Toxicology of Pesticides

Curtis Harper

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

EPA Registration Data

AcuteSubchronicChronicReproductive

Types of Pesticides

InsecticidesHerbicidesFungicidesFumigantsRodenticides

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

Normal Neuron

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

Organochlorine Classification

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

Reflex arc

Action Potential

Sites of DDT poisoning

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

Cyclodiene Sites

Cubane

Cl Cl

Cl

Cl

Cl

ClCl

Cl

KEPONE

O C

Cl

Cl

Cl Cl

Cl

Cl

Cl

ClCl

Cl

Mirex

C

Cl

Cl

Cl Cl

Cl

Cl

Cl

ClCl

Cl

ClCl

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)

Normal Neuron

Action Potential

Organophosphorus insecticide

Tetraethylpyrophosphate (TEPP)Extremely toxic

Parathion and ParaoxonHighly toxic

MalathionMuch less toxic

Pralidoxime

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

Pesticide Effects on Neurons

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

“Aging” of Acetylcholinesterase

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

Herbicides

Used to eliminate plant growthWith a few exceptions, they are not very toxic to humans

Herbicide Actions

Inhibition of PhotosynthesisInhibition of respirationGrowth Stimulants (Auxins)Inhibitors of protein, nucleic acid, or lipid, or carotenoid synthesis

Inhibition of Respiration

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

Agent Orange

Agent orange Contaminant

2,3,7,8-tetrachloro-dibenzop-dioxin (TCDD)

O

O

Cl

Cl

Cl

Cl

TCDD (dioxin)

Contaminant from synthesis of 2,4,5-T

Not a pesticideDescribed as most toxic substance on earth

Fungicides

Hexachlorobenzene (HCB)OrganomercurialsPetachlorophenolDithiocarbamates

Rodenticides

Rodenticidesα-napthyl thiourea (ATNU)Anticoagulants