Principles of Toxicology

Endang Mahati

Definitions
Toxicology

Complex subdivision which deals with toxic substances: detection, properties, effects and regulation of toxic substances, including poisons.
So what is a poison?

What is a poison?
Poison

Any substance which cause a harmful effect when administered either by accident or by design to a living organism
Poisoning is quantitative concept Any chemical at some specific dose and time is harmless, while the same chemical at other doses and time is toxic

What is Toxicology?
1. Primarily a multidisciplinary science that is based on other sciences including:
Pharmacology Pathology (disease/death) Chemistry Epidemiology

Hazard potential for harm Risk probability of producing Harm

2. Applied Science
Enhancement of the quality of life Protection of Environment To learn about life processes (i.e uncoupling agents)

Dose Response Curve related to Toxicity

Dose/Time Principle
While dose is the primary determinant of toxicity, effects of chemicals on the body are also a function of the length of time such substances are present.

Blood Plasma Level Toxicity

More simply

Dose makes the poison

It is the primary determinant of Toxicity

TOXIC SUBSTANCE inhalation orally intramuscularly intravenously

mucous membrane cells

endothelial cell portal vein

liver
endothelial cell systemic circulating blood site of action effects

other tissues

liver (metabolism)
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kidney (excretion)
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Toxicology in Modern Times

During the last 5 decades, toxicology has taken on new meaning

Thalidomide tragedy (1950s) - phocomelias and other birth defects Silent Spring Rachel Carson, DDT TV CSI, Quincy Increasing Drug Abuse Medical Malpractice suits (last 30 years)

Amelia total

Mgatidjan, INTROTOXIC-10

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Mgatidjan, INTROTOXIC-10

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Importance of Toxicology

1. Important because chemicals are responsible for at least 10,000 accidental deaths annually.
Children under 5 years old are usually poisoned by: Plants, cosmetics, salicylates, hydrocarbons, detergents and acetaminophen. Adult poisoning usually involves: Barbituates, carbon monoxide, salicylates, alcohol, narcotics and acetaminophen

2. Work place accidents associated with chemicals.

A. Drugs (alcohol, cocaine, marijuana, etc.) B. Manufactured Products

Importance of Toxicology (cont)

3. Litigation
A. ie. Drug/alcohol related accidents

4. Causation
A. Evidence of cause and effect based on exposure and dose.

Toxicological Terms
1. LD50 dose at which 50% die
Only animals TD50 dose at which 50% have toxicity Measure of harmfulness

2. T.I. Therapeutic Index

TD50 / ED50 The larger the number, the safer the drug Measure of safety

3. Acute Toxicity
Single dose within 24 hrs Defines intrinsic toxicity

Toxicological Terms (cont)

4. Chronic Toxicity
Daily exposure for up to a lifetime

5. TLV Threshold Limit Value

Concentration below which there is no expected untoward effect over a period of 8hrs/day 5 days/week NOEL no observable effect level ADI allowable daily intake ADI = (NOEL) / x x is some safety factor (i.e., 100)

Toxicological Terms (cont)

6. STEL Short term exposure level
4x a day, with the average being equal to the TLV

7. ALD Average Lethal Dose

Estimated from accidental deaths in humans

8. Toxicon
Toxic principle of a given chemical entity

Tylenol quinone imine CCl4 free radicals

9. Primary Determinant of Toxicology

Dose, Dose and Dose

Selective vs. Nonselective Toxicity

Nonselective
Nearly all chemical are nonselective in their actions Few chemicals are sufficiently selective to harm certain cells

Selective
One mans poison is another mans pill. What may be harmful to one specimen may be relatively harmless to another. Garden spray

II. Management of a Poisoning

Immediate measures are called for in every case of poisoning regardless of cause.
1. Support Vital Functions 2. ID drug poisoning as the problem 3. Reduce the amount of drug in the body

Support vital life functions (ABCs)

Airway endotracheal tube if needed, watch for fluid
accumulation in airway (i.e.. Aspiration of vomit)

Breathing Supplemental Oxygen, bag valve mask

(BVM) and respirator.

Circulation Monitor ECG, watch for arrhythmias, cardiac

arrest and shock

Vasogenic Shock faulty vasomotor tone, increase capillary permeability. Cardiogenic Shock inadequate cardiac output can be due to cardiac dilation (barbituate, Ca channel blocker)

General Treatment of a Comatose Patient

There are several general antidotes that are used in the treatment of comatose patients upon presentation at the hospital.
What are they?

Supportive Drug Therapy

Treat all patients who come into the hospital in a coma with glucose, insulin and naloxone. Use drugs to treat emergent conditions, ie:
Seizures anticonvulsants (valium) Cardiac Dysrhythmias anti-arrhythmias (lidocaine, digoxin) Severe Agitation anxiolytics (benzo)

How to ID the poison?

ID the poison
1. Patient history 2. Laboratory testing 3. Comparison of drugs or chemicals with known toxicology standards.

Identification of the Poison (Sample Types)

Urine - 1st choice easier to detect presence of the drug due to the accumulation of drug in the urine. Blood/Serum 2nd choice get exact serum levels to better identify the health effects of the drug (coma/stimulant panels)

Gastric Contents 3rd choice less helpful, but can tell if you should perform a gastric lavage.

Identify Poison (Tests)

Urine tests
Immunoassay (EMIT, ELISA) semiquantitative tests usually with automated instrumentation. Can detect cannabinoids, amphetamines, cocaine, barbs etc. Thin Layer Chromatography (TLC) ToxiLab, 4 stage solvents, qualitative test

Urine/Blood tests
High Performance Liquid Chromatography (HPLC), gas chromatography and Gas Chromatography/Mass Spectroscopy (GCMS) are quantitative tests that can detect many compounds. Coma and Stimulant panels

Can be done in 2 hours

Removal of the Drug (Emesis)

Utilize syrup of Ipecac to Induce emesis to remove unabsorbed drug.

Emesis inducers

Mechanical Apomorphine Syrup of ipecac Contraindications?

Contraindications of Emesis
Emesis is contraindicated in cases of:
Petroleum hydrocarbon solvent chemical pneumonitis Caustic acid or alkali agent (rupture) Seizing Patient Comatose Patient

Removal of the Drug (Gastric Lavage)

Gastric Lavage washing of the stomach. (early tx.) A tube is inserted through the nose or mouth, down the esophagus, and into the stomach. Sometimes a topical anesthetic may be applied to minimize irritation and gagging as the tube is being placed. Stomach contents can be removed using suction immediately or after irrigating w/ fluids through the tube.

Activated Charcoal/Cathartics
Activated Charcoal (AC)
Used to bind compounds and to prevent absorption in the GI tracts. (many drugs) Contraindicated with caustic agents and petroleum distillates due to the lack of absorption of these agents by the charcoal and risk of vomiting associated with the charcoal

Order of use of charcoal and ipecac Cathartics

Promotes rapid passage of poison through the GI tract Counteracts the constipative effects of AC I.E. sorbitol, Mg Citrate, Mg Sulfate

Removal of the Drug (Other)

Alteration of pH of urine to enhance excretion of the drug, useful for salicylates, chlorpropamide, etc (tx) Diuresis often used in conjunction with urine pH alteration

Dilution with water useful in the treatment of skin or eye exposure to harmful agents. ( no neutralizers)
Demulcents soothes mucous membranes and coats the stomach, i.e. milk of magnesia Hemodialysis blood transverses a semipermeable membrane that is bathed in dialysis solution or dialysate. Drugs or toxins diffuse across this membrane. (protein binding)

B. Antidotal Treatments (1. Complexation)

A. Heavy Metals
Chelators (BAL, EDTA) complexes with the metals making them inert

B. Heparin
Protamine (base) binds to acidic heparin to terminate its action and is excreted by glomerular filtration.

C. ToxinsBotulinum Toxin ALD- < 0.5mcg LD50=10ng/kg Most potent poison known, rapidly absorbed and prevents ACH release from nerve terminals Tx: ABCs, lavage, emesis, charcoal,Trivalent anti-toxin Mortality of 70% to 10% with treatment

Complexation (cont)
D. Organophosphates
Pralidoxime is a nucleophillic reagent that ties up the organophosphates and permits its excretion.

E. Cyanide
Binds to cytochrome oxidase, LD50= 2mg/kg Causes death in 1 to 15 minutes at high doses. Chelator is made in the body, methemoglobin (Fe3+)
Give Amyl Nitrites and Na Nitrite with O2 and whole blood to convert hemoglobin to methemoglobin (LD50 increases 5 fold) .

Antidotal Treatments (cont)

2. Enhancement of metabolic conversion to a safer form Example: Cyanide Poisoning and thiosulfate treatment (LD50 increases 3 fold)

CNRhodanese
Sulfur

SCN
Treatment: Give Thiosulfate (Sulfur source)

Antidotal Treatments (cont)

3. Inhibition of metabolic conversion to toxic forms.
A. Ethylene glycol / Methanol ethanol administration prevents Alcohol dehydrogenase (ADH) from converting these substances into toxic forms. (Km Mechanism of Toxicity)

4. Accelerating rate of excretion

Compete with reabsorption (Renal Tubules). I.e. For Sr2+ or Ra2+ radiation give Ca2+; For Br1poisoning give Cl1- to aid in excretion.

5. Competition for Essential receptors

A. Carbon Monoxide
CO is found in cigarette smoke (5%) and auto exhaust (9%). Not in natural gas itself. Commonly used as a means of suicide; over 5000 fatalities a year from CO poisoning. Carboxyhemoglobin is found in very small amounts in non-smokers ~2.5% of the bodys hemoglobin and 7-10% for smoker

TLV 35ppm STEL 200ppm (15min) ALD - 0.1%

CO has a 210x greater affinity for Hb than O2 does

Carbon Monoxide Poisoning

Carboxyhemoblobin Concentration 0-10% 20-30% 30-40% 40-60% Symptoms None Slight headache, exertional dyspnea Throbbing headache, fatigue, dizziness, SOB Severe headache, weakness, dizziness, confusion, dimness of vision (some have a cherry red appearance) Convulsions, coma, Respiratory collapse leading to death

>60%

Treatment: Artificial Respiration with pure O2 to promote displacement of CO

Competition for Essential receptors (cont)

B. Turbocurare/pancuronium
Cause a competition between the poison and Ach at the skeletal muscle endplate. Treatment: Cholinesterase Inhibitors (i.e. Neostigmine and physostigmine) Administration of ACH alone ineffective

C. Coumarin
Anticoagulant that interferes with synthesis of coagulation factors II, VII, IX and X. Treatment: Vitamin K

D. Opiates
Competition at opiate receptors with antagonists like naloxone and naltrexone.

6. Repair or Bypass effect of poison

A. Nitrites/sulfa drugs
Converts hemoglobin into methemoglobin, which reduces the ability of the blood to carry O2. Methylene blue causes a direct reduction of methhemoglobin back to hemoglobin.

B. Digitalis
Toxic effects include GI disturbances, neurologic, disorders and cardiac arrhythmias. Give antidote of Digibind

C. 5-Fluorouracil and 5-fluodeoxyuridine

Antitumor agents used to decrease DNA synthesis. Thymidine is a specific and effective antidote.

7. Blockade of receptors responsible for Toxic Effects

The toxic action and the therapeutic action are mediate by different receptors.
Anticholinesterases
Found in pesticides and chemical warfare agents. increases level of acetylcholine resulting in Cholinomimetic effects Atropine blocks muscarinic receptors to block the effect of the ACHe inhibitors. (anticholinesterases)

Toxicology

Toxidromes
Toxidromes are clinical syndromes that are essential for the successful recognition of poisoning patterns sindroma toksik. The most important toxidromes, clinically, are:
Sympathomimetics Sedative Hypnotics Opiates Anticholinergics Cholinergics Tricyclics (TCAs) Salicylates

Sympathomimetic Toxidrome
CNS Respiration Pupils Other Agitation, hallucinations, paranoia -Mydriasis Seizure, hypertension, tremor, hyperreflexia, hyperthermia Cocaine, amphetamines, PCP

Drugs

Sedative/Hypnotic Toxidrome
CNS Respiration Pupils Coma Decreased Mydriasis

Other

Hypothermia, decrease reflexes, hypotension

Alcohol, barbiturates, benzodiazepines

Drugs

Opioid/Opiate
CNS Respiration Pupils Coma Depression Pinpoint

Other

Hypothermia, hypotension, triad, histamine release

Opiates, morphine, codeine, propoxyphene, oxycodone, hydrocodone

Drugs

Anticholinergic Toxidrome
CNS Respiration Pupils Agitation --Mydriasis

Other

Drugs

Fever, dry skin, flushing, urinary retention (ACS) [Hot, dry, mad, red, blind] Anticholinergics, antidepressants

Cholinergic Toxidrome
CNS Respiration Pupils Coma (not quaternary) --PPP

Other

Drugs

Fasciculation, incontinence, salivation, wheezing, lacrimation, bradycardia (SLUDE) Organophosphates, carbamates, nicotine

Tricyclic Antidepressant Toxidrome

CNS Respiration Pupils Coma ---Mydriasis agitation

Other

Drugs

Arrythmias, convulsions, hypotension, mycoclonus, hyperthermias TCAs, amipramine, imipramine, desipramine

Salicylate Toxidrome
CNS Respiration Pupils Variable up or down Can increase or normal -----

Other

Drugs

Diaphoresis, tinnitis, agitation, alkalosis (early), acidosis (late), fever ASA, aspirin, (salicylates)

2. Base
Source Signs

Specific Poisons Frequently Encountered

Lye, liquid plumber, oven cleaner Swallowing is painful and difficult, vomitus thick and slimy and may contain blood, shock, esophageal strictures, causes progressive damage25% mortality ABCs, demulcents, lots of water, analgesics, steroids, antibiotics, no lavage or emetics

Treatment

Differences between acids and Bases

Acids 1. Immediate pain in buccal cavity and esophagus 2. Less often swallowed than bases No esophageal perforation
Bases 1. Primary cause of chemical burns 2. Rapidly penetrating liquefactive necrosis. 3. Primary effects on esophagus and only 20% on stomach. 4. Esophageal damage severe including perforation.

Specific Poisons Frequently Encountered

3. Opiates
Source Heroin, morphine, oxycodone, hydrocodone
Bilateral miosis (PPP), CNS depression, apnea, decrease in body temperature, heart rate and respiratory depression/arrest. ABCs, Naloxone, gastric lavage and supportive care.

Signs

Treatment

4. Meperidine
Source

Specific Poisons Frequently Encountered

Demerol

Signs

Treatment

Dilated pupils due to antimuscarinic effects, increase in HR, convulsions due to metabolite (nor-meperidine), respiratory depression/arrest, coma. Few fatalities with meperidine (tolerance). ABCs, Gastric lavage (if oral), diazepam for seizures and naloxone for depressive effects (not for tremors)

Specific Poisons Frequently Encountered 5. Atropine

Source Signs Atropine, Deadly Nightshade plant Dry mucous membranes, burning in throat, intense thirst, dilation of pupils, hot dry skin, hyperpyrexia, tachycardia, mania and delirium; death from respiratory failure Hot, dry, mad, red and blind. ABCs, Lavage with 4% tannic acid, pilocarpine or physostigmine, aspirin (antipyretic) and alcohol sponges.

Treatment

Specific Poisons Frequently Encountered 6. Barbiturates

Source
Signs

Suicide, automatism (forget you already took your dose) CNS depression (progressive), drowsiness, shallow rapid respiration, CV collapse, low body temp and death due to respiratory depression
ABCs, Lavage with KmNO4, charcoal, alkaline diuresis (NaHCO3), hemodialysis (long acting barbs)

Treatment

Specific Poisons Frequently Encountered 7. Benzodiazepines

Source
Signs

Treatment

Diazepam (long acting), alprazolam (short acting), triazolam (ultra short) Same as barbiturates, rarely fatal unless taken with ETOH or other CNS depressant due to synergistic CNS depression ABCs, emesis, gastric lavage, antidote: flumazenil short T1/2 may require multiple doses.

Specific Poisons Frequently Encountered

8. Ethanol
Source
Signs

Whisky, wine, beer etc.

Odor on breath, impaired motor coordination, slurred speech, dehydration, gastritis, hypothermia, coma and death due to respiratory depression ABCs, gastric lavage with bicarb, caffeine, hemodialysis (if >500mg%)

Treatment

Specific Poisons Frequently Encountered 9. Neuroleptics

Source Major tranquilizers, antipsychotic agents (phenothiazines, thioxanthenes) Signs Extrapyramidal signs (EPS), hyperactive, tardive dyskinesia, CNS depression, seizures, hypotension, poikilothermia Treatment ABCs, lavage (even hours hours later due to lower gastric motility), Treat arrhythmias as needed and diphenhydramine for EPS.

Specific Poisons Frequently Encountered 10. Kerosene

Source
Signs

Illuminating fuels, paint thinners

Euphoria, burning in the chest, headache, weakness, drowsiness, convulsions, death due to respiratory arrest or ventricular fibrillation ABCs, large amounts of water, olive oil and saline cathartic, antibiotics, corticosteroids to reduce kerosene pneumonitis, no emetics or lavage.

Treatment

Specific Poisons Frequently Encountered 11. Parathion

Source
Signs

Organophosphate insecticide
SLUDE, fixed pin point pupils, loss of muscle coordination, muscle twitching, mental confusion, death due to respiratory arrest. ABCs, atropine, pralidoxine, lavage with 5% NaHCO3, wash affected areas, avoid morphine, barbituates and phenothiazines.

Treatment

Specific Poisons Frequently Encountered 12. Salicylates

Source Signs Aspirin, percodan Deep and rapid breathing, tinnitis, hallucinations, convulsions, resp. alkalosis (adult), metabolic acidosis (child), respiratory and CV collapse Serum level > 400mcg/ml ABCs, emetics, gastric lavage 5% NaHCO3, monitor pH, barbituates or benzos for seizures, hemodialysis if needed.

Treatment

Specific Poisons Frequently Encountered 13. Acetaminophen

Source
Signs

Tylenol, Vicodin, Percocet

After depletion of glutathione, nausea, vomiting, elevated liver enzymes (SGOT, SGPT, bilirubin), hepatic necrosis and death due to hepatic failure. ABCs, emetics, lavage, charcoal, Nacetylcysteine to restore glutathione earlier the better (grapefruit juice), monitor liver enzymes.

Treatment

Acetaminophen Blood level Effects

Plasma levels of > 250mcg/ml at 3-5 hours post ingestion. Rumack Matthew nomogram Probable toxicity

Children (9-10yrs) are less susceptible to the toxic effect of acetaminophen.

Specific Poisons Frequently Encountered 14. Cocaine

Source
Signs

Coca plant, cocaine, crack

CNS stimulation, euphoria, cocaine bugs,halo lights, seizures, hallucinations, cardiac arrhythmias lead to cardiac arrest

Treatment ABCs, charcoal, diazepam (seizures), lidocaine (arrhythmias), no dialysis or lavage.

Forms of cocaine
Crack (type of free base)
Baking soda, hard rock, volatile

Cocaine HCL (salt)

Non-volatile, white crystalline powder

Specific Poisons Frequently Encountered 15. Phencyclidine (PCP)

Source
Signs

Angel dust, Sernyl (old veterinary general anesthetic) Psychosis, sensory analgesia, rotary nystagmus, hypertension, hyperactive reflexes, seizures.
Lock in padded room, diazepam, antipsychotic agent (Haloperidol), cranberry juice (100x increase in excretion)

Treatment

Specific Poisons Frequently Encountered 16. Tricyclic Antidepressants

Source
Signs

Amitryptyline, imipramine, doxepin

Anticholinergic Syndrome (ACS) [dry mouth, mydriasis, hyperpyrexia, increase HR, decreased GI motility] hallucinations, seizures, respiratory depression, cardiac arrhythmias (quinidine-like effect)

Treatment

ABCs, emesis, lavage, physostigmine (till ACS stops), treat arrhythmias (phenytoin, bicarb)

Specific Poisons Frequently Encountered 17. Methaqualone

Source
Signs

Quaalude, ludes (sedative/hypnotic)

Depersonalization, tongue discoloration, dizziness, nausea, hemorrhage, abstinence syndrome ABCs, emesis, lavage, hemodialysis

Treatment

Specific Poisons Frequently 18. Digoxin Encountered

Source Signs Digitalis, digoxin Headache, nausea, vomiting, blurred vision, delirium, slowed pulse, cardiac irregularities, hypokalemia, arrhythmias, ventricular fibrillationlow TI ABCs Dose adjustment, drug withdrawal, lavage, charcoal, emesis, Digibind, K+ supplement, treat arrhythmias (lidocaine, phenytoin, propranolol)

Treatment

Specific Poisons Frequently Encountered 19. Phenytoin

Source
Signs

Dilantin
Nystagmus, ataxia, drowsiness, seizuresdeath is rare but is usually due to ventricular fibrillation and cardiac arrest. Toxicity >25mcg/ml ABCs, emesis (if conscious), lavage, charcoal, cathartics, discontinue phenytoin

Treatment

Specific Poisons Frequently Encountered 20. Theophylline

Source
Signs

Aminophylline
CNS stimulation, hyperreflexia, cardiac arrhythmia, convulsions, death is due to respiratory failure. Toxic plasma level >20mcg/ml. ABCs, discontinue drug, charcoal, emesis, fluids and anticonvulsants (diazepam) as needed.

Treatment

21. Dioxin (2,3,7,8 TCDD)

Source Herbicides, cigarette smoke, smoke from burning trash and debris Chloracne (small yellow comedones) mainly on the face can last 30 years, hepatomegaly, fatigue, irritability, blurred vision, porphyria cutanea tarda (slate gray skin pigmentation), limited systemic effects, Death?? ABCs, alkaline diuresis, If recent ingestion: [emesis, lavage, charcoal, cathartic], mainly supportive care

Signs

Treatment

Dioxin Poisoning

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