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Raman Govindarajan, MD, PhD.
Regional Director
Medical and Scientific Affairs
Johnson and Johnson Asia Pacific
Toxicology Fundamentals
A Day in Toxicology
• The Fundamentals of Toxicology
• Preclinical Safety Assessment of Cosmetics & Toiletries
How? Case Studies
Toxicology: Fundamentals
• What is Toxicology?
The traditional definition of toxicology:
" the science of toxin ”.
Toxicology: Fundamentals
• What is Toxicology?
A more descriptive definition of toxicology:
"the study of the adverse effects of chemicals or physical agents on living organisms".
Toxicology: Fundamentals
Which one of the following is a toxin?
1. Alcohol
2. Aspirin
3. Water
4. Table salt
Toxicology: Fundamentals
Toxicity depends on the DOSE
Toxicology: Fundamentals
“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.”
-- Paracelsus
Toxicology: Fundamentals
• Toxicity depends on the dose– High oxygen level cause “oxygen intoxication”
Toxicology: Fundamentals
• Toxicity depends on the dose– High oxygen level cause “oxygen intoxication”– Too much water (several gallons) can cause
osmotic imbalance and brain damage
Toxicology: Fundamentals
• Toxicity depends on the dose– High oxygen level cause “oxygen intoxication”– Too much water (several gallons) can cause
osmotic imbalance and brain damage– 1 beer vs. a six pack of beer
Toxicology: Fundamentals
• Toxicity depends on the dose– High oxygen level cause “oxygen intoxication”– Too much water (several gallons) can cause
osmotic imbalance and brain damage– 1 beer vs. a six pack of beer– 1 sleeping pill vs. a bottle of sleeping pills
Toxicology: Fundamentals
• Toxicity depends on the dose– High oxygen level cause “oxygen intoxication”– Too much water (several gallons) can cause
osmotic imbalance and brain damage– 1 beer vs. a six pack of beer– 1 sleeping pill vs. a bottle of sleeping pills– 1 aspirin vs. a bottle of aspirins
Toxicology: Fundamentals
What is LD 50 ?
1. Fifty Lead molecules
2. A famous singer in 1950’s
3. A Latin dance introduced in 1950’s
4. A means to measure toxicity
Toxicology: Fundamentals
How is Toxicity measured by?
Toxicology: Fundamentals
Toxicity is measured by LD50:
Lethal Dose that kills
50% of the population
Toxicology: Fundamentals
Toxicity is measured by:
• LD50: Lethal Dose that kills 50% of the population
• Dosage measured in weight of toxin per body weight
Toxicology: Fundamentals
Dose-response curves are used to derive dose estimates of chemical substances. A common dose estimate for acute
toxicity is the LD50 (Lethal Dose 50%).
Toxicology: Fundamentals
Examples of LD50:
Chemical LD50 (ppm)
Nicotine 1
DDT 100
Table Salt 3000
Trichloroethylene 5000
Toxicology: Fundamentals
What is ED 10 ?
1. The 10th version of ET movie
2. Brief for the 10th Edward in the family
3. The 10th Executive Director in a company
4. Indication of the effectiveness of a substance
Toxicology: Fundamentals
Effective Doses (EDs) are used to indicate the effectiveness of a substance. Normally, effective dose refers to a beneficial effect (relief of pain). It might also stand for a harmful effect (paralysis). Thus the specific endpoint must be indicated.
Toxicology: Fundamentals
Effective Dose
Toxicology: Fundamentals
What does EC stands for?– 1. Title for a TV show starring a talking horse– 2. Effective concentration– 3. Exposure concentration – 4. New musical show in Broadway
Toxicology: Fundamentals
• EC10
This is the commonly used abbreviation for the exposure concentration of a toxicant causing a defined effect on 10% of a test population
Toxicology: Fundamentals
Absorption is the process whereby a substance moves from outside the body into the body.
Toxicology: Fundamentals
Toxicology: Fundamentals
Definition
Toxicology: Fundamentals
What is Toxicokinetics?
Toxicokinetics is the study of "how a substance gets into the body and what happens to it in the body".Essentially, it is the study of “the kinetics of all toxic substances”.
Toxicology: Fundamentals
Toxicity/Preclinical Safety Review
• Single Dose Study
• Multiple Dose Study: Subacute, Subchronic, Chronic
• Mutagenicity/Carcinogenicity Study
Toxicology: Fundamentals
Acute toxicity results from a single exposure to a poisonous substance.
Route of administration:
Oral, IV, IP, Dermal, Subcutaneous
Toxicology: Fundamentals
Acute toxicity results from a single exposure to a poisonous substance– Usually has an immediate life-threatening
effect
Toxicology: Fundamentals
Acute toxicity results from a single exposure to a poisonous substance– Usually has an immediate life-threatening
effect– Usually easily diagnosed
Toxicology: Fundamentals
Acute toxicity results from a single exposure to a poisonous substance– Usually has an immediate life-threatening
effect– Usually easily diagnosed– Most of the time there are antidotes that can
reduce the toxicity of the chemical
Toxicology: Fundamentals
Multiple Dose Tests:
Subacute: days to 2 wks
Subchronic: 4 - 13 wks
Chronic: 6 - 12 months in rodents
7 - 10 years in non-rodents
Study design depending on the objective of the study
Toxicology: Fundamentals
Chronic toxicity results from prolonged exposure to a poisonous substance over a long period of time
Toxicology: Fundamentals
Chronic toxicity results from prolonged exposure to a poisonous substance over a long period of time– No immediate effect but could be life-
threatening in the long term
Toxicology: Fundamentals
Chronic toxicity results from prolonged exposure to a poisonous substance over a long period of time– No immediate effect but could be life-
threatening in the long term– Usually hard to diagnose and treat
Toxicology: Fundamentals
Chronic toxicity results from prolonged exposure to a poisonous substance over a long period of time– No immediate effect but could be life-
threatening in the long term– Usually hard to diagnose and treat– Hard to distinguish effects from other
influences
Toxicology: Fundamentals
What is mutagenic?
1. Something to do with music
2. Something to do with DNA
3. Something to do with mutes
Toxicology: Fundamentals
• Mutagenesis
The process whereby a substance damages
DNA and produces alterations in or loss
of genes or chromosomes.
Toxicology: Fundamentals
Mutagenicity Tests– Ames Test
– Mammalian Chromosomal Aberration
– Micronucleus Test (in vivo)
Toxicology: Fundamentals
What is carcinogenic ?
1. A place that makes cars
2. Something to do with gambling
3. Something that can cause tumors
4. A place that repairs cars
Toxicology: Fundamentals
• Carcinogen A carcinogen is any substance which
causes cancer
Toxicology: Fundamentals
Carcinogenicity Studies• Traditional 2-year Bioassay– different routes of administration, use rats and mice – two year duration, expensive, labor-intensive– interspecies extrapolation problem, especially mice
Toxicology: Fundamentals
Carcinogenicity Studies• Traditional Testing– different routes of administration, use rats and mice
– two year duration, expensive, labor-intensive
– interspecies extrapolation problem, especially mice
• Transgenic Animal Testing – P53, Neonatal, TgAc, XPA, XPA/P53 and RasH2 models
– shorter testing period, less expensive, less labor-intensive
– have genes relevant to humans
– predictability? -- not enough data
Toxicology: Fundamentals
What is a reproductive toxin?
Toxicology: Basic
Reproductive toxicity is defined as adverse effects on the male and female reproductive systems that result from exposure to chemical substances.
Toxicology: Fundamentals
Which of the following causes reproductive toxicity?
1. Alcohol2. Vitamin A
3. Tobacco smoke (primary)
4. Aspirin
Toxicology: Fundamentals
Special Toxicity Studies
• Eye Irritation • Skin Irritation • Contact Sensitization • Comedogenicity• Genital/Mucus Membrane Irritation
Toxicology: Fundamentals
Irritation:
Any substance causing inflammation following immediate, prolonged, or repeated contact with skin or mucous membrane.
Toxicology: Fundamentals
• The most common cause of Occupational Skin Disease is irritation of the skin from contact with substances at work.
Toxicology: Fundamentals
Strong irritants (e.g. acids, alkaline or solvents) cause skin inflammation after a short period of skin contact.
Dermatitis from cement
Toxicology: Fundamentals
Weak irritants (such as water, detergents, coolants) cause inflammation after repeated exposures over a longer time.
Toxicology: Fundamentals
Dermal Irritation Tests
– Primary Irritation Test • Single Dose
– Cumulative Irritation Test• Multiple Dose
Toxicology: Fundamentals
• In intracutaneous irritation tests using albino rabbits, the raised blebs caused by injecting extracts of test materials are either resolved without causing any visible changes or produce inflammation marked by redness and swelling in the 24 to 72 hours following injection.
Toxicology: Fundamentals
Sensitization or hypersensitivity reactions usually occur as a result
of repeated or prolonged contact
with a substance that interacts
with the body's immune system.
Toxicology: Fundamentals
Which of the following is considered
to be a sensitizer?
1. Latex Gloves
2. DNCB (1-chloro-2, 4-dinitrobenzene)
3. Kathon®CG
4. All of the above
Toxicology: Fundamentals
After wearing natural latex gloves daily for several weeks or months, a person may develop a rash
Toxicology: Fundamentals
Biomaterials and devices that cause sensitization reactions do so by means of their extractable chemical caused cell-mediated immunity.
Toxicology: Fundamentals
Commonly Used Sensitization Tests
• Guinea Pig Maximization Test
(Magnuson-Kligman Test)
• Modified Buhler’s Test
• Local Lymph Node Assay
Toxicology: Fundamentals
Positive response to DNCB in a guinea pig, seen in the maximization test
Toxicology: Fundamentals
What does following compounds have in common?
1. Polycyclic aromatic hyrocarbons
2. Quinolones
3. Tetracyclines
4. PABA
Toxicology: Fundamentals
Ingredients absorb in the solar spectrum (280 - 400 nm)
• Photomutagenicity • Phototoxicity• Photosensitization • Photocarcinogenicity
Toxicology: Fundamentals
Studies to support Product Claims
• Ocular Irritation (Draize or TEP)
• Genital/Mucus Membrane Irritation
• Comedogenicity
• HET CAM – eye irritation test
Toxicology: Fundamentals
What is comedone?
Comedone:
A follicle that has been plugged with a combination of hardened oil (sebaceous material) and dead skin cells.
Toxicology: Fundamentals
Which of the following can causes a comedogenic reaction?
1. Cocoa Butter
2. Lanolin
3. Amydimethyl PABA
4. All of the above
Toxicology: Fundamentals
1. Cocoa Butter - a skin softener and lubricator. It is considered comedogenic and may cause allergic reactions.
2. Lanolin - a sheep’s wool derivative, it is highly comedogenic.
3. Amyldimethyl PABA - causes skin irritation.
4. All of the above
Toxicology: Fundamentals
• Skin Absorption Data
• Toxicokinetic and Pharmacokinetic Data
Other important information:
Toxicology: Fundamentals
Photosensitization :Hypersensitivity to light.
An abnormally heightened response, especially of the skin, to sunlight or ultraviolet radiation, caused by certain disorders or chemicals and characterized by a toxic or allergic reaction
Toxicology: Fundamentals
Safety Testing
• Knowledge of Toxicity is primarily obtained in 3 ways:– by studies using cells (in vitro)– by experimental studies using animals– by the study and observation of people during
normal use of a substance
Toxicology: Fundamentals
Four basic steps in the risk assessment process:
Toxicology: Fundamentals
Toxicology quiz
What is “toxicologist”?
1. A person who always kills my project
2. A person who is intoxicated
3. A person who can not make it to medical school
4. Our partner in R&D
Toxicology: Fundamentals
Formulator and Toxicologist works together
faster time to market !
Toxicology: Fundamentals
New Formulation
Toxicology: Fundamentals
New Formulation
Toxicology Testing
Toxicology: Fundamentals
New Formulation
Toxicology Testing To Market
Toxicology: Fundamentals
New Formulation
Toxicology Testing To Market