toxicology of pesticides - the university of north carolina at chapel hill lecture.pdf ·...
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PESTICIDES
A chemical, physical, or biological agent that will kill an undesirable plant or animal pest
All pesticides possess an inherent degree of toxicity to some living organism; otherwise they would be of no practical use.
Pesticide Use
Pesticides provide us with abundantly inexpensive, wholesome, and attractive fruits and vegetablesAgricultural production has increased 82% in the past 30 years due to pesticidesMedical Miracles
Medical MiraclesSuppression of typhus epidemic in Italy, 1943-1944Control of blindness in West Africa by killing the black fly that carried the diseaseControl of Malaria in Africa, Middle East, and Asia by eliminating the mosquito populations
Pesticide Danger
Of all the dangerous chemical substances to which we are exposed, only pesticides, antibiotic drugs, and anti cancer drugs are designed specifically to kill cells.
Target Species of Pesticides
Not very well developedNon-target species are affected because the have the same physiological systems as target organismsNo such thing as a completely safe pesticide
Vulnerability of Children
Greater exposureOn a body-weight: caloric consumption ratio Children are 2.5X adults. Diet less varied (fruit and milk)↑ Hand to mouth activitySkin surface area per body weight is double that of an adult↑ Rate of respiration
Vulnerability of Children
Greater physiological susceptibilityPeriod of rapid development of Nerve CellsLoss of organ function can be permanently imprinted↑ Absorption and ↓ elimination of pesticidesMetabolizing enzymes not fully developed
Safety of Pesticides
Depends on how they are usedMust be used according to the instructions on the labelAs long as they are used, accidental and/or incidental poisoning of wildlife, domestic stock, and humans will require treatment
INSECTICIDESMost chemical insecticides act by poisoning the nervous system of the target organismsCNS 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
Insecticide toxicity
A chemical that poisons the insect nervous system will will elicit similar effects on higher forms of life. Only the dosage will indicate the intensity of biological effects
Classes of Insecticides
Organochlorine InsecticidesOrganophosphate InsecticidesCarbamatesPyrethroid insecticidesBotanical Insecticides
Insectisticide General Mode of Action
Interference with transport of, Na+, K+, Ca2+, or Cl- ionsInhibition of specific enzyme activitiesContribution to the release or persistence of chemical transmitters at nerve endings
Organochlorine InsecticidesDichlorodiphenylethanes
DDTHexochlorocyclohexanes
Lindane or Benzene hexachlorideCyclodienes
DieldrinAldrin
ChlordeconeKeponeMirex
HISTORY OF DDT
WWII – DDT was used by the allies to suppress a typhus epidemic in Naples1943-1944 DDT was applied directly to the head of humans to control liceSuccess with DDT hastened the development of aldrin, dieldrin, endrin, chlordane, benzene hexachloride etc.
Insecticide advantages of DDT
Low volatilityChemical stabilityLipid solubilitySlow rate of biotransformation and degradation
Disadvantages of DDT
Persistence in the environmentBioconcentrationBiomagnification in food chainSilent Spring
Health Effects of DDT
Paresthesia of tongue, lips, and faceApprehensionIrritability, dizziness, vertigo, tremor, and convulsionsHypersusceptibility to external (light, touch, and sound)
Health Effects of DDT
Hypertrophy of hepatocytesHepatic tumorsNo epidemiological evidence linking DDT to carcinogenicity in humansLow rate of absorption through the skinHuman health effects minor
Health Effects of DDT
EstrogenicInduces EnzymesInterferes with reproduction
Insufficient Calcium to produce eggshells
DDTBanned in North America and Europe because of its harmful effects on wildlife and fresh water fish.Not banned in other countries because it is highly effective, inexpensive to manufacture, and safeDDT is making a comeback in other countries because it is the only effective agent against the spread of Malaria
Treatment of PoisoningDiazepam and phenobarbital are administered by slow injection to control convulsionsAnion-exchange resin, cholestyramine, increases the fecal excretion of the insecticide and inhibits the enterohepatic circulation. It binds the insecticide, reducing the reabsorption of the bound agent, causing fecal excretion of the bound material.
Other organochlorineisecticides: lindane
Lindane = Hexachlorocyclohexane (HCH)HCH is often Confused with Hexachlorobenzene (HCB): a fungicideVery similar to DDTMechanism of action unknown
Effects of Chlorinated Hydrocarbons on Inuit People
Inuit People450 People on small island in Canadian ArticMore polluted than any other place. Contain some of worlds most toxic chemicals. Concentration of chemicals 70-100 fold greater than other people
Effects of Chlorinated Hydrocarbons on Inuit People
SymptomsCancerBirth DefectsReproductive harmNeurological toxicityImmunotoxicityEndocrine Toxicity
Pesticides in ArticVolatile chemicals boil off into the air in tropical climateCarried by the winds until the hit cooler climatesCondense and fall to the earth (different groups of chemicals condense at different temperatures – fractional distillation)
Effects of Halogenated Hydrocarbons on Inuit People
ChemicalsPolychlorinated Biphenyls (PCB)Hexachlorobenzene (HCB)Hexchlorocyclohexane (HCH)
Other OrganochlorineInsecticides:Cyclodienes
Among the most toxic and environmentally persistent pesticides knownEfficiently absorbed through the skinSites of Action: Inhibits GABA action on chloride transport
Kepone and Mirex
Factory workers in Hopewell, VAKepone Shakes: tremors, altered gait, behavorial changes, headache, chest pains, impotence, weight loss, hepatosplenomegaly, etc.Discovered by veterinarian
Treatment for Kepone
Oral Cholestyramine:The anion-exchange resin causes up to 18 fold fecal excretion of kepone (chlordecone)Mechanism: Resin binds chlordeconeand prevents enterohepatic re-absorption and recirculation.
Anticholinesterase Insecticides
First synthesized in 1937 by German scientists Schrader and BayerTrial compounds were highly toxicUnder the Nazis in WWII, some were developed as warfare agentsPesticides used today are 4 generations away from those highly toxic chemicals
Anticholinesterase Pesticides
The replacement of DDT with parathion in 1950 resulted in a series of fatal poisoning.People were familiar with the fairly innocuous organochlorine insecticides and not prepared for the highly toxic anticholinesterases
Anticholinesterase Pesticides
Two ClassesEsters of Phosphoric acid (over 200 structures)Esters of Carbamic acid (over 25 structures)
Organophosphorus insecticide
Tetraethylpyrophosphate (TEPP)Extremely toxic
Parathion and ParaoxonHighly toxic
MalathionMuch less toxic
Kinetics
EH +AB EHAB BH +EA EH +AOH
Acetylcholine, Carbomate esters and Organophosphates: k+1 and k-1 = slowAcetylcholine: k2 = extremely fast, k3 = extremely fastOrganophosphates: k2 = moderately fast, k3 = extremely slowCarbamate esters: k2 = slow, k3 = moderately slow
EH = FREE EnzymeAB = SubstrateEHAB = Enzyme-Substrate ComplexBH = PART OF SUBSTRATEEA = PART OF SUBSTRATE
k+1
k-1
k2 k3
OPIDN
Organophosphate-Induced Delayed Neurotoxicity (OPIDN)Pesticides with High Potency
Leptophos and Mipofox
Pesticides with low PotencyParathion, chloropyrifos, fenthion, malathion
OPIDN: Mechanism
“Dying Back” degeneration of the large diameter axons occurInhibition of neuropathic target esterases (NTE)
NTE appears to have some uknown role I nerve lipid metabolism “Aging” of phosphate attached to NTE occurrs
OPIDN: Clinical SymptomsFlaccidity1st Symptoms occur 14 days post exposureMuscle weaknessShuffle gaitHypertonicityHyper-reflexiaAbnormal reflexesParalysis
Recovery begins in the reverse orderRecovery is seldom CompleteInjury to spinal Cord as well as lower limbs occur
OPIDN:Testing Requirements
All new organophosphate compounds must be tested for OPIDN before they are put on the Market marketTests must be carried out in Chickens
Pyrethroid Insecticides
Newest class of insecticidesNew analogs will be (hopefully):
More stable in light and airBetter persistenceLow mammalian toxicity
Pyrethroid Use
Household spraysFlea preparations for petsPlant sprays for homePlant sprays for greenhouses
Pyrethroid Poisoning
Similar to DDTNot highly toxic in animalsToxic ingredients
Chrysanthemic acidPyrethric acid
Gulf War syndrome (1990-1991) Symptoms
Respiratory difficultiesGastrointestinal disturbances
HeadacheLoss of MemoryFatigueMuscle & Joint PainAtaxiaSkin rash
Symptoms of Pyridostigmine toxicity
Muscle & Joint PainsAtaxiaSkin rashLoss of MemoryFatigue
Respiratory difficultiesGastrointestinal disturbances
Symptoms of Pyridostigmine poisoning
Respiratory difficultiesGastrointestinal disturbances
HeadacheLoss of MemoryFatigueMuscle & Joint PainsAtaxiaSkin rash
Gulf War syndrome (1990-1991) Suspected Cause
Soldiers are exposed to:DEET to protect against insect borne diseasesPermethrin to protect against insect borne diseasesPyridostigmine Bromide (PB): Antidote for nerve gas
Herbicide Actions
Inhibition of PhotosynthesisInhibition of respirationGrowth Stimulants (Auxins)Inhibitors of protein, nucleic acid, or lipid, or carotenoid synthesis
Chlorophenoxy Herbicides
Developed for both Chemical war agents and pesticide use (1946)Mimic auxins (plant hormones that stimulate growth)Used extensively in Viet Nam War to defoliate jungle
Chlorophenoxy ToxicitiesHeadacheDizzinessNauseaVomitingAbdominal painsDiarrheaRespiratory complications
Aching musclesTender musclesMyotoniaWeaknessFatigueRenal dysfunction
Chlorophenoxy Toxicities
No documented evidence of neurotoxicityNo evidence of tumor formationChloracne: Primary clinical symptomTeratogenic effects (cleft palate) also observed
TCDD (dioxin)
Contaminant from synthesis of 2,4,5-T
Not a pesticideDescribed as most toxic substance on earth