for OPIDN before they are put on the Market market • Tests must be carried out in Chickens OPIDN:Testing Requirements PON1 polymorphism: PON1 – human serum paraoxonase, enzyme important for lipid metabolisms that is also involved in metabolism of organophosphate compounds From: Hulla et al. Toxc. Sci. (1999) PON1R192 PON1Q192 Rapid hydrolysis of paraoxon Rapid hydrolysis of sarin, soman, diazoxon Two-dimensional enzyme analysis to characterize PON1 polymorphisms in human population: analyze hydrolysis of PON1 substrates, diazoxone vs. paraoxone (panel c) O PON1Q192/PON1Q192 ■ PON1Q192/PON1R192 ∆ PON1R192/PON1R192 Pyrethroid Insecticides • Newest class of insecticides • New analogs will be (hopefully): – More stable in light and air – Better persistence – Low mammalian toxicity Soderlund et al. (2002)
Importance of Structure-Activity-Toxicity Pyrethroid Use Relationships ·Household sprays A 从0 Flea preparations for pets ·Plant sprays for home -00 Plant sprays for greenhouses 0义o0 Pyrethroid Poisoning ·Similar to DDT Not highly toxic in animals ·Toxic ingredients Chrysanthemic acid Pyrethric acid NEON COTINOIDS 品 Systemic Dm Selectivity Figure 1.Nine neonicotinoid Class IP action Nerve target Inseets Rats factor Neonicotinoids -0.7o1.3+ nAChR 20912456 AChE 20 33 Methvlcartamates -I to 3 AChE 28 45 16 thiazolylmethyl,and 3-tetrahydro- 26 230 91 Pyrcthroids 4和9 Na+channel0.4520004500 chr(othin) (ABTnddemidd) 三 (n means of large data sets (11 to 83 items each)for rat acute oral and inect topical (principally four ABT-594 (2004) Caide (00)
9 Importance of Structure-Activity-Toxicity Relationships Soderlund et al. (2002) Pyrethroid Use • Household sprays • Flea preparations for pets • Plant sprays for home • Plant sprays for greenhouses • Similar to DDT • Not highly toxic in animals • Toxic ingredients – Chrysanthemic acid – Pyrethric acid Pyrethroid Poisoning Figure 1. Nine neonicotinoid insecticides and four nicotinoids. The neonicotinoids are nitromethylenes (C==CHNO2), nitroguanidines (C==NNO2), and cyanoamidines (C==NCN). Compounds with 6-chloro- 3-pyridinylmethyl, 2-chloro-5- thiazolylmethyl, and 3-tetrahydrofuranmethyl moieties are referred to as chloropyridinyls (or chloronicotinyls), chlorothiazolyls (or thianicotinyls), and tefuryl, respectively. The nicotinoids are naturally occurring [(−)-nicotine and (−)-epibatidine] and synthetics (ABT-594 and desnitroimidacloprid). Tomizawa & Casida (2004) Tomizawa & Casida (2004)
insects mammals olnmd (2004)
10 Tomizawa & Casida (2004)