TOXICOLOGY Toxicology is the study of substances toxic to the body - PowerPoint Presentation

Slide1

TOXICOLOGY

Slide2

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

Slide3

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

Slide4

Routes of exposure: ingestion, inhalation and transdermal absorption

Slide5

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

Slide6

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

Slide7

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 (> 50mg/

dL

blood alcohol)

Slide8

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

Slide9

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

Slide10

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

Slide11

Preferred method: enzymatic using alcohol dehydrogenase reagent

Common laboratory results: elevated GGT, AST, AST/ALT ration (>2.0), HDL and MCV

Fatal dose: 300-400 mL of pure alcohol consumed in less than one hour

Peak blood level: within an hour after intake of alcohol

Toxic blood level: > 400 mg/

dL

> 500 mg/

dL

(for hemodialysis)

Slide12

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

Slide13

Screening test: computation of

osmolal

gap

Preferred method: GC-MS

Fatal dose: 60-250 mL

Toxic blood level: > 50 mg/

dL

Slide14

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

Slide15

Antidote: activated charcoal

Fatal dose: 250 mL

Slide16

4. Ethylene glycol (1,2-ethanediol)

It is a common constituent of hydraulic fluid and 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

Slide17

Major metabolite: glycolic acid (cause of acute toxicity and death)

Preferred method: HPLC

Fatal dose: 100 grams

Slide18

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

Slide19

Carbon Monoxide (CO)

It binds with

heme

proteins (cytochromes, hemoglobin, and myoglobin) – binding of CO to cytochrome A3 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

Slide20

It has higher affinity for hemoglobin than does oxygen (200x 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)

Slide21

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)

Slide22

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

Slide23

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 A3 – inhibition of cellular respiration leads to metabolic acidosis due to increased lactic concentration in the blood

Slide24

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/mL

Slide25

D. Metals

All metals can be toxic if ingested in large quantities and absorbed in their ionized forms

Slide26

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

Slide27

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)

Slide28

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 multi-organ involvement

Acute fatal dosage: 120 mg (arsenic trioxide) and 30 ppm (arsenic gas)

Slide29

Antidote: British anti-lewisite (BAL) – for “arsenic rescue” of affected cells

Method:

Reinsch

test, atomic

absoprtion

spectrophotometry

Slide30

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

Slide31

It may also accumulate in renal tubules causing tubular damage

Toxic renal indicator: (+) GGT in urine sample

Slide32

3. Lead

Is a potent enzyme inhibitor – it blocks delta

aminolevulinic

acid (ALA)

synthetase

, pyrimidine-5’-nucleotidase and Na-K-dependent ATPase

Source: paints and gasoline

Mode of acquisition: ingestion or inhalation

Susceptible areas: central and peripheral nervous system

Slide33

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/

dL

Toxic blood level: > 70 µg/

dL

(definitive lead poisoning)

Requires chelation therapy (children): < 25 µg/

dL

Slide34

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

Slide35

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)

Slide36

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

Slide37

- 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

Slide38

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

Slide39

5. Anodic stripping voltammetry

Slide40

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

Slide41

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

Slide42

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/

dL

Significant exposure: > 50 µg/

dL

(whole blood)

Slide43

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

Slide44

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)

Slide45

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

Slide46

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

Slide47

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

Slide48

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)

Slide49

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

Slide50

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

Slide51

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

Slide52

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

Slide53

Cannabinoids

Urinary metabolite: 11-nor-deltatetrahydrocannabinol (THC-COOH)

Physiologic effects: reddening of the conjunctiva and increased pulse rate

Toxic effects: paranoia, disorientation, altered physical senses and

bronchopulmonary disorders