This presentation explains Basics of Toxicology and its Role in Drug development process

1. Basics of Toxicology & Its Role in
Drug development
-Mohana Thakkar
Date: 12/01/2024

2. Objective
• To comprehend basics of toxicology,
terminologies and necessity of Toxicology
studies during Drug development.
• To evaluate the safety of potential drug
candidates.
• To translate the animal model responses into an
understanding of the risk for human subjects.

3. Why is
Toxicology in
Drug
Development
important?
 Non-clinical safety studies are required to be performed on candidate drugs for
development of novel pharmaceuticals.
 To typically assess general toxicology (as determined by in vivo experiments), safety
pharmacology (effects on major organ systems, e.g. cardiovascular) and genetic toxicity
test.
 For Progression of candidate drugs from the “discovery phase” through clinical
development to regulatory submission and registration.
Discovery safety assessment of drug projects can be considered in two broad areas:
 Target-related safety: To identify unintended adverse effects in tissues other than
tissues of efficacy & apply Risk Mitigation and Management Strategies (RMMS). Eg:
limit exposure to the central nervous system for undesirable on-target neuronal
pharmacology.
 Chemistry-Related Safety: Number of approaches can be used to support chemical risk
assessment. For e.g. To identify a compound property or structural features that can cause
adverse effects.

4. Introduction to Toxicology : Terminology
What is Toxicology?
Toxicology is the study of how natural or man-made poisons cause undesirable effects in living organisms.
What are harmful or adverse effects?
Harmful or adverse effects are those that are damaging to either the survival or normal function of the individual.
What is Toxicity?
The degree to which a substance is poisonous or can cause injury. The toxicity depends on a variety of factors: dose, duration
and route of exposure, shape and structure of the chemical itself, and individual human factors.
What is Toxic?
This term relates to poisonous or deadly effects on the body by inhalation (breathing), ingestion (eating), or absorption, or by
direct contact with a chemical.

5. What is a Toxicant?
A toxicant is any chemical that can injure or kill humans, animals, or plants; a poison.
What is Selective Toxicity?
“Selective toxicity” means that a chemical will produce injury to one kind of living matter
without harming another form of life, even though the two may exist close together.
How Does Toxicity Develop?
Before toxicity can develop, a substance must come into contact with a body surface such as
skin, eye or mucosa of the digestive or respiratory tract.
What is a dose?
The dose is the actual amount of a chemical that enters the body. The dose received may be
due to either acute (short) or chronic (long-term) exposure.
An acute exposure occurs over a very short period of time, usually 24 hours.
Chronic exposures occur over long periods of time such as weeks, months, or years. The
amount of exposure and the type of toxin will determine the toxic effect.

6. GENERAL PRINCIPLE
Development of a pharmaceutical is a stepwise process involving evaluation of both animal & human efficacy
and safety information.
The goals of nonclinical safety evaluation generally include a characterization of toxic effects, dose
dependence, relationship to exposure and potential reversibility.
This information is used to estimate an initial safe starting dose & dose range for human trials and to identify
parameters for clinical monitoring for potential adverse effects.
Human clinical trials are conducted to investigate the safety and efficacy of a pharmaceutical, starting with a
relatively low systemic exposure in small number of subjects, followed by clinical trials in which drug exposure
usually increases by duration and/or size of exposed population.

7. Toxic agent or substance
Toxic agent is anything that can produce an adverse biological effect.
Toxic agents may be:
chemical (such as cyanide),
physical (such as radiation) and
biological (such as snake venom).

8. Systemic or
organ toxins
Toxic substances may be systemic toxins or organ toxins.
Systemic toxin: one that affects the entire body or many
organs rather than a specific site.
Eg: potassium cyanide is a systemic toxicant-it affects
virtually every cell and organ in the body by interfering with
the cell's ability to utilize oxygen.
Organ toxin: one that affects only specific tissues or organs
Eg: Benzene-it is primarily toxic to the blood-forming tissues.

9. Factors
determining
adverse
effects
 Intrinsic toxicity: Information on chemical properties and physical properties
of toxic agents can be found at several websites. Material Safety Data Sheets
are available for most chemicals.
 Dose: Amount of a substance administered at one time. Types of doses:
 Exposure dose: amount of xenobiotic encountered in the environment.
 Absorbed dose: actual amount of the exposed dose that enters the body.
 Administered dose: The quantity administered usually orally or by injection
 Total dose: the sum of all individual doses.
 Exposure conditions & Patterns of response:
Different patterns of exposure are related to different patterns of response.
• Epidemiology can be applied to find knowledge on the dose-response in
complex exposures.

10. Exposure conditions
Routes of exposure
Oral, Inhalation, Dermal, Parenteral
Frequency & duration of exposure
mixed exposures
environmental circumstances

11. Response of Host
 Metabolism of a xenobiotic (chemical substances
that are foreign to animal life) may result in
either detoxification (less toxic metabolites) or
bioactivation (more toxic metabolites).
 A xenobiotic itself may not cause cancer but a
metabolite of the xenobiotic may have
carcinogenic potential. (This is a form of
bioactivation).

12. Toxic effects: Categorization
 Generally categorized according to the site of the toxic effect.
 Toxic effect may occur at only one site (Specific target organ toxicity)
 May occur at multiple sites (Systemic toxicity)
 Types of systemic toxicity:
 Acute toxicity: usually a single dose or a series of doses received within a 24 hour period.
Eg: Convulsions and respiratory irritation.
 Subchronic Toxicity: results from repeated exposure for several weeks or months.
This is a common human exposure pattern for some pharmaceuticals and environmental agents.
Eg: Ingestion of coumadin tablets (blood thinners) for several weeks as a treatment for venous thrombosis can
cause internal bleeding.
 Chronic Toxicity: represents cumulative damage to specific organ systems and takes many months or years to
become a recognizable clinical disease. Eg: Cirrhosis in alcoholics

13. What is dose-response?
Dose-response is a relationship between exposure and health effect, that can be established by
measuring the response relative to an increasing dose.
What is the threshold dose?
There is a dose or exposure level below which the harmful or adverse effects of a substance are not
seen in a population. That dose is referred to as the ‘threshold dose’. This dose is also referred to as
the no observed adverse effect level (NOAEL), or the no effect level (NEL).

14. Dose-response relationship
• The dose-response relationship is the most
fundamental concept in toxicology. Generally,
the higher the dose, the more severe the
response.
• It is based on observed data from experimental
animal, human clinical or cell studies.
Knowledge of the dose-response relationship:
- establishes causality that the chemical has in
fact induced the observed effects.
- establishes the lowest dose where an induced
effect occurs – the threshold effect
- determines the rate at which injury builds up -
the slope for the dose response.

15. Dose
Estimates of
Toxic Effects
• 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%).
LD50: a statistically derived dose at which 50% of the individuals will
be expected to die.
Other dose estimates:
LD0: the dose at which no individuals are expected to die. This is just
below the threshold for lethality.
LD10: The dose at which 10% of the individuals will die.

16. Effective dose
• Indicates the effectiveness of a substance.
• Refers to a beneficial effect (relief of pain).

17. Toxic dose
• Indicates doses that cause adverse toxic effects.
• Two dose-response curves can be presented for the same drug, one for effectiveness
and the other for toxicity.
• A dose that is 50-75% effective does not cause toxicity whereas a 90% effective dose
may result in a small amount of toxicity.

18. DOSE SELECTION FOR GENERAL TOXICITY STUDIES
Generally, Limit doses for acute, sub chronic, and chronic toxicity studies of 1000 mg/kg/day for rodents
and non-rodents are considered appropriate.
Acute toxicity studies: Information has been obtained from single-dose toxicity studies in two mammalian
species using both the oral and a parenteral route of administration.
Repeated dose toxicity studies: Duration of the study is related to the duration, therapeutic indication
and scope of the proposed clinical trial.
Duration of study conducted in two mammalian species should be equal to or exceed the duration of
human clinical trials up to the maximum recommended duration of the repeated-dose toxicity studies.

19. Clinical development trials
 Repeated-dose toxicity studies in two species (one non-rodent) for a minimum duration of 2 weeks (Table 1)
would generally support any clinical development trial up to 2 weeks in duration.
Six month rodent and 9 month non-rodent studies generally support dosing for longer than 6 months in
clinical trials.
Table 1 Recommended Duration of Repeated-Dose Toxicity Studies to Support the Conduct of Clinical Trials:
Maximum Duration of
Clinical Trial
Recommended Minimum Duration of Repeated-Dose
Toxicity Studies to Support Clinical Trials
Rodents (e.g. Rats, mice) Non-rodents (e.g. Dog)
Up to 2 weeks 2 weeks 2 weeks
Between 2 weeks and 6
months
Same as clinical trial Same as clinical trial
> 6 months 6 months 9 months

20. Sub-disciplines of Toxicology
• Environmental Toxicology : concerned with the study of
chemicals that contaminate food, water, soil, or the atmosphere. It
deals with toxic substances that enter bodies of waters such as
lakes, streams, rivers, and oceans. This sub-discipline addresses
the question of how various plants, animals, and humans are
affected by exposure to toxic substances.
• Occupational (Industrial) Toxicology: concerned with health
effects from exposure to chemicals in the workplace.
• Regulatory Toxicology: gathers and evaluates existing
toxicological information to establish concentration-based
standards of “safe” exposure. The standard is the level of a
chemical that a person can be exposed to without any harmful
health effects.

21. • Food Toxicology: involved in delivering a safe and edible supply of food to the consumer.
• Clinical Toxicology: concerned with diseases and illnesses associated with short term or
long term exposure to toxic chemicals.
• Descriptive Toxicology: concerned with gathering toxicological information from animal
experimentation. Used to establish how much of a chemical would cause illness or death.
• Forensic Toxicology: used to help establish cause and effect relationships between exposure
to a drug or chemical and the toxic or lethal effects that result from that exposure.
• Analytical toxicology: identifies the toxicant through analysis of body fluids, stomach
content, excrement, or skin.
• Mechanistic Toxicology: the study of molecular, biochemical, cellular and tissue-level
interactions, pathways and changes leading to the toxicological effects of xenobiotics.
• makes observations on how toxic substances cause their effects. The effects of exposure can
depend on a number of factors such as: the size of the molecule, the specific tissue type or
cellular components affected, whether the substance is easily dissolved in water or fatty
tissues.

22. Classification of Toxic Agents
A. Heavy Metals
B.Solvents and Vapors
C. Radiation and Radioactive Materials
D. Dioxin/Furans
E. Pesticides
F. Plant Toxins
G. Animal Toxins
H. Subcategories of Toxic Substance Classifications : according to their:
• Effect on target organs (liver, kidney, hematopoietic system),
• Use (pesticide, solvent, food additive),
• Source of the agent (animal and plant toxins),
• Effects (cancer mutation, liver injury),
• Physical state (gas, dust, liquid),
• Labeling requirements (explosive, flammable, oxidizer),
• Chemistry (aromatic amine, halogenated hydrocarbon), or
• Poisoning potential (extremely toxic, very toxic, slightly toxic)
I. General Classifications of Interest to Communities
• Air pollutants
• Occupation-related
• Acute and chronic poisons

23. References
• An FDA/CDER perspective on nonclinical testing
strategies: Classical toxicology approaches and
new approach methodologies (NAMs)-Amy M.
Avilaa, Et al.
• ICH M3(R2) on non-clinical safety studies for the
conduct of human clinical trials and marketing
authorisation for pharmaceuticals.
• Principles of Toxicology ICasarett and Doull's
Toxicology: The Basic Science of Poisons
• Toxicology in the drug discovery and development
process-Michael A Dorato
• ICH M4S(R2): The CTD for the Registration of
Pharmaceuticals for Human Use: Safety-M4S(R2)

24. •Thank you