Introduction to Toxicology

Ray I. Ozolua, PhD

Definition and History

Toxicology is the science of poisons. Although it was once defined as the study of the
adverse effects of xenobiotics, it now includes the adverse effects of endobiotics such as the
reactive radicals. A more comprehensive definition is "the study of the adverse effects of
chemical, physical, or biological agents on living organisms and the ecosystem, including the
prevention and amelioration of such adverse effects."

Interest in the subject has grown over many centuries. The early man could identify
poisonous plants and animals and avoided them or used them as poisons in warfare, hunting
(recall that tubocurarine was isolated from the sap of Chondrodendron tomentosum which
the Amazonian hunters of South America poisoned the tips of their arrows with), and state
executions. Socrates was poisoned in 399 BC with hemlock (Conium maculatum) and the
Death cap (Amanita phalloides) killed Roman Emperor Claudius in 54 AD and Pope Clement
VII in 1534 AD. The first known collection of writings in the subject was by Moses
Maimonides: The Treatise on Poisons and Their Antidotes in 1198 AD. In the 16th century,
Paracelsus (Philippus Aureolus Theophrastus Bombastus von Hohenheim, 1493-1541) opined
that the responses of the body to plant poisons were due to specific chemicals in them.
Through series of dose-response relationships, he observed that while small doses or
concentrations of a substance could be harmless or even beneficial, high doses caused harm.
This led to his famous expression "All substances are poisons; there is none which is not a
poison. The right dose differentiates a poison and a remedy." Mathieu Joseph Bonaventure
Orfila, the 19th century Spanish physician is generally referred to as the founder of
Toxicology. He gave a systematic correlation of chemicals and their biological effects in a
book: A General System of Toxicology. The subject has grown alongside the expansion in
other fields of science thereby enabling the analysis of DNA, reactive radicals, and histology
as ways of understanding the mechanisms of toxicities.

The purpose of this lecture is to acquaint students with the subject and make it easier for
them to understand the topics to be taught by other lecturers.

Definitions of Terms

Toxic: The capability to cause harm or injury to a living entity such as cells, tissues, or
whole animal.

Toxins: Toxic substances that are of natural origin e.g. the venoms of scorpions and
snakes.

Toxicant: Any substance that is capable of causing harm.

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Toxicity: The degree to which harm can be caused. It is a function of several factors such
as degree of exposure, the dose/concentration, and route.

Poison: A substance that causes harm or injury to a living organism. The term is often used
for substances that harm the body through the oral route.

Exposure: It is a measure of the concentration and frequency of availability of a toxicant to

the body. The higher the exposure, the higher the risk involved.

Injury: The undesirable change that occurs in the body following exposure to a toxicant. It
may be reversible or irreversible. It depends on the chemical, nature of exposure, the health
and developmental state of the individual involved.

Antidote: An agent that mitigates or annuls the effects of a toxicant.

Branches of Toxicology

Like every subject, the scope keeps increasing. The major branches of toxicology are listed
below.

Environmental toxicology: It involves studying the harmful effects of chemical, biological

and physical agents on living organisms and the ecosystems. Examples include studying the
harmful effects of oil spillage and air pollution whether natural or man-made.

Occupational (Industrial) Toxicology: It examines the health effects of workplace

chemicals e.g. the effects of petrol on the health of fuel attendants and mechanics. It arose
from the quest to protect the health and safety of workers as a fundamental right.

Regulatory Toxicology: This aspect involves collecting data (experimental and

epidemiological) that will form the basis of safety decisions by regulatory agencies such as
the National Agency for Food and Drug Administration and Control (NAFDAC, Nigeria) and
the Food and Drug Administration (FDA, United States).

Food Toxicology: It examines the toxicological effects of food additives and high intake of
foods. It also examines the presence of toxicants in food and their possible effects.

Clinical Toxicology: It involves studying the adverse effects of toxicants on human and the
most beneficial treatment protocols to adopt. A similar branch is Veterinary Toxicology
which focuses on studying the adverse effects of toxicants and their treatments in animals.

Forensic Toxicology: This is the aspect of toxicology that pertains to law. It uses all of
science to investigate crimes and breaches of the law such as causes of death (homicide or
suicide), poisoning, and drug use (e.g. during sport competitions).

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Nature of Toxicants

Substances that cause harm are diverse and include pesticides, plant and animal toxins,
radiation and radioactive materials, solvents and vapours, and heavy metals. Substances
used for homicides, may not belong to any of the aforementioned classes because they may
be intentionally formulated and administered.

Routes of Intoxication

This is similar to routes of drug administration in pharmacology. The difference is that

whereas pharmacological routes are designed for specific purposes, toxicants are hardly
specially formulated. They can gain access to the body through the skin and mucous
membranes (e.g. HCN), through the lungs in which case size and shape of particles are
important, by ingestion, and through the eye. From these routes, the toxicant may be
absorbed into the systemic circulation.

Enhancement of Toxic Effects

As in Pharmacology, the effects of toxicants can be additive (arithmetic sum of the degree of
toxicity by each of the agent, e.g. 1 + 4 = 5), synergistic (toxicants work by different
mechanisms but the resultant effect is greater than would have been obtained by arithmetic
summing, e.g. 1 + 1 = 5), and potentiation (in which one agent is not a toxicant but its
presence enhances the toxicity of the toxicant, e.g. 0 + 2 = 5).

Antagonism

The effects of a toxicant can be antagonized by the administration of another. Such

antagonism forms the basis of management of toxicity by use of antidotes. More often,
antagonism is physiologic rather than through receptors.

Evaluation of Toxicity

Although there is no limit to the extent of evaluations that can be carried out in order to
understand the nature and degree of toxicity, one or more of the following may be used:

Median Lethal Dose/Concentration (LD50/LC50): This is the dose or concentration that

kills 50% of a population (e.g. rodents and insects). The evaluation is done as has been
taught in pharmacology.

Haematological evaluation: The possible harmful effects of a toxicant can be determined

by counting the red blood cells, white blood cells and the differentials (granulocytes,
neutrophils and eosinophils), and platelets. Other parameters that can give information

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include the packed cell volume, haemoglobin concentration, and mean corpuscular
haemoglobin concentration.

Plasma/serum electrolytes, urea and creatinine: Evaluation of Na+, K+, Cl-, HCO3-,
urea and creatinine concentrations in plasma or serum can give information on the effect of
a toxicant to the kidneys.

Plasma/serum levels of enzymes: The levels of aspartate transaminase (AST), alanine

transaminase (ALT), alkaline phosphatase (ALP), and gamma glutamyl transaminase (GGT)
among others can be used to assess the level of internal organ damage caused by a
toxicant. Some are quite specific e.g. ALT (liver) and ALP (bones) while some are not.

Plasma/serum proteins and bilirubin: These can be assayed to give information about
the state of the liver specifically.

Plasma/serum levels of lipids: The degree of derangement that has occurred following
exposure to a toxicant can be checked by assaying the levels of total cholesterol, low density
lipoproteins, high density lipoproteins, and triglycerides. Elevation in all except HDL can
suggest a tendency to cause atherosclerosis.

Histology/Biopsies: This may be carried out on tissues to assess the possible alterations
that may have been caused by the toxicant.

Toxicodynamics

Toxicodynamics describes the actions of a toxicant in the body and attempts to find
mechanistic basis for them. Like pharmacodynamics, it examines the adverse effects and
how they happen. This may involve interactions with receptors in the body, ions, second
messengers, enzymes, and other macromolecular components of cells, leading to their
activation or inhibition.

Toxicokinetics

This term describes what the body does to a toxicant. Like the term pharmacokinetics, it is
studied under the parameters of absorption, distribution, metabolism, and excretion (ADME).
Factors that influence pharmacokinetics also affect the kinetics of toxicants. Therefore, lipid
solubility as a factor that promotes absorption and distribution also promotes the absorption
and distribution of toxicants, and phases of metabolism of drugs (phases 1 and 2) also apply
to toxicants. Similarly, half-lives, volumes of distribution, protein binding, etc. also apply to
toxicants.

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Postscript

Deaths in most of the developing world are still largely mysterious. This is partly due to the
paucity of toxicologists to advise against harmful practices and to investigate the cause of
death for better prevention. Sadly, pharmacists have not sufficiently demonstrated interest in
this very rewarding subject. With knowledge of toxicology, the spectrum of relevance and
indispensability is wider for the pharmacist. Rare areas are almost always very rewarding.
Think about it!

RIO
Pharmacol & Toxicol
Uniben
January, 2022