midterm Flashcards
what are the most accessible tissues to measure exposure to metals?
Blood (recent, acute exposure)
Urine (recent, acute exposure)
Hair (not reliable – external contamination complicates analyses)
what are the best targets of metal toxicity ?
Metal binding proteins
namely enzymes
metals can also bind to non specific proteins
what are metallothioneins?
Many have no known enzymatic activity
May be involved in de-toxification of metals
Have high affinity for several essential and non-essential metals, such as Cd, Cu, Hg, Ag, and Zn
Transferrin: binds ferric iron in plasma
Ferritin: iron-storage protein in liver, spleen, and bone
Ceruloplasmin: converts plasma ferrous iron to ferric iron (to bind to transferrin)
what are two common types of transporters
Phosphate and sulfate transporters
what is chelation therapy
Chelation: metal ion binds to ligand with two donor atoms to form ring-structure
Metals may react with OH, COOH, SH, NH2, NH, and N
Metal plus ligand equals
complexation
what do chelating agents have to be ?
Characteristics of chelating agents
Water soluble
Resistant to biotransformation
Able to reach sites of metal storage
Capable of forming nontoxic complexes with toxic metals
Capable of being excreted
Have low affinity for essential metals
What is BAL
BAL (British Anti-Lewisite)
(2,3-dimercaptopropanol)
Developed during WWII as a specific antagonist to arsenical war gases
Based on observation that arsenic has affinity for sulfhydryl-containing substances
Also effective against mercury, cadmium, chromium, etc.
where is arsenic usually found
Commonly found in
Drinking water
Seafood
Pressure-treated wood
Cigarette smoke
Common exposure from
Pesticide and herbicide manufacturers
Smelting industries
where is arsenic released form and what is its mechanisms of toxicity?
Arsenic inhibits succinic dehydrogenase and uncouples oxidative phosphorylation
Leads to stimulation of mitochondrial ATPase activity
Arsenic inhibits the energy-linked functions of mitochondria in two ways
Competition with phosphate during oxidative phosphorylation
Inhibition of energy–linked reduction of NAD
Leads to decreased ATP production and increased H2O2
Leads to oxidative stress through ROS
Inorganic arsenic is released into the environment from
Copper, zinc, and lead smelters
Glass manufacturers
Chemical manufacturers
what are symptoms of arsenic
Neurotoxicity of PNS and CNS
Neurotoxicity begins with paresthesia and muscle tenderness
Neuropathy may affect sensory and motor neurons
Eventual demyelination of axon nerve fibers
Liver injury may also manifest as jaundice and may progress to cirrhosis
Reproductive and teratogenic effects
Malformation of fetus in animals
Effects have not been observed in humans with excessive occupational exposure
Carcinogenicity
Studies indicate cancer incidence in response to ingestion and inhalation
what is cadmium used for and what is the exposure like
Used in (as)
Electroplating, galvanizing, battery production
Non-corrosive
Pigment in paints and plastics
Exposure
Plants readily take up Cd from contaminated soil, water, and fertilizers
Enter food chain and can contaminate meats, fruit, and fish
Shellfish accumulate cadmium
what does acute and chronic cadmium toxicity look like?
Chronic toxicity
Chronic pulmonary disease (respiratory exposure)
Emphysema (respiratory exposure)
Renal tubular disease
Skeletal system problems (Cd may affect calcium metabolism)
Nephrotoxicity
Cd toxic to renal tubular cells and glomeruli (binds to sulfhydryl groups of critical proteins) and leads to proteinuria
Metallothioneins in kidney can bind cadmium – nontoxic
Toxicity may occur when systems become overwhelmed
Describe Lead and its exposure
Toxic metal detectable in practically all phases of the inert environment and all biological systems
Exposure
Food and drinking water
Lead-based indoor paint
Air (industrial emissions)
what are primary effects of lead in children?
Neurologic, neurobehavioral, and developmental effects in children
Vomiting
Lethargy
Ataxia
Encephalopathy
Coma
Death
Toxicity may manifest itself over time in children
Decreased attention span
Reading disabilities
what are common lead mechanisms of effect on the developing nervous system
Pb exposure results in modification of neuronal circuitry
-Alterations in noradrenaline, dopamine, and acetylcholine concentrations
-Impairs calcium homeostasis, calcium and NT concentrations play a role in frequency and sensitivity of nerve firing
Lead-induced peripheral neuropathy
Axonal degeneration
Schwann cell degeneration
Lead-induced hematologic effects
Lead-induced anemia
Pb affects heme synthesis
where does mercury exposure come from
Natural degassing of the earth’s crust (vapor) and pollution
this is how it gets into octane, the in gets methylated and accumulates in small fish, then get bio concentrated into larger fish, where we eat it
what are effects of mercury vapor toxicity?
Mercury vapor toxicity
Acute, corrosive bronchitis
CNS effects (tremors)
Memory loss
Gingivitis
Hg follow calcium pathways into saliva, reacts with bacteria resulting in a precipitate
Delirium
Hallucination
what are the effects of methylmercury toxicity ?
Major source of exposure is fish consumption
Symptoms include
Numbness
Ataxia (clumsy, stumbling gait)
Weakness
Vision/hearing loss
Tremors
Coma
Death
Disrupts protein synthesis, creates ROS
what is nickel
Ubiquitous in nature
Exposure may occur via inhalation, ingestion or through dermal contact
Exposure can also occur through food, jewelry, and cooking utensils
what does nickel toxicity look like?
Toxicity
Carcinogen (can cause cross-linking of DNA)
Allergen
Respiratory tract cancers in factory workers exposed to nickel sulfides and nickel oxides
Ni accounts for 4-9% of allergic dermatitis
Jewelry
Describe copper exposure and toxicity and what disease it can cause
Exposure
Drinking water
Food
Toxicity
Nausea
Hepatic necrosis
Death
wilsons disease
Accumulation of copper in liver, brain, kidneys
Due to inability to excrete copper (billiary)
what does iron do, and what are the effects of acute and chronic toxicity
Iron homeostasis very complex
Hemoglobin
Iron increases lipid peroxidation
Acute toxicity
Overdose
Vomiting
Liver damage
Coagulation defects
Renal failure
Chronic toxicity
Hereditary
Abnormal absorption from GIT
Excess Fe in diet
Effects
Liver dysfunction
Cardiovascular effects
what does zinc do and what can it cause
Approx. 200 enzymes require Zn as a cofactor
Zinc fingers (Zn + His) allow proteins to interact with DNA, hormone receptors and membranes
Excessive exposure to zinc is uncommon
Exposure
Seafood
Meat
Dairy Products
Legumes
Toxicity
GI distress
what is the function of a pesticide
The function of a pesticide is to kill or harm some form of life
Describe insecticides and the classes of insecticides?
All of the chemical insecticides in use today are neurotoxicants and they act by poisoning the nervous system of target (also non-target) organisms.
Classes of Insecticides:
Organochlorine Insecticides
Organophosphate/Carbamate Insecticides
Pyrethroid Insecticides
what are the 4 types of organochlorine insecticides
dichlorodiphenylethanes (e.g. DDT)
chlorinated cyclodienes (e.g. Endrin)
chlorinated cyclohexanes (e.g. lindane)
Chlordecone (e.g. kepone)
the organochlorineare chlorinated hydrocarbons
what are the properties of organochlorines that make them good insecticides
Properties which made them good insecticides:
low volatility
chemical stability
lipid solubility
slow rate of biotransformation and degradation
These properties also led to their demise because of their persistence in the environment, bioaccumulation, and biomagnification through the food chains.
what is kepone different thant DDT
Chronic exposure with kepone can cause impairment of spermatogenesis and epileptic convulsion, and skin rashes
what happens to the skin from organochlorine exposure
Patch test develops hyperpigmentation in 15-20% of subjects tested with dienochlor - resembles reaction to Balsam of Peru
what are DDT type pesticides mechanism
periodic sequences of persistent tremoring and/or convulsive seizures suggestive of repetitive discharges in neurons.
these tremors, seizures can be initiated by tactile and auditory stimuli, indicating that the sensory nervous system appears to be much more responsive to stimuli.
There is a characteristic prolongation of the falling phase of the action potential. The nerve membrane remains in a partially depolarized state and is extremely sensitive to complete depolarization again by very small stimuli.
why does DDT cause prolonged repolarization?
1) DDT affects the permeability of the nerve cell membrane to K+ ions reducing K+ transport across the membrane.
(2) DDT alters the Na+ channels, they open normally but are closed (inactivated) slowly.
(3) DDT inhibits neuronal ATPase activity particularly Na/K ATPase and Ca ATPase which play a role in repolarization of the neuron.
what is the function of chrloridinated cyclodine insecticide
These insecticides act in the CNS.
(1) Mimic the action of the chemical picrotoxin, a nerve excitant and antagonist of the neurotransmitter GABA found in the CNS.
GABA induces the uptake of chloride ions by neurons.
The blockage of this uptake results in only partial repolarization of the neuron and a state of uncontrolled excitation.
how is DDT broken down?
Very slow rate for DDT due to complex aromatic ring structure and chlorination. Half-life is 335 days in cattle.
DDT broken down to DDE both nonenzymatically and by cytochrome P450 reductive dechlorination. All metabolites are highly lipophilic.
what happens to aldrin and hepatchlor when metabolized
Aldrin and Heptachlor are converted by cytochrome P450 oxidation reactions to dieldrin and heptachlor epoxide without a change in lipid solubility or toxicity.
what can be given to control the convulsions ?
In addition to decontamination and supportive treatment, diazepam or phenobarbital may be administered to control the convulsions
what is the mechanism of action of organophosphate and carbamate insecticides
Both organophosphate and carbamate insecticides act by inhibiting the action of acetylcholinesterase (AchEase) at the synapse between two neurons or between a motor neuron and a muscle.
AChEase is the enzyme responsible for the breakdown of the neurotransmitter acetylcholine (ACh).
Organophosphate compounds are irreversible inhibitors of AChEase while carbamate compounds are reversible inhibitors of AChEase.
organophosphates cause damage that is irreversible
The reaction between an organophosphate and the active site on AChEase (a serine hydroxyl group) results in the formation of an intermediate that undergoes partial hydroylsis with the loss of the “Z” group, leaving a stable, phosphorylated, permanently inhibited enzyme.
Signs and symptoms are prolonged and persistent. Without intervention, the toxicity will persist until sufficient amounts of “new” AChEase are synthesized in 20 to 30 days
What are the ways to manage cholinesterase inhibitor poisoning ?
Collect serum, urine, & clothing samples
Hospitalize for severe symptoms
Specific treatment
Atropine
Pralidoxime (2-PAM)–OPs only
Workplace restrictions
What does Atropine do ?
Reverses SLUD, DUMBELS syndrome
Intravenous dose:
-Diagnostic
1 mg adult
0.01 mg/kg pediatric
-Therapeutic
1 mg - 4 mg adult
0.05 mg/kg pediatric
Repeat every 10-30 minutes
What does Pralidoxime do ?
(2Pam)
Enzyme aging occurs if not treated
Treatment effective within 48 hours
2-PAM reactivates cholinesterase
Cholinesterase levels rise
Both insecticides undergo what mechnaisms
phase 1 and phase 2
One reaction, oxidative desulphuration, results in a significant increase in toxicity. In parathion, methyl parathion and malathion, the presence of the P = S reduces the AChEase inhibiting properties of the compound.
what are the health effects of pyrethroid insecticides?
Low systemic toxicity
Respiratory sensitization
Asthma
Skin reactions
-Paresthesia
-Allergic dermatitis
what are pyrethroid insecticides used for ?
Examples of use
-Structural & agricultural
-Pet flea control
-Pediculicide
Vector control
-West Nile virus
-Aircraft “disinsection”
what is the pyrethrins mechanism of toxicity ?
Prolong inactivation of nerve membrane sodium channels
Pyrethroid structure
Type I (non-cyano)
Shorter inactivation
Type II (alpha-cyano)
Longer inactivation
Type I pyrethroids affect Na+ channels in nerve membranes (both sensory and motor) and gives long afterpotential similar to DDT.
Type II pyrethroids cause persistent depolarization and prolonged repetitive firing of sensory receptors and muscle fibers.
Both types also inhibit Ca/Mg ATPase resulting in increased intracellular Ca++ levels and increased neurotransmitter release
Treatment for pyrethrin and pyrethroid illness ?
Decontamination
Vitamin E cream
Symptomatic therapy
Remove from further exposure if needed
what are the health effects of glyphosate
Health effects
Case reports of eye, skin irritation
Death due to ingestion of large amounts
Experimental studies fail to show skin irritation
Mechanism of human toxicity unknown
Surfactant preservative?
what are the two chlorophenoxy herbicides ?
2,4,5-trichlorophenoxyacetic acid (2,4,5-T)
Derived from tetrachlorobenzene
Dioxin byproducts
2,4-dichlorophenoxyacetic acid (2,4-D)
Derived from phenol
Dioxin contaminants not present
what does acute and chronic toxicity look like for chlorophenoxy herbicides?
Acute
CNS depression
Skin, GI, mucous membrane irritation
Renal failure, myopathy
Chronic
Anemia, hepatic, renal effects
Tumor formation(?)
what are types of fumingants
Halogenated hydrocarbons
-Methyl bromide
-Ethylene dibromide, DBCP
Inorganic compounds
-Sulfuryl fluoride
Pro-fumigants
-Metam sodium
Metal phosphides
-Aluminum, Zinc, Magnesium
what are the characteristics of methyl bromide
High vapor pressure
Heavier than air
Odorless
-Chloropicrin (tear gas) added
Toxic mechanism
-Tissue methylation
what are the characteristics of methyl bromide acute toxicity
Vesicant
-Blistering dermatitis
Lower respiratory toxicant
-Delayed pulmonary edema
Central nervous system depressant
-Usual cause of death
CNS depression
Other CNS depressants
Pulmonary edema
Hepatic & renal disease
Acute severe asthma
what are chronic toxicity of methyl bromide
Central nervous system
-Cognitive, behavioral effects
-Polyneuropathy
Reproductive system
-Teratogen
-Genotoxic, mutagenic
what symptoms do the sulfuryl fluoride do ?
-Pulmonary
—Dyspnea, cough, delayed pulmonary edema, fatal hypoxia
-Renal
CNS
—Weakness, nausea, vomiting, restlessness, muscle twitching, seizures
what does metam sodium do ?
Hydrolyzes to mixture of irritants
health effects
-Irritant dermatitis
-Reactive airways dysfunction syndrome/asthma
what do phosphide compounds do and what are their characteristics ?
Metal phosphides hydrolyze
Aluminum, zinc, magnesium
Phosphine
Colorless, fish/garlic odor
Highly explosive, corrosive
Rapidly oxidizes to phosphoric acid
what are types of fungicides
Thiocarbamates
-Zineb, maneb, ziram, thiram
Pthalimide derivatives
-Captan, captafol,
Substituted aromatics
Chlorothalonil, hexachlorobenzene
Inorganic
Sulfur
what are health effects of fungicides
Acute
Irritant & allergic dermatitis
Chronic
Chronic dermatitis
Possible carcinogens
Thiocarbamates resemble what
Resemble rubber accelerator thiuram
Sensitization reported in exposed workers
what does chlorothalonil do
Fungicide- substituted aromatic
Blue-gray pigmentation in antecubital area
Positive skin reaction to chlorothalonil
Diagnosis: Ashy dermatitis
-Disruption of basal membrane of epidermis
Melanin deposits in dermis
Elemental sulfur
fungicide
Potent skin irritant
-Animal experiments equivocal
Airway irritant
types of rodenticides
Botanicals
Red squill – effects heart
Strychnine – blocks glycine receptors in spinal cord - convulsions
Inorganics
Phosphorous – GI track
Thallium – hair loss, nervous system
Zinc phosphide – GI track
Anticoagulants
Warfarin – inhibits blood clotting
Vacor – newer blood clot inhibitors
what is toxinology?
Specialized area of toxicology that deals specifically with animal, plant, and microbial toxins
The science of toxic substances produced by or accumulated in living organisms, their properties and their biological significance for the organisms involved
what is a poison
Any agent capable of producing an adverse response in a biological system
difference between poisonous animals vs venomous animals
Poisonous Animals
Animals whose tissues, either in part or in their entirety, are toxic
No mechanism or structure for delivery of their poisons
Venomous Animals
Animals that are capable of producing a poison in highly developed glands
Toxin can be delivered during a biting or stinging act
venom contains
Proteins
Amines
Lipids
Steroids
Free amino acids
Histamine
Phospholipases
Etc.
what are the problems with venom analysis
Venom must be “taken apart” to look at components
Quality of venom may be destroyed
Interplay between various components may be lost
bioavailability of venoms is determined by
Determined by:
Composition
Molecular size
Amount or concentration gradient
Solubility
Degree of ionization
Rate of blood flow to exposed tissue
Site of exposure (or route of exposure!)
Is venom injected?
what are the 4 ways venom absorption happens
Injection (possible IV injection!)
Active transport
Facilitated diffusion
Pinocytosis
describe the action of venom
Tissue destruction
Receptor-mediated toxicity
-Receptors have highly variable degrees of sensitivity
-Complex venoms may affect many receptor types (or even sub-types)
what are factors affecting distribution of venom
Protein binding
Variations in pH
Membrane permeability
Rate of blood flow to a particular site
Etc.
what are arthropods
Insects, crustaceans, arachnids (scorpions, spiders), and myriapods (centipedes) that are characterized by a chitinous exoskeleton and a segmented body to which jointed appendages are articulated in pairs
More than one million species
All are not significantly venomous
Most don’t have fangs or stingers long or strong enough to penetrate human skin
what are the signs and symptoms of scorpion envenomation?
Signs and symptoms of scorpion envenomation
Localized pain
Swelling
Mild paresthesia
Tachycardia and hypertension
Rare systemic reactions including fever and muscle fasciculations in adults
Systemic reactions in children more common; lead to motor weakness and respiratory paralysis
Symptoms often resolve in 12-36 hours
What is spiders name scientific and what does the venom do
Latrodectus (Widow spiders)
Found worldwide in temperate and tropical climates
Only female has fangs large enough to penetrate human skin
Venom affects neurotransmitter release
what does latrodectus venom contain
latrotoxins
Major latrotoxin is a presynaptic toxin which depolarizes neurons by increasing [Ca2+]i
Stimulates exocytosis of neurotransmitter at nerve terminals
how do latrodectus bites look like
Clinical symptoms include numbing pain in affected extremity
Pain, cramping, and rigidity in large muscle masses
Local skin reactions rare
Muscle fasciculations
Rarely fatal
Describe Loxosceles bites
Initial sting
Burning sensation at bite site
Swelling and redness in mild bites
Serious bite cases exhibit hemorrhage, blistering, pustule formation, necrosis
Systemic effects may include fever, nausea, hematuria
Rarely fatal
What are ticks and what disease do they cause?
type of arachnida
Saliva is toxic
Microbacterial organisms transmitted by ticks
Rocky Mountain spotted fever, typhus, tick-borne encephalitis, Lyme disease
what is lyme disease caused by, and what happens during lyme disease
Caused by bacterium Borrelia burgdorferi
The action of Borrelia toxin is to prevent, through its action as a proteolytic enzyme, the release of the neurotransmitter acetylcholine
Bite symptoms include fever, headache, fatigue, and a characteristic circular skin rash at bite site
If left untreated, infection can spread to joints, lymph nodes, the heart, and the nervous system
If caught early, antibiotic therapy is often successful
what are chilopoda
Centipedes
Found worldwide
First pair of legs are modified poison jaws
Venom contains proteinases, esterases, histamine, etc.
Venom causes redness and swelling
Necrosis rare
what is teh scientific name of caterpillars
lepidoptera
Most possess urticating hairs (setae) which are attached to unicellular poison glands at the base of each hair
In most cases, itching and redness subside shortly
what are fire ants name and what do their venoms do
Formicidae (Ants)
Solenopsis (Fire ants) are clinically important
Native to S. America and Southern US
Venom contains formic acid, and alkaloids
Stings give rise to intense burning, swelling, pustule formation, and necrosis
Severe envenomations may result in respiratory difficulties and rarely death
what are bees name and what do their venom contain
Apidae (Bees)
Venom contains phopholipase A, histamine, etc.
what are true bugs and what do their venom contain
insecta
Heteroptera (True bugs)
Six legs, most have wings
Venom has protease function (digestive enzymes)
Some bugs have no mechanism to deliver their venom and are therefore poisonous!
Envenomation usually very mild
what are poison arrow frogs
amphibians
they are classified and dendrobates and phyllobates
Describe the arrow frogs poison
Batrachotoxin
Arguably the most toxic naturally produced poison
Steroidal alkaloid with high specificity for certain nerve structures in the peripheral nervous system
Sodium channel blocker
-Locks the channel in the open position
Results in constant stimulation and release of acetylcholine
-Muscles contract and are unable to relax
Death may result from respiratory paralysis
what is a heloderma suspectum and what is the venom like
Gila monster
Venom contains phospholipases as well as proteolytic and hyaluronidase activities (increases tissue permeability)
Venom drawn up via capillary action along grooves in the teeth
describe the 3 types of venoms from reptiles- snakes
Crotalid venoms: Rich in proteolytic activity and thrombin-like enzymes
Vipirid venoms: Moderate-rich in proteolytic activity and thrombin-like enzymes
Elapid venoms: Little or no proteolytic activity (although phospholipases may be strongly represented), few thrombin-like enzymes, neurotoxic activity! Venoms may cause death in as little as 5-10 minutes
Describe what happens in terms of mortality from 3 venoms
Crotalid and viper envenomation
-Hypotension/shock from decrease in circulating blood volume secondary to capillary permeability
-Elapid envenomation
Respiratory arrest from neurotoxic activity
what do antivenoms contain
Contain neutralizing antibodies
-Monovalent or polyvalent
Antibodies bind to venom components rendering them ineffective
what is anaphylaxis and anaphylaxis shock
All venoms have the capability of inducing anaphylaxis
Anaphylaxis is an acute systemic (rapid, multi-system) and severe allergic reaction
Anaphylactic shock—will usually lead to death in minutes if left untreated
what causes anaphylaxis
Symptoms of anaphylaxis are related to the action of IgE and other anaphlatoxins, which act to release histamine and other signaling substances
In addition to other effects, histamine induces vasodilation of arterioles and constriction of bronchioles in the lungs – also known as bronchospasm (constriction of the airways)
May occur in response to venom or antivenom!
what is a solvent ?
A solvent is a liquid at room temperature used to dissolve other substances
examples like alcohol, glycols, aldehyde, ketones
what are properties of solvents
Solubility
Non-flammability/
Flammability/
Explosivity
Volatility
Metabolism
Complex mixtures
Routes of solvent exposure
Inhalation
Absorption
-skin
-mucous membranes
Ingestion
Injection
General Toxicological Principles-1 is
Solvent exposure affected by airborne concentration, solubility, and exposure frequency.
Higher vapor concentrations for enclosed spaces with poor ventilation, and with solvents having a high vapor pressure.
When inhaled, lipid-soluble solvents will easily enter the blood
Solvents also can pass through the skin, although not usually a significant route of exposure.
Solvents often de-fat or irritate the skin.
General Toxicological principles-2
-Toxic effects of solvents include:
depression of the central nervous system, and
irritation of membranes and tissues.
-CNS depression tends to increase as the length of the carbon chain increases.
–Molecules with more than 5 carbons generally are not volatile enough to cause hazardous exposures.
-CNS-depressant properties are increased with the addition of halogens and alcoholic functional groups:
alkanes <alkenes <alcohols <organic acids <esters <ethers <halogenated compounds
General Toxicological Principles-3
All organic chemicals can cause tissue irritation.
-Solvents can extract lipids from cell membranes, casing irritation and cell damage.
As the molecular size increases, the potential for irritation increases
In general, irritation increases with the addition of functional groups
Unsaturated compounds are stronger irritants than their saturated counterparts
Hepatic effects of solvents
Chemical hepatitis, with transaminases indicating hepatocellular injury
Steatosis (fatty liver), occasionally progressing to hepatic necrosis
Possible cirrhosis on recovery
Reduced metabolism of other xenobiotics
? Acetylcysteine
Mechanisms of hepatotoxicity
-free radical formation
-Halogenated hydrocarbons have greatest toxicity
carbon tetrachloride, chloroform»_space;
1,1,1-trichloroethane, trichlorethylene»_space;
non halogenated hydrocarbons
Describe the renal toxicity of solvents
Acute tubular necrosis
-acute heavy exposure
-halogenated HCs, glycols, toluene, petroleum distillates
Glomerulonephritis
-chronic, long term exposure
-gasoline implicated
Describe acute central neurotoxicity of solvents
General anesthesia-like activity or selective inhibition
narcosis
euphoria
agitation (disinhibition)
dyscoordination, ataxia, dysarthria
What is TCE
It is a chlorinated hydrocarbons
TCE is a widely used solvent for metal degreasing
At high acute exposure TCE can cause respiratory depression and cardio toxicity
There is a weak association between TCE exposure and multiple myeloma, Hodgkin disease and cancers of the prostate, skin and cervis
The IARC concluded that TCE is “probably carcinogenic to humans” based on its assessment of sufficient evidence in animals and limited evidence in humans
Describe relationship between TCE and the Air and drinking water
TCE contamination in ground water can release TCE vapors to the subsurface
At many sites these vapors may then enter buildings from below, similar to radon
Indoor air concerns may lead to cleanup of groundwater not considered a current or potential drinking water source (e.g., water table aquifers), and therefore not subject to drinking water regulations
There is no single regulatory standard set by rulemaking for TCE in air
Describe the metabolism of TCE
With rare exceptions, the toxicities associated with TCE are thought to be mediated by metabolites rather that by the parent compound
The majority of TCE undergoes oxidation via cytochrome P450s, with a small proportion being conjugated with GSH via glutathione transferases
TCE Human risk assessment describe it
The human relevance of TCE induced rodent tumor is an unresolved issue
For liver tumors: humans appear to be similar to rats than mice in the oxidative metabolism capacity
For kidney tumors evidence exists that the rat have a greater GSH metabolism capacity
With regards to lung cancer, the CYP450 content and the number of Clara Cells in the human lung are but a fraction of those in the mouse
Based on the above, it appears that direct extrapolation from rodent data would overstate human TCE cancer risk
Describe carbon tetrachloride and chloroform chcl3
they are organic solvents
and halogenated hydrocarbons
Carbon tetrachloride, CCl4
–Strong CNS depressant
–Potent liver toxin
—–Acute exposure can cause death
——Chronic exposure can cause cirrhosis
Chloroform, CHCl3
–CNS depressant
–High exposure levels can cause liver and kidney damage and cardiac arrhythmias.
Describe vinyl chloride
-Vinyl chloride , CH2CHCl
–Skin irritant with CNS depressant properties
–Much industrial hygiene concern over this chemical is due to its carcinogenic potential
—–Chronic exposure may result in liver cancer (angiosarcoma) and other cancers as well.
Describe methylene chloride
Methvlene chloride, CH2Cl2
Not as toxic as the other chlorinated methanes
A suspected carcinogen
An excellent solvent
Widely used in industry
The 1997 OSHA methylene chloride standard should result in a reduction in the use of this chemical.
what is beneze and what does it do
organic solvent
aromatic hydrocarbon
Benzene has been used for many industrial purposes, component of gasoline
High exposure levels can cause death by CNS depression or cardiac arrhythmias
Skin exposure causes dermatitis
Inhalation of high concentrations may result in bronchial irritation or pulmonary edema.
Chronic exposure causes blood disorders of aplastic anemia and leukemia.
Victims of chronic benzene poisoning usually have a red blood cell count that is only 50% of normal.
what is an alkyl benzene
organic solvent
alkyl benzene
Alkyl benzenes include toluene, xylenes, etc.
More powerful narcotic effect than benzene
Not known to cause blood disorders
what is ethanol
organic solvent
alcohol
Irritant and a depressant
The toxicology of this compound is well know through centuries of voluntary ingestion
It does not have the neurotoxic properties of methanol
what is methanol
organic solvent
alcohol
Methanol, CH3OH (wood alcohol, methyl alcohol)
Common industrial solvent
Methanol poisoning may result in blindness, other neurological damage, or death.
-Methanol poisoning 8 - 36 hrs after ingestion
-Caused by compounds produced by methanol metabolism
-Inhibited by administering ethanol
what is the mechanism of toxicity for methanol
Mechanism of toxicity
Methanol slowly metabolized to formaldehyde
Formaldehyde rapidly metabolized to formic acid
-Acidosis
-Ocular toxicity
what is a methanol specific antidote
Fomepizole (4-methylpyrazole)
Inhibits alcohol dehydrogenase
Produces same end result as ethanol without causing intoxication
What is ethylene glycol description
Antifreeze (95% ethylene glycol)
Tastes sweet
Kids, animals like taste/drink large quantities
What is ethylene glycol mechanism
Mechanism of toxicity
Metabolized via alcohol dehydrogenase to glycoaldehyde then to glycolic , glyoxylic, and oxalic acids
Acids lead to anion gap metabolic acidosis
Oxalate binds with calcium
-Forms crystals causing tissue injury
-Produces hypocalcemia
what does ethylene glycol overdose presentation look at 3 hours and 4-12 hours
Overdose Presentation (first 3-4 hours)
Patient may appear intoxicated
Gastritis, vomiting
Increase in osmolar gap
No initial acidosis
Overdose Presentation (after 4-12 hours)
Anion gap acidosis
Hyperventilation
Seizures, coma
Cardiac conduction disturbances, arrhythmias
Renal failure
Pulmonary, cerebral edema
what is ethylene glycol management look like after overodse
Lavage if within 2 hours
Sodium bicarbonate
Fomepizole or ethanol
Folic acid, pyridoxine, thiamine (enhance metabolism of glyoxylic acid to nontoxic metabolites)
Describe aldehydes
organic solvents
-Aldehydes are strongly irritating to mucous membranes
Can cause CNS depression, but their irritating nature usually prevents significant exposure.
-Formaldehyde is regulated by OSHA as a carcinogen.
-Can cause sensitization in about 4 - 8% of the population.
-Glutaraldehyde
–Commonly used in hospitals to sterilize endoscopes and other equipment
–Also causes sensitization.
Describe ketones
organic solvents
CNS depressants
Irritating effects cause workers to avoid high exposures
-Toxic properties of ketones generally increase with increasing molecular weight.
Acetone, (2-propanone) is a relatively safe solvent, as its principle toxic effect is irritation.
Describe ethers
Organic solvents
Anesthetic effect of ethers increases with the size of the molecule
Very flammable, and they can be easily oxidized to explosive peroxides.
Ethyl ether, CH3CH2OCH2CH3 (diethyl ether)
Had been widely used as an anesthetic
Describe phenols
Phenols are extremely irritating, capable of causing severe burns from direct contact.
Phenol is cytotoxic to all cells and tissues, and is toxic by all routes of exposure
-Rapidly absorbed through the skin
-Fatalities have resulted within 10 minutes of skin exposure.
what is delayed contact sensitivity
Delayed contact sensitivity
aka allergic contact dermatitis
standard chemistry for sensitizers
-low molecular weight (haptens)
-react with cutaneous proteins
poison ivy and poison oak
develops after one or more contacts
subsequent exposure elicits response dependent on dose
3-5 weeks to develop skin reactivity
what is contact urticaria
nettles
-hollow, stinging hairs inject chemical into skin
-mixture of acetylcholine, histamine, and serotonin
causes local vasodilation, sweating and pain
recovery in 3-5 days
what is phototoxicity
parsnips, caraway, dill, parsley and citrus
sensitize skin to long-wave UV light
contain furocoumarins
skin burns within 6-24 hours of contact
range from mild irritation to severe blistering
relieved with aspirin or corticosteroids
What is primary chemical irritation in plant skin injury
spurges, buttercups and wild pepper
resembles contact with corrosive acid
affected by dose, exposure time, genetics, temperature and humidity
serious eye damage possible
keratoconjunctivitis with transient blindness
Plant toxins- Gastrointestinal
Direct stomach irritation - Nausea, vomiting and diarrhea
California buckthorn (sacred bark), tung nut, horse chestnut (active is called esculin), pokeweed
Antimitotic (stops cell division) – Nausea, vomiting, confusion, delirium
Lily family, glory lily, crocus, may apple
Colchicine (gout treatment)
Lectin toxicity – nausea, diarrhea, headache, confusion, dehydration, death
Wisteria, castor bean (Ricinus communis)
Ricin – block protein synthesis very toxic 5 to 6 beans can kill a child
Plant toxins that cause cardiovascular 1
Digitalis like glycosides – cardiac arrhythmias
Foxglove (Digitalis purpurea), squill, lily of the valley
Contain glycosides that are similar to digitalis
The toxic effects is identical to that of Digitalis toxicity: nausea, vomiting and cardiac arrhythmias
What are vasoactive chemicals
Mistletoe (berries contain toxin)
Cardiovascular
Toxin is called phoratoxin (produces hypotension, bradychardia, negative ionotropic effects and vasoconstriction of the vessels of skin and skeletal muscle)
Claviceps purpurea (ergot) is a fungus parasitic on grains of rye- this has caused an outbreak in several European countries in the Middle ages known as “Saint Anthony’s fire”.
what are plant toxin effects on heart nerves
Heart nerves – decreased heart rate and blood pressure, general weakness
Lily, hellebore, death camas, heath family, monkshood, rhododendron
Alkaloids, aconitum, grayanotoxin (concentrated in honey) (honey poisoning)
It consists of marked bradbradycardia, hypotension, weakness, GI upset and in severe cases respiratory depression
The toxins gets into the honey from the nectar collected by the bees from the flowers (Rhododendrom ponticum)
what plants cause seizures
Water Hemlock, mint family
what plant toxins induce stimulation of nervous system
Excitatory Amino Acids – headache, confusion, hallucinations
Red alga (produces Kainic acid), Green alga (produces domoic acid). In 1987 there was a serious outbreak in Canada in individual eating mussels containing domoic acid)
coffee bean, tea, cola nut, caffeine most widely consumed stimulant in the world
what plant causes aberrant behavior
very excitable, muscle weakness, death
locoweed
What plant causes neurotoxic death
Poison hemlock (Conium maculatum)
Coniine – neurotoxic alkaloid – Poison used by Socrates
what plant causes paralysis?
demyelination of peripheral nerves is caused by
Buckthorn, coyotillo, tullidora (U.S., Mexico)
what plant causes atropine like effects like
dry mouth, dilated pupils, confusion, hallucinations, memory lose
Solanaceae family – jimsonweed, henbane, deadly nightshade (Atropa belladonna), angles trumpet (atropine and scopolamine)
what plants cause nueromuscular effects
mild stimulation to muscle paralysis, respiratory failure (curare), death Coffee bean, tea, cola nut
Tobacco – South American – Strychnos family (curare) Blue green alga (anatonin A)
what plant toxins effect the liver
Hepatitis” and cirrhosis of liver - From contaminated grain
Ragwort or groundsel
Pyrrolizidine alkaloids – attack liver vessels – effects humans, cattle but some species resistant
Liver failure and death
Mushrooms – “Death cap” (Amanita phalloides)
Amatoxin and phalloidin effects RNA and protein synthesis
Liver cancer
Fungus that grows on peanuts, walnuts, , etc…plant
Alfaltoxins– produced by fungus in poorly stored grain
what plant toxins effect reproduction
Teratogen – malformations in offspring (sheep)
Veratrum californicum – native to North America
Veratrum – blocks cholesterol synthesis – seen offspring of mountain sheep
Abortifacients
Legumes (Astrogalus)
Bitter melon seeds (Momordica)
Swainsonine toxin – stops cell division
Lectins - halt protein synthesis– used by humans
what happens with the toxicity of alpah amintin
through interference with RNA polymerase II, prevents the transcription of DNA
what do phalotoxins do
are rapid-acting and interrupt actin polymerization, impair cell membrane function, has limited absorption
what do mushrooms containg Monomethylhydrazine contain in terms of toxicity
Toxicity is due to gyromitrin which is metabolized to monomethylhydrazine
This metabolite reacts with pyridoxine resulting in inhibition of pyridoxal phosphate-related enzymatic reactions
symptoms of monomethylhydrazine mushrooms
Headache, nausea, vomiting, seizures, and hepatorenal failure
Symptoms occur 6-10 hours after ingestion
Toxin may be eliminated with cooking but inhalation of cooking fumes may cause poisoning
the therapy for monomethyl mushrooms
Pyridoxine, in dose of 25 mg/kg
C. Muscarine-Containing Mushrooms do what to the human body
no lethality,
Small amounts of muscarine are in Amanitia muscaria
Symptoms: SLUDGE within 0.5-2 hours
Salivation, Lacrimation, Urination, Diaphoresis, Gastrointestinal motility, Emesis
Therapy: Atropine
Coprine-Containing Mushrooms mechanism symptoms and therapy
Rarely fatal
Coprine has a disulfiram like effect(Blocks acetaldehyde dehydrogenase)
Toxic if alcohol is consumed within 48-72 hours after mushroom
Symptoms: Flushing, headache, hypotension, histamine induced vasodilation
Therapy: Supportive, anti H1 and anti H2, prostaglandin inhibitors
what is colchichine
Antiinflammatory effects mediated by ability to inhibit microtubule and PMN activity
May cross placenta + found in breast milk
What is ricin
a potent cytotoxin (toxic at cellular level) concentrated in the castor bean also contains highly toxic glycoproteins that block the synthesis of other good proteins causing cell death
used as a lubricant, boiling makes it non- toxic
what are routes and symptoms of ricin poisoning
Intravenous-Introduced into a puncture or cut.
Inhalation- Aerosolized liquid or powder inhaled directly into the lungs.
Ingestion- Ricin enters through contaminated food or water into the stomach.
Symptoms range from fever, cough, nausea, chest tightness, sweating, cyanosis, hypo tension (very low blood pressure), dyspnea (labored breathing). Circulatory and respiratory collapse occur within 36-72 hrs leading to death.
what is ricin mechanism of action
Death from Castor beans is caused by two lectins in the beans: Ricin I and Ricin II (more toxic)
Ricin II consists of two chains of amino acids. The A chain inactivates the 60s ribosomal subunit of cells by depurination of a single adenosine residue within the 28s rRNA and blocks protein synthesis
Exposure to high or very warm temperatures and or high humidity will diminish the strength of the toxin (denaturing effect).
