o

PHARMACEUTICAL TOXICOLOGY ​
PRELIMS | BSPH 3201 | PROF. Georgie Torato, RPh
💋
SEMESTER 2
SY. 2024-2025

○​ permits mechanistic toxicologist to

Dosis sola facit venenum
identify and protect genetically susceptible
●​ All substances are poisons; there is none that is not individuals from harmful environment
poison. The right dose differentiates a poison from exposure based on their genetic make-up
a remedy” ●​ Example: Thalidomide
●​ stated by Philippus Aureolus Theophrastus ○​ ADE: Phocomelia (absence limbs/limb
Bombastus von Hohenheim (Paracelsus) deformity)- originally marketed as a
●​ roots the basic principle of toxicology sedative for pregnant women
●​ only the dose makes the difference between a drug ○​ banned in 1962 due to ADE (birth defect)
and a poison ○​ mechanistic toxicology demonstrated on
TOXICOLOGY how thalidomide causes phocomelia
●​ study of poison ○​ Rediscovered for leprosy and aids and tx
●​ is the study of the adverse effects of xenobiotics for anti-inflammatory disease and cancer
(chemicals or physical agents) on living organisms 2)​ Environmental Toxicology
○​ Chemical Agents: Drugs ●​ focuses on the impacts of chemical pollutants in
○​ Physical Agents: Excessive/loud noise, the environment on biological organisms,
vibration, optical radiation, extreme specifically studying the impacts of chemicals on
temperature, electromagnetic fields, cell non- human organisms
site towers ●​ focuses on:
●​ originates from the words “toxikon” & “logia” ○​ Fish
○​ Toxikon: Arrow poison ○​ Birds
●​ ​ Logia: to study/speak ○​ Terrestrial animals
●​ requires the knowledge and techniques of various ●​ Subdiscipline: Ecotoxicology
fields of science: ○​ Focuses more on the effects of chemical
○​ Biochemistry pollutants on the population dynamics of
○​ Chemistry the ecosystem
○​ Biology ○​ focuses more on the impacts of toxic
○​ Genetics substances and population dynamics
○​ Mathematics
3)​ Descriptive Toxicology
○​ Pharmacology
○​ Physiology ●​ concerned directly with toxicity testing which
○​ Physics provides information for safety evaluation and
regulatory requirements
HISTORY OF TOXICOLOGY
●​ Descriptive Toxicologist
●​ toxicology began during the time when:
4)​ Developmental Toxicology
○​ Plant extracts were used as drugs/poison
○​ Animal venom were used in hunting ●​ study of adverse effects on the developing
●​ Father of Toxicology: Mathieu Joseph organism that may result from exposure to
Bonaventura Orfila chemical or physical agents before conception,
○​ Founder of the science of toxicology during prenatal or postnatal development
○​ First toxicologist that used autopsy ●​ Subdiscipline: Teratology
material and chemical analysis ○​ Focuses on the defects induced during
systematically as a legal proof of development between conception and
poisoning birth
DIFFERENT AREAS OF TOXICOLOGY 5)​ Forensic Toxicology
1)​ Mechanistic Toxicology ●​ a hybrid of analytic chemistry & fundamental
toxicological principle that focuses primarily on
●​ deals with the mechanism of toxic action (MOTA) medicolegal aspects of the harmful effects of
of poisons chemical on human and animals
○​ Determines how a toxic substances causes ●​ aid in establishing the cause of death and
its effects in the body determining its circumstances in a post-mortem
●​ toxicodynamic of a substance investigation
●​ deals with the cellular, biochemical and molecular ●​ SOCO have forensic toxicologists
mechanisms by which chemical exert toxic effects
in living organisms 6)​ Occupational Toxicology
●​ Subdiscipline: Toxicogenomics ●​ deals with the harmful effects of poison in an
○​ Deals on the MOTA of poisons on the occupational setting or working area
genome/genetic material ●​ Example:Asbestos - during the dark ages

SODIUM 💋 1
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PHARMACEUTICAL TOXICOLOGY
PRELIMS | BSPH 3201 | PROF. Georgie Torato, RPh
​ 💋
SEMESTER 2
SY. 2024-2025

○​ causes asbestosis due to prolonged fungi, and bacteria

exposure to the silicate material in
asbestos which accumulates in the lungs Toxicant -toxic substances that are produced by or are
-exposure in asbestos factory has caused by-product of anthropogenic (human) activities
asbestosis to mesothelioma (lung cancer) -Examples:
●​ Polyaromatic Hydrocarbons
7)​ Reproductive Toxicology -produced by the combustion of
●​ study of the occurrence of adverse effect on the organic matter
●​ Combustion of coal -for energy
male and female reproductive system that may production
result from exposure to chemical or physical agents ●​ Cigarette smoking
8)​ Regulatory Toxicology
●​ responsible for deciding on the basis of data
Classification of Toxic Agents Based on its Composition
provided by descriptive and mechanistic
toxicologist whether a drug or other chemical 1.​ Chemical Agent
poses a sufficiently low risk to be marketed for a
stated purpose for a subsequent human or 2.​ Physical Agent
environmental exposure resulting from its use.
●​ regulatory, mechanistic toxicologists are involved
in establishing of the standards for the amount of Toxic agents may also be classified in terms of their:
chemicals permitted in food, drugs, ambient air,
industrial atmosphere, and drinking water -FDA Physical State -Gas, Solid, Liquid
have regulatory toxicologists
Chemical Stability / -explosive, flammable, oxidizer
9)​ Clinical Toxicology Reactivity
●​ designates an area of professional emphasis in
Chemical Structure -aromatic, amine, halogenated hydrocarbon
realm of medical science
●​ concerned with the disease caused by or uniquely Poisoning Potential -extremely toxic, very toxic, slightly toxic
associated with toxic substances
●​ study the toxic effects of poison on a patient Biochemical MOA -alkalinizing agent, cholinesterase inhibitor,
through either accidental or intentional exposure methemoglobin producer
●​ clinical toxicologists are usually physicians/doctors Note: this classification is more informative
(irritants / corrosives) than any other
undergone: classification since it makes it easier to
○​ Specialized training determine the antidote
○​ Emergency medicine and poison
management
10)​Experimental Toxicology POISON
●​ concerned with the observation of toxic effects of ●​ agent capable of producing a deleterious response
poison in a biological system in a biological system
●​ uses laboratory parameters ●​ it may cause serious body harm, injury, and even
●​ Parameters: LC50, LD50, & TLV death
○​ LC50: Lethal Concentration 50 - lethal ●​ in general, toxic agents are termed as poisons
concentration that causes adverse effects TYPES OF POISONS (based on their action)
on 50% of the test population ●​ there effects ranges from acute (less serious) to
○​ LD50: Lethal Dosage 50 - lethal dose that severe and even death
cause adverse effects on 50% of the test TYPES DESCRIPTION EXAMPLES
population
○​ TLV - Threshold Limit Value -maximum True Poison -still poisonous no Snake Venom
amount of substances allowable for matter how diluted it is
repeated exposure without producing ADE
Irritant -causes irritation to the Corrosive Acid
CLASSIFICATION OF TOXIC AGENTS contact area Caustic Base
●​ Classification of toxic agents is based on the
interest and needs of classifier Neurotics -direct effect on the Hallucinogen (LSD
central nervous system - Lysergic Acid
Classification of Toxic Agents Based on its Sources Diethylamide)

Toxin -toxic substances produced by biological Carcinogen -stimulates the growth Benzene
system of cancer cells
-toxic substances produced by plants, animals,

SODIUM 💋 2
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PHARMACEUTICAL TOXICOLOGY
PRELIMS | BSPH 3201 | PROF. Georgie Torato, RPh
​ 💋
SEMESTER 2
SY. 2024-2025

Teratogen -affects the developing Thalidomide Overdosing - term for intentional exposure
fetus (Original Form) - Example: Opioid Overdose

Asphyxiant -causes difficulty of CO

breathing (dyspnea) Methane Gas SPECTRUM OF UNDESIRED EFFECTS
(CH4)
●​ The intoxicated person will experience undesired
Lacrimator -stimulates the flow of Organophosphate effects of the substance which can range from less
tears Tear Gas serious to severe.
Pepper Spray ●​ This spectrum/range of undesired effects varies
from one substance to another due to the variety/
Sternutator -causes sneezing Veratrine
Capsaicin
diversity of the toxic agents.

Asthenic -causes muscle Neuromuscular

weakness Blockers
-Vecuronium
- Atracurium
- Succinylcholine

Narcotic -causes stupor, Opioids

narcosis, insensibility - Morphine
- Codeine ●​ The spectrum of the undesired effects of chemicals
are broad. Some substances produce deleterious
Tetanic -acts directly on the Strychnine
spinal cord causing - causes spastic effects while others don’t depending on its
spasmodic and tetanic paralysis components.
contraction of the opisthotonus ●​ Each drug will produce a number of effects but
muscles (arching of the usually only one effect is associated with the
back)
- inhibits the main primary objective of the therapy while the other
inhibitory neuron of effects are referred to as the undesirable/side effects
the spinal cord of the drug for that therapeutic indication.
(glycine) ●​ the spectrum of undesired effect can be classified
- Clostridium
tetani: as:
inhibits GABA in A.​ Undesired (Side Effect)
the brain a.​ Generally, side effects are categorized as
undesirable when it is NOT part of the
therapy goals.
RELATED TERMINOLOGY TO TOXICOLOGY b.​ However NOT all side effects are
●​ Any event that a person/patient is exposed to these undesirable.
toxic agents, we can say that that person is c.​ There are drug side effects that may be
intoxicated, poisoned, or overdosed. utilized to treat/manage another condition.
Intoxication - general term pertaining to toxicity associated d.​ Example: Drowsiness side effect of 1st
with any chemical substances generation (Diphenhydramine,
- general term to describe any person exposed Chlorphenamine) anticholinergic effects
to poisons or toxic agents which diminishes
their physical and mental control
may be used as sleep aid to manage
●​ ranges from acute diminish to insomnia
severe diminish B.​ Adverse Effect (Toxic Effect)
- may be further classified as poisoning a.​ Adverse/Toxic effects are side effects that
(accidental) or overdosing (intentional) when
there is a presence of severe adverse reaction
are NEVER desirable and are ALWAYS
- Example:Alcohol intoxication deleterious to the well-being of the human
●​ classified as intoxication because it FACTORS THAT AFFECT THE SPECTRUM OF
only entails diminished mental and UNDESIRED EFFECTS
physical activities and does not
have severe adverse reaction 1.​ Allergic Reaction
●​ although it is intentional, it cannot
be classified as overdosing since it ●​ immunologically mediated adverse reaction to
is not specific to which substance chemical resulting from previous sensitization to
has caused the toxicity
that chemical or to a structurally similar one
Poisoning - term for accidental intoxication or exposure
-dose-related
- Example: Food Poisoning ●​ manifestations of allergic reaction are numerous
○​ They may involve various organ systems
that range in severity. From minor skin

SODIUM 💋 3
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PHARMACEUTICAL TOXICOLOGY ​
PRELIMS | BSPH 3201 | PROF. Georgie Torato, RPh
💋
SEMESTER 2
SY. 2024-2025

disturbance (minor allergic reaction) to ○​ succinylcholine is used for muscle

fatal anaphylactic shock (severe allergic relaxation especially during operations.
reaction) ○​ there is rapid metabolic degradation by the
○​ Minor Skin Disturbances: Dermatitis butyrylcholinesterase thus muscle
■​ Urticaria relaxation only last for a short period of
■​ Itching time
■​ Rashes a.​ Butyrylcholinesterase
■​ Inflammation of the conjunctiva i.​ aka pseudocholinesterase
○​ Anaphylactic shock ii.​ enzyme normally present in the
■​ Bronchoconstriction bloodstream
●​ Related Terms: iii.​ lack of this enzyme causes
○​ Hypersensitivity - most often used to prolonged muscular relaxation
describe this allergic state especially in the and apnea since there is no
field of science and medicine enzyme to metabolize
○​ Allergic Reaction - considered as a succinylcholine
layman’s term 3.​ Immediate vs Delayed Toxicity
○​ Sensitization Reaction
●​ Example: Formation of Hapten-protein Complex ●​ Immediate Toxicity: develops rapidly after single
○​ produces antibodies that fight off foreign administration
substances introduced in the body causing ●​ Delayed Toxicity: delayed effects occurs after
the allergic reactions lapses of some time (may even occur 30 years after
exposure)
2.​ Idiosyncratic Reaction ●​ NOTE: Substances that cause immediate effect
●​ refers to a genetically determined abnormal usually do not produce delayed effect
reactivity to a chemical ●​ Example: Exposure to Carcinogenic Substances
●​ response is similar to that of all individuals but may (Delayed)
take form of extreme sensitivity to low doses or ○​ carcinogenic substances usually have a
extreme insensitivity to high doses of the chemical long latency period of 10/20/30 years from
●​ occurs due to genetic polymorphism of drugs initial exposure before tumors are
●​ Example: Glucose-6-phosphate dehydrogenase observed in humans
deficiency (G6PD) - that causes hemolytic anemia ○​ Organophosphorus/ Organophosphates
○​ drugs taken by these patients should be on insecticides
the smallest dose ■​ Delayed neurotoxicity /
●​ Occurrence of Toxicity among G6PD patients: Neuropathy
○​ experience severe adverse reaction with ■​ covalent binding (irreversible) /
bacterial/viral infections covalent modification of an
○​ taking pain killers or fever lowering enzyme referred to as a
drugs (aspirin) neuropathy target esterase
○​ taking antibiotics with “sulf” in their ●​ In contrast, most substances produce immediate
names (sulfonamides) toxic effects but do not produce delayed effects.
○​ taking nitrofurantoin ●​ Example: Exposure to Acids and Bases
○​ taking anti-malarial drugs with (Immediate)
“quinine/quinidine” in their names ○​ Organ most affected: Brain & CNS
(primaquine, quinidine) 4.​ Reversible vs Irreversible Toxic Effects
○​ intake of fava beans/broad beans
○​ Exposure to naphthalene (moth balls) ●​ determined by the ability of the tissue to regenerate
●​ Note: Oxidative drugs should be avoided: ●​ Regenerating Tissue:
○​ Aspirin ○​ Reversible → Less severe toxic effects
○​ Sulfonamides ●​ Non-regenerating Tissue:
○​ Nitrofurantoin ○​ Irreversible → Severe toxic effects
○​ Dapsone ●​ Example:
○​ Primaquine ○​ Liver Tissue as target of toxic agents -
○​ Quinidine High ability to regenerate → Reversible
●​ Patients that exhibit prolonged muscular Toxic Effects
relaxation and apnea (inability to breathe) lasting ○​ CNS (Brain/Spinal Cord) as target of toxic
for several hours when exposed to even a standard agents - No ability to regenerate →
dose of succinylcholine Irreversible because the cells of the CNS
cannot regenerate

SODIUM 💋 4
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PHARMACEUTICAL TOXICOLOGY ​
PRELIMS | BSPH 3201 | PROF. Georgie Torato, RPh
💋
SEMESTER 2
SY. 2024-2025

○​ Teratogen & Carcinogen - exposure to Additives - combined effect of two chemicals is equal to
these substances are usually irreversible the sum of the effects of each agent given
alone
5.​ Local Toxicity vs Systemic Toxicity - it can increase the effect of a toxicant
●​ Local Toxicity: -Example: Warfarin (Coagulant) + Related
Coagulants = Additional Bleeding
○​ Occur at the site of the first contact
between biological system & toxicants Potentiation - one substance does not have toxic effect on
○​ Substances that have predominantly local a certain organ or system but when added to
effect, the frequency with which tissues another chemical, it makes that chemical much
react depends largely on the portal of entry more toxic
- chemical reaction between two compounds
○​ Common Target Organ in Local that produced less toxic product
Toxicity: - Example: Isopropanol + Carbon
■​ Skin Tetrachloride = ↑ Hepatotoxicity
■​ Gastrointestinal Tract ●​ Isopropanol: not hepatotoxic when
taken alone
■​ Respiratory Tract ●​ Carbon tetrachloride :
○​ Example: hepatotoxic when taken alone
■​ Ingestion of caustic ●​ Together: hepatotoxicity effects
(Gastrointestinal Tract) from carbon tetrachloride compared
when it was taken alone
■​ Inhalation of irritant (Respiratory
tract) Synergistic - when combined effects of two
●​ Systemic Toxicity: chemicals are much greater than the sum of
○​ Requires absorption & distribution of the the effects of each agent given alone
poison from the point of entry to produce - both substances have the same toxicity
thereby exaggerating the effect
deleterious effects​ -Example: Alcohol + Paracetamol = ↑ Liver
○​ alternative local effect damage
○​ Most chemicals that produce systemic ●​ Both alcohol and paracetamol can
toxicity usually elicit their major toxicity cause liver damage. Together they
can produce greater liver damage
in only one or two target organs compared to when there are taken
○​ Target Organs : organs that are the target alone
of toxic agents and is where toxicity is
elicited Antagonism - occurs when two chemicals administered
○​ Most frequently involved target organ together interfere with each other’s action or
one interfere with action of the other
in systemic toxicity: (Ranked from most - antagonistic effects of chemicals are often
to least) very desirable in toxicology since it is used as
■​ CNS (Brain & Spinal Cord) a basis for many antidotes
■​ Circulatory System (Blood & - cancellation of effects
Hematopoietic System)
■​ Visceral Organs (Liver, Kidney,
Types of Antagonism
Lungs, Skin)
■​ Muscle and Bone Functional -two chemicals counterbalance each other by
●​ Remote Toxicity (Physiologic) producing opposite effects on the same
○​ Toxicity is exhibited from the point of physiologic function
entry (local) to the systemic effect -Example: EPI + Histamine
●​ EPI: adrenergic agonist;
○​ “tanan iya ma agihan mag show ug toxic vasodilation & bronchoconstriction
effects” ●​ Histamine: binds to H1 receptor;
vasoconstriction & bronchodilation
6.​ Interaction of Chemicals ●​ Drugs oppose each other’s effects
●​ chemical interactions are known to occur by a
number of mechanisms: Chemical -aka inactivation
-chemical reaction between two compounds
○​ Alterations in absorption that produces less toxic product
○​ Protein binding -Example: Metal + Chelating Agents
○​ Biotransformation and excretion of one or ●​ Chelating Agents:
both of the interacting toxicants Dimercaprol/British Anti-Lewisite
(BAL)
●​ the response of the organism to combination of ●​ Metals: Mercury, Arsenic, Lead
toxicants may be increased or decreased because of ●​ Chelating agents are used to
the toxicologic responses at the site of action manage metal toxicity
- Heparin + Protamine Sulfate
Types of Chemical Interactions: ●​ Protamine sulfate manages heparin

SODIUM 💋 5
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PHARMACEUTICAL TOXICOLOGY
PRELIMS | BSPH 3201 | PROF. Georgie Torato, RPh
​ 💋
SEMESTER 2
SY. 2024-2025

toxicity
Toxic agents generally produce the greatest effect and most
rapid response when given directly into the bloodstream via
Dispositional - occurs when the ADME of the chemical is intravenous route
altered so that the concentration & duration of ●​ the spectrum of toxicity is greater when the
the chemical at the target organ is diminished characteristic of exposure through route and site of
- Example: Ipecac & Charcoal:
●​ Ipecac prevent absorption of the exposure is by intravenous route
toxicants through vomiting Ranked from the route that causes the greatest adverse
●​ Charcoal prevent absorption of the effects to the route that least causes adverse effects:
toxicants through adsorbing the a.​ Intravenous
toxic agents to its surface
- Osmotic Diuretic Agents b.​ Inhalation
●​ increase excretion/alter pH of the c.​ Intraperitoneal
urine d.​ Subcutaneous
e.​ Intramuscular
Receptor -two chemical bind to the same receptor then f.​ Intradermal
(Pharmacologic) produce opposite effects
-Example: g.​ Oral
●​ Organophosphate (Cholinergic h.​ Dermal
agonist) + Atropine (Anti- Note: The route of administration can influence the toxicity
cholinergic) of agents
●​ Receptor Blockers + Receptor
Agonists ●​ Example: An agent that acts on the CNS but is
●​ Morphine (Opioid agonist) + efficiently detoxified in the liver is expected to be
Naloxone (Opioid antagonist) less toxic if it is given orally compared when it is to
be given via intravenous or inhalation. This is
because the oral route requires nearly all the dose
7.​ Tolerance to pass through the liver before reaching the
●​ a state of decrease responsiveness to a toxic effect systemic circulation and finally to the CNS
of a chemical resulting from prior exposure to that 2.​ Duration and Frequency of Exposure
chemical or to a structurally related chemical
●​ Mechanisms:
○​ Dispositional Tolerance: Decreased Acute Exposure - <24 hours
amount of toxicant reaching the site where - Common Exposure Routes:
●​ Intraperitoneal
the toxic effect is produced ●​ Intravenous
○​ Desensitized Tissue: Due to reduced ●​ Subcutaneous
responsiveness of a tissue to the chemical ●​ Oral Intubation
●​ Dermal Application
CHARACTERISTICS OF EXPOSURE - may occur with single administration,
Any toxic agents in a biological system are not produced by continuous exposure, or repeated exposure
a chemical agent unless that agent or its metabolic
breakdown products reach appropriate sites in the body at a Subacute exposure -<1 month
-repeated exposure to a chemical through any
concentration and for a length of time sufficient to produce route of administration (but commonly oral)
toxic manifestation.
Subchronic - 1-3 months
The rationale behind the potential toxicity of the toxic exposure -repeated exposure to a chemical through any
(high/low toxicity) is based on route & site of exposure and route of administration (but commonly oral)
the frequency and duration of exposure.
Chronic Exposure - >3 months
-repeated exposure to a chemical through any
FACTORS THAT AFFECT THE route of administration (but commonly oral)
CHARACTERISTICS OF EXPOSURE
1.​ Route and Site of Exposure How can duration and frequency of exposure affect the
magnitude of the toxic effects?
Major routes or pathways by which toxic agents gain access
●​ It affects the magnitude of the toxic effects by the
to the body are:
dose.
●​ Gastrointestinal Tract (Ingestion)
●​ ↓ duration & frequency of duration ↓ dose of toxic
●​ Lungs (Inhalation)
agent ↓magnitude of toxic effects
●​ Skin (topical, percutaneous, dermal administration
●​ ↑ duration & frequency of duration ↑ dose of toxic
and other parenterals such as intravenous,
agent ↑magnitude of toxic effects
intramuscular, and subcutaneous
How can we correlate the dose to the characteristics of
exposure and the magnitude/intensity of the toxic effect?

SODIUM 💋 6
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PHARMACEUTICAL TOXICOLOGY ​
PRELIMS | BSPH 3201 | PROF. Georgie Torato, RPh
💋
SEMESTER 2
SY. 2024-2025

●​ By a dose-response relationship because all - can be used to determine the therapeutic

interaction between chemicals and biological index/therapeutic window/margin of safety
systems follow the concept of the dose-response - In any given dose an individual in the population is
relationship classified either as a responder or non-responder
-the characteristics of exposure and the spectrum of toxic - answers the question “Is the sample population Quantal
effects come together in the correlative relationship referred Dose-Response Relationship responsive or not?”
to as dose-response relationship - describes a drug effect which is binary (either present or
absent)
DOSE-RESPONSE RELATIONSHIP - Quantal Response to a drug is observed in a population,
and is either present or absent in any single individual
●​ correlates the exposure to the substance with the
- Quantal dose-response graphs plot the rate of an
changes in body functions and health
outcome occurrence in a population against the drug dose
●​ a key concept in toxicology is the quantitative
relationship between the concentration of a
xenobiotic in the body and the magnitude of the DOSE-RESPONSE GRAPH
biological effect it produces
●​ General Principle: The higher the dose the more
severe the response
●​ the magnitude of the effect of a xenobiotic is
usually a function of the amount of xenobiotic to
which a person is exposed (i.e., “the Dose Makes
the Poison)
●​ In any given population, there will be a range of
sensitivities to a xenobiotic. It is extremely useful
to know what is the average sensitivity of a
population to a xenobiotic, and what the average
dose required to elicit a toxic response will be.

TYPES OF DOSE-RESPONSE RELATIONSHIP

1.​ Individual Dose-Response - Threshold Dose
Relationship ●​ at the point at which the toxicity first appears -from
- describes the response of an individual/organism to that point the curve increases with higher dose level
varying doses of the chemical (Graded response) - At a dose of 100 mg/kg, more than 75% of the population
●​ Graded Response to a drug seen in an individual has exhibited toxicity
and increases with dose measures response per - Chemical indicated in the graph above is very toxic
dose: because minimal increase in the dose causes increase in the
○​ measures response per dose intensity of the response
○​ measurements are done per person - The steeper the slope the more toxic the substance
- describes a drug effect which increases in proportion to (Toxicology)
increasing drug dose - The steeper the slope the more potent the substance
- dose relatedness of the response often results from an (Pharmacology)
alteration of a specific biochemical process - Individual Dose-Response Relationship measures the
●​ Manifests different responses from each dose response for each dose
- graded dose-response graphs plot the response to a drug
against its concentration
- Curve: Sigmoid curve (shaped like a letter S)
●​ aka Graded Dose-Response Relationship
○​ Because of graded response
●​ aka Continuous Scale Dose-Response
Relationship
○​ Because the measured effect is continuous
over a range of doses
2.​ Quantal Dose-Response Relationship
- aka All-or-none Dose-Response Relationship
- characterizes the distribution of individual responses to
different doses in a population of individual organism

SODIUM 💋 7
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PHARMACEUTICAL TOXICOLOGY
PRELIMS | BSPH 3201 | PROF. Georgie Torato, RPh
​ 💋
SEMESTER 2
SY. 2024-2025

- Slope of Chemical A is more steep than the slope of another form of life even though the two may
Chemical B making Chemical A more toxic exist in intimate contact
●​ Small changes in the dose of Chemical A increases - Reason for selective toxicity:
the intensity of response ●​ differences in the accumulation of
toxic compounds in various tissues
●​ Large doses of Chemical B is required to increase ●​ differences in the ability of various
the intensity of response tissues to transport or biotransform
- Chemical B will give off the toxicity response first the chemical into the ultimate toxic
because its threshold dose is lower than that of Chemical A product
- due to differences in ADME or biochemical
processing of the toxicant by different
QUANTAL DOSE-RESPONSE RELATIONSHIP mechanisms
- Example:
●​ Insecticides - lethal to insects but
not toxic to other animals

Species differences - differences between species are attributable

to differences in metabolism and or due to
anatomical or physiological differences
- Example: Rat vs Dogs (Anatomical
Differences)
●​ rats cannot vomit/expel the
toxicants before they are absorbed
or cause severe irritation
●​ dogs are capable of vomiting to
expel the toxic substances
consumed​
- Effective Dose 50 (ED50)
●​ the dose that will produce beneficial effects to 50% Individual - genetic polymorphism
of the population Differences in ●​ responsible for idiosyncratic
- Toxic Dose 50 (TD50) response reactions
- even within a species, there may be still
●​ the dose that will produce toxic effects to 50% of subtle genetic differences in the individual
the population - Example: Slow Acetylators vs Fast
- Lethal Dose 50 (LD50) Acetylators
●​ the dose that will kill 50% of the population ●​ Slow Acetylators:
○​ Caucasian
- The dose that causes a response beyond 100% of the ○​ higher drug levels of
population is considered toxic blood (Increased toxic
- Dose value between ED50 and LD50 is referred to as the Response)
therapeutic window/margin of safety ○​ should be given low
doses
●​ Fast Acetylators: -Aisan, Eskimos
Combination of Individual and Quantal Dose-Response ○​ lower drug levels of
Relationship blood
○​ should be given higher
doses

Definition of terms

Harmful (Adverse - those that are damaging to either the survival

Effects) or normal function of the individual

Hazard likelihood that injury will occur in a given

situation or setting

Risk expected frequency of the occurrence of an

undesirable effect arising from the exposure to
a chemical or physical agent
REASONS FOR VARIATION IN TOXIC
RESPONSES Toxidromes a group of signs and symptoms & al;boratory
findings that suggest a specific ingestion

Variation Definition

Selective Toxicity - means chemical produces injury to one

kind of living matter without harming

SODIUM 💋 8