Toxicology Exam 6 Flashcards
What is the function of pesticides?
Substances that kill or control (prevent, repel or mitigate) pests: Ideally specific to the targeted pest
What are the types of pesticides?
- Insecticides
- Herbicides
Other less common:
- Fungicides, Rodenticides, etc…
- Fumigants
What factors drive the use of pesticides?
Absorption
Occupational exposures
Environmental exposures
How does absorption drive the use of pesticides?
- Respiratory Track
- Dermal absorption
- Small amounts via GI
- Accidental child or animal ingestion
- Pesticide residues in food and populations at risk
How do occupational exposures drive the use of pesticides?
- Manufacturing
- Formulating
- Manipulation and Application
- Harvesting of crops
How do environmental exposures drive the use of pesticides?
Contaminated soil and water → Food and drinking water
What are the factors modulating environmental exposure impact?
- Persistence
- Biomagnification
What is the EPA?
Environmental Protection Agency (EPA)
What is the role of the EPA?
- Registers pesticides for use
- Establishes maximum allowable levels of residues to be enforced by federal agencies
- Assess risks and cumulative effects of exposures of at-risk populations
How many pesticides are registered through the EPA, and what is the cost?
> 140 pesticides registered
~$50-$100 million
What information is required for the EPA to register pesticides for use?
- Chemistry - Biotransformation/degradation
- Environmental fate
- Drift
- Impact on non-targeted species
- Persistence and Bioaccumulation - Occupational Exposure
- Toxicology
- Performance and Efficiency
What are the primary targets of Insecticides?
Primary Target: Nervous System
Impairment of neuromuscular and peripheral CNS communication
Inhibitors of Acetylcholinesterases
What are examples of insecticides?
Organophosphates (OP)
Carbamates
Neonicotinoids
Axonic excitotoxins
Avermectins
Rotenoids
What insecticides impair AChE function?
OPs and carbamates
What insecticides impair AChR function?
Neonicotinoids
What insecticides impair voltage-gated Na+ channel function?
- Chlorinated ethanes
- Pyrethroids
What insecticides impair Inhibitory post-synaptic Cl- channels (GABA or glutamate-activated) function?
- Hexachlorocyclohexanes
- Cyclodienes
- Pyrethorids II
- Avermectins
What is the pesticidal function of Organophosphates (OP)?
- CarbEs provide resistance in insects, while PTEs detoxify more efficiently OP in the liver
- Irreversible inhibition of acetylcholinesterase (AChE)
What is the pesticidal function of Carbamates?
- Esters of N-methyl carbamic acid
- Inhibit AChE
- Reversible
Where is the use of Organophosphates (OP) permitted?
- Most OPs were banned from residential use since 2001.
- Used as agricultural pesticides and mosquito abatement in public spaces is permitted.
What is the pesticidal function of Organochlorine (OC)?
- Successfully used in the control of malaria and typhus.
- Banned for the most part, but due to their low-cost DDT, hexachlorocyclohexane (HCH), aldrin, and dieldrin are still used in developing countries
What is the pesticidal function of Neonicotinoids?
Bind strongly overstimulating and blocking ACh receptors in insects, causing paralysis and death
How do neonicotinoids harm pollinators?
Strong experimental evidence that they harm pollinators (bees)
- Ability to reproduce
- Ability to fly
- Contribute to extinction
What is the pesticidal function of Axonic excitotoxins?
They prevent the closure of voltage-gated Na+-channels or inhibition of postsynaptic Cl–channels
What are the differences between Organochlorine and OPs?
Less soluble than OPs and carbamates but more persistent
What is the pesticidal function of pyrethroids?
Pyrethroids = synthetic compounds that duplicate pyrethrins
High potency, low mammalian toxicity, low persistence.
What is the pesticidal function of Avermectins?
Insecticides and Parasite control
How does Ivermectin work?
Ivermectin binds with high affinity to Glutamate-gated Cl- channels in invertebrate nerve and muscle cells, causing an increase in the permeability of the cell membrane to Cl- with hyperpolarization of the nerve or muscle cell. Hyperpolarization results in paralysis and death of the parasite either directly or by causing the worms to starve.
What is the pesticidal function of Rotenoids?
Organic farming
Inhibitor of the mitochondrial electron transport chain
- ROS formation
- Impaired bioenergetics
What disease can Rotenoids cause?
Parkinson’s disease
What are the two types of herbicide classification?
Selective and non-selective
How are herbicides classified based on their mode of application?
- Contact
- Translocated
How are herbicides classified based on where they are applied?
- Pre-planted
- Pre- and Post-emergent
How do herbicides effect (plants, weeds, vegetation)?
- Growth retardation
- Kill or severely injure
What are the mechanisms of herbicides?
- Cell membrane disruptors: Paraquat
- Inhibition of photosynthesis or respiration: Atrazine
- Inhibition of cell division
- Inhibition of protein and lipid synthesis
- Inhibition of specific enzymes: Glyphosate
- Regulators of growth
What are examples of Bipyridyl herbicides?
Paraquat, Diquat
What is the mechanism of Bipyridyl herbicides?
Redox cycling and Oxidative Damage
- Formation of free radicals and other reactive oxygen species (ROS)
- Depletion of the redox cofactor NADPH
What is the difference between Paraquat and Diquat?
- Paraquat accumulates in the lung and kidney
- Diquat accumulates in the GI tract, kidney, and the eye
How does the herbicide class Atrazine affect the environment?
- Inhibits Photosystem II
- Pre-emergent control of broad-leaved weeds.
Contamination of ground and drinking water is very common. - Feminization of leopard frogs.
Endocrine disruptor
What is the mechanism of Phosphonomethyl aminoacids herbicides?
Inhibits 5-enolpyruvylshikimate-3-phosphate synthase that generates an amino acid intermediate (EPSP)
What is the mechanism of Glufosinate herbicides?
- Glutamine synthetase
NH4 - Mammals can cope to a certain limit via other metabolic pathways
What are the classes of fungicides?
Dicarboximides or Dithiocarbamates
Inorganic
Where do Dicarboximides or Dithiocarbamates come from, and what is the method of their fungicidal mechanism?
- Associated with metal ions
- Inactivate –SH groups in amino acids, proteins, and enzymes.
How do Dicarboximides or Dithiocarbamates affect humans?
Affect Thyroid function
What is the mechanism of organic fungicides?
Cu sulfate–> Nonspecific denaturation of proteins and enzymes
What are examples Rodenticides?
- Phosphides (Mitochondrial ETC)
- Fluoroacetic acid
- Coumarin or Warfarin (anticoagulant)
- Bromethalin (Uncouples mitochondrial oxidative phosphorylation)
- Thioureas (reductant)
What is the mechanism of Fluoroacetic acid?
- Mitochondrial Aconitase
- Citrate cannot be dehydrated to cis-aconitate by aconitase and therefore blocks the TCA cycle
What is the mechanism of Coumarin or Warfarin?
(Anticoagulant)
- Antimetabolite of vitamin K, inhibits the formation of prothrombin
- Hemorrhage
What do Thioureas (reductant) cause?
Pulmonary edema and pleural effusion
What is the mechanism of Bromethalin?
Uncouples mitochondrial oxidative phosphorylation
What is metal?
- Most elements in the periodic table are metals
- Propensity to lose electrons and react with oxygen (O2) to form oxides.
What are the physical properties of metals?
High reflectivity, electrical and thermal conductivity, mechanical ductility, and strength
Where are metals found?
- Distributed naturally by biological or geological activity or by anthropogenic activity
- Their levels increase due to
Geological events
Anthropogenic activities - Uses: Industry (technology), agriculture and medicine
What are anthropogenic sources of metal?
- Lifestyle
Smoking
Urban areas - Accidental
- Diet
- Occupational
Mining, Smelting
What are the Natural / Endemic Metal Intoxications sources?
- Arsenic
- Selenium
- Thallium
- Animals can be used as sentinels of environmental contamination
What are the 4 classifications of metals?
- Alkali and alkaline-earth metals (essential)
- Essential transition metals
- Xenobiotic heavy metals
- Metalloids
What are examples of Alkali and alkaline-earth metals (essential)?
Sodium (Na), potassium (K), magnesium (Mg) and calcium (Ca)
What are examples of Essential transition metals?
Copper (Cu), manganese (Mn), iron (Fe) and zinc (Zn)
What are examples of Xenobiotic heavy metals?
Mercury (Hg), lead (Pb) and cadmium (Cd).
What is an example of metalloids?
Arsenic (As) are considered to have chemical and physical properties of both metals and non-metal elements.
What are the Functions of Homeostasis of essential metals?
- Cofactors of many enzymatic processes
Cells and organisms have evolved complex homeostatic mechanisms to handle essential metals
Transport
Compartmentalization
Protein binding
What is the mechanism of toxicity for iron (Fe)?
- Fe is a redox-active metal that catalyzes the formation of ROS.
- Fe is required as a cofactor of several enzymes, including those of mitochondrial respiration and heme enzymes (Fe-S clusters).
What disease can iron (Fe) cause?
Hereditary hemochromatosis
Mutations in the Human homeostatic iron regulator (HFE) gene (interacts with transferrin) excessive intestinal absorption of dietary iron, resulting
How is iron (Fe) normally transported through the body?
Iron import can occur via endocytosis of Fe3+-bound transferrin receptor 1 or via Fe2+ importers DMT1
Intracellular Fe is stored in ferritin.
Export occurs through ferroportin
What is the function of copper (Cu) under normal conditions?
Cofactor of many enzymes involved in cellular respiration ( cytochrome C oxidase, CCO), radical detoxification (superoxide dismutase, SOD1), and biosynthesis of macromolecules.
What is the mechanism of copper (Cu) transport?
- CTR1 transporters accept Cu+ from carriers
1) CCS distributes Cu to SOD1 (antioxidant), while 2) Atox1 transfers Cu to the secretory pathway and nucleus.
- Cu is also delivered to cytochrome C oxidase (CCO) in mitochondria by Cox17, Cox11 and Sco1. Cu-ATPases (ATP7A and ATP7B) transport Cu to the secretory pathway
What diseases can copper toxicosis cause?
Wilson Disease and Menkes Disease
What is Wilson Disease?
What causes it?
How is it treated?
- Autosomal recessive genetic disorder (ATP7B)
- Accumulation of Cu in the brain, liver, kidneys, and cornea as a result of impaired biliary excretion
- Liver transplantation or chelation therapy
What is Menkes Disease?
What is it caused by?
How does Menkes Disease affect different breeds of dogs?
- X-linked recessive disorder (ATP7A)
- Abnormal intestinal Cu absorption with a secondary deficiency in Cu-dependent mitochondrial enzymes.
- Dogs:
Bedlington Terriers: COMMD1 (unclear function [traffic of ATP7A and B?]) and ABCA12 (a gene close related to ATP7B) mutations
Labradors ATP7A and ATP7B mutations lead to copper toxicosis and liver failure.
What is Manganese (Mn) intoxication?
Mn2+ intoxication in humans is commonly described as manganism, a neurological condition that shares several overlapping features with Parkinson’s disease.
What is the function of Manganese (Mn) under normal conditions?
Mn2+ is a key constituent of some metalloenzymes (MnSOD, mitochondrial superoxide dismutase) and is a required cofactor for the function of other enzymes (glutamine synthetase), as well as for the synthesis of proteins and vitamins.
Mn2+ modulates oxidative stress, which is crucial for normal brain activity.
How does Manganese (Mn) intoxication affect someone?
-Mn2+ exposure affects the neurotransmission of dopamine
-Mn2+ affects normal neurotransmission of glutamate and GABA
-Mn2+ exposure activates microglial cells with the production of proinflammatory cytokines
-Mn2+ exposure impairs the proteasome system, autophagy, and endosomal trafficking leading to abnormal protein aggregation.
-Mn2+ induces mitochondrial dysfunction, inducing the production of ROS
What is the function of zinc (Zn) under normal conditions?
- Zn has a structural role in proteins and activates substrates for nucleophilic attack
Why do essential metals become toxic?
Toxicity linked to either:
- An increased exposure and accumulation (very rarely)
- An impairment in the proper intracellular homeostasis
What is the function of xenobiotic heavy metals?
Xenobiotic (heavy) metals have no physiological functions.
What are some examples of xenobiotic heavy metals?
Lead (Pb)
Mercury (Hg)
Cadmium (Cd)
What are the sources of lead (Pb)?
How is it absorbed?
What are its negative effects?
- Sources: gasoline, industrial processes, paint, water pipes, solder in canned food
- Absorption: Inhalation and ingestion of Pb and Pb-containing particles or products
- Neurotoxic and alterations during neurodevelopment
- Anemia