Introduction to Introduction to ToxicologyToxicology

What is What is toxicology?toxicology?• Is the science of poisons, including not only their physical and chemical effects but also their detection and antidotes

• The branch of pharmacology that deals with the nature and effects and treatments of poisons (Xenobiotics)

• Is the study of the adverse effects of chemicals on living organisms.

•It is the study of symptoms, mechanisms, treatments and detection of poisoning, especially the poisoning of people.

The science of toxicology, or the science of poisons, is the study of the harmful effects of chemicals on living organisms.

Scientists who study these harmful

effects and assess the probability of their occurrence are called toxicologists.

Toxicology encompasses the study of the adverse effects of chemicals on living organisms.

Toxicology assesses the probability of hazards caused by such effects.

Toxicology estimates the results of these effects on animal and human populations.

Toxicity – is the ability of the substance to produce injury upon reaching a susceptible site in/on the body

Cont…Cont…• Toxicological studies consider

the cause, circumstances, effects and limits of safety of unintended harmful effects of food, food additives, drugs, household and industrial products or wastes.

• Toxicological studies deal with adverse effects ranging from acute to long-term.

• The important science of toxicology has direct relevance to human health, the environment and major sectors of the economy.  

• The scientific community, governments, industry and the public all require information on the effects of potentially hazardous substances to balance the benefits which society receives against the hazards that may occur from their use and misuse.

The term “toxicity” is used to describe the nature of adverse effects produced and the conditions necessary for their production.

Four Major Disciplines of Four Major Disciplines of ToxicologyToxicology

MECHANISTIC◦Elucidate the cellular

and biochemical effects of toxins.

◦Provides basis of therapy designs and develop tests for assessment

DESCRIPTIVE◦Uses results from

animal experiments to predict the level of exposure harmful to humans (risk assessment)

Four Major Disciplines of Four Major Disciplines of ToxicologyToxicology

FORENSIC◦Concerned with

medicolegal consequences of toxin exposures

◦To establish and validate analytical performance of methods used as evidence for legal purposes

CLINICAL◦Study the

interrelationships between toxin exposure and disease states

◦Both diagnostics and interventions

Sub-disciplines of ToxicologySub-disciplines of Toxicology

• Economic toxicology– Concerned with

chemicals used in drugs, food additives, pesticides and cosmetics

• Forensic toxicology– Involves the medical and

legal aspects of poisonous materials when death or severe injury is the result of their use

– Helps to establish cause and effect relationships between exposure to a drug or chemical and the toxic or lethal effects that result.

• Clinical toxicology– Is concerned with

diseases and illnesses associated with short term or long term exposure to toxic chemicals.

The term “toxicant” refers to toxic substances that are produced by or are a by product of human-made activities.

Cont…Cont…

Environmental toxicology◦ Evaluates the synergistic

effects of chemicals in the environment

◦ Studies chemicals that are contaminants of food, water, soil, or the air.

– Deals with toxic substances that enter the waterways, such as lakes, streams, rivers and oceans.

Fact: Most common problems include water-borne bacteria and viruses, waste heat from electrical plants, radioactive wastes, sewage, and industrial pollution.

The term “toxin” refers to toxic substances that are produced naturally.

Cont…Cont…

Industrial (Occupational) toxicology◦Evaluates the effects

of pollutants in the working environment

◦Protects workers from toxic substances and makes their work environment safe.

Fact: Occupational diseases caused by industrial chemicals account for an estimated 50,000 to 70,000 deaths and 350,000 new cases of illness each year in the United States.

General functions of a General functions of a toxicologisttoxicologist

• Gathers data about poisons

• Identifies the substance causing poisoning

• Quantifies the amount of poisons

• Interprets laboratory results

• Controls the marketing of the poisons

• Determines whether the substance is hazardous or not

• Provides antidote for every causative agent

• Gives advice about treatment

• Monitors certain chemical substance in patients

Some individuals who contributed Some individuals who contributed to the field of toxicologyto the field of toxicology

• Moses Maimonides (1135-1204)

• A famous Jewish Philosopher, Maimonides was born in Spain and he was educated at the University of Fes.

• Among other things, Maimonides wrote the famous Treatise on Poisons and Their Antidotes.

Cont…Cont…

Paracelsus (1493-1541)

Famous for his words "the dose makes the poison“

“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”

Cont…Cont…

• Francois Magendie (1783-1855)

• Born in France, Magendie researched the different motor functions of the body in relation to the spine, as well as nerves within it.

• In addition, he researched the effects of morphine, quinine, strychnine, and a multitude of alkaloids.

• Noted as the father of experimental pharmacology.

Cont…Cont…

• Mathieu Joseph Bonaventure Orfila /Mateu Josep Bonaventura Orfila i Rotger) (April 24, 1787 – March 12, 1853) was a Spanish-born French toxicologist and chemist, the founder of the science of toxicology.

Cont…Cont…

Emil Fischer 1852-1919

Emil Fischer synthesized caffeine and received the nobel prize in chemistry in 1902.

4 bases in in classifying poisons4 bases in in classifying poisons

A. Bases on its analysisB. Based on the organ or system

considered the target site of the effect of the chemical

C. Mechanism of toxicityD. Manner of exposure

Classification of Toxic AgentsClassification of Toxic Agents

Heavy MetalsSolvents and VaporsRadiation and Radioactive MaterialsDioxin/FuransPesticidesPlant ToxinsAnimal Toxins

Characteristics of exposureCharacteristics of exposure

Characteristics and condition of exposure

Route of administration

Time and frequency of exposure

Dose delivered

Physical and chemical form of the substance

1. Acute exposure – an exposure in which the dose is delivered in a single event and the absorption process is rapid

1. Chronic exposure – the dose is delivered at some frequency over a period of time

Measurement of toxicity related to:

Types of exposure

Routes of AdministrationRoutes of Administration

A. Pulmonary - administration via the lungs; the duration of exposure would ordinarily long (inhalation of toxic gases)

B. GIT or oral – administration is through the mouth in which the result is delayed due to the absorption process and distribution of the toxic substances to its active sites will have the bearing on the effects observed

Cont…Cont…

C. Parenteral routes◦Intravenous◦Subcutaneous ◦Intramuscular◦Intradermal◦Intraperitoneal◦Intraspinal

D. Topical

Spectrum of Spectrum of toxic effectstoxic effects

Acute effect• Effects that occur or

develop rapidly after a single administration

Chronic effect• Those that are

manifested after the elapse of some time

1. Local effects– Effects that occur at

the site of the first contact between the biologic system and the toxicant

2. Systemic effects– Are effects that

require absorption and distribution of the toxicant to a site distant from its entry point effects are produced (frequently involved is the CNS)

Types of effects based on locus of action

Classification of toxicants based Classification of toxicants based on their relative toxicitieson their relative toxicities

Toxicity ratings Commonly used terms

Probable human lethal dose LD

6 Super-toxic < 5mg/Kg (a taste <7gtts)

5 Extremely toxic 5-50mg/Kg (bet 7gtts – 1tsp)

4 Very toxic 50-500mg/Kg (bet 1tsp – 1oz)

3 Moderately toxic 0.5-5g/Kg (bet 1oz – 1pint)

2 Slightly toxic 5-15g/Kg (bet 1 pint – 1 quart)

1 Practically non-toxic 15g/kg (>1 quart)

Cases of poisoning Cases of poisoning generally fall into 3 generally fall into 3 categoriescategories

1. Exposure to a known poison

2. Exposure to an unknown substance which may be a poison

3. Disease of undetermined etiology in which poisoning must be considered as part of the differential diagnosis

1. Complete history

2. Complete physical examination

3. Appropriate laboratory examination

Diagnostic workup of a patient who may be a

victim of poisoning

General measures in the General measures in the management of poisoningmanagement of poisoning

• Poisoning–Defined as an overdose of drugs, medicaments,

chemicals and biological substances

• Self-Poisoning/Parasuicide– Used to refer to the deliberate ingestion of more than the

therapeutic dose of a drug or a substance not intended for consumption, usually by an adult in a moment of distress; dose who die are classed as suicides rather then parasuicides regardless of whether or not this was the intended outcome

• Accidental Poisoning– Non-intentional ingestion overdose or exposure to drugs,

medicaments or poisonous substances

The general approach to the The general approach to the poisoning patient may be divided poisoning patient may be divided into:into:

I. Emergency stabilization

II. Clinical EvaluationIII. Elimination of the

poisonIV. Excretion of

absorbed substances

V. Administration of antidotes

VI. Supportive therapy and observation

VII. Disposition

Emergency StabilizationEmergency Stabilization

ABCDE◦Airway obstruction◦Breathing difficulties◦Circulatory inadequacies◦Drug-induced CNS depression◦Electrolyte or metabolic abnormalities

The greatest contributor to death from drug overdose is loss of airway protective reflexes with subsequent airway protection by flaccid

tongue, pulmonary aspiration of gastric contents or respiratory arrest.

Techniques to clear airwayTechniques to clear airway

SNIFFING POSITION◦The neck is flexed forward and the head

extended◦Should not be used if there is any suspicion of

neck injury

Cont… Cont…

1. The fingers of one hand are placed under the mandible, which is gently lifted upward to bring the chin anterior.

2. The thumb of the same hand depresses the lower lip to open the mouth.

3. The thumb may also be laced behind the lower incisors and, simultaneously, the chin is gently lifted.

CHIN-LIFT

Cont…Cont…

JAW THRUST◦Technique to open the

airway by placing the fingers behind the angle of the jaw and bringing the jaw forward; used when a patient may have a cervical spine injury

◦To create forward movement of the tongue without flexing or extending the neck

Cont…Cont…

HEAD-DOWN LEFT SIDED POSITION◦Allows the tongue to fall forward and secretions

or vomitus to drain out of the mouth

IntubationIntubation OROTRACHEALIndications1. Inadequate oxygenation

(decreased arterial PO2, etc.) that is not corrected by supplemental oxygen supplied by mask or nasal prongs.

2. Inadequate ventilation (increased arterial PCO2).

3. Need to control and remove pulmonary secretions (bronchial toilet).

4. Need to provide airway protection in an obtunded patient or a patient with a depressed gag reflex (for example during a general anesthesia).

Contraindications1. Severe airway trauma or

obstruction that does not permit safe passage of an endotracheal tube. Emergency cricothyrotomy is indicated in such cases.

2. Cervical spine injury, in which the need for complete immobilization of the cervical spine makes endotracheal intubation difficult.

Cont…Cont…Preparing the

Proceduremnemonic SALTSuction. This is extremely

important. Often patients will have material in the pharynx, making visualization of the vocal cords difficult. Pulmonary Aspiration should be avoided.

Airway. the oral airway is a device that lifts the tongue off the posterior pharynx, often making it easier to mask ventilate a patient.

The inability to ventilate a patient is bad. Also a source of O2 with a delivery mechanism (ambu-bag and mask) must be available.

Laryngoscope. This lighted tool is vital to placing an endotracheal tube.

Tube. Endotracheal tubes come in many sizes. In the average adult a size 7.0 or 8.0 oral endotracheal tube will work just fine.

Cont… Orotracheal IntubationCont… Orotracheal Intubation

Advantages1.Performed under

direct vision2.Insignificant risk of

bleeding3.Patient need not be

breathing spontaneously

4.Higher success rate

Disadvantages 1.Frequently requires

neuromuscular paralysis

2.Requires neck manipulation

Cont… IntubationCont… Intubation

NASOTRACHEAL◦where a tube is

passed through the nose, larynx, vocal cords, and trachea

◦BLIND technique

Cont…Cont…

Advantages◦ May be performed

in a conscious patient without requiring neuromuscular paralysis

◦ Better tolerated once placed

Disadvantages◦Perforation of the

nasal mucosa with epistaxis

◦Stimulation of vomiting in an obtunded patient

◦Patient must be breathing spontaneously

◦Difficult in infants anatomically because of anterior epiglottis

Clinical EvaluationClinical Evaluation

A. History B. Physical examination

1. Time of exposure2. Mode of exposure3. Intake of other

substances4. Circumstances prior

to poisoning5. Current medication6. Past medical history7. Any home remedy

taken

HYPOTHERMIA◦ A condition in which the

patient has a rectal temperature of < 30oC

◦ May be due to overdose of : Alcohol CO Opioids Sedative-hypnotics Barbiturates

Cont… Physical ExaminationCont… Physical Examination

HYPERTHERMIA◦A condition when the

rectal temperature is > 40oC

◦May be due to overdose of: Antihistamines Amphetamines Cocaine Anticholinergic Isoniazid

HYPOGLYCEMIA◦An abnormally

diminished content of glucose in the blood

◦A common finding in alcohol intoxication and salicylates toxicity

HYPOCALCEMIA – reduction of blood calcium below normal; commonly seen in

dancing firecrackers, jatropa seed ingestion, complications of severe animal

bites and stings

Physical ExaminationPhysical Examination

1. Evaluate general status of patient

2. Examine patient skinTachycardia – CO, HCN, organophosphates, ethanol

Bradycardia – digitalisHypertension – cocaine,

caffeine, amphetamines, nicotine

Hypotension – antidepressant, heroine, opiates, sedative-hypnotics

Needle tracks, bruises and lacerations

Cutaneous bullae – Barbiturates and CO poisoning

Diaphoresis - organophosphates, salicylates and amphetamine toxicity

Jaundice – acetaminophen/hepatotoxic agents

Dry skin and hyperpyrexia - atropine and anticholinergic agents

Flushing – alcohol, CN and CO

Cont… Cont…

3. Patients breath/odor 4. Auscultate

Bitter almonds – CNFruity – Diabetic

ketoacidosisRotten eggs – Sulfur

dioxide, hydrogen sulfide

Garlic – organophosphates, arsenic

For the presence of rales

Pulmonary edema

Cont…Cont…

5. Listen to patient’s heart6. Check the abdomen7. Do a complete neurologic examination

◦Using the Glasgow Coma Scale

◦ The scale comprises three tests: eye, verbal and motor responses. The three values separately as well as their sum are considered. The lowest possible GCS (the sum) is 3 (deep coma or death), while the highest is 15 (fully awake person).

Glasgow Coma Scale

1 2 3 4 5 6

EyesDoes not open eyes

Opens eyes in response to painful stimuli

Opens eyes in response to voice

Opens eyes spontaneously

N/A N/A

VerbalMakes no sounds

Incomprehensible sounds

Utters inappropriate words

Confused, disoriented

Oriented, converses normally

N/A

MotorMakes no movements

Extension to painful stimuli

Abnormal flexion to painful stimuli

Flexion / Withdrawal to painful stimuli

Localizes painful stimuli

Obeys Commands

Elimination of PoisonsElimination of PoisonsA. External decontamination

◦ Discard patient’s clothing◦ Bathe or shower the patient◦ Copious irrigation with water in eye

contaminationB. Empty the stomach – emesis and gastric

lavageC. Limit Gastrointestinal Absorption – activated

charcoal lavageD. Dialysis and HemoperfusionE. Whole bowel irrigation

Differences in response to toxicant in a population due to:

Genetics; Gender; Age; Nutritional Status; Health Condition; Previous or concurrent exposure to other

substances

EXCRETION: Absorption, EXCRETION: Absorption, Distribution and MetabolismDistribution and Metabolism

Absorption Distribution

Intravenous – 100% bioavailable (no limiting factors)

Inhalation – must penetrate alveolar sacs of lungs, then into the capillary bed

Ingestion – requires absorption through the GIT

Dermal/topical – requires absorption through the skin

Translocate throughout the body

Blood carries to and from its sites of action

Stored/deposited (adipose tissues, bones – lead and fluoride

Organs biotransformation

Elimination

Cont… Cont… Metabolism

ExcretionParent compound are modified by the organism via the enzymes

Primary objective is to make chemical agents more soluble to water for easier excretion

Urinary – water soluble products are filtered out of the blood

Exhalation – volatile compounds

Biliary excretion via fecal excretion – liver biotransformed bile small intestine fecesBiotransformation

occur: liver; lungs; kidneys and intestines

GASESGASESCarbon monoxideHydrogen cyanide

Formaldehyde

- colorless, tasteless, odorless and non-irritating gas- a by-product of incomplete combustion

- 0.1ppm is the average concentration of CO in the atmosphere- in heavy traffic the concentration may exceed 100ppm

- the brain and heart are the organs mostly affected

CARBON MONOXIDECARBON MONOXIDE

Sources Mechanism of toxicitySmoke inhalation in firesAutomobile exhaust

fumesFaulty or poorly

ventilated charcoal. Kerosene and gas stoves

Cigarette smokeMethylene chloride – a

solvent in paint removers in metabolized to CO

CO binds to hemoglobin with an affinity 210 – 250 times that of O2 reduced oxyhemoglobin saturation and decreased blood O2-carrying capacity

-Inhibits cytochrome oxidase, further disrupting cellular function

- known to bind to myoglobin impaired myocardial contractility

Net effects

1. Tissue hypoxia2. Anaerobic

metabolism3. Lactic acidosis

Once CO is discontinued, dissociation of the hemoglobin-CO complex occurs and CO is excreted through the lungs

At room air the CO half-life is 4 to 6 hours

Half-life decreases to 40 to 80 minutes when breathing 100% O2

Half-life is 15 to 30 mins with hyperbaric O2 therapy

-A normal non-smoking adult has COHb level of < 1% saturation- Smokers will exhibit 5 – 10% saturation depending on the habit

Principal Signs of CO intoxication: Principal Signs of CO intoxication: HYPOXIAHYPOXIA

1. Psychomotor impairment2. Headache and tightness in the temporal

area3. Confusion and loss of visual acuity4. Tachycardia, tachypnea, syncope and

coma5. Deep coma, convulsion, shock and

respiratory failure

Estimated CO concentration

COHb % Symptoms

Less than 35ppm (cigarette smoking

5 None, or mild headache

0.005% (50ppm) 10 Slight headache, dyspnea on vigorous

exertion

0.01% (100ppm) 20 Throbbing headache, dyspnea with

moderate exertion

0.02% (200ppm) 30 Severe headache, irritability, fatigue, dimness of vision

0.03%-0.05% (300-500ppm)

40-50 Headache, tachycardia,

confusion, lethargy, collapse

0.08%-0.12% (800-1200ppm)

60-70 Coma, convulsions

0.19% (1900ppm) 80 Rapidly fatal

Toxic dose Diagnosis

Permissible exposure limit (PEL) is 35ppm as an 8-hour time weighted average

Immediate dangerous to life or death (IDLH) is 1500ppm or 0.15%

Several exposure to 1000ppm or 0.1% may result in 50% saturation of COHb and fatal poisoning

History of exposure (locked garage

Cherry red skin coloration or bright red venous blood

Measurement of COHb

Treatment Decontamination

Emergency and supportive measures

Specific drug and antidote: Administer OXYGEN in the highest possible concentration

Remove patient from exposure and give supplemental O2

Rescuers should wear self-contained breathing apparatus

Enhance Elimination: HYPERBARIC OXYGEN which provides 100% oxygen under 2-3 atm

pressure

HYDROGEN CYANIDEHYDROGEN CYANIDE

Synonyms:

CYCLONFormonitrileHydridonitridocarbonHydrocyanic acid

(prussic)

CN binds avidly to iron in the ferric forming cyanoferric complex inactivation of iron containing enzymes

- A colorles, very volatile gas or liquid and resembling an odor that of bitter almonds

- Lighter than air rises and diffuses rapidly- By-product of burnt plastics, wood and many natural and

synthetic materials

Mechanism of toxicity Clinical Presentation

CN produces tissue and cellular hypoxia by reversibly binding into cytochrome A and by inhibiting re-oxidation

Inhibits electron transport; prevent cellular respiration and decrease ATP production

Produce severe metabolic acidosis

Cyanohemoglobin which cannot transport oxygen

Initially (tachypnea)Respiratory

depression and cyanosis

HypotensionConvulsionComaDeath will occur in

minutes at significant amount because it is a fast acting poison

TreatmentTreatment

1. Amyl nitrite (inhalation) and Sodium nitrite (IV)

◦ To pull the CN-ions away from cytochrome A CNmethHb is converted to MethHb by using specific oxidants

◦ MethHb indirectly competes with ferri-cytochrome A to form a methHb-CN complex (non-toxic)

2. Sodium thiosulfate (IV) is given which reacts with CNMethHb to form thiocyanate which is harmless and is easily excreted in the urine

3. Hydroxycobalamine (orally) – which binds to CN to form cyanocobalamine (non-toxic)

FormaldehydeFormaldehyde

Pungent odor Preset in fabrics,

paper and construction materials

Formalin – 37%-40% as disinfectant and tissue fixative which may contain 6-15% methanol as stabilizer

Use as disinfectant in hemodialyzers

Sporocidal Preparation of

vaccines Preservative

(embalming)Irritant (carcinogen)

Mechanism of toxicity Metabolism

Causes precipitation of proteins and will cause coagulation necrosis of exposed tissues

Gas is highly soluble in liquids and when inhaled produces immediate local irritation of the upper respiratory tract and has been reported to cause spasm and edema of the larynx

Produces formic acid and may accumulate and will result to metabolic acidosis

Toxic Dose: PEL of 1ppm; IDLH of 2ppmIt has been reported that as little as 30 mL of 37% formalin will result to death

Clinical PresentationClinical Presentation

Gas exposure will produce irritations of the eyes and inhalation can produce cough, wheezing sounds and pulmonary edema

Ingestion may cause severe corrosive esophageal and gastric injury, depending on the concentration◦ Metabolic acidosis may be cause by formic acid

accumulation from metabolism of formaldyhyde or methanol

Hemolysis has occurred when formalin was accidentally introduced into the blood through contaminated hemodialysis equipment

TreatmentTreatment

Methanol containing solutions – administer ethanol and folic acid

Formate intoxication due to formaldehyde alone be given folic acid

DecontaminationDecontamination

When inhaled: remove patient from exposure and give supplemental O2

Skin and eye: remove exposed clothing and wash with running water and soap or irrigate exposed eyes with copious normal saline

Ingestion: check and assess for gastric injury perform gastric lavage; do not force emesis◦Administer activated charcoal