PRINSIP-PRINSIP TOKSIKOLOGI

Dr.dr. Nurdiana, Mkes

TOKSIKOLOGI :
Ilmu yang mempelajari efek samping bahan kimia
termasuk obat terhadap organisma hidup
Area toksikologi khusus yang ptg utk kedokteran :
Forensic toxicology kombinasi kimia analitik
dan toksikologi dasar yang memperhatikan
aspek medikolegal
Clinical toxicology fokus pada penyakit yang
disebabkan atau secara unik berhubungan
dengan substansi toksik


What is a Poison?

All substances are poisons;
there is none that is not a poison.
The right dose
differentiates a poison and a remedy.
Paracelsus (1493-1541)
Measures of Toxicity

Toxicity of chemicals is determined in the
laboratory
The normal procedure is to expose test
animals
By ingestion, application to the skin, by
inhalation, gavage, or some other method which
introduces the material into the body, or
By placing the test material in the water or air
of the test animals environment
Measures of Toxicity

Toxicity is measured as clinical endpoints
which include
Mortality (death)
Reproductive tox
(teratogenesis,reproduction
performance,perinatal and postnatal tox)
Carcinogenicity (ability to cause cancer),
and,
Mutagenicity (ability to cause heritible
change in the DNA)
Duration of Exposure

Three terms are commonly used to
describe the duration of dose(s)

Acute
Subchronic

Chronic
Duration of Exposure:
Acute Exposure

Application of a single or short-term
(generally less than a day) dosing by a
chemical
Animal: mouse, rat, female,male
Examination: death animal in a 14 day period
(weight, behavioral, lethargy, food
consumption etc)
Information: LD50,target organ, reversibility,
dose-response
Measures of Toxicity:
The Median Lethal Dose

LD
50

The amount (dose) of a chemical which
produces death in 50% of a population of test
animals to which it is administered by any of a
variety of methods

mg/kg
Normally expressed as milligrams of substance
per kilogram of animal body weight

Measures of Toxicity:
The Median Lethal
Concentration
LC
50

The concentration of a chemical in an
environment (generally air or water) which
produces death in 50% of an exposed
population of test animals in a specified time
frame

mg/L
Normally expressed as milligrams of substance
per liter of air or water (or as ppm)

Fig. 16.5, p. 400
100
75
50
25
0
2 4
6
8 10
12 14
16
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Dose (hypothetical units)
LD
50
Toxicity
LD50 measured in mg/kg of body weight
LD50 Examples
Supertoxic < 0.01mg dioxin, botulism,
mushrooms
Extreme. Toxic <5mg heroin, nicotine
Very Toxic 5-50mg morphine, codeine
Toxic 50-500mg DDT, H2SO4, Caffeine
Mod. Toxic 500mg-5g aspirin, wood alcohol
Slight. Toxic 5g-15g ethyl alcohol, soaps
Non-Toxic >15g water, table sugar
Duration of Exposure:
Subchronic Exposure

Toxic symptoms are expressed after
repeated applications for a timeframe less
than half the life expectancy of the
organism (90 days)
Examination: body weight, food consumtion,
respiratory and cardiovascular distress,
motor and behavioral abnormalities etc
At the end of the 90-day blood and organ
collected for analysis
Duration of Exposure:
Chronic Exposure

Expression of toxic symptoms only
after repeated exposure to a
chemical in doses regularly applied to
the organism for a time greater than
half of its life-expectancy
Mice : 18 m 24 m
Rats : 2-2.5 y
What is a Response?

Response (symptoms) could be on the
molecular, cellular, organ, or organism level
(interference w/receptor,membrane
function,cellular energy production, biomolc,
calsium homeostasis etc)
Local vs. Systemic
Reversible vs. Irreversible
Immediate vs. Delayed
Graded vs. Quantal
degrees of the same damage vs. all or none
Primary Routes of Exposure

There are three primary routes by which
organisms are exposed to pesticides

Oral
Dermal
Inhalation
Primary Routes of Exposure:
Oral Exposure
Any exposure which occurs when the chemical is taken
in through the mouth and passes through the
gastrointestinal tract

ADME (target organ adverse effect is dependent
upon the concentration of active compound at the
target site for enough time ), Not all organs are
affected equally, greater susceptibility of the target
organ, higher concentration of active compound
Liver, Kidney Lung, Neurons, Myocardium, *Bone
marrow
Primary Routes of Exposure:
Dermal Exposure

Exposure of the skin
Animal : back (0.5 of liquid ang 0.5 g of solid,
1-inch square, one intact and two abraded
skin sites, 4 h)
Examination: erithema,edema, corrosive
action

Primary Routes of Exposure:
Inhalation Exposure
Occurs when a chemical is breathed into the
lungs through the nose or mouth

Significant route of exposure for aquatic
organisms

Not of toxicological concern until it crosses from
the lung into the body (unless the chemical is
corrosive)



PREVENSI DAN TERAPI KERACUNAN

Untuk kepentingan klinik, semua agen toksik dibagi 2 klas :
1. Agen toksik yang memerlukan terapi spesifik atau ada
antidotnya
2. Agen toksik yang tidak memerlukan terapi spesifik
Sebag. besar obat dan bahan kimia lain Tx simtomatik

fungsi vital
Keracunan obat terutama Tx supportive
Prinsip penting dalam toksikologi klinik :
Treat the patient, not the poison

Terapi keracunan akut :
1.Mempertahankan fungsi vital
2.Mengusahakan konsentrasi racun di jaringan
yang penting serendah mungkin dg cara
mencegah absorbsi dan meningkatkan eliminasi

Mencegah absorbsi racun selanjutnya dengan :
Emesis -merangsang pharynx di bag.posterior
-Ipecac
-Apomorphine
Gastric lavage
Chemical adsorbtion activated charcoal

Inaktivasi bahan kimia
-antidote
-netralisasi asam atau basa
Purgation
- Katartik
- WBI : whole bowel irrigation
Bila keracunan melalui inhalasi atau kulit :
-pindahkan pasien dari sumber racun
-bersihkan kulit yang terkena dg air
-pakaian yg terkena racun dilepas
-Bila kena mata secepatnya irigasi dg air selama 15
menit
MENINGKATKAN ELIMINASI RACUN
- Biotransformasi atau
- Ekskresi lewat empedu
- Ekskresi lewat urin
- Dyalisis
ANTAGONIS ATAU INAKTIVASI BAHAN KIMIA YG
DISERAP
I ngested toxin: A poison that is consumed
orally.
Poisoning by Ingestion
About 80% of all accidental ingestions of poisons
occur in children 1 to 3 years of age
Most result from household products
Poisoning in adults is usually intentional, although
accidental poisoning from exposure to
chemical in the work place also occurs.
Toxic effects of ingested poisons may be
immediate or delayed, depending on the
substance ingested


Common Types of Household Poisons
Assessment and Management
The primary goal of physical assessment of
poisoned patients is to identify the poisons
effects on the three vital organ systems most
likely to produce immediate morbidity and
mortality:
Respiratory system
Cardiovascular system
Central nervous system
Five Signs of Major Toxicity
Coma
Cardiac dysrhythmias
GI disturbances
Respiratory depression
Hypotension or hypertension



HISTORY
What was ingested? (obtain samples of substance,
vomitus)
Route of intoxication?
When was the substance ingested?
How much of the substance was ingested?
Use of alcohol or other possibly potentiating
substances?
Was an attempt made to induce vomiting?
Has an antidote or activated charcoal been
administered?
Patterns of drug habituation or abuse?
Does the patient have a psychiatric history
pertinent to suicide attempts or recent episodes of
depression?

Physical Exam
Pay special attention to:
Skin condition (cyanosis, pallor, wasting, needle
marks, staining)
Pupil responses, impaired vision
Signs of caustic ingestion, burning
Amount of salivation, breath odor, presence of
vomitus
Breath sounds for evidence of aspiration,
atelectasis, pulmonary secretions
Cardiac dysrhythmias
Abdominal pain


General Principles of Management
Prevent aspiration, consider intubation
Reduce or prevent absorption
DO NOT induce vomiting in most cases
Use of gastric lavage and/or activated charcoal
may be preferred
Maintain airway, breathing and circulation
Gastric Lavage
A method of GI decontamination that may be superior to
ipecac-induces emesis
Advantages:
Immediate recovery of a portion of the gastric contents (if
performed within 1 hour of ingestion)
Control of lavage duration
Direct access for administration of activated charcoal


Tehnik gastric lavage
Use large bore (36-40 French) orogastric tube, smaller 24-28
French NG tube may be too small to remove gastric contents
Place the patient in left lateral Trendelenburg to minimize
chance of aspiration
Insert tube through mouth into esophagus and advance until
tip is placed in the stomach
Check tube placement by insufflation of air into stomach with
syringe while auscultating
Infuse 150-200 mL aliquots of tap water or NS in adults,
50-100 mL >5 years
Drain stomach contents after each infusion, return volume
should be approximately equal to what was infused
Continue until return fluid comes back clear
Follow with activated charcoal


Potential complications gastric lavage:
Patient agitation
Inadvertent tracheal intubation
Esophageal perforation
Aspiration pneumonitis
Fluid and electrolyte imbalances in pediatric patients

Activated charcoal:
A medication that works by binding
to certain poisons, preventing
them from being absorbed into the
body.
Used only for ingested toxins.
Activated Charcoal Trade Names
InstaChar

Actidose

LiquiChar

SuperChar

Two Types of
Activated
Charcoal
Contraindications to Charcoal
Altered mental status
Ingestion of an acid or alkali
Inability to swallow
History of recent seizures
Charcoal with Sorbitol should NOT
be used in small children
Administration of Activated Charcoal
Shake container thoroughly.
Activated Charcoal continued
Pour liquid into container.
Activated Charcoal continued
Have patient drink full dose.
Administration of Fluids and
Drugs
Assure airway, breathing, and
circulation
Establish IV of NS
If unresponsive, consider thiamine,
naloxone but only if each is indicated
If extrapyramidal effects are present,
consider use of diphenhydramine 25-50
mg IV
Extrapyramidal
Control and coordinate the postural, static,
supporting and locomotor mechanisms
Affecting extrapiramidal tracts and
characterized by involuntary movement,
changes in muscle tone and abnormal
posture (Parkinsons)
Side effect mimics disease and caused by
drugs that block dopamine receptor sites
Contaminated Food
Causes:
Bacteria
Viruses
Toxic chemicals
Seafood poisonings
Common symptoms:
Diffuse abdominal pain
Nausea, vomiting, diarrhea
Rarely life threatening
Contaminated Food
Basic treatment largely supportive
Perform initial and focused assessments
Collect samples of suspected source of
poisoning
Establish and maintain airway
Administer high-flow oxygen, intubate and
assist ventilation as needed
Establish IV with NS or LR
Contact poison control
Poisonous Plants
Common sources of poisoning include plants,
trees, and mushrooms
Obtain sample of suspected agent
Signs of possible toxic mushroom poisoning
Excessive salivation, lacrimation, diaphoresis
Abdominal cramps, nausea, vomiting, diarrhea
Decreasing levels of consciousness
Contact poison control center for guidance,
possible administration of atropine
Ethylene Glycol
A colorless, odorless, watersoluble
liquid
Commonly used in windshield deicers,
detergents, paints, radiator antifreeze,
and coolants
Commonly misused by alcoholics as a
substitute for ethanol
Ethylene Glycol/Methanol
Common signs and symptoms include
abdominal pain, nausea, vomiting, signs
of intoxication, tachypnea, hyperpnea
Irreversible blindness
Methanol (Wood Alcohol)
A common industrial solvent obtained
from distillation of wood
Found in a variety of products, such as gas
line antifreeze, windshield washer fluid,
paints, paint removers, varnishes, canned
fuels such as sterno, and many shellacs
Onset of symptoms after ingestion
ranges from 40 minutes to 72 hours
Treatment
Ensure ABCs
Establish IV
Contact poison control
Consider sodium bicarbonate (50 mEq)
if poison control unavailable
Consider 30-60 mL of 86 proof ethanol
p.o.
Transport rapidly
Ethanol
Impede metabolism of ethlene glycol or
methanol to toxic metabolites
Competes for enzymes needed for
metabolism
Strong Acids and Alkalis
Strong acids and alkalis may cause burns to the
mouth, pharynx, esophagus, and sometimes the
upper respiratory and GI tracts
Ingestions of caustic and corrosive substances
generally produce immediate damage to the
mucous membrane and the intestinal tract
Acids generally complete their damage within 1 to 2
minutes after exposure
Alkalis, particularly solid alkalis, may continue to cause
liquefaction of tissue and damage for minutes to hours
Signs and Symptoms
Facial burns
Pain in the lips, tongue, throat, or gums
Drooling, trouble swallowing
Hoarseness, stridor, shortness of breath
Shock secondary to bleeding or
vomiting
Management
Establish an airway, consider intubation,
or if necessary, cricothyrotomy
Contact poison control
Gastric lavage or charcoal often
contraindicated
IV with NS or LR
Rapid transport
Hydrocarbons
A group of saturated and unsaturated
compounds derived primarily from crude
oil, coal, or plant substances
Found in many household products and in
petroleum distillates
Hydrocarbons
Viscosity is the most important physical
characteristic in potential toxicity
The lower the viscosity, the higher the risk
of aspiration and associated complications
Clinical features of hydrocarbon
ingestion vary widely, depending on the
type of agent involved
May be immediate or delayed in onset
Signs and Symptoms
Burns due to local contact
Wheezing, dyspnea, hypoxia, and
pneumonitis due to aspiration or inhalation
Headache, dizziness, slurred speech,
ataxia (irregular or difficult-to-control
movements), and dulled reflexes
Foot and wrist drop with numbness and
tingling
Cardiac dysrhythmias
Management
Most are not life-threatening
Occasionally gastric lavage may be of
benefit
In seriously symptomatic patients,
protect the airway and establish an IV if
NS or LR
Contact poison control
Transport
Isopropanol (Isopropyl
Alcohol)
A volatile, flammable, colorless liquid
with a characteristic odor and
bittersweet taste
Rubbing alcohol is the most common
household source of this agent
Used in disinfectants, degreasers,
cosmetics, industrial solvents, and cleaning
agents
Isopropanol (Isopropyl
Alcohol)
Common routes of toxic exposure
Intentional ingestion as a substitute for
ethanol
Accidental ingestion
Inhalation of high concentrations of local
vapor, as from alcohol sponging of febrile
children (a harmful and inappropriate
procedure)
Isopropanol (Isopropyl
Alcohol)
More toxic than ethanol but less toxic
than methanol or ethylene glycol
A potentially lethal dose in adults is 150 to
240 mL
In children, any amount of ingestion should
be considered potentially toxic
After ingestion, the majority of
isopropanol (80%) is metabolized to
acetone
Signs and Symptoms
Usually present within 30 minutes
CNS and respiratory depression
Abdominal pain
Gastritis
Hematemesis
Hypovolemia
Management
Airway maintenance and ventilatory
support with 100% oxygen
Gastric lavage
IV with NS or LR and fluid resuscitation
PRN
ECG monitoring
Rapid transport
Metals
Infants and children are high-risk groups
for accidental iron, lead, and mercury
poisoning due to their immature immune
systems or increased absorption as a
function of age
Iron Poisoning
Approximately 10% of the ingested iron
(mainly ferrous sulfate) is absorbed
each day from the small intestine
After absorption, the iron is converted,
stored in iron storage protein, and
transported to the liver, spleen, and bone
marrow for incorporation into hemoglobin
Signs and Symptoms
Hematemesis
Abdominal pain
Shock
Liver failure
Metabolic acidosis with tachypnea
Eventual bowel scarring and possible
obstruction
Management
Protect the airway and oxygenation
Gastric lavage
Charcoal contraindicated
IV with NS or LR titrated to support the
blood pressure
Rapid transport
Lead Poisoning
Metallic lead has been used by humans
for more than 5000 years
Was not widely recognized as a potential
health hazard until 1978 when it was
banned from household paints in the
United States
Common sources of lead older glazes
and paints
Signs and Symptoms
Headache, irritability, confusion, and
coma
Memory disturbances
Tremor, weakness, and agitation
Abdominal pain
Management
Protect the airway
Consider gastric lavage if it is an acute
ingestion
Activated charcoal is contraindicated
IV with NS or LR
Transport
Mercury Poisoning
Mercury is the only metallic element that is
liquid at room temperature
Used in thermometers, sphygmomanometers, and
dental amalgam (dental fillings)
Various compounds of mercury are used in some
paints, pesticides, cosmetics, drugs, and in certain
industrial processes
All forms of mercury (except dental amalgam)
are poisonous
Signs and Symptoms
Headache, irritability, confusion, and
coma
Memory disturbances
Tremor, weakness, and agitation
Abdominal pain
Management
Protect the airway
Consider gastric lavage if it is an acute
ingestion
Activated charcoal is contraindicated
IV with NS or LR
Transport
Cyanide Poisoning
Pathophysiology
Cyanide binds cytochrome oxidase
causing cellular asphyxia
Cyanide
Refers to any of a number of highly toxic
substances that contain the cyanogen
chemical group
Cyanide is present in many household items
Cyanide poisoning may result from:
Inhalation of cyanide gas (most rapid effects)
Ingestion of cyanide salts, nitriles, or
cyanogenic glycosides
Infusion of nitroprusside
Absorption in fires
Cyanide
Fast-acting toxin - cellular asphyxiant
Signs and symptoms include: burning
sensation in the mouth and throat,
headache, combative behavior,
hypertension, tachycardia, tachypnea,
pulmonary edema with respiratory
depression