Chemical Pesticides Mode of Action and Toxicology

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Jørgen Stenersen CRC Press 2004
Chapter 1 Introduction ......................................................................................1 1.1 Motivation.......................................................................................................1 1.2 Pesticides and opinion ..................................................................................2 1.2.1 The fly in the soup............................................................................2 1.2.2 Low-tech food production...............................................................3 1.2.3 Conclusion..........................................................................................3 1.3 A great market................................................................................................4 1.3.1 The number of chemicals used as pesticides ...............................4 1.3.2 Amounts of pesticides produced....................................................4 1.3.3 Marketing

Chapter 1 Introduction ......................................................................................1 1.1 Motivation.......................................................................................................1 1.2 Pesticides and opinion ..................................................................................2 1.2.1 The fly in the soup............................................................................2 1.2.2 Low-tech food production...............................................................3 1.2.3 Conclusion..........................................................................................3 1.3 A great market................................................................................................4 1.3.1 The number of chemicals used as pesticides ...............................4 1.3.2 Amounts of pesticides produced....................................................4 1.3.3 Marketing ...........................................................................................6 1.3.4 Dirty dozens.......................................................................................7 1.4 Nomenclature, definitions, and terminology ............................................9 1.4.1 Toxicology, ecotoxicology, and environmental toxicology .........9 1.4.2 Pesticides, biocides, common names, chemical names, and trade names..............................................................................10 1.4.3 Chemical structures are versatile .................................................12 Helpful reading.....................................................................................................13 Biochemistry and cell biology ............................................................................13 General toxicology................................................................................................13 Insect biochemistry, plant physiology, and neurophysiology.......................13 Pesticides ................................................................................................................14 Side effects of pesticides......................................................................................14 Chapter 2 Why is a toxicant poisonous?......................................................15 2.1 Seven routes to death..................................................................................15 2.1.1 Enzyme inhibitors ...........................................................................16 2.1.2 Disturbance of the chemical signal systems...............................16 2.1.3 Toxicants that generate very reactive molecules that destroy cellular components .........................................................17 2.1.4 Weak organic bases or acids that degrade the pH gradients across membranes .........................................................17 2.1.5 Toxicants that dissolve in lipophilic membranes and disturb their physical structure ....................................................18 2.1.6 Toxicants that disturb the electrolytic or osmotic balance or the pH ..........................................................................................182.1.7 Strong electrophiles, alkalis, acids, oxidants, or reductants that destroy tissue, DNA, or proteins .........................................18 2.2 How to measure toxicity ............................................................................18 2.2.1 Endpoints..........................................................................................18 2.2.1.1 Endpoints in ecotoxicology and pest control ..............19 2.2.1.2 Endpoints in human toxicology.....................................19 2.2.2 Dose and effect ................................................................................20 2.2.3 Dose and response ..........................................................................21 2.2.3.1 Dose–response curves for the stable fly .......................24 2.2.3.2 Scatter in dose–response data ........................................25 2.2.4 LD50 and related parameters........................................................26 2.2.5 Acute and chronic toxicity.............................................................27 2.3 Interactions....................................................................................................27 2.3.1 Definitions ........................................................................................28 2.3.2 Isoboles..............................................................................................29 2.3.3 Mechanisms of interactions...........................................................30 2.3.4 Examples...........................................................................................30 2.3.4.1 Piperonyl butoxide ...........................................................30 2.3.4.2 Deltamethrin and fenitrothion .......................................32 2.3.4.3 Atrazine and organophosphate insecticides ................32 Chapter 3 Pesticides interfering with processes important to all organisms.........................................................................................35 3.1 Pesticides that disturb energy production...............................................35 3.1.1 Anabolic and catabolic processes .................................................35 3.1.2 Synthesis of acetyl coenzyme A and the toxic mechanism of arsenic...........................................................................................36 3.1.3 The citric acid cycle and its inhibitors.........................................36 3.1.3.1 Fluoroacetate .....................................................................36 3.1.3.2 Inhibitors of succinic dehydrogenase ...........................37 3.1.4 The electron transport chain and production of ATP...............38 3.1.4.1 Rotenone ............................................................................38 3.1.4.2 Inhibitors of electron transfer from cytochrome b to c1 ..................................................................................40 3.1.4.3 Inhibitors of cytochrome oxidase...................................41 3.1.4.4 Uncouplers.........................................................................41 3.1.5 Inhibition of ATP production........................................................42 3.1.5.1 Organotin compounds.....................................................43 3.1.5.2 Diafenthiuron ....................................................................44 3.1.5.3 Summary............................................................................45 3.2 Herbicides that inhibit photosynthesis ....................................................45 3.2.1 Weak organic acids .........................................................................49 3.2.2 Free radical generators...................................................................49 3.2.3 D1 blockers........................................................................................51 3.2.3.1 Urea derivatives................................................................51 3.2.3.2 Triazines .............................................................................523.2.4 Inhibitors of carotene synthesis ....................................................53 3.2.4.1 Amitrole .............................................................................53 3.2.4.2 Aclonifen............................................................................53 3.2.4.3 Beflubutamid.....................................................................53 3.2.5 Protoporphyrinogen oxidase inhibitors ......................................54 3.3 General SH reagents and free radical generators...................................54 3.3.1 Mercury.............................................................................................54 3.3.2 Other multisite fungicides .............................................................56 3.3.2.1 Perhalogenmercaptans.....................................................56 3.3.2.2 Alkylenebis(dithiocarbamate)s and dimethyldithiocarbamates...............................................57 3.3.2.3 Fungicides with copper ...................................................58 3.4 Pesticides interfering with cell division...................................................59 3.4.1 Fungicides.........................................................................................61 3.4.1.1 Benomyl .............................................................................61 3.4.1.2 Thiofanate-methyl ............................................................61 3.4.1.3 Carbendazim .....................................................................62 3.4.1.4 Thiabendazole ...................................................................62 3.4.1.5 Diethofencarb ....................................................................62 3.4.2 Herbicides.........................................................................................62 3.4.2.1 Trifluralin ...........................................................................62 3.4.2.2 Carbetamide ......................................................................63 3.5 Pesticides inhibiting enzymes in nucleic acid synthesis.......................63 3.5.1 Sporulation-inhibiting fungicides.................................................63 3.5.2 Inhibition of incorporation of uridine into RNA.......................64 Chapter 4 Bacillus thuringiensis and its toxins ..........................................67 4.1 The mechanism of action of δ-endotoxins...............................................68 4.2 Biotechnology ...............................................................................................70 4.3 Engineered plants ........................................................................................70 4.4 Biology ...........................................................................................................70 4.5 Commercial products ..................................................................................71 Chapter 5 Specific enzyme inhibitors ..........................................................73 5.1 Inhibitors of ergosterol synthesis ..............................................................73 5.1.1 Inhibition of HMG-CoA reductase...............................................74 5.1.2 Inhibition of squalene epoxidase..................................................75 5.1.3 DMI fungicides................................................................................76 5.1.4 Examples of DMI fungicides from each group..........................78 5.1.4.1 Azoles and triazoles.........................................................78 5.1.4.2 Pyridines and pyrimidines .............................................78 5.1.4.3 Piperazines.........................................................................79 5.1.4.4 Amines................................................................................79 5.1.4.5 Morpholines.......................................................................80 5.1.5 Conclusions ......................................................................................815.2 Herbicides that inhibit synthesis of amino acids ...................................81 5.2.1 The mode of action of glyphosate................................................81 5.2.2 Degradation of glyphosate ............................................................83 5.2.3 Selectivity..........................................................................................84 5.2.4 Mode of action of glufosinate .......................................................84 5.2.5 Inhibitors of acetolactate synthase ...............................................86 5.3 Inhibitors of chitin synthesis......................................................................88 5.3.1 Insecticides .......................................................................................88 5.3.2 Fungicides.........................................................................................90 5.4 Inhibitors of cholinesterase ........................................................................90 5.4.1 Acetylcholinesterase .......................................................................90 5.4.2 Organophosphates ..........................................................................95 5.4.2.1 Naturally occurring organophosphorus insecticides.........................................................................97 5.4.3 Carbamates.......................................................................................97 5.4.3.1 Molecular structure and potency of inhibition ...........98 5.4.4 Development of organophosphorus and carbamate insecticides........................................................................................99 5.4.4.1 Parathion and similar compounds ..............................103 5.4.4.2 Aliphatic organophosphates.........................................107 5.4.4.3 Examples of carbamates ................................................107 5.5 Other enzymes inhibited by organophosphates and carbamates .....109 5.5.1 The butyrylcholinesterases ..........................................................109 5.5.2 The neurotoxic target enzyme (NTE) ........................................ 110 5.5.3 Carboxylesterases.......................................................................... 113 Chapter 6 Interference with signal transduction in the nerves............ 115 6.1 Potency of nerve poisons.......................................................................... 115 6.2 Selectivity .................................................................................................... 115 6.3 The nerve and the nerve cell ................................................................... 116 6.4 Pesticides that act on the axon ................................................................ 117 6.4.1 Impulse transmission along the axon........................................ 117 6.4.2 Pesticides ........................................................................................ 119 6.4.3 Pyrethroids ..................................................................................... 119 6.4.4 DDT and its analogues.................................................................124 6.5 Pesticides acting on synaptic transmission ...........................................125 6.5.1 Inhibitory synapses.......................................................................126 6.5.2 Pesticides ........................................................................................127 6.5.2.1 Lindane.............................................................................127 6.5.2.2 Fipronil .............................................................................130 6.5.2.3 Cyclodiene insecticides..................................................130 6.5.2.4 Avermectins .....................................................................130 6.5.3 The cholinergic synapses .............................................................131 6.5.3.1 Atropine ...........................................................................133 6.5.3.2 Nicotinoids and neonicotinoids ...................................1346.5.3.3 Cartap ...............................................................................136 6.5.4 Calcium channels as possible targets for insecticides ............136 6.6 Summary .....................................................................................................137 Chapter 7 Pesticides that act as signal molecules....................................139 7.1 Insect hormones .........................................................................................139 7.1.1 Insect endocrinology.....................................................................139 7.1.2 Juvenile hormone ..........................................................................140 7.1.2.1 American paper towels .................................................141 7.1.2.2 Juvenile hormone agonists as pesticides....................141 7.1.2.3 Antagonists......................................................................143 7.1.3 Ecdysone.........................................................................................143 7.1.3.1 Phyto-ecdysones .............................................................144 7.1.3.2 Synthetic ecdysteroids used as insecticides ...............145 7.1.3.3 Azadirachtin ....................................................................145 7.2 Behavior-modifying pesticides ................................................................146 7.2.1 Definitions ......................................................................................147 7.2.2 Pheromones....................................................................................148 7.2.3 Structure–activity relationships ..................................................148 7.2.3.1 Alarm and trail pheromones ........................................149 7.2.3.2 Aggregation pheromones..............................................149 7.2.4 Pheromones used as pesticides and lures.................................151 7.2.4.1 Coleoptera........................................................................151 7.2.4.2 Lepidoptera......................................................................152 7.2.4.3 Fruit flies ..........................................................................153 7.2.4.4 Aphid food deterrent.....................................................154 7.2.4.5 Mosquito repellents........................................................154 7.5 Plant hormones ..........................................................................................155 Chapter 8 Translocation and degradation of pesticides .........................161 8.1 The compartment model ..........................................................................161 8.1.1 The bioconcentration factor.........................................................164 8.1.2 The half-life ....................................................................................164 8.1.3 The area under the curve.............................................................165 8.1.4 Example ..........................................................................................165 8.1.4.1 Disappearance of dieldrin in sheep.............................165 8.1.4.2 Dieldrin uptake in sheep...............................................166 8.2 Degradation of pesticides by microorganisms .....................................166 8.2.1 Degradation by adaption.............................................................166 8.2.2 Degradation by co-metabolism...................................................167 8.2.3 Kinetics of degradation ................................................................167 8.2.4 Importance of chemical structure for degradation..................168 8.2.5 Examples.........................................................................................169 8.2.5.1 Co-metabolism and adaptation....................................169 8.2.5.2 Parathion and other pesticides with nitro groups....1718.2.5.3 Ester hydrolysis of carbaryl..........................................171 8.2.5.4 Mineralization of dalapon.............................................172 8.2.6 The degraders ................................................................................172 8.3 Soil adsorption ...........................................................................................173 8.3.1 Why are chemicals adsorbed?.....................................................173 8.3.2 Examples.........................................................................................173 8.3.2.1 Measurements of adsorption........................................175 8.3.3 Desorption ......................................................................................177 8.4 Evaporation.................................................................................................178 8.4.1 Example ..........................................................................................179 8.5 Biotransformation in animals ..................................................................180 8.5.1 Oxidation ........................................................................................181 8.5.2 Epoxide hydrolase.........................................................................184 8.5.3 Glutathione transferase ................................................................185 8.5.4 Hydrolases......................................................................................187 8.5.5 Glucoronosyltransferase and sulfotransferase .........................187 8.5.6 Stereospecific biotransformation.................................................188 8.6 Designing pesticides that have low mammalian toxicity...................189 8.6.1 Acephate .........................................................................................190 8.6.2 Malathion and dimethoate ..........................................................191 8.6.3 Nereistoxin .....................................................................................192 Chapter 9 Resistance to pesticides ..............................................................193 9.1 Definitions ...................................................................................................193 9.2 Resistance is an inevitable result of evolution......................................194 9.2.1 Time for resistance development................................................194 9.2.2 Questions about resistance ..........................................................196 9.2.2.1 Are resistant insects more robust than sensitive ones?.................................................................196 9.2.2.2 Is resistance caused by one allele in one gene locus?.......................................................................196 9.2.2.3 Do pesticides cause resistance?....................................197 9.3 Biochemical mechanisms..........................................................................197 9.3.1 Increased detoxication..................................................................199 9.3.1.1 DDT dehydrochlorinase ................................................199 9.3.1.2 Hydrolases .......................................................................200 9.3.1.3 CYP enzymes in insects.................................................200 9.3.1.4 CYP enzymes in plants..................................................201 9.3.2 Insensitive target enzyme or target receptor site ....................201 9.3.2.1 Acetylcholinesterase.......................................................201 9.3.2.2 kdr resistance ..................................................................202 9.3.3 Resistance in fungi........................................................................203 9.3.3.1 Benzimidazole .................................................................203 9.3.3.2 Sterol biosynthesis inhibitors........................................2049.3.4 Atrazine resistance and plants made resistant by genetic engineering .................................................................204 9.3.5 Resistance to glyphosate ..............................................................205 9.3.5.1 Summary..........................................................................207 9.3.6 Resistance to older biocides used as pesticides.......................207 9.3.7 Resistance to third- and fourth-generation pesticides............208 9.4 How to delay development of resistance ..............................................208 9.4.1 Refuge strategy..............................................................................209 9.4.2 Mixing pesticides with different modes of action and different detoxication patterns....................................................210 9.4.3 Switching life-stage target ...........................................................210 9.4.4 Increased sensitivity in resistant pests ......................................210 9.4.5 Inhibition of detoxication enzymes............................................210 9.5 Conclusions................................................................................................. 211 Chapter 10 Pesticides as environmental hazards.....................................213 10.1 Pesticides are poisons................................................................................213 10.1.1 Pesticides are xenobiotics.............................................................215 10.1.2 Various types of bias ....................................................................217 10.1.2.1 Publication bias...............................................................217 10.1.2.2 Test bias............................................................................218 10.1.2.3 Extrapolation bias...........................................................219 10.1.3 Benchmark values .........................................................................220 10.2 Required toxicological tests for official approval of a pesticide...............................................................................................220 10.3 Analysis of residues in food and the environment..............................222 10.3.1 Definitions ......................................................................................222 10.3.2 Sampling.........................................................................................223 10.3.3 Sample preparation.......................................................................223 10.3.4 Analysis...........................................................................................224 10.3.4.1 Chromatographic methods ...........................................224 10.3.4.2 Biological methods .........................................................225 10.4 Pesticide residues in food.........................................................................226 10.4.1 Toxicity classification of pesticides.............................................226 10.4.1.1 Classification of carcinogenecity..................................227 10.4.2 Definitions of ADI and NOEL and tolerance limits................227 10.4.2.1 ADI....................................................................................227 10.4.2.2 NOEL................................................................................228 10.4.2.3 Residue tolerance limits ................................................228 10.4.3 Comparing health hazards of pesticides with other toxicants present in the market basket......................................229 10.5 Elixirs of death ...........................................................................................230 10.5.1 Nomenclature and structure of dioxins ....................................23110.5.2 Dioxins in pesticides.....................................................................232 10.5.2.1 Vietnam ............................................................................232 10.5.2.2 Presence of dioxins in pesticides in general ..............233 10.5.3 Toxicology.......................................................................................234 10.5.4 The target........................................................................................234 10.5.4.1 Dioxin and metabolism of caffeine..............................236 10.5.5 Analysis...........................................................................................237 10.5.5.1 Saturday, 12:30, July 10, 1976........................................238 10.5.6 Summary.........................................................................................239 10.6 Angry bird-watchers, youth criminals, and impotent rats...............................................................................................239 10.6.1 Clear Lake.......................................................................................240 10.6.2 Peregrine falcons and other birds of prey ................................242 10.6.2.1 Borlaug’s warning ..........................................................244 10.6.2.2 DDT and impotence? .....................................................246 10.7 Conclusions.................................................................................................246

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