TOXICOLOGY BRANCHES OF TOXICOLOGY

THROWBACK 1. Clinical toxicology - deals with emergencies (overdose,

Paracelsus - 1493 - 1541 poisonings, attempted suicides), compound identification,
 every substance is poisonous S&S management, poison control, emergency care -ome
 the body's response to those chemicals depends on poisoning
the dose given/taken 2. Forensic toxicology - medicolegal aspect of toxicology,
TOXICOLOGY establish relationship between tissue residual level and
 “the science of poisons” probable cause of death
 “the study of the adverse effects of chemicals or 3. Industrial toxicology - worker safety
physical agents on living organisms” 4. Environmental toxicology
TOXICOLOGIST 5. Biochemical and molecular toxicology - determining MOA
 a scientist that determines the harmful effects of of chemicals at a molecular level, potential toxic effects,
agents and the cellular, biochemical and molecular effects of chemicals of the genes, DNA
mechanisms responsible for their effect 6. Product development toxicology - corporate setting,
TOXICANT service and pre-clinical toxicology for product development,
 agents; the substances that produce adverse establishes safe doses for people
biological effects of any nature. 7. Regulatory toxicology - industry and government setting,
 It may be chemical, physical (UV lights, radiation) in deciphers and analyzes toxicological date for risk estimation,
nature. safe level for human drugs (BFAD or FDA)
 Effects are various, acute, chronic, etc.
TOXIN TOXIC AGENT
 protein; the specific proteins produced by living  anything that can produce an adverse biological
organisms (mushroom toxin or tetanus toxin). effect
 Most of these exhibit immediate effect.  it may be chemical (cyanide), physical (radiation) or
POISONS biological (snake venom)
 part toxicant; the toxicants that cause immediate TOXIC SUBSTANCE
death or illness when experienced in small amounts  a material with toxic properties
XENOBIOTIC  it may be a discrete toxic chemical or a mixture of
 the general term used for foreign substance taken toxic chemicals
into the body.  a toxic substance may not always have a constant
 these may produce beneficial effects like composition
pharmaceuticals or harmful or toxic effects such as  e.g. lead acetate, asbestos, gasoline
lead ORGANIC TOXINS INORGANIC TOXINS
NON TOXIC  substances that were  specific chemicals that are
OR LETHAL originally derived from not derived from living
SUBSTANCE TOXIC DOSE
BENEFICIAL DOSE living organism organisms (minerals)
DOSE  these contain carbon and  these are generally
often are large molecules smaller molecules
ALCOHOL
(Ethanol 0.05% 0.1% 0.5%  these can be synthesized consisting of only a few
blood levels) (that is man-made) as atoms (e.g. nitrogen
well as obtained from dioxide)
Carbon natural sources
Monoxide
(% <10% 20-30% >60%
 Toxic substances may also be systemic toxins or
hemoglobin
bound) organ toxins
 a systemic toxin is one that affects the entire body
Secobarbital or many organs rather than a specific site
(sleep aid, 0.1md/dL 0.7mg/dL >1mg/dL  e.g. potassium cyanide
blood levels) TOXICANTS
0.65gm 9.75gm 34gm  may also affect only specific tissues or organs while
Aspirin
(2 tablets) (30 tablets) (105 tablets) not producing damage to the body as a whole.
 These specific sites are known as target organs
400mg 1400 mg 12000mg
Ibuprofen target tissues
(2 tablets) (7 tablets) (60 tablets)
 e.g. benzene, lead
 GERM CELLS AND SOMATIC CELLS CIRCUMSTANTIAL EVIDENCE
GERM CELLS  obtained from patient's history or actual interview.
 Are the cells involved in the reproductive process  It is deducted from various events and facts that the
and can give rise to a new organism. patient underwent.
 They only have a set of chromosomes.  It is not a strong evidence.
 Toxicity to these kind of cells can cause effects on PORT-MORTEM EVIDENCE
the developing fetus (birth defects, abortions)  gathered from an autopsy or post-mortem
SOMATIC CELLS examination is performed.
 Are all body cells except reproductive cells.  the pathologist will examine samples such as tissues,
 They have two sets of chromosomes. organs, and body fluids after the patient dies.
 Toxicity to these kind of cells causes a variety of toxic EXPERIMENTAL EVIDENCE
effects to the exposed individual (dermatitis, cancer,  done by administering the suspected substance to
death) some living animal to note the effects or symptom
CLASSIFYING POISONS/ TOXICANTS that is very similar to the effects and symptoms of a
 TARGET ORGAN person.
 INTENDED USE CHEMICAL EVIDENCE
 SOURCE  it is the detection of suspected substance via
 SPECIAL EFFECT analysis of samples of body fluids collected
 PHYSICAL STATE SYMPOMATIC EVIDENCE
 TOXICITY  the Poisoning S&S or effects are observed in the
 CHEMICAL STRUCTURE patient
 MECHANISM OF ACTION
TARGET ORGANS DOSE
> organ specific examples:  the amount of a substance administered at one
time.
> liver - hepatotoxin
TYPES OF DOSE
> kidneys - nephrotoxin
EXPOSURE DOSE
> heart - cardiotoxin  the amount of xenobiotic encountered in an
> ears - ototoxin environment
> brain - neurotoxin ABSORBED DOSE
> lungs - Pneumotoxin  the actual amount of the exposed dose that enters
> intestines – enterotoxin the body
INTENDED USE ADMINISTERED DOSE
> pesticides  the quantity administered usually orally or via
> herdicides injection
> solvents TOTAL DOSE
> drug  the sum of all the individual doses
> food
PHYSICAL STATE
FRACTIONING
> liquid
 a total dose usually decreases the probability that
> solid
the total dose will cause toxicity.
> gas  The reason for this is that the body can repair the
SPECTRUM OF EFFECT effect of each sub-toxic dose is sufficient time passes
> LOCAL VS. SYSTEMIC before another dose is given.
> REVERSBLE VS. IRREVERSIBLE
> IMMEDIATE VS. DELAYED  The units used in toxicology are basically the same units
> HYPERSENSITIVITY used in medicine.
> CHEMICAL INTERACTION  The gram (g) is the standard unit.
> TOLERANCE  However, most exposures will be smaller quantities thus
EVIDENCES OF POISONING milligrams (mg) is most commonly used.
C - circumstantial
P - post-mortem The clinical and toxic effects of a dose must be related to
E - experimental age and body weight. For example, a 650mg of Tylenol may
C - chemical be toxic thus children's dose for Tylenol is about 80mg. A
S - symptomatic better means to aow for comparison of effectiveness and
toxicity is the amount of substance administered on a body
weight basis. A common dose measurement is mg/kg which
stands for mg of substance per kg of body weight.
Another important aspect is time over which the dose was
administered. This is specially important for exposures of
several days or for chronic exposures. Day is the commonly
used unit thus the usual dosage unit is mg/kg/day.
DOSE RESPONSE
 the dose-response relationship is a fundamental and
essential concept in toxicology.
 It correlates exposure and spectrum of induced
effects.
 Generally, the higher the dose, the more severe the
response.
A THRESHOLD for toxic effects occurs at the point where the
body's ability to detoxify a xenobiotic or repair toxic injury
has been exceeded. For most organs, there is a reserve
capacity so that loss of some organs does not cause
decreased performance.
For example, the development of cirrhosis in the liver may
not result in a clinical effect until over 50% of the liver has
been replaced by fibrous tissues.
DOSE ESTIMATES OF TOXIC EFFECTS
 Dose-response curves are used to derive dose
estimates of chemical substances.
 A common estimate for acute toxicity is LD50 (lethal
dose 50%).
 This is a statistically derived dose at which 50% of
the individuals will be expected to die.
Effective doses
 this is used to indicate the effectiveness of a
substance.
 Normally, effective dose refers to the beneficial
effect (relief of pain) and it may also stand for
harmful effect (paralysis).
 Thus the specific endpoints must be indicated.
 The usual terms are:
o ED0-effective for 0% of the population
o ED10- effective for 10% of the population
o ED50- effective for 50% of the population
o ED90- effective for 90% of the population
Toxic doses (TDs)
 utilized to indicate doses that cause adverse toxic
effects. the usual dose limits are listed below:
o TD0- toxic to 0% of the population
o TD10- toxic to 10% of the population
o TD50- toxic to 50% of the population
o TD90- toxic to 90% of the population
THERAPEUTIC INDEX
 used to compare the therapeutically effective dose to the
toxic dose.
 The TI is a statement of relative safety of a drug. It is the
ratio of the dose producing toxicity to the dose needed
to produce the desired therapeutic response.
 the common method used to derive the TI is to use the
50% dose-response points.
 TI = LD50/ED50
 eg. if the LD50 is 200 and the ED50 is 20mg, the TI would
be 10 (200/20).
 A clinician would consider a drug if it had a TI of 10 than
if it had a TI of 3 which means the higher the TI the safer
the drug or substance.
The use on the ED50 and LD50 doses to derive the TI may be
misleading as to safety. Depending on the slope of the dose-
response curves for therapeutic and lethal effects. To
overcome this deficiency, toxicologists often use another
term to denote the safety of a drug - the MOS or Margin of
Safety.
THE MARGIN OF SAFETY
 is usually calculated as the ratio of the dose that is just
within the lethal range (LD01) to the dose that is 99%
effective (ED99).
 MOS = LD01/ED99
 the physician must use caution in prescribing a drug in
which the MOS is less than 1
Other terms that can also be used are:
 LC50 median lethal concentration, used in inhalational
routes
 TLC - threshold limit concentration, also TLV (treshold
limit value), maximum amount that a chemical is
considered safe
 bioavailability - rate and extend of drugg absorption
 Vd - volume of distribution, hypothetical volume of bodt
fluid in which the drug is distributed
 T 1/2 - half-life, time required to reduce the blood
concentration of drug to half
 pH=pKa - half neutralization point, pH at which ionized
and unionized portion of the substance is equal
TOXIC EFFECTS
 toxicity can result from adverse cellular, biochemical
or macromolecular changes.
 Examples are:
 cell replacement such as fibrosis
 damage to an enzyme system
 disruption of protein synthesis
 production of reactive chemicals in the cell
 DNA damage
Some xenobiotics may also act indirectly by:
 modification of an essential biochemical function
 interference with nutrition
 alteration of a physiological mechanism
FACTORS INFLUENCING TOXICITY
 form and innate chemical activity
 dosage (esp the dose-time relationship)
 exposure route
 species
 age
 sex
 ability to be absorbed
 metabolism
 distribution within the body
 excretion
 presence of other chemicals
The form of a substance may have a profound impact on its
toxicity especially for metallic elements.
 eg. toxicity of metallic vapor differs greatly from the
mhyl mercury (liquid). chromiun Cr3+ is relatively
nontoxic while Cr8+ causes skin or nasal corrotion
and lung cancer
The innate chemical activity of substances varies greatly.
some can quickly damage cells causing immediate death,
others slowly interfere only with a cell's function.
 eg. hydrogen canide binds to cytochrome oxidase
resulting in cellular hypoxia and rapid death nicotine
binds to cholinergic receptors in the CNS altering
nerve conduction and inducing gradual onset of
paralysis
The dosage is the most important and critical factor in
determining if a substance will be an acute or chronic
toxicant.
 Virtually all chemicals can be an acute toxicants if in
sufficiently large dosage are administered. Often the
toxic mechanisms and target organs are different for
acute and chronic toxicity.
Toxicant Acute Toxicity Chronic Toxicity
Ethanol CNS depression Liver cirrhosis
Arsenic GI damage Skin/liver cancer
Exposure route is important in determining toxicity. Some
chemicals may be highly toxic by one route but not by others.
Two major reasons are differences in absorption and
distribution within the body.
 eg. ingested chemicals. when absorbed from the
intestine, distribute first to the liver and may be
immediately detoxified inhaled toxicants
immediately enter the general blood circulation and
can distribute throughout the body prior to being
detoxified by the liver
Most species differences are attributable to differences in
metabolism. Others may be due to anatomical or
physiological differences.
 eg. rats cannot vomit and expel toxicants before
they are absorbed or cause severe irritation,
whereas humans and dogs are capable of vomiting
 Selective toxicity refers to species differences in
toxicity between two species simultaneously
exposed. This is the basis of effectiveness of
pesticides.
 eg. insecticides are lethal to insets but are relatively
nontoxic to animals, antibiotics are electively toxic to
microorganisms while virtually nontoxic to humans
Age may be important in determining the response to
toxicants. Some chemicals are more toxic to infants or the
elderly than to young adults.
Although uncommon, toxic responses can vary depending on
sex.
 eg. male rats are 10 times more sensitive to DDT
than female rats but are twice more sensitive to
parathion compared to male rats
The ability to be absorbed is essential for systemic toxicity to
occur Some chemicals are readily absorbed than others. The
rates and extent of absorption may vary greatly depending of
the form of the chemical and the route of exposure.
 eg. nearly all alcohols are readily absorbed when
ingested, whereas there is virtually no absorption for
most polymers.
 Ethanol is readily absorbed in the GI tract but poorly
absorbed through the skin.
 organic mercury is readily absorbed from the GI
tract; inorganic lead sulfate is not
Metabolism (aka biotransformation) is a major factor in
determining toxicity. the products of metabolism are known
as metabolites. There are two types of metabolism -
detoxification and bioactivation.
 Detoxification is the process by which a xenobiotic is
converted to a less toxic form. this is a natural
defense mechanism of the organism. Generally this
process converts lipid-soluble compounds to polar
compounds.
 Bio activation is the process by which a xenobiotic
may be converted to a more reactive or toxic forms.
The distribution of toxicants and toxic metabolites
throughout the body ultimately determines the site where
toxicity occurs. A major determinant of whether or not a
toxicant will damage cells is its lipid solubility. If a toxicant is
lipid-soluble, it readily penetrates cell membranes. many
toxicants are stored in the body. Fat tissue, liver, kidney, and
bones are the most common storage deposits. The blood
serves as the main avenue for distribution. Lymph also
distributes some minerals.
The site and rate of excretion is another major factor
affecting the toxicity of a xenobiotic. The kidney is the
primary excretory organ, followed by the GI tract, and the
lungs (for gases). Xenobiotics may also be excreted in sweat,
tears, and milk.
 A large volume of blood is filtered through the
kidney. Lipid-soluble toxicants are reabsorbed and
 concentrated in the kidney cells. Impaired kidney
function causes slower elimination of toxicants and
increases their toxic potential.
The presence of other chemicals may decrease toxicity
(antagonism), add to toxicity (addition), increase toxicity
(synergism or potentiation) of xenobiotics.
 eg. alcohol may enhance the effect of mani
antihistamines and sedatives
 antidotes function by antagonizing the toxicity of a
poison (atropin counteracts poisoning by
organophosphate insecticides)
SYSTEMIC TOXIC EFFECTS
Toxic effects are generally categorized according to the site of
the toxic effect. In some cases, the effect may occur only at
one site. This site is referred to as specific target organ, and
some may occur at multiple sites referred to as systemic
toxicity.
The following are types of systemic toxicity:
 Acute toxicity
 Subchronic toxicity
 Chronic toxicity
 Carcinogenicity
 Developmental toxicity
 Genetic toxicity (somatic cells)
ACUTE TOXICITY
 This occurs almost immediately (minutes/ hours/
days) after an exposure. An acute exposure is usually
a single dose or a series of doses received within a
24 hour period. Death s a major concern in cases of
acute toxicity.
SUBCHRONIC TOXICITY
 this results from repeated exposure for several
weeks or months. This is a common human exposure
pattern for some pharmaceuticals and
environmental agents.
CHRONIC TOXICITY
 this represents a cumulative damage to specific
organ systems and takes many months or years to
become a recognizable clinical disease.
 Damages due to subclinical individual exposures may
go unnoticeable.
 With repeated exposures or long-term continual
exposure, the damage from these subclinical
exposures slowly builds up (cumulative damage)
until the damage exceeds the threshold for chronic
toxicity.
 Ultimately, the damage becomes so severe that the
organ can no longer function normally and a variety
of chronic toxic effects may result.
CARCINOGENICITY
 is a complex multistage process of abnormal cell
growth and differentiation which can lead to cancer.
At least two stages are recognized. They are
initiation in which a normal cell undergoes
irreversible changes and promotion in which
initiated cells are stimulated to progress to cancer.
chemicals can act as initiators and promoters.
 The initial neoplastic transformation results from the
mutation of the cellular genes that control norml cell
function. The mutation may lead to abnormal cell growth.
It may involve loss of suppressor genes that sually restrict
abnormal cell growth, as well as many other factors
(hormones, growth factor, immune supression)
 a tumor (neoplasm) is simply an uncontrolled growth of
cells. Benign tumors grow at the site of origin, does not
invade adjacent tisues or metastisize; and generally are
treatable. Malignant tumors (cancer) invade tissues or
migrate to distant sites (metastasis). They are more
difficult to treat and often cause death.
DEVELOPMENTAL TOXICITY
 this pertains to adverse toxic effects to the
developing embryo or fetus. this can result from
oxicant exposure to either parent before conception
or to the mother and her developing embryo-fetus.
 TYPES:
o Embryolethality- failure to conceive,
spontaneous abortion or stillbirth
o Embryotoxicity- growth retardation or
delayed growth of specific organ system
o Teratogenicity- reversible conditions that
leave permanent birth defects in the live
offspring (cleft palate, missing limbs)
Chemicals can cause developmental toxicity by two methods. They
can act directly on cells of the embryo causing cell death or cell
damage, leading to abnormal organ development. A chemical may
also induce a mutation in a parent's germ cell which is transmitted
to the fertilized ovum. Some mutated fertilized ova develop into
abnormal embryo.
GENETIC TOXICITY
 results from DNA damage and altered genetic
expression. This process is known as mutagenesis.
The genetic change is referred to a mutation and the
agent causing the change is a mutagen.
 TYPES:
o GENE MUTATION-change in DNA sequence
within a gene
o CHROMOSOME ABERRATION- change in
chromosome structure
o ANEUPLOIDY/POLYPLOIDY-increase or
decrease in number of chromosomes
If the mutation occurs in a germ cell, the effect is heritable. There is
no effect on the exposed person; rather the effect is passed on to
future generations. If the mutation occurs in a somatic cell, it can
cause altered cell growth (eg. cancer) or cell death (eg.
teratogenesis) in the exposed person.
ORGAN SPECIFIC TOXIC EFFECTS
 Blood/ Circulation toxicity
 Dermal/ Ocular toxicity
 Genetic toxicity (germ cells)
 Hepatotoxicity
 Immunotoxicity
 Nephrotoxicity
 Neurotoxicity
  Reproductive toxicity
 Respiratory toxicity
Cardiovascular and Blood toxicity
 results from xenobiotics acing directly on cells in
circulating bloof, bone marrow and heart.
 hypoxia due to CO binding of hemoglobin preventing
O transport
 decrease in circulating leukocytes due to
chloramphenicol damage to bone marrow cells
 leukemia due to benzene damage of bone marrow
cells
 arteriosclerosis due to cholesterol accumulation in
the arteries and veins
Dermal Toxicity
 may result from direct contact or internal
distribution to the skin. effects range from mild
irritation to severe changes such as corrosivity,
hypersensitivity, and skin cancer.
 dermal irritation due to skin exposure to gasoline
 dermal corrotion due to skin exposure to sodium
hydroxide
 dermal hypersensitivity due to skin exposure to
poison ivy
 skin cancer due to ingestion or arsenic or skin
exposure to UV light
Eye Toxicity
 reults from direct contact or internal distribution to
the eye. The cornea and conjunctive are directly
exposed to toxicants.
 Thus, conjunctivitis and corneal erosion may be
obsrved following occupational exposure to
chemicals. Chemicals in the circulatory system can
distribute to the eye and cause corneal opecity,
cataracts, retinal and otic nerve damage
 acids and strong alkali may cause severe corneal
corrosion
 corticosteroids may cause cataracts
 methanol (wood alcohol) may damage the optic
nerve
Hepatotoxicity
 toxicity to the liver, bile duct and gall bladder. The
liver is particularly susceptible to xenobiotics due to
a large blood supply and its role in metabolism. Thus
it is exposed to high doses of the toxicant or its toxic
metabolites.
PRIMARY FORMS DEFINITION
OF
HEPATOTOXICITY
Steatosis (fatty lipid accumulation in the hepatocytes
liver)
Chemical inflammation of the liver
hepatitis
Hepatic necrosis death of the hepatocytes
Intrahepatic backup of bile salts into the liver cells
cholestasis
Hepatic cancer cancer of the liver
Cirrhosis chronic fibrosis, often due to alcohol
Hypersensitivity immune reaction resulting in hepatic
necrosis
Immunotoxicity
 the toxicity of the immune system. It can take
several forms namely hypersensitivity (allergy and
autoimmunity), immunodeficiency, and uncontrolled
proliferation (leukemia and lymphoma)
 The normal function of the immune system is to
recognize and defend against foreign invaders. This
is accomplished by production of cells that engulf
and destroy the invaders or by antibodies that
inactivate foreign material.
 contact dermatitis due to exposure to poison ivy
 systemic lupus erythematosus in workers exposed
to hydralazine
 immunosuppression by cocaine
 leukemia induced by benzene
Nephrotoxicity
 the kidney is highly susceptible to toxicants for two
reasons. A high volume of blood flows through it and
it filters large amounts of toxins which can
concentrate in the kidney tubules. Nephrotoxicity is
toxicity to the kidneys and can result in systemic
toxicity causing:
o decreased ability to excrete body waste
o inability to maintain body fluid and
electrolyte balance
o decreased synthesis of essential hormones
(eg. erythropoietin)
Neurotixicity
 represents toxicant damage to cells of the central
nervous system (brain and spinal cord) and the
peripheral nervous system (nerves outside the CNS).
The primary types of neurotoxicity are:
 neuronopathies (neuron injury)
 axonopathies (axon injury)
 demyelination (loss of axon insulation)
 interference with neurotransmission
Reproductive Toxicity
 involves toxicant damage to either the male or
female reproductive system. Toxic effects may
cause:
o decreased libido and impotence
o infertility
 o interrupted pregnancy (abortion, fetal 1+0=2
death or premature delivery)  expose to one chemical results in the other chemical
o infant death or childhood morbidity produing an effect greater than if given alone
o altered sex ratio and multiple births  occurs when a chemical that does not have a specific
o chromosome abnormalities and birth toxic effect makes another chemical more toxic
defects  the hepatotoxicity of carbon tetrachloride is greatly
o childhood cancer enhanced by the presence of isopropanol. Such
exposure may occur in the workplace
Respiratory Toxicity  Normally, warfain is bound to plasma albumin so
 relates to effects on the upper respiratory system that only 2% of the drug is active. Drugs which
(nose, pharynx, larynx, trachea) and the lower compete for binding sites on albumin increases the
respiratory tract (bronchi, bronchioles, and lung level of free warfarn to 4% causing fatal
alveoli) The primary types of respiratory toxicity are: hemorrhage.
o pulmonary irritation (itchy throat)
o asthma/ bronchitis Antagonism
o reactive airwway disease 1+1=0
o emphysema - COPD  exposure to one chemical results in a reduction of
o allergic alveolitis effects of the other chemical
o fibrotic lung disease  often a desirable effect in toxicology and is the basis
o pneumoconiosis for most antidotes
o lung cancer
Functional antagonism- 2
TOXICODYNAMICS - chemicals counterbalance eachother by producng
Chemical Interactions oposite effects on the same physiologi function (eg.
 Additive epi+diazepam)
 Synergism Chemical antagonism (inactivation)
 Potentiation - chemical reation between 2 compounds that
 Antagonism produce a less toxic product (eg. chelators and
metals)
Additive Dispositional antagonism
1+1 = 2 - alters ADME so that concentration or duraion at
 a combination of two or more chemicals is a dum of target site is diminished (eg. ipecac, charcoal,
the expected individual responses. diuretics)
 the most common type of interaction Receptor antagonism (blockers)
 2 CNS depressants taken at the same time, a - clinical treatment by competitive binding to the
tranquilizer and alcohol. Often causes depression same receptor(eg. attropine and organophosphates
equal to the sum of that caused by each drug to block cholinesterase receptors)
 Oganophoosphate insecticides interfere with nerve
conduction. The toxicity of the combination of two TYPE OF TOXIC EFFECT TOXIC EFFECT COMBINED
INTERACTION CHEMICAL A CHEMICAL B EFFECT
organophosphate insecticides is equal to the sum of CHEMICALS A + B
each
ADDITIVITY 20% 30% 50%
Synergism ANTAGONISM 20% 30% 5%
1+1=3 POTENTIATION 0% 20% 50%
 exposure to one chemical causes a dramatic increase SYNERGISM 5% 10% 100%
in the effect of another chemical
 this interaction can have serious health effects. This table quantitatively illlustrates the percent of the
Exposure to chemical may drastically increase the population affected but individual exposure to chemical A
effect of another chemical. and chemical B as well as exposure to combination of
 exposure to both cigarette smoke and radon results chemicals A and chemical B. It also gives the specific
in a significantly higher risk for lung cancer than the interactions.
sum of the risks for each. Toxicokinetics
 The combination of exposure to asbestos and  is the study of kinetics of a poison
cigarette smoke results in a significantly greater risk  this is essentially the study of how a substance gets
for lung cancer than the sum of the risks of each. into the body and what happens to it in the body
 The hepatotoxicity of a combination of ethanol and
carbon tetrachloride is much greater than the sum of A - Absorption - the substance enters the body
the hepatotoxicity of each D - Distribution - the substance moves from the site of entry
Potentiation to other areas of the body
M - Metabolism - the body changes the substance into new industrial chemicals. Exposure of the public to inadequately
chemicals tested drugs or environmental agents has resulted in several
E - Excretion - the substance or its metabolites leave the body notable disasters. By the mid-twentieth century, disasters
Absorption were becoming commonplace with increasing rate of
development of new synthetic chemicals. Knowledge of
Route of Exposure potential toxicity was absent prior to exposures of the

decreasing onset
- injection/ intravascular general public.
- inhalation
- skin/ eye absorption Knowledge of toxicity of xenobiotics to humans is derived by
- ingestion/ oral three methods:
- dermal
 Clinical Investigation
 Epidemiological studies
 Adverse Reactions to drug reports
Absorption through: Clinical Investigations
 intravenous - 100% bioavailability  the administration of chemicals to huan subjects
 inhalation - absorbed systematically; with careful clinical observations and laboratory
 effective route for substance <0.5 micrometers measurement.
 skin/ dermal - skin is lipophilic  these are a component of the Investigational New
 oral - most common route of administration Drug Application IND) submitted to the FDA. Clinical
Investigations are conducted only after the non-
Duration of exposure: clinical laboratory studies have been completed.
 acute = 1 day or <24 hours Toxicities using human subjects require strict ethical
 subacute = 30 days or less considerations. They are primarily conducted for new
 subchronic = 1 - 3 months pharmaceutical applications submitted to FDA for approval.
 chronic = more than 3 months
The FDA investigations are conducted in three phases.
Elimination PHASE 1 - conducting of testings of the drug in a small group
 Biliary of 20-80 patients. Information obtained in this phase is used
 Renal to design phase 2 studies. In particular to determine the
 Fecal drug's pharmacokinetics and pharmacological effects,
 Respiratory elucidate its metabolism and study the mechanism of action
Pharmacokinetic Parameters of the drug
 Volume of Distribution - defined as the apparent
volume into which a substance is distributed PHASE 2 - studies are more extensive involving several
o a large Vd implies that the drug is readily hundred patients and are used to determine the sort-term
accessible to measures aimed at purifying side effects of the drug, determine the risks associated with
blood, such as hemodialysis. the drug and evaluate the effectiveness of the drug for
o Vd >5L/kg are antidepressants, treatment of a particular disease or condition
antipsychotics, antimalarils, opioids,
propranolol, and verapamil PHASE 3- studies are expanded controlled and uncontrolled
o drugs with very small Vd (<1L/kg) includes trials conducted with several hundred to several thousand
salicylates, ethanol, phenobarbital, lithium, patients. They are designed to gather additional information
valproic acid and phenytoin about the effectiveness and safety, evaluate overall benefit -
 Clearance - measure of volume of plasma that is risk relationship of the drug, and provide the basis for the
cleared of drug per unit time precautionary information that accompanies the drug.

In planning for detoxification strategy it is important to know

the contribution of each organ to total clearance.
TOXICITY TESTING METHODS
The knowledge of toxicity is primarily obtained through study
and observation of people during normal use of a substance
or from accidental exposures, experimental studies using
animals, and studying using test subjects. Most chemicals are
now subject to stringent government requirements for safety
testing before they can be marketed. These is especially true
for pharmaceuticals, food additives, pesticides, and
Epidemiology Studies
 these are conducted using human populations to
evaluate whether there is a causal relationship
between exposure to a substance and adverse
health effects. These studies differs from clinical
investigations in that individuals have already been
administered the drug during medical treatment or
have been exposed to it in the workplace or
environment. This studies measures the risks of
illness or death in an exposed populations compared
 to the risk in an identical (eg, same age, sex, race.
social status, etc.) unexposed population.
 exposure status. Recall bias
Cohort (group) Studies
 the most commonly conducted epidemiology
studies. They frequently involve occupational
exposures.Exposed persons are easy to identify and
exposure levels are usually higher than in the
general public. There are two types of cohort
studies:
TYPE DEFINITION
Prospective cohorts are identified based on
cohort study current exposures and followed into
the future
Retrospecive cohorts are identified based on past
cohort exposure conditions and follow-up
studies proceeds forward in time
to determine if the epidemiologial data are meaningful,
standard, quantitative measures of effect are employed. The
most commonly used are:
DEFINITION
odds ratio the ratio of risk of disease in a case-
(O/R) control study for an exposed study
group to an unexposed study group. n
O/R=2 means that the exposed
grouphas twice the risk as the non-
exposed group
Standardized the relative risk of death based on a
mortality ratio comparison of an exposed group to
(SMR) non-exposed group. An SMR=150
indicates that there is a 50% greater
risk
relative risk the ratio expressing the occurrence of
(RR) disease in an exposed population to
that of unexposed population. An RR-
175 indicates a 75% risk
 there are a number of aspects in designing an
epidemiology study. The most crucial are
appropriate controls, adequate time span, and
statistical ability to detect an effect.
 the control population used as a comparison group
must be as similar as possible to that of the test
group.
 the statistical ability to detect an effect is referred to
as the power of the study. To gain precision, the
study and control populations should be as large as
possible.
Epidemiologists attempt to control errors that may occur in
the collection of date. These errors, aka bias errors, are of
three main types:
TYPE DEFINITION
selection bias occurs when the study group is
not representatives of the
population from which it came
information occurs when the study subjects
bias are misclassified as to disease or
occurs when individuals are
asked to remember exposures
or conditions that existed years
before
confounding occurs when the study and
bias control populations differ with
respect to factors which may
influence the occurance of the
disease.
Animal testing for toxicity
 animal tests for toxicity are conducted prior to
human clinical investigations as pert of the non-
clinical laboratory tests for pharmceuticals. For
pesticides and insecticides, human testing is rarely
conducted. Animal test results often represent the
only means by which toxicity in humans can be
effectively predicted.
 with animal tests chemical exposure can be precisely
controlled, environmental conditions can be well-
controlled, virtually any type of toxic effect can be
evaluated and the mechanism by which toxicity
occurs can be studied
 methods to evaluate toxicity exists for a wide variety
of toxic effects. Some procedures fr rooutine safety
testing have been standardized. Standardized animal
toxicity tests are highly effective in detecting toxicity
that may occur in humans. Concern for animals
welfare has resulted in tests that use humane
proceduresand the number of animals needed for
statistical relliability.
Standardized tests ave been developed for the following
effects:
 Acute toxicity
 Subchronic toxicity
 Chronic toxcity
 Carcinogenicity
 Reproductive toxicity
 Developmental toxicity
 Derml toxicity
 Ocular toxicity
 Neurotoxicity
 Genetic toxicity
Species selection varies with the toxicity tests to be
performed. There is no single species of animal that can be
used for all toxicity tests. Different species may be needed to
assess different types of toxicity. In some cases, it may not be
possible to use the most desirable animals for the testing
because of animal welfare or cost considerations. For
example, the use off monkeys and dogs is restricted to special
cases, even if they represent the species that may react
closest to humans. Rodent and rabbits are most commonly
used laboratory species due to their availability, low cost in Observation Period 90 days (same as treatment period)
breeding and housing, and past history in producing reliable
results. Chronic Toxicity
The toxicologist attempts to design an experiment to  determines the toxicity from exposure for a
duplicate the potential exposure of humans as closely as substantial portion of a subjects life. They are similar
possible. to the subchronic tests except that they extend over
For example the route of exposure should stimulate a longer period of time and involve larger groups of
taht of human exposure like that of inhalational, animals. Basic parameters of these tests are:
oral, dermal, the age of test anmals should relate to PARAMETER DESCRIPTION
that of humans (testing is usually done with young
Species rodent and non-rodent (rat and dog0 -
adults although newborn and pregnant animals may
recommended two species; for
be sed in some cases), for most routine tests, both
comparison
sexess are used because sex differences in toxic
responses are minimal except for some with Age young adult
hormonal properties, dose levels are normally Number of 20 of each sex for rodents, 4 of each sex
selected so as to determine the threshold as well as animals for non-rodents per dose level
dose-response relationship, usually a minimum of
Dosage tree dose levels recommended; includes
three dose levels are used.
a toxic level and NOAEL; exposures
generally for 12 months; FDA requests
Acute Toxicity
24 months for food chemicals
 generally the forst tests conducted. they provide
Observation 12 - 24 months
data on the relative toxicity likely to arise from a
Period
single or brief exposure.
 Standardized tests are available for oral, dermal, and
inhalational exposures. Basic parameters for these
tests are: Carcinogenicity
PARAMETER DESCRIPTION  similar to chronic toxicity tests. However they
Species rats - for oral and dermal tests; extend over a longer period of time and require
rabbits - for dermal tests larger groups of animals in order to assess the
Age young adults potential for cancer. Basic parameters of these tests
Number of animals 5 of each per dose level are:
Dosage three dose levels recommended; PARAMETER DESCRIPTION
exposures are single dose or Species testing in two rodent secies - rat and
fractionated doses up to 24 hours mouse - preferred due to relatively short
for oral and dermal studies and 4 life span
hour exposure for inhalational Age young adults
studies Number of 50 of each sexper dose level
Observation Period 14 days animals
Dosage three dose levels recommended; highest
Subchronic Toxicity should produce minimal toxicity; exposure
 employed to determine toxicity likely to arise from periods are at leaast 18 months for mice
repeated exposures of several weeks to several and 24 months for rats
months. Standardized tests are available for oral, Observation 16 - 24 months for mic and 24 - 30 months
dermal, and inhalational exposures. Detailed clinical Period for rats
observations and pathology examinations are
conducted. Basic parameter of these tests are: Reproductive Toxicity
PARAMETER DESCRIPTION intended to determine the effects of substances on gonadal
Species rodents (usually rats) - for oral and function, conception, birth, and the growth and development
inhalational studies; rabits - for of the offspring. The oral route is preferred. Basic parameters
dermal studies; non-rodents (usually for these tests are:
dogs) recommended as a second PARAMETER DESCRIPTION
species for oral studies Species rats - recommended
Age young adults Age young adult
Number of animals 10 of each sex for rodents, 4 of each Number of 20 of each sex per dose level
sex for non-rodents er dose level animals
Dosage three dose levels plus a control Dosage three dose levels recommended; highest
group; include a toxic dose level plus dose should produce toxicity but not
NOAEL; exposures are 90 days
 mortality in parents; lowest should not
produce toxicity
Observation test substance given to parental animals
Period (P1) prior to mating,uring pregnancy and
through weaning of F1 offspring;
substance the given to selected F1
offspring during their growth into
adulthood, mating and production of an
F2 generation, until the /f2 generation is
21 days old
Developmental Toxicity
detects the potential for substance to produce embryotixicty
and birth defects. Basic parameters of these tests are:
PARAMETER DESCRIPTION
Species two species recommended: rat, mouse,
hamster, and rabbit are most commonly
used
Age young adult females
Number of 20 pregnant females per dose level
animals
Dosage at least three dose levels are used;
throughout organ development in the
fetus for teratogenic effects; starts with
parents prior to breeding, continue
during pregnancy all developmental
effects
Observation offspring sacrifices and examined day
Period prior to expected birth for teratogenic
effects; offspring observec for growth
retardation and abnormal function
through infancy and examined for
teratogenic effects
Dermal Toxicity
determine the potential for an agent to cause irritation and
inflammation of the skin. This may be the result of direct
damage to the skin cells by a substance. It amy also be an
indirect response due to sensitization from prior exposure.
Basic paramenters of these tests are:
PARAMETER DESCRIPTION
Primary Dermal dedtermines direct toxicity. The
Irritation substance is applied to the skin of 6
albino rabbits for 4 hours and the
rabbits are observed for 2 hours for
irritation.
Dermal assays for immune hypersensitivity of
Sensitization the skin. It consists of two phases. In
the sensitization phase, the test
substance is applied to the skin of
guinea pigs for 4 hours. There should
be no skin inflammation. At least one
week later, the substance is reapplied
to the skin. This is known as e
challenge phase. An inflammatory
reaction indicates that the skin has
been sensitized to the substance.
Neurotoxicity
A battery of standardized neurotoxicity tests have been
developed to supplement the delayed neurotoxicity tests in
domestic chickens (hens). The hen assay determines delayed
neurotoxicity reulting from exposure to anticholinergic
substances, such as certain pesticides. The hens are
protected from the immediate neurological effects of the test
substance and observed for 21 days for delayed
neurotoxicity. Other neurotoxicity tests includes
measurements of:
MEASUREMENT DESRIPTION
Motor activity tests for decreased motor activity,
such as cage movement. Rats or mice
are used
Peripheral nerve tests for electrical conduction in
conduction motor and sensory nerves. Rodents
are exposed for 90 days to the test
substance
Neuropathology estor nerve damage by microscopic
examination. This is one aspect of
other standardized toxicity tests
Genetic Toxicity
determined using a wide range of test species including
whole animals and plants. A variety of tests have been
developed to measure gene mutations, chromosome
changes, and DNA activity. The most common gene mutation
tests are:
TEST DESCRIPTION
Microorganism Salmonella typhimurium and E. coli
are commonly used bacterial tests.
The s. typhimurium assay is
commonly known as the Ames test.
Yeast are also used to detect gene
mutation in culture systems
Mammalian two main cell lines used are the
cells maouse lymphona and Chinese
hamster ovary (CHO) cells
Fruit flies Orosophila melanogester is used to
detect sex-linked recessive lethal
mutations
Mice the mouse specific locus test is thajor
gene mutation test that employs
whole animals. Exposed mice are
bred and bserved for hereditary
changes
 Organochlorines
4 categories:
POISONS  Indane, Chlordane, Aldrin
Agricultural Poisons  Chlorobenzene, DDT, Phenothane
CLASSIFICATION EXAMPLES  BHC, Lindane, Gammaxan
Insecticides Pyrethroids, Organophosphates,  Camphenes, Toxaphene, Strobane
Carbamates, Manganese compounds Absorption: fatal dose
Herbicides Bipyridyls, Chlorophenoxy,
Giyphosate, Acetanilides, Triazines
Fungicides Thiocarbamates, Dithiocarbamates,
Cupric salts, Tiabendazoles, Triazoles,
Dicarbomides, Dinitrophenols,
Organotin compounds, Miscellaneous
Insect repellants Diethyltoluamide (DEET)
Rodenticides Warfarin, Indanodiones
Fumigants Aluminum and Zinc phosphates,
Methyl bromide, Ethylene dibromide

Organophosphates
 malathion (Maloxon), parathion (Paraoxon) -
pesticides
 MOA: irreversibly inhibits acetylcholinesterase which
results in abundance of acetylcholine
 treatment: Atropine, 2-PAM (Pralidoxime
(Acetylcholinesterase Regenerator))
Muscarinic Nicotinic
Diarrhea Skeletal Muscles
Urination Muscle Fasiculations
Miosis Twitching
Bradycardia Ganglionic
Bronchoconstriction Tachycardia
Emesis Hypertension
Excitation
Lacrimation
Salivation
Sweating

Carbamates
 derivatives of carbonic acid
 Aldicarb (temik), Aminocarb (metacil), Aprocarb
(baygon), Carbaryl (sevin), Carbofuran (furaxdan)
 HIGHLY TOXIC: Carbaryl, Carbofuran, Propoxur,
Methomyl
 same Signs and symptomswith organophosphates
and appears within 15 minutes to 2 hours
 treatment: specific antidote - Atropine
 pralidoxime may diminish some severity of
symptoms and help prevent some morbidity
 improves respiratory functions and patient well
being
 differ Toxicologically from organophosphates
 spontaneously hydrolyse AChterase enzymatic site
within 24-48 hours
 does not penetrate CNS = less neurotoxic