Toxic Effects of PesticidesPesticides 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 populationsPesticides 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 pesticidesRachel Carson's Silent Spring. Written over the years 1958 to 1962, it took a hard look at the effects of insecticides and pesticides on songbird populations throughout the United States,whose declining numbers yielded the silence to which her title attests. (from Amazon.com)Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Klaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001 World production (1995): 2.6x109kgUS production (1997): 0.54x109kgWorld production of DDT (1943-74): 2.8x109kgRegulations (US):Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)Established in 1947 under USDATurned over to the EPA in 1972FDA retains authority over monitoring residues in foodsUSDA is responsible for monitoring residues in meat and poultryFood Quality Protection Act (1996)Special 10-fold safety factor and other precautions added to consider possible effects in infants and childrenKlaassen, CD. CASARETT AND DOULL's Toxicology: The Basic Science of Poisons. McGraw-Hill 2001Vulnerability of ChildrenGreater 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 respirationVulnerability of ChildrenGreater 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 developedKlaassen, 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: ExampleStenersen, 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 synthesisAmino acid synthesisChitin synthesisCholinesterase• Hormone-like and behavior-modifying agentsModes of action of pesticides:Disturbance in energy productionNaturally occurring compoundBlocks electron transfer from NADH to ubiquinone in mitochondriaHighly toxic to fishStenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Disturbance in energy productionStenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Inhibition of photosynthesisStenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Herbicide 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 radicalsInterference with cell divisionCommon mode of action: inhibition of tubulin – blockage of microtubules that separate chromosomes during cell divisionInhibition of nucleic acid synthesisSporulation-inhibiting fungicidesHerbicides inhibiting incorporation of uridine into RNA(chloroacetanilides and phenylamides)Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Inhibition of ergosterol synthesisSqualeneepoxidaseStenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Inhibition of ergosterol synthesis14-α-demethylase (CYP51)Demethylase (DMI)-inhibiting fungicides:Azoles and triazolesPyridines and pyrimidinesPyperazinesAminesMorpholinesStenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Inhibition of amino acid synthesisGlyphosate(Roundup®, Vision®):Inhibits 5-enolpyruvyl-shikimate-3-phosphate synthase (EPSP)Gluphosinate(Basta®, Total®):Inhibits glutamine synthaseStenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Inhibition of choline esterase or action potential• Organochlorine Insecticides• Organophosphate Insecticides•Carbamates• Pyrethroidinsecticides• Botanical InsecticidesKlaassen, 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 lifeStenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004General Modes of ActionPesticides acting on the axon (impulse transmission):• Interference with transport of, Na+, K+, Ca2+, or Cl-ionsPesticides acting on synaptic transmission:• Inhibition of specific enzyme activities:GABA-ergic (inhibitory) synapsesCholinergic synapses• Contribution to the release or persistence of chemical transmitters at nerve endingsStenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004Organochlorine Insecticides• Dichlorodiphenylethanes–
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