UNIT 2 -Week (4-5): Mechanisms of Toxicity & Toxicokinetics

Intended Learning Outcomes (ILO)

At the end of the unit, you are expected to:

1. Describe the mechanism of toxicity of poisons.

2. Determine the toxicokinetics of poisons.

3. Describe the primary routes of exposure and their effect on

toxicant absorption and distribution.

Introduction
Gupta (2016) stated that toxicokinetics refers to the study of
absorption, distribution, metabolism/biotransformation, and excretion
(ADME) of toxicants/xenobiotics in relation to time. The basic kinetic
concepts for the absorption, distribution, metabolism, and excretion of
chemicals in the body system initially came from the study of drug actions or
pharmacology; therefore, this area of study is traditionally referred to as
pharmacokinetics.
This unit will focus on the routes and exposure of toxicants in our
body. Please proceed immediately to the “Unlocking of Difficulties” in order
to understand the terms used in the Lecture notes.

Unlocking of Difficulties

To attend the following intended learning outcomes the lesson of the

course, you need to fully understand the following essential knowledge that
will be laid down in the succeeding pages. Please note that you are not
limited to exclusively refer to these resources. Thus, you are expected to
utilize other books, research articles and other resources such as e-journals
and various pharmacy mobile applications.

Key Terms:

▪ DRUG METABOLISM- is the term used to describe the

biotransformation of pharmaceutical substances in the body so
that they can be eliminated more easily.

▪ DRUG ABSORPTION– is the process of a drug moving from its

site of delivery into the bloodstream.
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 ▪ DRUG DISTRIBUTION- refers to the movement of a drug to and
from the blood and various tissues of the body (for example, fat,
muscle, and brain tissue) and the relative proportions of drug in
the tissues.

▪ DRUG EXCRETION- is the removal of drugs from the body, either

as a metabolite or unchanged drug.

▪ TOXICOKINETICS- encompasses rates of absorption,

distribution, metabolism (biotransformation), and excretion
(ADME) of toxicants or toxins.

Lecture Notes

Do you have any idea on how toxic substances are absorbed,

metabolized, distributed to various sites and tissues or even
how they are excreted in our body? In this unit, we will
determine the toxicokinetics of toxicants.

I. TOXICOKINETICS OF CHEMICALS
▪ Toxicity involves toxicant delivery to its target or targets and
interactions with endogenous target molecules that may trigger
perturbations in cell function and/or structure or that may initiate
repair mechanisms at the molecular, cellular, and or tissue levels.

▪ Biotransformation to harmful products is called toxication or

metabolic activation.
Example:
When methanol is metabolize into formic acid which can cause
blindness

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 Figure 1: Toxication of methanol
(Berland, 2020)

▪ Biotransformations that eliminate the ultimate toxicant or prevent its

formation are called detoxications.
Example:
The inhibition of alcohol dehydrogenase is fundamental to the
treatment of methanol poisoning which causes metabolic acidosis,
blindness and death.

Figure 2: Detoxications of alcohol

(Massachusetts Medical Society, 2021)

▪ Apoptosis, or programmed cell death, is a tightly controlled,

organized process whereby individual cells break into small
fragments that are phagocytosed by adjacent cells or macrophages
without producing an inflammatory response.

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 Figure 3: Apoptosis
(Online Biology Notes, 2020)

▪ Toxicokinetics
➢ refers to the quantitation of the time course of toxicants in the
body during the processes of absorption, distribution,
metabolism, and excretion (ADME) or clearance of toxicants.
➢ It is a reflection of how the body handles toxicants as indicated
by the plasma concentration of that xenobiotic at various time
points

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 Figure 4: Toxicokinetics
(Springer Nature Switzerland, 2020)

II. FACTORS AFFECTING CHEMICAL DISPOSITION

1. If the rate of absorption is low → high concentration at the site of
action to cause toxicity is not attainable.

2. Distribution of a toxicant concentrated in a tissue other than the

target organ → Decrease toxicity

3. Biotransformation of chemical →Formation of less toxic or more

toxic metabolites at fast or slow rate.

4. The rapid eliminated chemical from an organism → the lower will be

its concentration of toxicity in target site.

III. ABSORPTION OF TOXICANTS

▪ CHEMICAL ABSORBED INTO THE BLOODSTREAM
➢ through any of the major barriers is distributed, at least to
some extent,
➢ throughout the body, including the site where it produces
damage.
➢ This site is called the target organ or target tissue.

▪ CELL MEMBRANES
➢ Toxicants usually pass through a number of cells, such as the
stratified epithelium of the skin, the thin cell layers of the lungs
or
➢ the gastrointestinal (GI) tract, capillary endothelium, and
ultimately the cells of the target organ.
➢ The basic unit of the cell membrane is a Lipid bilayer composed
primarily of phospholipids, glycolipids, and cholesterol.

▪ A toxicant may pass through a membrane by:

1. PASSIVE TRANSPORT
➢ Most toxicants cross membranes by simple diffusion, following
the principles of Fick’s law which establishes that chemicals

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 traverse from regions of higher concentration to regions of
lower concentration without any energy expenditure.

➢ Small hydrophilic molecules (up to about 600 Da) permeate

membranes through aqueous pores in a process termed
paracellular diffusion, whereas hydrophobic molecules diffuse
across the lipid domain of membranes (transcellular
diffusion).

2. SPECIALIZE TRANSPORT
➢ Cell provides energy to translocate the toxicant across its
membrane.
➢ Some compounds are too large to pass through aqueous pores
or too insoluble in lipids to diffuse across the lipid domains of
membranes.
➢ Three Types of Specialize Transport: FACILITATED DIFFUSION,
ACTIVE TRANSPORT & XENOBIOTIC TRANSPORTER

2.1. FACILITATED DIFFUSION

➢ Carrier mediated transport that exhibits the properties of
active transport except that the substrate is not moved
against an electrochemical or concentration gradient.

2.2. ACTIVE TRANSPORT

→It is characterized by:
✓ Movement of chemicals against electrochemical or
concentration gradients

✓ Saturability at high substrate concentrations,

✓ Selectivity for certain structural features of chemicals,

✓ Competitive inhibition by chemical cogeners or compounds

that are carried by the same transporter,

✓ Requirement for expenditure of energy, so that metabolic

inhibitors block the transport process.

2.3. XENOBIOTIC TRANSPORTER

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 ➢ Xenobiotic transporters are responsible for the uptake of
some chemicals into cells, and extremely important for the
export of chemicals out of cells.

➢ Some microsomal enzyme inducers will enhance the

plasma disappearance and biliary excretion of some
xenobiotics that are not biotransformed in the intact
animal, as well as in isolated hepatocytes.

➢ This is due to an up-regulation of xenobiotic transporters.

As a result, some microsomal enzyme inducers will enhance
the elimination and decrease the toxicity of some chemicals
by enhanced transport (Klaassen, 2002).

IV. EXCRETION & REABSORPTION OF TOXICANTS

▪ Excretion is the removal of xenobiotics from Blood and their return
to the external environment.
▪ Excretion is a physical mechanism, whereas biotransformation is a
chemical mechanism or eliminating the toxicant.
▪ Some chemicals may be excreted through:
✓ Excretion rom the mammary gland in breast milk,
✓ Excretion in bile,
✓ Excretion into the intestinal lumen from blood.
✓ Volatile, nonreactive toxicants such as gases and volatile
liquids diffuse from pulmonary capillaries into the alveoli
and are exhaled.

▪ Reabsorption of toxicants in the blood are filtered at the

glomerulus into the renal tubules.
▪ These filtered toxicants may reenter the blood by diffusing
through peritubular capillaries.
▪ This reentry is facilitated by tubular fluid reabsorption which
increases intratubular fluid concentration and residence time
of non-reabsorbed chemical by slowing urine flow.

Focus Questions

Guide questions for Unit 2 discussions:

1. What are the factors that affects the toxicokinetics of toxicants?
2. What will happened if toxicants are not easily eliminated in our body?

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Related Readings
Related readings will be posted via schoology to supplement the
foundation of the topics discussed in Unit 2 module.

Learning / Assessment Activities

Learning assessment will be served as your assignment and quiz and will be
given via schoology at the end of the week after our virtual consultation.

References

Canadian Centre for Occupational Health & Safety retrieved last February 8,
2021 from
https://www.ccohs.ca/oshanswers/hsprograms/hazard_risk.html

Klaasen, Curtis D., Casarett and Doull’s Toxicology The Basic Science of
Poisons, Third edition, McGraw-Hill, 2015

Luisetto, M., Pharmaceutical Care and Toxicology, a Synergy in High Risk

Situation. Journal of Applied Pharmacy, 2016

Murpy, John. Clinical Pharmacokinetics, 6th Edition, 2017.