Toxicology

PWM OLLY INDRAJANI

2012

What is toxicology?
The study of the negative effects of
chemicals on living things
A chemical is considered toxic
depending on
How much of it is necessary to cause
harm
How easily it can enter the body
2

Chemicals in the body

Distribution - spread throughout the
body
Metabolism - broken into smaller
chemical compounds
Storage - kept in the body for a long
time
Excretion - passed out through urine,
feces, exhaled air, or sweat
3

Toxic effects
Toxic chemicals disrupt the
normal functions of the body.
Effects can be
Local - at the site of exposure
Systemic - affecting the entire
body
target organs - organs or systems
where symptoms of exposure appear
4

Dose and response

The reaction is dependent on the
amount of the chemical
received, but...
Some doses are so small they
produce no response
Once the maximum reaction has
occurred, increasing the dose
doesnt change the reaction
5

Dose-response curve alcohol

Death
Labored breathing
Response

Coma
Sleep
Slurred speech
Relaxed
No effect

Dose

Important Relationship

For water at STP (standard

temperature [23oC] and pressure [15
psi])
1 cc

1ml

1g

Which means that

1 liter of water = 1 kg
1 mg / kg = 1 ppm
1mm3 / liter = 1 ppm
1 mg / liter = 1 ppm

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, 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)
Teratogenicity (ability to cause birth defects)
Carcinogenicity (ability to cause cancer), and,
Mutagenicity (ability to cause heritible change
in the DNA)

At this time we will discuss 2 measures of

mortality the LD50 and the LC50

Measures of Toxicity:
The Median Lethal Dose
LD50
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
LC50
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)

Routes of exposure
In order for a chemical to cause
injury, it must enter the body
Inhalation
Ingestion
Absorption through the skin
Injection

Operating Engineers National

Hazmat Program

13

Primary Routes of Exposure:

Oral Exposure
Any exposure to pesticide/ poison which
occurs when the chemical is taken in
through the mouth and passes through the
gastrointestinal tract
During oral exposure, although carried
within the body, the pesticide is still
outside of the body cavity

Primary Routes of Exposure:

Dermal Exposure
Exposure of the skin to a pesticide
Most common route of human exposure
With proper hygiene this type of exposure is
generally not serious unless there is a
specific, rapid toxicological effect (often
eye effects) which is of concern

Pesticide Application

Primary Routes of Exposure:

Inhalation Exposure
Occurs when a pesticide 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)

Duration of Exposure
Three terms are commonly used to
describe the duration of dose(s)
Acute
Chronic
Subchronic

Acute and chronic effects

Acute - lasting hours
Chronic - lasting a
long time - possibly
years

Operating Engineers National

Hazmat Program

20

Duration of Exposure:
Acute Exposure
Application of a single or short-term
(generally less than a day) dosing by
a chemical
If toxic symptoms are expressed, they
are referred to as symptoms of
acute toxicity

Acute and chronic exposures

Acute - sudden, brief
A bee sting

Chronic - repeated small doses over

time
Smoking cigarettes for years

Operating Engineers National

Hazmat Program

22

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 lifeexpectancy
If toxic symptoms are expressed, they are
referred to as symptoms of chronic
toxicity

Duration of Exposure:
Subchronic Exposure
Toxic symptoms are expressed after
repeated applications for a timeframe less
than half the life expectancy of the
organism but more often than a single
dose or multiple doses applied for only a
short time
If toxic symptoms are expressed, they are
referred to as symptoms of subchronic
toxicity

 Largest number of deaths were:

analgesics
Antidepressants
sedative/hypnotics/antipsychotics
Stimulants
street drugs
cardiovascular drugs
alcohols

 Of all deaths:
5% increase compared to 1999
88% occurred in 20- to 99-year old
individual
The mortality rate was higher in
intentional rather than unintentional
exposures (79% vs 10.5%, respectively).

DIAGNOSIS
History and
physical
examination
Vital signs
Ocular findings
Mental status,
behaviour and
muscle tone
Poison control
center consultation

Laboratory
evaluation:
Anion gap
Osmolal gap
Oxygen saturation
gap
Toxicology
screening

History and Physical

Examination
Although the history is important, it
may be unreliable or incomplete
Consider that family members,
friends, and pharmacists may have
additional information

 In the absence of a classic presentation or

toxidrome, separating patients with
suspected poisoning into broad categories
based on:

vital signs
ocular findings
mental status
muscle tone

can help determine drug or toxin

class

Vital Signs
Anticholinergic and
sympathomimetic substances
increase heart rate, BP, and
temperature
In contrast organophosphates,
opiates, barbiturates, -blockers,
benzodiazepines, alcohol, and
clonidine cause hypothermia,
bradycardia, and respiratory
depression.

Ocular Findings
Anticholinergics and sympathomimetics cause
mydriasis
In contrast to anticholinergics overdose, the
pupils remain somewhat light responsive in
cocaine intoxication
Horizontal nystagmus is common in alcohol
intoxication
Other drugs causing nystagmus are lithium,
carbamazepine, solvents, meprobamate, quinine,
and primidone
Phencyclidine and phenytoin cause horizontal,
vertical, and rotary nystagmus

Mental Status, Behavior, and Muscle

Tone

Laboratory Evaluation

Anion gap
Osmolal gap
Oxygen saturation gap
Toxicology screening

Anion gap
The normal range of anion gap may
vary from 3 to 12 mEq/L in some
laboratories
An increase in anion gap ( 20 mEq/L)
suggests:
lactic acidemia
Uremia
Ketoacidemia
selected intoxications

 A normal anion gap does not preclude

intoxication because most toxins do not
elevate the anion gap or there may be a
coexisting condition that lowers the gap (Table
10)
Common among these conditions is
hypoalbuminemia for every 1 g/L decrease
in the plasma albumin, the anion gap falls by
2.5 mEq/L
Also, in methanol or polyethylene glycol
poisoning, concurrent ethanol use delays the
development of an elevated anion gap
metabolic acidosis
In this case, an elevated osmolal gap may
be the only early clue to the diagnosis

Osmolal Gap
Low-molecular-weight drugs and
toxins increase the discrepancy
between measured and calculated
plasma osmolality (Table 12)
Normal plasma osmolality is 285 to
295 mOsm

 The calculated value is determined

as follows:
1.86[Na] + BUN/2.8 + glucose/18 +
ethanol/4.6

Oxygen Saturation Gap

An oxygen saturation gap is present
when there is more than a 5%
difference between the saturation
calculated from an arterial blood gas
and the saturation measured by cooximetry
Co-oximetry determines oxygen
saturation by detecting the absorption
of four different wavelengths, enabling
it to directly measure levels of four
types of hemoglobin species:

Oxyhemoglobin
Reduced hemoglobin
Carboxyhemoglobin
Methemoglobin

 However, arterial blood gas analysis

calculates oxygen saturation from the
measured oxygen tension using an
assumed standard oxygen-hemoglobin
dissociation curve
Toxins that are associated with an
elevated oxygen saturation gap include
carbon monoxide, methemoglobinemia,
cyanide, and hydrogen sulfide
(sulfhemoglobin is not routinely
measured by co-oximetry)

 Pulse oximetry estimates oxygen

saturation by emitting a red light
(wavelength of 660 nm) absorbed
mainly by reduced hemoglobin and
a near-infrared light (wavelength of
940 nm) absorbed by
oxyhemoglobin

Resuscitation
first priority in treating poisoned
patients
assessment and stabilization of
cardiopulmonary function (e.g., the
ABCs)

use of antidotes
very rare take precedence over
stabilization of ABCs

 empiric administration of antidotes

("coma cocktail")
supplemental oxygen
naloxone
glucose
thiamine
should be considered after medical
history, vital signs, and immediately
available laboratory data
these treatments are simple,
inexpensive, and generally without
undue risk of an adverse reaction when
used appropriately

 naloxone
is a competitive opioid antagonist
no any intrinsic toxicity
can be administered IV/IM
use in a hypoventilating opioid-intoxicated patient
who is not intubated
opioid intoxication often presents with classic triad
CNS depression
miosis
unreliable as the sole indication for naloxone administration
because
many other toxins can produce small pupils along with mental
status depression
some opioids classically leave pupil size unaltered (e.g.,
meperidine, propoxyphene)

respiratory depression
only a respiratory rate of <12 breaths/min is useful as a predictor
of response to naloxone

 duration of action 20-60 min

if become re-sedated may require
additional naloxone doses either in
intermittent boluses
continuous infusion
administration of 2/3 dose of naloxone that
fully aroused the patient in the initial bolus,
infused over an hour, with dose adjustments
made as directed by the patient's ventilatory
status

risks of naloxone treatment

precipitation of acute opioid withdrawal
syndrome
vomiting from withdrawal can result in aspiration
thus administration of large doses of naloxone
should be discouraged

PRINCIPLES OF
GASTROINTESTINAL
DECONTAMINATION

Gastrointestinal (GI) decontamination refers to

therapies that may decrease the amount of poison
absorbed from the GI tract lumen.
The following methods of GI decontamination are
available:
A. Induced emesis
B. Gastric lavage
C. Activated charcoal
D.Whole-bowel irrigation

A. Induced Emesis
Induced emesis utilizes syrup of ipecac to induce
vomiting, theoretically emptying the stomach and
reducing absorption of an ingested agent.
Syrup of ipecac induces vomiting by activation of
both local and central emetic sensory receptors.
Induced emesis has largely been abandoned in
clinical practice. The most recent policy statements
released by both the American Academy of
Pediatrics(2003) and the American Association of
Poison Control Centers (2005)discourage the use of
syrup of ipecac in the out-of-hospital setting.

B. Gastric Lavage
INDICATIONS
Ingestion of a
substance with high
toxic potential and:
Within 1 hour of
ingestion
Ingested substance is
not bound by
activated charcoal or
has no effective
antidote.
Potential benefits
outweigh risks.

CONTRAINDICATIONS
Substance not meeting
above indications
Spontaneous emesis
Diminished level of
consciousness/unprotected
airway reflexes (intubate
first)
Ingestion of hydrocarbons
or caustic agents
Foreign body ingestion
Patient is at high risk for
esophageal or gastric
injury (GI hemorrhage,
recent surgery, etc.).

TECHNIQUE
Recommended tube size is 3640 French for adults, 22
28 French for children.
Secure airway via intubation, if necessary.
Position patient in left-lateral decubitus position, with
head lowered below level of feet.
Confirm tube placement following insertion.
Aspirate any available stomach contents.
Lavage with 250 mL (1015 mL/kg in children) aliquots of
warm water or saline.
Continue until fluid is clear and a minimum of 2L has
been used.
Instill activated charcoal through same tube, if indicated.
COMPLICATIONS
The primary risks are vomiting, aspiration, and
esophageal injury or perforation.

C. Activated Charcoal
INDICATIONS

CONTRAINDICATIONS

Ingested substance is poorly

adsorbed by AC (eg, iron,
lithium, heavy metals,toxic
alcohols).
Diminished level of
consciousness/unprotected
airway reflexes (AC can be
Patient presents within 1
given by naso- or orogastric
to 2 hours after ingestion.
tube following intubation)
Patient has ingested a
Patient presents over 2 hours
potentially dangerous
after ingestion.
amount of a poison
Ingestion of caustic agents
adsorbed by charcoal
Cases where endoscopy will
be required

Activated charcoal (AC) is

ingested by the patient in
order to adsorb poisons
within the GI tract lumen.

DOSE

RISKS

The recommended dose

of AC is a 10:1 ratio
relative to the ingested
poison(ie, ingestion of 1
g of poison requires 10
g of AC). Hence, the
commonED practice of
administering 50 to 100
g (1 g/kg) of AC to an
overdose patient may
be inadequate for larger
ingestions.

The primary risk of singledose AC is vomiting.

Constipation and diarrhea
Bowel obstruction does
not occur from single-dose
AC.
Repeated doses of
cathartics given with
charcoal may cause
dehydration or electrolyte
abnormalities.

D. Whole -Bowel Irrigation

Whole-bowel irrigation (WBI) flushes the GI tract to decrease the transit timeof luminal contents, thereby limiting absorption

INDICATIONS
Removal of ingested
drug packets (eg,
body stuffers)
Large ingestion of a
sustained-release drug
Potentially toxic
ingestion that cannot
be treated with
activated charcoal (eg,
lithium, lead, iron)

CONTRAINDICATIONS
Diminished level of
consciousness/unprotec
ted airway reflexes
(intubate first)
Decreased GI motility
or bowel obstruction
Significant GI
hemorrhage
Persistent emesis

DOSE

COMPLICATIONS

Polyethylene glycol (PEG)

solution is administered
at a rate of 12 L/hour.
This rate of
administration usually
requires a naso- or
orogastric tube.
Endpoints for therapy are
the appearance of clear
rectal effluent or a total
irrigation volume of 10 L.

The primary risk

associated with WBI is
vomiting.
Patient discomfort:
Bloating, cramping, and
flatulence
WBI with balanced PEG
solutions does not
generally cause
electrolyte
abnormalities.

PRINCIPLES OF ENHANCED
ELIMINATION
The goal of enhanced elimination is to increase the
clearance of a poison from the body after it has been
systemically absorbed.
The following methods of enhanced elimination are
available:
A. Multiple-dose activated charcoal
B. Urinary alkalinization
C. Hemodialysis

Enhanced Elimination:
Drug Characteristics and
Examples

A. Multiple-Dose Activated Charcoal

Uses repeated doses of activated charcoal (every 24
hours) to increase poison clearance.
MDAC exerts its effects through disruption of
enterohepatic circulation or direct adsorption across
the GI mucosal surface.
RISKS
The risks associated with MDAC are similar to those
with AC; however,there is a greater risk of bowel
obstruction with MDAC.

INDICATIONS
Drugs that have
enterohepatic circulation
and can possibly be
treated with MDAC
include:

Phenobarbital
Carbamazepine (Tegretol)
Theophylline
Aspirin
Dapsone

CONTRAINDICATIONS

MDAC is
contraindicated in the
same settings as AC.

B. Urinary Alkalinization
Urinary alkalinization attempts to increase renal
elimination of a drug by increasing urine pH.
Urinary acidification to increase the clearance of
weak bases is not recommended due to the risk of
renal injury.
RISKS
Can precipitate hypokalemia and decrease ionized
calcium levels

INDICATIONS
Urinary alkalinization
only affects the
clearance of drugs
that are weak organic
acids.
Aspirin (most common
use for alkalinization)
Phenobarbital
Formic acid

CONTRAINDICATIONS

Poisoning with agents

that are not weak
organic acids and are
not primarily cleared
by the kidneys
Patients who cannot
tolerate excess
sodium/water loading
(eg, CHF, renal failure)

C. Hemodialysis
Hemodialysis (HD) directly removes toxins from
a patients plasma, using the same technology
applied to renal failure.
RISKS
HD requires central venous access, with all the
usual accompanying risks
(bleeding, pneumothorax, etc.).
HD must be used cautiously in patients that are
hemodynamically unstable.

INDICATIONS

CONTRAINDICATIONS

For HD to be useful in a
poisoned patient, the
ingested poison should
have the following
characteristics:

Toxins that do not

Low molecular weight
satisfy the conditions
Low plasma protein-binding
listed above.
Small volume of distribution
Poor endogenous clearance
HD can also treat severe
acidosis caused by a toxin,
even if the toxin it self is not
readily dialyzable.

Thank you