TOXICOLOGY Toxicology is the study of substances toxic
TOXICOLOGY
� Toxicology is the study of substances toxic to the body � Absorption of toxins in the GIT is by passive diffusion – this process requires that the substance cross cellular barriers � Toxins that are not absorbed from the GIT do not produce systemic effects but may produce local effects – diarrhea, bleeding and malabsorption of nutrients
� � In cases of drug overdose, CBC, serum electrolytes, BUN, glucose, urinalysis and blood gas must be determined Common substances causing acute toxicity: alcohol, acetaminophen, salicylate, abuse substance and carbon monoxide
� Routes of exposure: ingestion, inhalation and transdermal absorption
Terminologies � � � Acute toxicity – single, short-term exposure to a substance Chronic toxicity – repeated exposure for extended period of time TD 50 – is the dose that would be predicted to produce a toxic response in 50% of the population
Terminologies � � LD 50 – is the dose that would predict death in 50% of the population ED 50 – is the dose that would be predicted to be effective or have a therapeutic benefit in 50% of the population
I. Toxic Agents � � A. Alcohol - are common CNS depressants - cause disorientation, euphoria, confusion, and may progress to unconsciousness, paralysis and even death Symptoms of alcohol intoxication begin when the concentration is > 0. 05% w/v (> 50 mg/d. L blood alcohol)
1. Ethanol (grain alcohol) � � Is the most common abused drug; a CNS depressant It causes diuresis by inhibiting ADH It is readily absorbed in the GIT and diffuses easily in tissues Ethanol abuse causes acidosis through accumulation of ketones and lactate and also through direct generation of hydrogen ions as alcohol is oxidized; it also adds osmolality to blood
� � � Symptoms of intoxication: blurred vision, incoordination, slurred speech and coma; “hangover symptoms” are due to the effects of acetaldehyde Antidote for chronic intoxication: diazepam (for alcoholic mania) Specimen precaution: specimen must be capped at all times to avoid evaporation of alcohol; prior to blood collection, alcohol-free skin cleanser must be used instead of isopropanol
� � � Specimen: serum (capillary and arterial blood samples are preferred, it reflects the concentration of ethanol in the brain) Major metabolic pathways: conversion of ethanol to acetaldehyde and acetyl coenzyme A by hepatic alcohol dehydrogenase Methods for testing: enzymatic, gas-liquid chromatography and electrochemical oxidation
� � � Preferred method: enzymatic using alcohol dehydrogenase reagent Common laboratory results: elevated GGT, AST/ALT ration (>2. 0), HDL and MCV Fatal dose: 300 -400 m. L of pure alcohol consumed in less than one hour Peak blood level: within an hour after intake of alcohol Toxic blood level: > 400 mg/d. L > 500 mg/d. L (for hemodialysis)
2. Methanol (wood alcohol) � � � Is a commonly used solvent and a contaminant of homemade liquors It is converted first to formaldehyde, then finally to formic acid in the liver by alcohol dehydrogenase Symptoms of intoxication: frank blindess (ocular toxicity) and metabolic acidosis
� � Screening test: computation of osmolal gap Preferred method: GC-MS Fatal dose: 60 -250 m. L Toxic blood level: > 50 mg/d. L
3. Isopropanol (rubbing alcohol) � � � It is rapidly absorbed by the GIT It is metabolized by hepatic alcohol dehydrogenase to acetone Symptoms of intoxication: CNS depression and hypertension Indication of toxicity: elevated levels of acetone in the blood and urine Preferred method: gas chromatography
� � Antidote: activated charcoal Fatal dose: 250 m. L
4. Ethylene glycol (1, 2 ethanediol) � � It is a common constituent of hydraulic fluid antifreeze It is converted to oxalic acid and glycolic acid (toxic products) by hepatic alcohol dehydrogenase. Indication of toxicity: deposition of calcium oxalate crystals in renal tubules Mode of treatment: inhibit the action of acohol dehydrogenase
� � � Major metabolite: glycolic acid (cause of acute toxicity and death) Preferred method: HPLC Fatal dose: 100 grams
B. Carbon Monoxide (CO) � � It is a colorless, odorless, tasteless gas; very toxic substance It is produced by incomplete combustion of carbon-containing substances like gasoline engines, organic materials in fire and cigarette smoke
Carbon Monoxide (CO) � It binds with heme proteins (cytochromes, hemoglobin, and myoglobin) – binding of CO to cytochrome A 3 results to inhibition of cellular respiration and electron transport whereas binding to hemoglobin and myoglobin reduces oxygen supply to cardiac and skeletal muscles, and direct damage to the muscles, respectively
� � � It has higher affinity for hemoglobin than does oxygen (200 x faster than oxygen) – impairs oxygen transport by binding to hemoglobin producing carboxyhemoglobin It stimulates production of nitrous oxide resulting to hypotension and neurologic changes Major toxic effect: diminish available oxygen to the tissues or tissue hypoxia due to inhibition of the oxyhemoglobin saturation (shift to the left of the oxygen dissociation curve)
� � � Toxic level: 20% CO Susceptible organs: brain and heart Indication of acute toxicity: “cherry-red” color of the face Sample for testing: EDTA whole blood Definite method for testing: cooximetry (carboxyhemoglobin measurement)
C. Cyanide � � It can exist as a solid, liquid, gas or in solution It is a super toxic substance (fast-acting toxin) and death may occur less than an hour It is a component of insecticides and rodenticides; common suicidal agent It is also a pyrolysis product – burning of plastics
� � It expresses its toxicity by binding to iron (ferric and ferrous forms) containing substances like hemoglobin and cytochrome oxidase – resulting to tissue and cellular hypoxia It inhibits cellular respiration, electron transport and ATP formation by preventing reoxidation of cytochrome A 3 – inhibition of cellular respiration leads to metabolic acidosis due to increased lactic concentration in the blood
� � � Toxic effect: inhibition of the electron transport chain and cell death Indication of toxicity: “odor of bitter almonds” breath and altered mental status Antidote: sodium thiosulfate, amyl and sodium nitrite Toxic symptoms: tachypnea, convulsions and coma Toxic levels: > 2µg/m. L
D. Metals � All metals can be toxic if ingested in large quantities and absorbed in their ionized forms
1. Arsenic � � Is a component of ant poisons, rodenticides, paints and alloys It is a common homicide or suicide agent; common agent of heavy metal poisoning It inhibits sulfhydryl enzymes throughout the body; it crosses the placenta It expresses its toxicity by high affinity binding to the thiol groups in proteins
� � � The used of hair and nails (“Mees lines”) as specimens are important in the evaluation of long-term (chronic) exposure Blood and urine specimens are for assessment of short-term (acute) exposure Toxic forms: sodium arsenate, copper arsenite, carbarsone, tryparasamide and arsine gas (most toxic)
� � Symptoms of intoxication: hyperpigmentation, dryness of the mouth, difficulty in swallowing, anorexia and bloody diarrhea Indication of toxicity: “odor of garlic” breath and metallic taste Toxic effects: intravascular hemolysis, hemoglobinemia, nephrotoxicity, and multiorgan involvement Acute fatal dosage: 120 mg (arsenic trioxide) and 30 ppm (arsenic gas)
� � Antidote: British anti-lewisite (BAL) – for “arsenic rescue” of affected cells Method: Reinsch test, atomic absoprtion spectrophotometry
2. Cadmium � � It is utilized in electroplating and galvanizing It is a significant environmental pollutant – pigment in paints and plastics Poisoning can result from ingestion of acidic foods stored or prepared in metal containers made up of cadmium Toxicity may result to destruction of type 1 epithelial cells in the lung and decreased resistance to bacterial infections
� � It may also accumulate in renal tubules causing tubular damage Toxic renal indicator: (+) GGT in urine sample
3. Lead � � Is a potent enzyme inhibitor – it blocks delta aminolevulinic acid (ALA) synthetase, pyrimidine-5’-nucleotidase and Na-Kdependent ATPase Source: paints and gasoline Mode of acquisition: ingestion or inhalation Susceptible areas: central and peripheral nervous system
� � � Indications of toxicity: urinary aminolevulinic acid, free RBC proporphyrin and presence of basophilic stippling in RBC Toxic dose: > 0. 5 mg/day Fatal dose: 0. 5 g CDC cutoff level in children: < 10 µg/d. L Toxic blood level: > 70 µg/d. L (definitive lead poisoning) Requires chelation therapy (children): < 25 µg/d. L
Lead chelators: EDTA and dimercaptosuccininc acid (DMA) � Toxic effects: � - It interferes with vitamin D and heme synthesis pathways by inhibiting delta aminolevulinic acid (ALA) synthetase, producing anemia � - it inhibits pyrimidine-5’-nucleotidase and Na-K-dependent ATPase resulting to diminished integrity of the red cell membrane �
� � � It combines with the matrix of bone and persists in this area for a long time ) half-life is 32 years) Low-level exposure may cause behavioral changes – hyperactivity and attentional deficit disorder, and also affects intelligence quotient scores (decrease score). It has a characteristic “wrist drop or foot drop” manifestation (peripheral neuropathy)
� � Toxic effects: encephalopathy, nephrosis, anorexia, peripheral neuropathy, birth defects, anemia, behavioral changes and compromised immunity Methods: Samples: whole blood, urine and hair - whole blood is the sample of choice for quantitative testing because lead is bound to the red blood cells, and it will produce the greatest sensitivity
� � � - urine is used for assessment of recent lead exposure Testing for the diagnosis of lead poisoning should include analysis of morning urine for delta ALA Serum or plasma should not be used because lead is rapidly eliminated from plasma
� � � � Laboratory tests: 1. Screening tests A. Zinc protoporphyrin test (Fluometric test) B. ALAD (δ-ALA dehydrase test) – sensitive method, decreased urine ALAD activity in lead poisoning 2. In-vivo x-ray fluorescence of bones – to determine lead burden 3. Atomic absorption spectrophotometry 4. Inductively coupled plasma emission spectrophotometry
� 5. Anodic stripping voltammetry
4. Mercury � � � It binds with sulfhydryl proteins It is a potent enzyme inhibitor – it inhibits catecholamine-o-methyltransferase, an enzyme essential in the metabolism of catecholamines It has the ability to “amalgamate” – mix or merge with other substances
� � Forms of mercury: elemental or metallic mercury, mercurous, mercuric and alkyl mercury Modes of acquisition: inhalation, skin absorption and ingestion Symptoms of toxicity: hypertension, tachycardia and sweating – “cardinal signs” of pheochromocytoma or mimics that adrenal gland disorder General toxic effect: organ dysfunction – lungs, kidney and CNS
� � � � Major toxic effect of elemental mercury: pink disease (acrodynia) and erethism Major toxic effect of alkyl mercury: congenital Minimata disease Major route of excretion: through the bile (part of the bile fluid) Samples: whole blood and 24 hour-urine Method: Reinsch test Reference level: < 10 µg/d. L Significant exposure: > 50 µg/d. L (whole blood)
� � Exposure and route of absorption: - small drops f mercury and benchtops and floors can poison the environment in a poorly ventilated room If inhaled or absorbed through the skin it can pass through the blood-brain barrier, and can accumulate in the CNS The presence of this substance in blood may result to loss of glomerular integrity
II. Drugs of Abuse � � Almost all drugs of abuse are basic drugs (amine derivatives) which contain benzene rings; barbiturates are acidic drugs Many of the abused drugs act directly on dopaminergic neurotransmitter systems, especially the limbic system (smell brain)
� � A positive drug screening test cannot differentiate casual user from chronic or habitual user, likewise detect the time frame of using the drug or dose of the drug taken Designer drugs – are modified forms of established drugs of abuse
1. Amphetamines � � � Is therapeutically used for the treatment of narcolepsy and attentional deficit disorder It increases mental alertness and physical capacity, and has anorectic property It is structurally related to dopamine and catecholamines
Amphetamines � � It causes the release (together with cocaine) of dopamine from the brain leading to a “pleasant feeling” (so called “high”) among users 3, 4 -methylenedioxymethamphetamine (MDMA or ‘ecstasy’), a derivative of methamphetamine is a popular recreational abused drug (designer drug); has psychedelic effects
Amphetamines � � � Examples: amphetamine, methamphetamine and methylphenidate (Ritalin, for treatment of hyperactive children) Amphetamine-like compounds: ephedrine, pseudoephedrine and phenylpropanolamine Cause of false-positive reactions: presence of antihistamine (diphenhydramine)
Amphetamines � � � Sign of acute intoxication: hyperpyrexia Acute psychotic syndromes: auditory and visual hallucinations, suicidal tendency and paranoia Toxic effects: palpitation, hypertension, cardiac arrhythmias, convulsions, pancytopenia, mental impairment and teeth grinding
2. Annabolic steroids � � � Are chemically associated to the male hormone testosterone (dihydrotestosterone and testosterone) It improves athletic performance by increasing muscle mass Toxic effects: chronic hepatitis, atherosclerosis, abnormal platelet aggregation and cardiomegaly
3. Cannabinoids � � � Naturally occuring cannabinoids: marijuana and hashish Tetrahydrocannabinol (THC), is the most potent component or the psychoactive substance of marijuana THC a lipophilic substance, distributes in the adipose tissue; it easily enters the brain; it induces a sense of well-being and euphoria; it is a hallucinogen
Cannabinoids � � � THC is also associated with impairment of memory and intellectual functions After a single use; THC-COOH can be detected in urine for 3 -5 days; up to 4 weeks for chronic user Principal psychoactive agent: delta-9 tetrahydrocannabinol
Cannabinoids � � � Urinary metabolite: 11 -nordeltatetrahydrocannabinol (THC-COOH) Physiologic effects: reddening of the conjunctiva and increased pulse rate Toxic effects: paranoia, disorientation, altered physical senses and bronchopulmonary disorders
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