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Any substance designed for selective toxicity/lethality ot certain organisms
pesticides
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Pesticides are important to toxicologists because of their
- toxicity to man via acute or chronic exposure
- toxicity to non-target organisms in the environment
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Four broad groups of pesticides based of target of undesirable organisms
- insecticides
- herbicides
- fungicides
- rodenticides
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Four broad groups of insecticides
- chlorinated hydrocarbons
- organophosphates
- carbamates
- botanicals
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In the US _____ regulates pesticide use under _____ act and _____ act.
- EPA
- Federal insecticide, fungicide and rodenticide act
- Federal food, drug and cosmetic act
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Federal insecticide, fungicide and rodenticide act
EPA registers pesticides for use
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Federal food, drug and cosmetic act
EPA establishes max allowable levels of pesticide residues in foods and animal feeds
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Food quality and protection act
gives EPA the mandate to assess risk of pesticides to infants and children
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Other regulations concerning pesticides
- safe drinking water act
- clean air act
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Chloronated insecticides
- compounds containing chlorine substituents
- DDT
- Chlordane
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Absorption & elimination of chlorinated hydrocarbons
- well absorbed from GIT, skin and inhalation
- highly lipid soluble = accumulation in fat tissues
- elimination is not first order, slow release from fat stores
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Uses of chlorinated insecticides
- agriculture
- structural pest control
- malaria control programs
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chlorinated hydrocarbon used for treatment of head/body lice and scabies
lindane
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Low toxicity chlorinated hydrocarbons
- LD50 > 1g/kg
- hexachlorobenzene
- methoxychlor
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Moderate toxicity chlorinated hydrocarbons
- LD50 > 50mg/kg
- Chlordane
- DDT
- Kepone
- Lindane
- Mirex
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High toxicity chlorinated hydrocarbons
- LD50 <50 mg/kg
- Aldrin
- Deldrin
- Endosulfan
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Lower toxicity rating =
less toxic and higher acceptable daily intake (ADI)
-
Mechanism of action with chlorinated hydrocarbons
- inhibit calcium ion transprot
- interfere w/ inactivation of sodium channels
- cause rapid firing of neurons
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Acute sx of ingestion of chlorinated hydrocarbons
- n/v
- paresthesia of tongue/lips/face
- confusion
- tremor/coma/seizures
- respiratory depression
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Duration of toxicity with hydrocarbons may be prolonged due to ____ results in
- high lipid solubility
- recurrent or delayed onset of seizures
- arrhythmias due to sensitization to catecholamines
-
Treatment of chlorinated hydrocarbon ingestion
- no specific antidote
- treat sx
- ventricular arrhythmias may respond to bbs such as propranolol
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Use of chlorinated hydrocarbon insecticides has been banned in ____ and ____ because of _____.
- North America
- Europe
- Environmental impact
-
Once chlorinated hydrocarbons ____ into the soil, they do not ____. ____ may be poor in ____.
- adsorb
- desorb
- adsorption
- sandy soil
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Best known organochlorine insecticide introduced to control malaria
DDT
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Dose of DDT required for acute toxicity in humans
10 mg/kg
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DDT is metabolized in animals by ___ and ____ is more persistent than the parent compound.
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T1/2 for DDT stored in fat
6 months
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Acceptable yearly intake for humans given by _____ guidelines is _____/yr.
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DDT is more harmful in the ____ rather than the ____.
-
Discontinuation of use of DDT mainly due to
environmental impact on wildlife rather than toxicity to humans
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Organophosphates and carbamates
- largely replaced organochlorinated hydrocarbons
- known as cholinesterase inhibitors
- used as pesticides or warfare agents
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organophosphates used as warfare agents
- GA (Tabun)
- GB (Sarin)
- GD (Soman)
- GF and VX
- extremely potent organophosphates
-
Hosehold insect sprays often contain
low potency organophosphates or carbamates
-
Many commercial products contain solvents such as
toluene or xylene
-
Organophosphate mechanism of toxicity
- irreversible inhibition of acetylcholinesterase through phosphorylation at the esteratic site allowing accumulation of ACH
- results in AchE aging unless antidotal treatment is given
- also phosphorylate neuropathy esteraces leading to paralysis and axonal degredation
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Malathion
- requires metabolism to malaoxon
- takes place redily in insects but not humans
- selective toxicity
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Carbamate mechanism of toxicity
- inhibit AchE by carbamoylation of esteratic site
- binding is reversible
- toxicity is breif and self limited
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Fenitrothion (organophosphate)
highly lipophilic and stored in fat tissue = persisting toxic effects
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Carbamate kinetics
- poorly absorbed across the skin compared with organophosphates
- except aldicarb (concentration in fruit)
-
Organophosphate kinetics
well absorbed by inhalation, ingestion and through the skin
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Degree of toxicity with organophosphoates/carbamates affected by:
- rate of exposure
- metabolic degredation of the agent
- rate of metabolism of organophosphates to the more toxic "oxon" derivatives
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"nerve gases"
- developed for chemical warfare
- direct and powerful AchE inhibitors
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Clinical presentation of organophosphate/carbamate poisoning occurs within ___ of exposure
occur w/in 1-2 hrs of exposure (may be delayed w/ skin exposure)
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Clinical manifestation of OP/C exposure
- muscarinic, nicotinic and CNS effects
- possibility of chemical pneumonitis if hydrocarbon solvent is aspirated
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Muscarinic manifestations of OP/C poisoning
- vomiting, diarrhea, abd. cramps (GI activation)
- bronchospasm
- miosis
- bradycardia
- salivation & sweating
- dehydration and shock may result
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Nicotinic effects of OP/C poisoning
- muscle fasciculation/tremor and weakness
- death caused by respiratory muscle paralysis
-
CNS effects of OP/C
- agitation
- seizure
- coma
- peripheral neuropathy
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Intermediate syndrome with OP/C
- recurrent muslce weakness may occur within several days of exposure (up to 15 days)
- occurs in 20-50% of cases
- not an effect of AchE inhibition
-
Labs for OP poisoning
- plasma pseudocholinesterase level
- red blood cell acetylcholinesterace activity
- wide inter-individual variability
-
More reliable measure of OP toxicity
- 25% depression in activity in red blood cells
- PschE may be depressed due to genetic deficiency
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Carbamate poisoning
- reversible AchE inhibition
- spontaneous recovery within several hours
- no intermediate syndrome
- assay of blood and urine for specific agents (not available for several hours)
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Treatment of OP/C poisoning
- antimuscarinic agent (atropine)
- Pralidoxime (2-PAM) - specific antidote
- Diacetylmonoxime (DAM) - binds oxime groups
-
Atropine use in OP/C poisoning
- most clinically important in pt with wheezing or bronchorrhea.
- will reverse muscarinic bu not nicotinic effects
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Pralidoxime (2PAM)
- specific antidote for OP toxicity
- acts to regenerate the enzyme
- does not reactivate plasma cholinesterase
- reverse muscle weakness
- most effective if started w/in 24hr of exposure
- not recommended for carbamate toxicity
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Should be given empirically if the exact toxic agent is not identified and the pt shows significant toxic effects
2-PAM
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Botanical insecticides
- insecticides derived from natural sources
- Nicotine
- rotenone
- pyrethrum
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Nicotine
- free alkaloid (not salt) readily absorbed through skin
- binds post synaptic ACH receptors
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Toxic dose of nicotine causes
stimulation rapidly followed by blockade of nerve transmission
-
Treatment of Nicotine toxicity
- maintain vital signs
- suppress convulsions
-
Rotenone mechanism and toxicity
- inhibits mitochondrial e- transport system
- GIT irritation
- conjunctivitis
- rhinitis/pharyngitis
- dermatitis
- treatment is symptomatic
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Pyrethrum consists of six known insecticidal esters which are
- pyrethrin I & II
- Cincerin I & II
- Jasmolin I & II
-
Pyrethrums are found in
a lot of household spray insecticides
-
Toxicities with pyrethrums
- contact dermatitis
- sodium channel paralysis (not high in mammals)
- CNS excitation and convulsion (large dose) - treat with diazepam
- cutaneous paresthesia observed in workers spraying pyrethrums
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Herbicides
- chlorophenoxy herbicides
- dipyridyl hermicides
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Major chlorphenoxy compounds
- 2,4-D (dichlorophenoxyacetic acid)
- 2,4,5-T (trichlorophenoxyacetic acid)
-
Agent orange
mixture of di & trichlorophenoxy acetic acid + TCCD (tetrachlorodienzo-p-dioxin)
-
commercially available 2,4-D
does not contain TCDD
-
concentrated 2,4-D formulations contain
petroleum solvents
-
Mechanism of toxicity for chlorophenoxy herbicides in plants
growth hormone stimulator
-
Mechanism of toxicity for chlorophenoxy herbicides in animals
- widespread muscle dmg
- death due to v-fib
- mechanism unknown
- occupational exposure => non-hodgkins lymphoma or soft tissue sarcoma
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Clinical presentation of chlorophenoxy poisoning and treatment
- tachycardia
- muscle weakness & spasms
- intractable hypotension
- coma
- death w/ in 24 hours
- treatment is symptomatic
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Dipyridyl herbicides & use
- paraquat - large scale control of marijuana
- diquat
- used for weed control and defoliants
-
Paraquat is available in the US as
20-37% liquid
-
Diquat is available in the US as
8-36% liquid
-
Mechanism of action for dipyridyl herbicides
- react with NADPH producing highly reactive free radicles which destroy tissue through peroxidation
- accumulates in alveolar type I and II cells
-
paraquat is taken up into the lungs and retained by an active process because of structural similarity to
- diamines & polyamines such as:
- putrescine
- spermine
- spermidine
-
paraquat in the lungs causes
- lung edema
- alveolitis
- progressive fibrosis of the lung
-
smoking marijuana sprayed with diquat or paraquat causes
delayed fibrosis of the lung
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Signs of dipyridyl toxicity
- first sign is hematemesis & bloody stool
- respiratory distress may appear within a few days
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Treatment of dipyridyl toxicity
- limit absorption by admin. of activated charcoal followed by lavage with 1% bentonite solution of fuller's earth which adsorbs paraquat
- avoid excessive O2 administration; may aggrivate peroxidation in lungs
- hydrocortisone & furosemide & dialysis
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Fungicides
- chlorinated hydrocarbons
- alkyl mercury compounds
-
alkyl mercury compounds 3 different forms
- elemental
- inorganic
- organic - readily absorbed
-
use of mercury containing fungicides has led to
water contamination via run-off from fields
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Toxicity associated with mercury compounds
- Organic mercury is lipid soluble and distributes to the CNS where it is oxidized
- causes neurological damage
- metal ions interact with -SH on proteins
- crosses placenta & is teratogenic
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fetal red blood cells concentration methyl mercury ____% more than adult rbcs
30%
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symptoms of acute fungicide poisoning
- memory loss
- paresthesia
- ataxia
- narrowing of the visual field
- loss of muscle coordination
- emotional instability
- cerebral palsey
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most severly affected by fungicide poisoning
children and new borns born with cerebral palsy
-
methylmercury T1/2
70 days
-
-
fluoroacetate is also known as
- compound 1080
- sodium fluoracetate
- sodium mono-fluoracetate (SMFA)
-
SMFA
- one of the most toxic substances known
- inhibits aconitase in krebs cycle
-
Fluoroacetate
- tasteless, odorless, water soluble white powder
- removed from market b/c of hazard
-
fluroacetamide
- compound 1081
- similar toxicity
-
Mechanism of toxicity for fluoroacetate
- incorporated into the krebs cycle as fluoroacetyl CoA which binds the enzyme aconitase
- cellular metabolism is blocked
- cells & tissues die
- clinical effects delayed 30min to several hours until fluocitrate is metabolized
-
Toxic dose of fluorocitrate
- 1 mg = serious toxicity
- 5 mg/kg = death
-
Clinical manifestation of fluroacetate toxicity
- n/v/d
- metabolic acidosis
- renal failure
- agitation/confusion
- seizure/coma
- respiratory arrest, pulmonary edema
- ventricular arrhythmias
-
Treatment of fluroacetate poisoning
- no antidote
- monoacetin (glyceryl monoacetate) used in monkeys but not approved in humans
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Warfarin
- inhibits hepatic synthesis of Vitamin K dependent coagulation factors II, VII, IX and X.
- Only synthesis of new factors are effected
- effect is delayed until currently circulating factors are degraded
-
Most common anticoagulant rodenticide available today is the
- long acting super warfarins:
- brodifacoum
- pindone
- valone
- may produce effects for weeks to months
-
Peak effects of warfarin
- 2-3 days
- duration of a single dose is 2-7 days
-
Clinical presentation of warfarin toxicity
- excessive anticoagulation
- ecchymoses
- conjunctival hemorrhage
- bleeding gums
- hematuria
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Treatment for warfarin toxicity
- vitamin K1 (phytonadione)
- not vitamin K3 (menadione)
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