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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 kgUS production (1997): 0.54x109 kgWorld production of DDT (1943-74): 2.8x109 kg

Regulations (US):

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)

Established in 1947 under USDATurned 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 childrenKlaassen, 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

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 synthesisAmino acid synthesisChitin synthesisCholinesterase

• 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

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 divisionCommon 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

Squaleneepoxidase

Stenersen, J. Chemical pesticides: Mode of Action and Toxicology. CRC Press 2004

Inhibition of ergosterol synthesis

14-α-demethylase (CYP51)

Demethylase (DMI)-inhibiting fungicides:Azoles and triazoles

Pyridines and pyrimidinesPyperazines

AminesMorpholines

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

• Pyrethroidinsecticides

• 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

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) synapsesCholinergic 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 DDT1,1,1-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 whoeat 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• 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

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 characte-rize 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

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 neonicotinoidinsecticides 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-tetrahydro-furanmethyl moieties are referred to as chloropyridinyls (or chloronicotinyls),chlorothiazolyls (or thianicotinyls), and tefuryl, respectively. The nicotinoidsare naturally occurring [(−)-nicotine and (−)-epibatidine] and synthetics (ABT-594 and desnitroimidacloprid).

Tomizawa & Casida (2004)

Tomizawa & Casida (2004)

Tomizawa & Casida (2004)