Flashcards in Lecture 17: Pesticide Toxicology Deck (19):
any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest.
The Nervous System/Neurophysiology
most of chemical insecticides used today are neurotoxicants that poison the nervous system
Types of Major Insecticides:
1. Organochlorine Compounds
1. Dichlorodiphenylethanes—target Na+ channel (DDT)
2. Polychlorocycloalkanes and Fipronil: target GABA receptor (lindane, aldrin, dieldrin, endosulfan)
2. Pyrethroids—target Na+ channel (deltamethrin, cypermethrin)
3.Organophosphate Compounds—target Acetylcholinesterase (eg.Chlorpyrifos,malathion, diazinon, parathion)
4. Methylcarbamates—target acetylcholinesterase (carbaryl, aldicarb)
5. Neonicotinoids—target nicotinic acetylcholine receptor (imidacloprid)
All Major Currently Used Insecticides Disrupt Neurotransmission
Both insects and mammals are dependent on 3 major neurotransmitters for transmission of neural signals from neurons to neurons and/or neurons to muscles:
Gamma-aminobutyric acid (GABA)
DDT Primary Mode of Action
1. Binds to a peripheral site on the voltage-gated sodium channel to keep the Na+ channel open (independent of voltage-change)
-Causes hyperstimulation of nerves and muscles by slowing
-repolarization keeping the membrane in a partially depolarized state
Insect: tremors (“DDT jitters”) followed by paralysis and death in a few hours to days (topical LD50 27 micrograms/bee)
Human/mammals: (oral LD50 300-350 mg/kg)
-at high oral doses, DDT results in paresthesia of tongue, lips, and face
-Hypersusceptibility to external stimuli (light, sound, touch)
-Irritability, dizziness, and vertigo; tremor and convulsions
-Symptoms arise 6-24 hours after exposure to large doses >10 mg/kg DDT
-Liver damage (necrosis) and increased incidence of liver tumors at high concentration
DDT and Cancer:
-Epidemiology: Up to 1991, many epidemiological studies have shown positive or negative correlations between DDT and tumors in humans
-Since then, DDT has been implicated in liver tumors and multiple myeloma (is cancer of the plasma cells in bone marrow) after occupational exposure to DDT.
-DDT can also induce CYPs without getting metabolized by CYPs (like TCDD)
Can cause the increase of ROS
-Mutagenicity assays revealed mixed results—no mutations in bacterial or mouse cell lines, but caused chromosomal abberations in mouse but not rat bone marrow cells in vivo.
DDT can result in increased tumors in mice at ~70-80 weeks
DDT and resistance
Declined use of DDT was due mainly to resistance developed quickly in many insect species
-increased dehydrochlorinase enzyme to detoxify DDT
-nerve insensitivity (mutation in the Na+ channel that confers DDT resistance—”knockdown resistance”
-Synthetic Pyrethroid Insecticides include: permethrin, cypermethrin, deltamethrin and many more
-These synthetic pyrethroids entered the marketplace in 1980 but, by 1982, accounted for more than 30 % of worldwide insecticide usage
**considered the safest insecticide due to fast biodegradability
LD50 for rat oral is 820-1500 mg/kg; no tissue damage at 1000ppm in diet; resmethrin has lowest acute toxicity
-arise from a much older class of botanical insecticides, pyrethrum, a mixture of six insecticidal esters extracted from dried pyrethrum or chrysanthemum flowers
-Mode of action: Na+ channel agonist (opening of sodium channels, like DDT)—causes depolarization of membranes—tremors, convulsions
Insect Na+ channel is 100-fold more sensitive to pyrethroids than mammlian channels
Neonicotinoids: The Newer Class of Insecticides
Nicotinoids—derived from nicotine, from tobacco plants—use started in 1600 and 1700s and commercial extracts were developed in 1900 and used until 1940—higher mammalian toxicity than insect toxicity.
Neonicotinoids—next generation insecticides derived from nicotinoid structures—works on sucking insects, aphids, leafhoppers, fleas (cats and dogs), chewing insects
-Effective at low application rates
-Not environmentally persistent
-Show negligible toxicity towards vertebrates
-Possess unique and selective mechanisms of action
-No case of toxicity in humans yet
-The most important insecticide in terms of sales
Mode of Action of Neonicotinoids
Neonicotinoids are nAChR agonists that compete with ACh—causes continual depolarization (tremors, convulsions), followed by desensitization (paralysis, death) because neonicotinoid agonists cannot be terminated like ACh (via AChE).
Fundamental differences between the nAChRs of insects and mammals confer remarkable selectivity for the neonicotinoids.
Herbicide: any compound that is capable of either killing or severely injuring plants
Some of the very early chemicals, such as sulfuric acid, arsenic trioxide, copper sulfate were very toxic and nonselective
In the 1930s, many studies were done to find agents to selectively destroy certain plant species.
Controversy around these chemicals is on mutagenicity, teratogenicity, and carcinogenicity associated with the parent compound or contaminants.
Chlorphenoxy Compounds Herbicidal
Mode of action: mimic the action of auxins, hormones chemically related to indoleacetic acid, that stimulate growth
Auxins regulate many processes in the plant, including cell growth and differentiation. (eg. indole acetic acid or IAA).
It is often said that plants exposed to herbicides with this mode of action “grow themselves to death”.
Uncontrolled, unsustainable growth ensues causing stem curl-over, leaf withering, and eventual plant death.
Mammalian Toxicity associated with Chlorphenoxy Compounds
-The chlorphenoxy herbicides are no longer the agents of choice because of concerns over the formation of TCDD, as a consequence of poorly monitored manufacturing practices or improper product storage in steel drums sitting besides runways under the tropical sun.
-Mammalian poisoning signs have included chloracne, skin, eye, and respiratory tract irritation, dizziness, nausea, neurotoxicity, that seems to be attributable to TCDD. (carcinogenicity, reproductive and developmental toxicity, neurotoxicity, and acute toxicity)
Used on corn for grassy and broadleafed weeds
One of the most highly used herbicides for corn and grain
Mode of Action: strong inhibitors of photosynthesis—selectivity depends on ability of tolerant crops to metabolize the parents compound whereas susceptible plants do not
atrazine induces aromatase and promotes the conversion of testosterone to estrogen. This disruption in steroidogenesis likely explains the demasculinization of the male.
Mechanism of Atrazine Action
Atrazine inhibits cyclic nucleotide phosphodiesterase (PDE) ---> cAMP levels increase --> activates SF-1 --> activase aromatase gene expression
Organic food is food produced according to organic standards, which means grown without
the use of conventional pesticides, as well as artificial fertilizers or sewage sludge
antibiotics and growth hormones in animals
ionizing radiation for processed foods or food additives.
While organic food accounts for 1–2% of total food sales worldwide, the organic food market is growing rapidly, far ahead of the rest of the food industry, in both developed and developing nations.
World organic food sales were US $23 billion in 2002.
The world organic market has been growing by 20% a year since the early 1990s, with future growth estimates ranging from 10-50% annually depending on the country.
Amanita Muscaria Mushroom
Muscarine is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species.
-It was first isolated from Amanita muscaria in 1869 and was the first parasympatho-mimetic substance ever studied and causes profound activation of the peripheral parasympathetic nervous system that may end in convulsions and death.
-Muscarine has no effects on the central nervous system because it does not cross the blood-brain barrier due to its positively charged nitrogen atom.