Anda di halaman 1dari 40

Basic Concepts in Toxicology

Dr. Lynn R. Panganiban


National Poison Management & Control Center
U.P. College of Medicine-
Philippine General Hospital
GENERAL INSTRUCTIONAL OBJECTIVE:

To understand the basic principles


of toxicology and their applications
Specific Behavioral Objectives:

•  To define basic concepts in


toxicology
•  To discuss the factors affecting
responses to toxic agents
•  To know the general classification of
toxic effects
•  To discuss the dose-response
relationship
DEFINITION OF TERMS

TOXICOLOGY
the study of the adverse effects of chemical,
physical and biological agents on living organisms

TOXICITY
is the ability of a substance to cause injury to
biologic material
DEFINITION OF TERMS

POISON
Any agent that is capable of producing
deleterious effect(s) in a biological system,
seriously injuring function or producing death.
XENOBIOTIC
Substance that is not naturally produced within an
organism

TOXIN
Poisonous substance produced by plants, animals,
or bacteria
DEFINITION OF TERMS

TOXICANT
An agent capable of producing symptoms of
intoxication or poisoning

POISONING
An overdose of drugs, medicaments,
chemicals and biological substances
DEFINITION OF TERMS

RISK
the potential (likelihood) that injury (biological damage)
will occur in a given situation

EXPOSURE
is the amount of chemical that is available for absorption

SAFETY
is the probability that harm will not occur under specified
conditions (the inverse of risk)
RISK
the potential (likelihood) that injury
(biological damage)
will occur in a given situation
RISK = (TOXICITY) x (EXPOSURE)

TOXICITY
is the ability of a substance to cause
injury to biologic material

EXPOSURE
is the amount of chemical that is
available for absorption
Factors Affecting Responses to Toxic Agents

Chemical & physical properties of the


substance (physical state, solubility,
reactivity, vapor pressure, etc.)

Individual factors
Exposure situation (age, sex, nutritional
(duration, frequency, status, genetic background,
route, dosage) general health status)
Individual practices
CHEMICAL & PHYSICAL PROPERTIES

PHYSICAL STATE: liquid, gas, fume, mist. Dust, vapor, etc.

SOLUBILITY: in biological fluid/material such as water, blood


and lipids (fat)

VAPOR PRESSURE: > 1 mm Hg rapid volatilization

VAPOR DENSITY: > 1 (heavier than air)

REACTIVITY: chemical and biological


EXPOSURE SITUATION: DURATION

ACUTE EXPOSURE: is the condition wherein the animal


is exposed to a chemical for less than 24 hours usually as
a single dose or in divided doses within 13 hours; for the
inhalational route, exposure is continuous for 4 hours

SUBACUTE EXPOSURE: involves repeated daily exposure


of the animal to the chemical for less than one month (usually
21 days) by a specific route
EXPOSURE SITUATION: DURATION

SUBCHRONIC EXPOSURE: involves repeated


daily exposure of the animal to the chemical for 90 days
or 3 months

CHRONIC EXPOSURE: the animal is exposed to the


chemical throughout its lifetime: for 2 years in rats and mice,
or even longer for dogs and non-human primates
EXPOSURE SITUATION: FREQUENCY

Frequency is critical to the concentration levels


of the substance in biological fluids/at target site(s);
may be expressed as number of exposures/time period
EXPOSURE SITUATION: ROUTE

The major routes by which toxic substances gain


access to the body are through INGESTION
(gastrointestinal), INHALATION (lungs), DERMAL or
PERCUTANEOUS (skin) and PARENTERAL
EXPOSURE SITUATION: ROUTE

Descending order of effectiveness toxicity :

1.  Parenteral
2.  Inhalational
3.  Intraperitoneal
4.  Intramuscular
5.  Subcutaneous
6.  Intradermal
7.  Oral and dermal
EXPOSURE SITUATION: ROUTE
EXPOSURE SITUATION: DOSAGE

Dosage (Dose) is the most critical factor in determining


whether the intrinsic potential of a substance will be
expressed; is the unit of chemical/unit of biological
system (mg/unit body weight; mg/body surface area;
mL/unit body weight, etc.)
Philippus Aureolus Theophrastus Bombastus von
Hohenheim-Paracelsus (1493-1541)

“ All substances are


poisons; there is none
which is not a poison.
The right dose differentiates
a poison from a remedy. “
The toxicological tenet that the DOSE
makes the POISON may no longer apply.
INDIVIDUAL FACTORS

•  AGE
•  SEX
•  GENETIC BACKGROUND
•  NUTRITIONAL STATUS
•  GENERAL HEALTH STATUS
•  ABSORPTION/DISTRIBUTION/METABOLISM
AND EXCRETION
Children

Exposure patterns and


susceptibility are different
Women Factors: Physical location,
breathing zones, oxygen
Because regeneration consumption, food consumption,
of germ cells
type of food consumed,
does not occur
in females,
growth and development factors
the outcome(s) Transplacental and breast milk
of damage to oocytes
can be significant.
Improper use of chemicals/drugs

Indoor pesticide spraying


Mispackaged drugs/chemicals

Mispackaged
chemicals can lead
to children
accidentally
ingesting
them
Availability of chemicals/drugs
Improper storage of chemicals/drugs
Recycling of containers
Home as a toxic environment

HOME
Location of poisoning
(NPMCC 2005 stats)
Occupational factors
Family members bring contaminated
working clothes and equipment
at home

“Levels of chlorpyrifos
in house dust in farm
workers’ homes were
5 times higher than
levels in nonfarmworkers’
homes.” (EHP 110:549-553)
Improper disposal of c hemicals
and containers
General Classification of Toxic Effects

•  Allergic reactions
•  Idiosyncratic reactions
•  Immediate or acute toxicity
•  Delayed or chronic toxicity
•  Reversible effects
•  Irreversible effects
•  Local toxicity
•  Systemic toxicity
CHEMICAL INTERACTIONS

•  INDEPENDENT EFFECT
substances qualitatively and quantitatively exert their
own toxicity independent of each other
•  ADDITIVE EFFECTS
the combined effect of exposure to two chemicals
is equal to the sum of the effects of exposure to each
chemical alone (3+5=8)

•  SYNERGISTIC EFFECTS
the combined effect of exposure to two chemicals, given
at the same time, is much greater than the sum of the
effects of each substance given alone (3+5=30)
DOSE-RESPONSE RELATIONSHIP

•  is the most fundamental concept


in toxicology.

•  exists when a consistent mathematical


relationship describes the proportion of
test organisms responding to a specific
dose for a given exposure period.
TWO TYPES OF D-R RELATIONSHIPS

1.  GRADED RESPONSE


describes the response of an individual to varying
doses of a chemical in which a measured effect
is continuous over a range of doses

2. QUANTAL RESPONSE
shows the distribution of a population of individuals
given different doses of a chemical based on a
specific end-point; “all or none”
Important Features of a D-R curve

Resistant

Slope of
the curve
Midpoint of the curve

Sensitive
Important Features of a D-R curve

THRESHOLD - the dose at which


the first response is observed Resistant
as a result of toxicity Slope
testing;
of
below this dose, no responses
the curve
Midpoint of the curve
are observed

Sensitive
Midpoint of the Curve

MEDIAN LETHAL DOSE (LD50)

 estimated dose causing death in 50% of the exposed


population under the defined condition of the test

 not a biological constant

 not equivalent to acute toxicity

 provides a measure of the relative toxicity of an agent


compared to other agents
TOXICITY RELATIONSHIPS

POTENCY
(the lower
or smaller
dose, the
more potent)

Toxicant A is more potent than toxicant B


TOXICITY RELATIONSHIPS

EFFICACY
(Higher efficacy when
the d-r relationship
continues over a
greater range of doses)

Toxicant B is more efficant than toxicant A


TOXICITY RELATIONSHIPS

MIXED OR REVERSED
TOXICITY (when one toxicant
is not consistently more potent
over the range of doses tested
as compared to another toxicant)

LD10: B more potent than A


LD50: A more potent than B