Flashcards in Final Study Guide: Toxicology and Heavy Metals Deck (72)
Definition of Toxicology
The study of the adverse effects of a chemical, physical or biological agent on living organisms and the ecosystem including the prevention of such adverse effects in...
What is Toxicity?
The ability of a material to damage a biological system, cause injury, or impair function.
What factors affect toxicity?
Dose, route of exposure, chemical species, along with age, gender, genetics, and nutritional status of exposed individuals.
What is a hazard?
Something that can cause harm and is defined by the inherent properties of the harmful agent.
What is a risk?
The chance or probability that a defined harm will actually occur from a specific hazard.
What is risk assessment?
takes into account both the probability of harm (based on expected frequency and duration of exposure to a hazardous agent) as well as the severity of the hazard itself.
Risk = Hazard + Exposure
What is Toxicokinetics?
It refers to the ADME and clearance of a toxic substance
What is Toxicodynamics?
It refers to the interaction of toxic substance and the body.
What is ADME?
Adsorption, Distribution, Metabolism, and Excretion
What is Clearance?
plasma cleared per unit time
*Includes both the renal and hepatic contributions
In what two ways does Clearance occur?
-Drug or toxin is METABOLIZED into other chemical species
-Drug or toxin is removed from the body by ELIMINATION from a specific organ
If a substance is 95% metabolized by the liver to a totally inactive from and the remaining 5% excreted by the kidney then will a therapy that increases the renal excretion of it be of much benefit for improving clearance?
Under normal conditions Elimination of most drugs/chemicals is proportional to what?
Their plasma concentration
(1st order kinetics)
What happens when plasma levels become very high?
Protein binding and normal metabolism can both become saturated.
What happens when protein binding and normal metabolism both become saturated?
The rate of elimination can become fixed,
(Zero order Kinetics), and more drug will be delivered directly to the circulation in unbound fraction that is not readily able to be metabolized and cleared by renal and hepatic mechanisms.
What happens at toxic doses of a drug or toxin?
Normal kinetics may be altered to reflect prolonged half-life and increased toxicity (Larger, unbound free fractions)
What is volume of Distribution (Vd)?
apparent volume in which a substance is distributed throughout the body.
What are characteristics of compounds with large Vd's?
Implies a substance will not be easily accessible to purification attempts (e.g. hemodialysis)
Examples: antidepressants, antipsychotics, antimalarials, and opioids.
What are characteristics of compounds with smaller Vd's?
Are generally more accessible and thus better candidates for hemodialysis.
Examples: Salicylates, ethanol, phenobarbital.
What is Bioaccumulation?
accumulation of toxic agent in an individual when the uptake of the agent exceeds the organism's ability to metabolize/excrete it across time.
*one organism across time
What is Biomagnification?
Increases in relative amount of a contaminant in member of a population as it passes up the food chain.
What is a heavy metal?
Natural elements (metals) that have a high atomic weight and possess a density at least five dimes greater that that of water. (i.e. specific density > 5 gm/cm3)
What are the 4 (toxic?) heavy metals in this lecture?
*chromium, nickel, and tin are also examples of heavy metals widely used in commercial manufacturing.
At low doses some heavy metals are what?
(Typically iron, manganese, cobalt, and zinc)
*large amounts can be toxic
Deficiencies in essential metals may cause what?
Worsening of outcomes from heavy metal poisoning.
What are the exposure sources for Lead (#1)
Soil and Dust, pre-1977 paint chips, lead based paint on toys, contaminated water, industrial pollution, folk remedies for colic (Azarcon) and pica.
Does lead serve any physiological role in the body?
At what level of exposure does lead have an adverse effect?
Any level of exposure
*Lead levels >5 micrograms per deciliter is the reference level at which CDC recommends public health actions be initiated.
Where is lead absorbed by the body?
Respiratory tract via lungs (50-70%)
GI tract (5-10%)
Also poorly absorbed through the skin
How much lead is absorbed if it is ingested?
Adults only absorb 10-15%
Children absorb > 50%
-Children and pregnant women absorb more lead because their bodies have greater demands for both calcium and iron
Most acutely absorbed lead is stored where?
RBC's (Half-life of 20-40 days), but chronic exposure builds a repository in bone (90% of lead burden that can last years to decades.
How much lead is excreted in the urine?
At what levels is lead poisoning subtle and difficult to diagnose?
45 mcg/dL in children
60 mpg/dL in adults
* Serum levels greater than 5mcg/dL have been shown to cause neurocognitive defects in children.
What is the primary cause of lead's toxicity?
Its ability to bind sulfhydryl groups found on many enzymes and cofactors.
What is the most sensitive target organ for lead poisoning?
The developing CNS
*causes cognitive defects
(BLL of 5mcg/dL has been shown to cause an average loss of 6.1 IQ points)
What is another sensitive system that is affected by lead toxicity?
The immune system
*decreases leukocytes causing immunosuppression
What else can lead exposure lead to?
-Lead exposure alters the permeability of blood vessels and damages the cell membranes of RBCs
What is an oral indication of Lead poisoning?
Gingival lead lines
What is the treatment for Lead intoxication?
-Remove from exposure
-Provide Supportive Care (encephalopathy)
-Provide Chelation therapy
What consist of Chelation Therapy?
-Edetate Calcium Disodium (EDTA) 30-50mg/kg/day IV
-Followed by oral Succimer
*These reduce blood levels which may mobilize skeletal stores of lead. Therefore after chronic exposure, REBOUND INTOXICATION is very likely as lead leaves the bone depot.
What is Mercury also known as?
*the only metallic element that is liquid at standard room temp and pressure.
What are exposure sources of Mercury?
-Ingestion of Methyl-mercury foods.
-Fish and Meat
-Industrial pollution (mining and smelting)
-improper use or disposal of mercury
-Azogue (Folk remedies) 10x more than thermometer.
What is the mechanism of Mercury Toxicity?
Highly reactive with Selenium, which is an essential dietary element required for thioredoxin reductase to prevent and reverse oxidative damage.
*thioredoxin reductase restores vitamin C and E, counteracting oxidative damage in the body
What are signs of Chronic Mercury infection?
Tremors, Psychiatric Disturbances, Gingivostomatitis, Depression, Memory Loss, Insomnia, Irritability, mood disturbances, distorted vision, confusion, hallucinations, numbness/tingling in hands, mouth, and feet.
According to the CDC there is no convincing evidence of harm caused by the low doses of thimerosal in vaccines?
What is the treatment for Mercury Intoxication?
1) Remove exposure hazard
2) IV hydrocortisone (for Inhaled exposure)
- to reduce pulmonary complications
3) Chelating Agents
-dimercaprole (only acute), succimer, unithiol
What are the exposure sources of Arsenic?
Medical products (Arsenite (As3+) Chemo for leukemia.
What are the toxicokinetic effects of Arsenic?
-60 Hour half-life in blood
-Binds to sulfhydryl groups in keratinized tissues (Hair, nails, skin (where it acts as a depot)
-Primary excretion by kidney (small amount in sweat and feces)
What are the aoxicodynamics of Arsenic?
-interferes with enzyme function
-interferes with signal transduction
-Hemolytic effects on RBCs
-Carcinogenic effects in lung, skin, and bladder
What are the symptoms of Acute Arsenic Intoxication?
Metallic/garlic taste, profound vomitting, abrupt gastroenteritis, hypotension, metabolic acidosis, cardiac dysfunction, pancytopenia, and peripheral neuropathy.
What is the treatment for Acute Arsenic Intoxication?
-Decontamination and supportive care
-Chelation with UNITHOL (IV) or DIMERCAPROL (IM) 4-6 hours
-If exposure is even suspected, empiric chelation should be started.
What do survivors of Arsenic toxicity often develop?
-Bone Marrow Suppression (anemia, leukopenia)
What are the symptoms for Chronic Arsenic intoxication?
Fatigue, anorexia, anemia, weakness, GI Complaints, peripheral neuropathy, Hyperpigmentation and Hyperkeratosis of skin hands and feet. Prolonged QT interval, cirrhosis, cancer of lung, skin, and bladder.
What is the treatment for Chronic Arsenic Intoxication?
-Dietary supplementation with folate promotes methylation and excretion
-***Chelators offer NO therapeutic benefit since chronic arsenosis leads to irreversible damage to several vital organs and is an established carcinogen
What is Arsine Gas and what are the symptoms from its acute intoxication?
-Colorless, odorless gas at low concentrations, garlic-like smell at high, that is generated when arsenic containing metals come in contact with strong acids.
-Hemolysis, headache, nausea, vomitting, diarrhea, dyspnea, abdominal pain, jaundice, and renal failure 1-3 days later.
What is the treatment for Arsine Gas intoxication?
Blood exchange hemodialysis and transfusions, aggressive hydration.
*Chelators of no Significant therapeutic benefit.
What do Chelators do?
Render heavy metal ions unavailable for covalent interactions with functional groups of enzymes and other cellular targets.
*increases excretion and/or redistributes bound mono, bi, or poly dentates.
What heavy metals are less effectively treated by Chelators?
Those with a longer half-life in an organ
*most effective if given ASAP after exposure.
What are three Chelating Agents?
What is Dimercaprol used for?
-Monotherapy for acute Arsenic and/or Mercury poisoning
-Combo therapy with edetate calcium disodium for severe Lead Poisoning.
*Contraindicated for use alone after chronic exposure to lead, since it redistributes larger doses of lead to CNS.
What are some other characteristics of Dimercaprol?
-Not-Water Soluble (Can't be given orally)
-Half-life 4-8 hours
-Narrow Therapeutic Index
*Adverse Effects- hypertension, tachycardia, nausea, vomiting, salivation, lacrimation, pain, increased clotting times.
What are some of the Characteristics of Unithiol?
*Water Soluble Derivative of Dimercaprol
-Oral or IV administration
-Peak blood levels by 4 hours
-Half life = 20 Hours
*Increases renal excretion of mercury, arsenic, and lead.
*Uthinol is not FDA approved, but is good for acute and chronic poisoning with many metals and metalloids.
It may lessen acute arsenic and mercury toxicity.
What are some of the Characteristics of Succimer?
-Water soluble form of dimercaprol (oral use only)
-Increases Urinary lead excretion
-FDA approved when lead blood is >45 mcg/dL
- May also be useful for acute arsenic and mercury
- Minor Diarrhea/GI upset (10%)
-Mild rashes (5%)
What is the method of action of Succimer?
Binds to cystine to form mixed disulfides which are excreted by the kidney (half-life = 2-4 hours)
What are some of the Characteristics of Edetate Calcium Disodium?
-FDA indicated as 1st line treatment for chelation of lead.
-only chelates extracellular lead
- IV only
-1 hour half life
-Excreted 100% by the Kidney
What are some Contraindications for use of Edetate Calcium Disodium?
- for use in Anuric patients
-Don't use > 5 days due to nephrotoxicity
What is biocompatibility?
the ability of a material to elicit an appropriate biological response in a given application in the body.
*these do not produce a toxic or immunological response when exposed to the body or bodily fluids.
What are the 4 criteria of Dental Material biocompatibility?
1. Should not be harmful to pulp or soft tissues
2. Should to contain toxic diffusible substances that may be released and absorbed into the circulatory system to cause systemic toxicity.
3. Should be free of potentially sensitizing agents that may cause allergic reactions.
4. Should have NO carcinogenic potential
When is the greatest amount of mercury released in amalgam?
During dry polishing (44 mcg)
*2nd placement (6-8 mcg)
*3rd wet polishing (2-4 mcg)
What is important to do with Zinc Phosphate cements?
Use proper mix or use a resin modified glass ionomer instead.
*if its too wet it can release phosphoric acid into the dentin tubules damaging the pulp.
What are some Characteristics of Cyanide?
-NOT a heavy metal
-Prevents the cells of the body from getting oxygen and ATP causing them to die.
-inhibits cytochrome C oxidase in the ETC.