TOXICOLOGY PRELIMS ➢ Heart – Digitalis, Oxalic acid

TOXICOLOGY(PRELIM) ➢ Stomach – Antimony, Arsenic

➢ Urinary organs – Cantharides
Poison
➢ Uterus – Ergot
• Is any agent capable of producing a ➢ Lungs – Chlorine (gas)
deleterious response in a biological system ➢ Blood – CO
• Any substance that can cause severe organ
Factors that modify the effects of Poisons:
damage or death if ingested, breathed in,
injected into the body or absorbed through 1. Those attributed to the individual
the skin. ➢ Age
➢ Health
Types of Poisoning
➢ Habit
a) Acute poisoning ➢ Sex
b) Chronic poisoning ➢ Sleep
➢ Exhaustion
Legal point of view:
➢ Idiosyncrasy
1. Accidental – poison was taken without ➢ mental / physical state
intention to cause death ➢ condition of the stomach
2. Suicidal – poison was taken voluntarily for ➢ characteristic & amount of the
the purpose of taking his own life stomach content
3. Homicidal – poison was taken willfully, 2. those attributed to the poison
wantonly and with intent to cause death to ➢ physical state / form of poison
the victim ➢ mode of administration
4. Undetermined – the history is hazy as to ➢ size of dose
how the poison was obtained and why it ➢ association with other poisons
was administered (chemical, mechanical)
➢ dilution
Kinds of Poisons:
Classification of Poisons according to:
1) Corrosive poison – one which by contact
chemically causes local destruction of ➢ Origin
tissue. When swallowed, it usually produces ➢ Characteristic effects / properties
nausea, vomiting and local distress. Ex. ➢ Chemical properties
Acids &alkalies ➢ Physiological effects
2) True poison – still poisonous no matter how ➢ Site of action
Highly diluted. Ex. Atropine & strychnine a. According to Origin:
3) Cumulative poison – one which increases • Vegetable- Morphine, Atropine,
suddenly in its intensity of action after slow Aconitine, Nicotine
addition of it. Ex. Ipecac, Calomel, Lead, • Animal – Snake venom, Epinephrine,
Carbon monoxide, Strychnine, Mercury and Insulin
Arsenic • Mineral – Arsenic, Mercury,
Antimony molecule
Some poisons affect certain organs in particular:
• Synthetic – Barbiturates,
➢ Brain – Opium, Barbiturate, Alcohol Antihistamine, Tranquilizers
➢ Spinal cord – Strychnine
➢ Motor system of nerves – Curare
 b. According to characteristic effects ➢ Mineral alkalies
1. Corrosive poisons- ex. Mineral acids, ▪ Carbonates &
glacial acetic acid, alkalies Hydroxides of:
a) Irritant – Arsenous acid, ▪ Ammonium
Antimony, Potassium ▪ Potassium
tartrate, Oxalic acid ▪ Sodium
b) Gaseous poisons – Hydrogen II.Organic
sulfide, Chlorine, CO ➢ Volatile organic poisons
2. Systemic poisons act on the nervous ▪ Alcohol
system or upon the heart, liver, ▪ Chloral hydrate
kidneys or lungs with having any ▪ Chloroform
special corrosive or irritant effect ➢ Alkaloids
such as: ▪ Atropine
➢ Strychnine ▪ Brucine
➢ Brucine ▪ Colchicine
➢ Cyanide ➢ Animal poisons
➢ Aconitine ▪ Bee
3. Biological poisons poisoning that ▪ Wasp
may result from ingestion of food ▪ Insect bites
contaminated with dangerous ➢ Organic acids
pathogenic bacteria such as ▪ Acetic acid
➢ Mushrooms ▪ Oxalic acid
➢ Shellfish ▪ Tartaric acid
c. According to chemical properties: ➢ Glycosides
I.Inorganic ▪ Digitoxin
➢ Volatile Non-metallic ▪ Salicin
poisons ▪ Santonin
▪ Bromine ▪ Solanine
▪ Chlorine ➢ Bacterial food poison
▪ Iodine ▪ Toxins
▪ Phosphorous d. According to physiological effects:
▪ Hydrogen sulfide 1) Corrosives
➢ Metallic poisons 2) Irritants – produces irritation and/or
▪ Antimony inflammation of the mucous
▪ Arsenic membrane and characterized by
▪ Barium pain in the abdomen, vomiting and
▪ Copper purging Ex. Arsenic, Croton oil,
▪ Lead Cantharides
▪ Mercury 3) Asphyxiants – exerts their effects by
▪ Silver interfering with the oxidation of the
➢ Mineral acids tissues
▪ Chromic acid 4) Narcotics – produce stupor,
▪ Hydrobromic acid complete or incomplete insensibility
▪ HCL or loss of feeling Ex. Opium, Alcohol,
▪ Nitric acid Heroine
 5) Neurotic poison – actions directed
specially to the brain and spinal cord
6) Tetanics – act directly upon the
spinal cord producing spasmodic
and continuous contraction of the
muscles as a result of stiffness or
immobility of the parts to which
they are attached Ex. Strychnine
7) Deliriants – act upon the brain as to
disorder the mental faculties and
produce confusion of will power or
delirium Ex. Atropine
8) Depressants / Sedatives – agents
which retard or depress
physiological action of an organ Ex.
Cocaine, Nicotine
9) Asthenics / Exhaustives – agents
which produce exhaustion and
cause marked loss of vital or
muscular power Ex. Hydrocyanic
acid Digitoxin
e. According to the site of action:
1) Local effects – part of the body with
which the poison comes in contact
2) Remote effects – organs at distance
from the part to which poison has
been applied
3) Combined effects – poison is not
only localized at the site but also
affects remote organs
Numbers in Toxicology:
• Extremely toxic – 1 mg/kg or less
• Highly toxic – 1 to 50 mg/kg
• Moderately toxic – 50 to 500 mg/kg
• Slightly toxic – 0.5 to 5 g/kg
• Practically nontoxic – 5 to 15g/kg
• Relatively harmless – more than 15 g/kg
Modes of Death:
• Death beginning at the brain (Coma)
• Death beginning at the heart (Syncope)
• Death beginning at the lungs (Asphyxia)
Keypoints
• Toxicology is the study of the adverse
effects of xenobiotics on living systems
• Toxicology assimilates knowledge and the
techniques from biochemistry, biology,
chemistry, genetics, mathematics,
medicine, pharmacology, physiology, and
physics
• Toxicology applies safety evaluation and
risk assessment to the discipline
HISTORY OF TOXICOLOGY
In all branches of toxicology, scientists
explore the mechanisms by which chemicals
produce adverse effects in biological
systems. Activities in these broad subjects
complement toxicologic research.
Antiquity
• Knowledge of animal venoms and plant
extracts for hunting, warfare, and
assassination presumably predate recorded
history.
• One of the oldest known writings, the Ebers
Papyrus (circa 1500b.c.), contains
information pertaining to many recognized
poisons, including hemlock, aconite,
opium, and metals such as lead, copper,
and antimony The Book of Job (circa 1400
b.c.I speaks of poison arrows (Job 6:4)
• Hippocrates (circa 400 b.c.) added a
number of poisons and clinical toxicology
principles pertaining to bioavailability in
therapy and overdosage.
• Theophrastus (370–286b.c.), a student of
Aristotle, included numerous references to
poisonous plants in De Historia Plantarum.
• Dioscorides, a Greek physician in the court
of the Roman emperor Nero, made the first
attempt at classifying poisons as plant,
animal and mineral in his book De Materia
Modica, which contains reference to some
600 plants
• One legend tells of Roman King Mithridates
VI of Pontus, who was so fearful of poisons
 that he regularly ingested a mixture of 36
ingredients as protection against
assassination. On the occasion of his
imminent capture by enemies, his attempts
to kill himself with poison failed because of
his successful antidote concoction. T is tale
leads to use of the word mithridatic as an
antidote or protective mixture
• Because poisonings in politics became so
extensive. Sulla issued the Lex Cornelia
(circa 82 b.c.), which appears to be the first
law against poisoning and later became a
regulatory statute directed at careless
Middle Ages
• The writings of Maimonides (Moses ben
Maimon, a.d. 1135–1204) included a
treatise on the treatment of poisonings
from insects, snakes, and mad dogs
(Treatise on Poisons and Their Antidotes
1198). Maimonides described the subject of
bioavailability, noting that milk, butter, and
cream could delay intestinal absorption.
• Catherine de Medici tested toxic
concoctions, carefully noting the rapidity of
the toxic response (onset of action), the
effectiveness of the compound (potency),
the degree of response of the parts of the
body (specificity and site of action), and the
complaints of the victim (clinical signs and
symptoms).
Renaissance
• Philippus Aureolus Theophrastus
Bombastus von Hohenheim- Paracelsus
(who called himself Paracelsus) (1493–
1541), a physician-alchemist, formulated
many revolutionary views that remain
integral to the structure of toxicology,
pharmacology, and therapeutics today. He
focused on the primary toxic agent as a
chemical entity, and held that:
1. experimentation is essential in the
examination of responses to
chemicals
2. one should make a distinction
between the therapeutic and toxic
properties of chemicals
3. these properties are sometimes but
not always indistinguishable except
by dose, and
4. one can ascertain a degree of
specificity of chemicals and their
therapeutic or toxic effects.
• These principles led Paracelsus to articulate
the dose-response relation as a bulwark of
toxicology
Age of Enlightenment
• Magendie (1783–1885), Orfila (1787–1853),
and Bernard (1813–1878) laid the
groundwork for pharmacology,
experimental therapeutics, and
occupational toxicology.
• Orfila, a Spanish physician in the French
court, used autopsy material and chemical
analysis systematically as legal proof of
poisoning. His introduction of this detailed
type of analysis survives as the
underpinning of forensic toxicology. Orfila
published a major work devoted expressly
to the toxicity of natural agents in 1815.
• Magendie, a physician and experimental
physiologist, studied the mechanisms of
action of emetineand strychnine. One of
Magendie's more famous students, Claude
Bernard, contributed the classic treatise. An
Introduction to the Study of this
Experimental Medicine
• German scientists Oswald Schimiedeberg
(1838–1921) and Louis Lewin (1850-1929)
made many contributions to the science of
toxicology. Schmeideberg trained
approximately 120 students who later
populated the most important laboratories
of pharmacology and toxicology throughout
the world, Lewin published much of the
early work on the toxicity of
narcotics,
 methanol
glycerol
acrolein
chloroform
20TH CENTURY TOXICOLOGY: THE AWAKENING
OF UNDERSTANDING
With the advent of anesthetics and
disinfectants in the late 1850s, toxicology as
it is currently understood began. The
prevalent use of “patent” medicines led to
several incidents of poisonings from these
medicaments, which, when coupled with
the response to Upton Sinclair's exposé of
the meatpacking industry in The Jungle,
culminated in the passage of the Wiley Bill
in 1906, the first of many U.S. pure food
and drug laws.
During the 1890s and early 1900s, the
discovery of radioactivity and the vitamins,
or vital amines,” led to the use of the first
large-scale bioassays (multiple animal
studies) to determine whether these “new”
chemicals were beneficial or harmful to
laboratory animals.
One of the first journals expressly dedicated
to experimental toxicology, Archiv für
Toxikologie, began publication in Europe in
1930. T at same year the National Institutes
of Health (NIH) was established in the
United States. As a response to the tragic
consequences of acute kidney failure after
taking sulfanilamide in glycol solutions, the
Copeland bill was passed in 1938.
AFTER WORLD WAR II
• The mid-1950s witnessed the strengthening
of the U.S. FDAS commitment to toxicology
• Shortly after the Delaney amendment, the
firstAmerican journal dedicated to
toxicology, Toxicology and Applied
Pharmacology
• The 1960s started with the tragic
thalidomide incident, in which several
thousand children were born with serious
birth defects, and the publication of Rachel
Carson's Silent Spring (1962). Attempts to
understand the effects of chemicals on the
embryo and fetus and on the environment
as a whole gained momentum. New
legislation was passed, and new journals
were founded. Cellular and molecular
toxicology developed as a subdiscipline, and
risk assessment became a major product of
toxicologic investigation
21ST CENTURY TOXICOLOGY
• The sequencing of the human genome and
that of several other organisms has
markedly affected all biological sciences,
including toxicology. Genetically modifying
organisms is now common place and those
possessing orthologs of human genes
INTRODUCTION TO TOXICOLOGY
• Toxicology is the study of the adverse
effects of chemicals onliving organisms. A
toxicologist is trained to examine the
natureof those effects (including their
cellular, biochemical, andmolecular
mechanisms of action) and assess the
probability oftheir occurrence.
• The varietyof potential adverse effects from
the abundant diversity ofchemicals upon
which our society depends often demands
specialization in one area of toxicology.
Different Areas of Toxicology
• A mechanistic toxicologist identifies the
cellular, biochemical,and molecular
mechanisms by which chemicals exert
toxiceffects on living organisms (see
Chapter 3 for a detailed discussion of
mechanisms of toxicity). Mechanistic data
may be usefulin the design and production
of safer chemicals and in rationaltherapy for
chemical poisoning and treatment of
 disease. In riskassessment, mechanistic data
may be very useful in demonstrating that an
adverse outcome observed in laboratory
animals is directly relevant to humans.
Toxicogenomic permits the application of
genomic, transcriptomic, proteomic, and
metabolomic technologies to identify
descriptive and mechanisticinformation
that can protect genetically susceptible
individuals from harmful environmental
exposures, and to customize drugtherapies
based on their individual genetic makeup.
• A descriptive toxicologist is concerned
directly with toxicitytesting, which provides
information for safety evaluation
andregulatory requirements. Toxicity tests
(described later in thischapter) in
experimental animals are designed to yield
in formation that can be used to evaluate
risks posed to humans andthe environment
by exposure to specific chemicals.
• Regulatory toxicologist has the
responsibility for deciding,on the basis of
data provided by descriptive and
mechanistictoxicologists, whether a drug or
another chemical poses a sufficiently low
risk to be marketed for a stated purpose.
• Forensic toxicology is a hybrid of analytic
chemistry and fundamental toxicologic
principles that focuses primarily on
themedicolegal aspects of the harmful
effects of chemicals onhumans and animal.
• Clinical toxicology is concerned with
disease caused by oruniquely associated
with toxic substances (see Chapter 32)
• Environmental toxicology focuses on the
impacts of chemical pollutants in the
environment on biological
organismspecifically studying the impacts of
chemicals on nonhumanorganisms such as
fish, birds, terrestrial animals, and plants.
• Ecotoxicology, a specialized area within
environmental toxicology, focuses
specifically on the impacts of toxic
substanceson population dynamics in an
ecosystem (see Chapter 29).
• Developmental toxicology is the study of
adverse effects onthe developing organism
that may result from exposure tochemical
or physical agents before conception (either
parent)during prenatal development, or
postnatally until the time ofpuberty.
Teratology is the study of defects induced
duringdevelopment between conception
and birth.
• Reproductive toxicology is the study of the
occurrence ofadverse effects on the male or
female reproductive system thatmay result
from exposure to chemical or physical
agents (seeChapter 20)
Toxicology and Society
• Knowledge about the toxicologic effect of a
compound affectsconsumer products,
drugs, manufacturing processes,
wastecleanup, regulatory action, civil
disputes, and broad policydecisions. The
expanding infuence of toxicology on
societalissues is accompanied by the
responsibility to be increasinglysensitive to
the ethical, legal, and social implications of
toxicologic research and testing.There are
several ethical dilemmas in toxicology.
First, experience and new
discoveries in the biological sciences
havemphasized the need for well-
articulated visions of human,animal,
and environmental health.
Second, experience withthe health
consequences of exposure to such
things as lead,asbestos, and tobacco
has precipitated many regulatory
andlegal actions and public policy
decisions.
Third, we have anincreasingly well-
defined framework for discussing
our socialand ethical responsibilities.
Fourth, all research
involvinghumans or animals must be
 conducted in a responsible
andethical manner.
Fifth, the uncertainty and biological
variability inherent in the biological
sciences requires decision making
with limited or uncertain
information.
General Characteristics of the Toxic Response
• Virtually every known chemical has the
potential to produceinjury or death if it is
present in a sufficient amount. Table 2-
1shows the wide spectrum of dosages
needed to produce deathin 50% of treated
animals (lethal dose 50, LD30).
Chemicalsproducing death in microgram
doses are often consideredextremely
poisonous. Note that measures of acute
lethality suchas LDs, may not accurately ref
ect the full spectrum of toxicity,or hazard,
associated with exposure to a chemical. For
example,some chemicals with low acute
toxicity may have carcinogenicor
teratogenic effects at doses that produce
no evidence of acutetoxicity. For a given
chemical, each of the various effects
thatmay occur in a given organism will have
their own doseresponse relationship
CLASSIFICATION OF TOXIC AGENTS
• The term toxin generallyrefers to toxic
substances that are produced by biological
systems such as plants, animals, fungi, or
bacteria.
• The term toxicant is used in speaking of
toxic substances that are producedby or are
a by-product of human activities.
• Toxic agents may beclassified in terms of
their physical state, chemical stability
orreactivity, general chemical structure, or
poisoning potential.No single classification
is applicable to the entire spectrum oftoxic
agents and, therefore, a combination of
classificationsis needed to provide the best
characterization of a toxicsubstance.
SPECTRUM OF UNDESIRED EFFECTS
• Intherapeutics, e.g., each drug produces a
number of effects, butusually only one
effect is associated with the primary
objectiveof the therapy; all the other effects
are referred to as undesirableor side
effects. However, some of these side effects
may bedesired for another therapeutic
indication. Some side effects ofdrugs are
always deleterious to the well-being of
humans.I ese are referred to as the adverse,
deleterious, or toxic effectsof the drug
Allergic Reactions
• Chemical allergy is an immunologically
mediated adverse reaction to a chemical
resulting from previous sensitization to
thatchemical or to a structurally similar one.
• The terms hypersensitivity, allergic
reaction, and sensitization reaction are
used todescribe this situation (see Chapter
12). Once sensitization hasoccurred, allergic
reactions may result from exposure to
relatively very low doses of chemicals.
• Importantly, for a given allergic individual,
allergic reactions are dose-related.
Sensitizationreactions are sometimes very
severe and may be fatal.Most chemicals
and their metabolic products are not
sufficiently large to be recognized by the
immune system as a foreign substance and
thus must first combine with an
endogenousprotein to form an antigen (or
immunogen). Such a molecule iscalled a
hapten.
• The hapten-protein complex (antigen) is
thencapable of eliciting the formation of
antibodies. Subsequentexposure to the
chemical results in an antigen-antibody
inter-action, which provokes the typical
manifestations of an allergythat range in
severity from minor skin disturbance to
fatal anaphylactic shock.
 Reversible versus Irreversible Toxic Effects
• Some toxic effects of chemicals are
reversible, and others areirreversible. If a
Idiosyncratic Reactions chemical produces pathological injury to a
• Chemicalidiosyncrasy refers to a genetically tissue, the ability of that tissue to
determined abnormal reactivity to a regenerate largely determineswhether the
chemical. effect is reversible or irreversible. Liver
• The response observed is tissue hashigh regeneration ability and most
usuallyqualitatively similar to that observed injuries are, therefore,reversible. However,
in all individuals but maytake the form of CNS injury is largely irreversible becauseits
extreme sensitivity to low doses or cells are differentiated and cannot be
extremeinsensitivity to high doses of the replaced. Carcinogenicand teratogenic
chemical. For example, someindividuals are effects of chemicals, once they occur, are
abnormally sensitive to nitrites and other usually considered irreversible toxic effects.
sub-stances capable of oxidizing the iron in
hemoglobin. This produces methemoglobin, Local versus Systemic Toxicity
which is incapable of binding • Local effects occur at the siteof first contact
andtransporting oxygen to tissues. between the biological system and the
Consequently, they may sufferfrom tissue toxicant.
hypoxia after exposure to doses of • In contrast, systemic effects require
methemoglobin-producing chemicals, absorption and distributionof a toxicant
whereas normal individuals would from its entry point to a distant site, at
beunaffected. It is now recognized that which deleterious effects are produced.
many idiosyncratic drugreactions are due to Most substances, except for highly reactive
the interplay between an individual's materials, produce systemic effects. Some
abilityto form a reactive intermediate, materials can produce both effects.
detoxify that intermediate,and/or mount an • Most chemicals that produce systemic
immune response to adducted toxicity usually elicittheir major toxicity in
proteins.Specific genetic polymorphisms in only one or two organs, which are referred
drug-metabolizing enzymes,transporters, or to as the target organs of toxicity of a
receptors are responsible for many of particular chemical.
theseobserved differences. • Paradoxically, the target organ of toxicity is
often not thesite of the highest
Immediate versus Delayed Toxicity concentration of the chemical.Target
• Immediate toxic effects occur or develop organs in order of frequency of
rapidly after a singleadministration of a involvement in systemic toxicity are the
substance CNS;
• Delayed toxic effectsoccur after the lapse the circulatory system;
of some time. Most substances the bloodand hematopoietic system;
produceimmediate toxic effects. However, visceral organs such as the liver,
carcinogenic effects of chemicals usually kidney, and lung; and the skin.
have long latency periods, often 20 to 30 Muscle and bone are seldomtarget
years afterthe initial exposure, before tissues for systemic effects.
tumors are observed in humans.