XENOBIOTICS

A xenobiotic is a chemical substance found within an organism that is not naturally

produced.

Xenobiotics can be defined as any foreign substances which the body does not recognize
such as drugs, pollutants, as well as some food additives and cosmetics.

Some naturally occurring chemicals become xenobiotics when present in the environment at
excessive concentrations.

ADME

A. Absorption (absorption external membrane barriers - Skin, G.I tract, lungs)

Xenobiotics must cross one of these barriers to exert their toxicities in the body. However
during this process they usually pass through various cell membranes.

Main absorption routes/barriers

1. ORAL-GASTRO INTESTINAL TRACT (GI)

Mouth and oesophagus: Little absorption occurs in here.

Stomach (pH: 1-3):Weak organic acids are absorbed here due to acidic media. (Surface
area:<5m2)

Small intestine(pH:7-8): The greatest absorption of xenobiotics takes place in here

(Surface area: 200m2 ) particularly alkaline ones and food. The rate of absorption increases
with the residency time. The residency time of a xenobiotic in here depends on intestinal
motility (ability of an organism to move).

Colon and rectum: Absorption is negligible in here. (Surface area : <m2)

2. INHALATION-LUNG

Xenobiotics such as gases, vapors of volatile liquids and aerosols are absorbed by this
route. The absorption of gas depends on its solubility in blood. The physical form and
particle size of the xenobiotic determines penetration. Particular very small particles (<1µm
in diameter) are able to reach alveoles and can enter bloodstream.

3. DERMAL-SKIN

Human skin comes into contact with many toxic agents such as pesticides and other
environmental and occupational chemicals. A multilayered barrier not very permeable. The
rate - determining barrier is the upper layer of epidermis.
B. Distribution (Between blood plasma and tissues, pools, depots, sinks

Xenobiotics must pass a number of cell membrans to enter systemic circulation, to move
within and leave the body.

Basic mechanisms of xenobiotic transmembrane transport

A xenobiotic may pass through a membrane by

1. Passive transfer (simple diffusion)

 Most xenobiotics cross membranes by passive transfer

 It does not need cellular energy of assistance.
 The driving force for the transport across the membrane is the concentration
gradient (from higher to lower concentration) between the two compartments.

2. Facilitated diffusion

3. Active transport

4. Endocytosis(phagocytosis and pinocytosis)

After entering the blood, a xenobiotic may distribute throughout the body to organs or
tissues.

The xenobiotics are often concentrated in a specific tissue which may or may not be their
site of toxic action.

Storage of xenobiotics in body constituents:

Binding to the plasma proteins

• Xenobiotics bind to several plasma proteins such as albumin and globulins.

• Protein-binding in the plasma greatly affects distribution, prolongs the half-life within
the body, and affects the threshold for toxicity.

• Important drug interaction leading toxicity is seen at plasma protein binding level.

Liver and Kidney as storage depot

• These organs have a high capacity for binding multitude of xenobiotics.

• Protein such as metallothionein have high affinity for metals namely Cd. Such
bindings serve as a storage depot and cause the accumulation of the toxicants.

Fat as a storage depot

• Many lipid-soluble xenobiotics are stored in body fat.

• DDT and polychlorinated biphenyls (PCBs) are stored in adipose tissue.

• Due to the relatively low blood flow, fat is a rather stable depot.
Bone as storage depot

• Lead (Pb) is stored in bone but not toxic to bone.

• However, chronic effects of fluoride deposition (skeletal fluorosis) and radioactive

strontium (osteosarcoma) are well documented.

Physiological barriers:

1. The blood-brain barrier

BBB is less permeable than most other areas of the body. Only lipid soluble xenobiotics
cross this barrier. Not fully developed at birth, and thus some xenobiotics could be more
toxic to newborns than to adults.

2. The placental barrier

The placental barrier between mother and fetus is the ‘leakiest’ barrier and is a very poor
block to chemicals. The placenta is composed of several layers of cells acting as a barrier
for the diffusion of substances between the maternal and fetal circulatory systems.

Xenobiotics can cross this barrier. (e.g. Ethanol, Pb-lead) but should be having molecular
weight less than 1000. Major factors in xenobiotic transfer to the fetus: Lipid solubility,
Plasma protein binding

C. METABOLISM: PHASE-1: Oxidation, PHASE-2: conjugation

METABOLISM – is “changed” so that it can be excreted.

Biotransformation of xenobiotics plays a major role in their detoxification as well as their

bioactivation to toxic metabolites

Biotransformation of xenobiotic is defined as the conversion from one chemical form to

another.

A number of factors influence the biotransformation of a toxicant, such as genetic

constitution, age, sex, species, strain, nutritional status, underlying diseases and
concomitant exposures to other xenobiotics with enzyme-inducing and/or enzyme-inhibiting
activities.

Biotransformation converts the xenobiotics to more water-soluble products so that they

can be more readily eliminated from the body via the urine and/or faeces. Biotransformation
is often assumed to be detoxification, leading to an increased elimination of less-toxic
metabolites. However, sometimes this process can also lead to bioactivation.

Without biotransformation, lipophilic xenobiotics would be excreted from the body so slowly
that they would eventually overwhelm and kill an organism.

An important consequence of biotransformation is that the physical properties of a xenobiotic

are generally changed from those favoring absorption (lipophilicity) to those favoring
excretion in urine or feces (hydrophilicity).
Phase 1 & Phase 2

Phase 1: Functionalization reactions/oxidation

Phase 2: Conjugation reactions

D. EXCRETION

Xenobiotics are excreted/eliminated from the body in the form of the parent compounds,
their metabolites and/or their conjugates.

The primary excretion/elimination routes:

1. Urinary-Renal
2. Fecal
3. Respiratory-Exhalation

4. Other

Urinary-Renal

Renal excretion consists of 3 distinct processes namely:

• Glomerular filtration

About 99% of the filtrate is reabsorbed into blood, the remaining 1% is excreted as urine.

• Active tubular secretion (takes place at proximal tubule of the nephron)

Xenobiotics can be excreted into urine by active secretion at proximal tubule of the nephron.

Protein bound xenobiotics, polar metabolites and conjugates are readily secreted by this
mechanism.
 • Tubular excretion (takes place at distal tubule of the nephron)

Xenobiotics can be reabsorbed from urine into blood capillaries via passive diffusion at distal
tubule of the nephron. Urine pH greatly affects reabsorption or urinary excretion.

If the urine is alkaline, weak acids are more ionized and thus excreted largely.

If the urine is acidic, weak acids are more less ionized and reabsorbed largely. As a result
renal excretion is reduced.

Fecal Excretion

Excretion in feces occurs by two ways:

a) Biliary excretion

b) Direct intestinal excretion

Respriratory-Exhalation-excretion

The lungs are also an important excretion route for xenobiotics (and/or their metabolites) in
the gaseous phase of blood.

Xenobiotics are eliminated by passive diffusion. e.g. Ethanol, anesthetic gases

ACUTE & CHRONIC TOXICITY

1. Acute- usually a single exposure for less than 24 hours.

2. Subacute- exposure for 1 month or less.
3. Chronic- exposure for more than 3 months.
4. Subchronic- exposure from 1 to 3 months.

Acute toxicity can be defined as toxicity that comes speedily to a crisis, that is, the toxicity
showed over a short period of time.

The results of acute test in mammalian toxicity test are expressed as an LD50 or the lethal
dose to 50% of the test population that occurred over a given period of time.

In aquatic toxicity tests, the results are expressed as an LC50.

The LC50 is the concentration that caused the mortality to the test population in a given
period of time.

The time is generally 48h for invertebrate test organisms and 96h for fish.

LD stands for Lethal Dose. LD50 is the amount of material, given all at once, which causes
the death of 50% of a group of test animals.

Dermal and oral is the most common route of entry or administration

Acute toxicity is the ability of a chemical to cause ill effect relatively soon (period of minutes,
hours (up to 24) or days (up to about 2 weeks) but rarely longer) after one oral administration
or a 4-hour exposure to a chemical in air.

Chronic toxicity - toxicity that develops over longer periods of time.

The endpoint of chronic toxicity test can be death but generally other endpoints such as
reproductive effects (number of offspring produce or egg laid), changes in growth rates,
changes in organism behaviour.
Probit plot of various effects. Dose–response data can be plotted using a probit scale to
extrapolate data: probability units obtained from standardised normal distributions are plotted
against the logarithm of the dose of a substance when quantal (or graded) responses have
been measured (in this case a therapeutic effect, a toxic effect and death, respectively). Log-
dose data provide linear plots, which make it easy to extrapolate the data. ED50 = the dose
that produces the desired effect in 50% of the population; TD50 = the dose that produces the
defined toxicity in 50% of the population, and LD50 = the dose that produces death in 50% of
the population. The LD50 is one way to measure the short-term poisoning potential (acute
toxicity) of a material
EXPOSURE ASSESSMENT

Exposure – defined as contact over time and space between a person and one of more
biological, chemical or physical agents (contact with outer part of the human body with a
carrier medium such as air, water, food, dust or soil).

Exposure assessment – to identify and define the exposure that occur, occurred or are
predicted to occur in human population.

Exposure concentration – (mg/L, mg/kg, mg/m3) is defined as the concentration of an

environmental agent in the carrier medium at the point of contact with the body,

Aspects important in exposure analysis

1. Agents – biological, chemical, physical components, complex mixtures

2. Sources – antrapogenic-natural, area-point, stationary-mobile, indoor-outdoor
3. Transport/carrier medium – water, soil, dust, food, breathing polluted area, touching
contaminated surface
4. Exposure concentration – mg/kg (food), mg/L (water), mg/m3 (air), mg/m2
(contaminated surface)
5. Exposure routes – inghalation, ingestion, dermal contact, multiple ways
6. Exposure duration – seconds, minutes, hours, days, weeks, months, years, lifetime
7. Exposure frequency – continuous, intermittent, cyclic, random, rare
8. Exposure settings – occupational, environment, residential, indoors, outdoors
9. Exposed population – general, occupational, subgroups, individuals
10. Geographic scope – site/ source specific, local, regional, national, international, global
11. Time frame: past, present, future, trends

Exposure assessment steps

1. Source of contamination: source of contaminant release into the environment

2. Environmental media and transport mechanism: transport mechanisms serve to

move contaminants form the source to points where human exposure can occur (air,
groundwater, surface water, surface soil, sediment, biota)

3. Point exposure: a location of potential or actual human contact with a contaminated

medium

4. Route of exposure: means by which the contaminant actually enters or contacts the
body either through ingestion, inhalation, dermal contact.

5. Receptor population: persons who are exposed or potentially exposed to the

contaminants.
How can chemicals disrupt the endocrine system?

1. Directly stimulate of inhibit the endocrine system

Cause overproduction or underproduction of hormones (e.g. an over or underactive

thyroid), Antiandrogen

2. Block the effects of a hormone

3. Mimic aor partly mimic naturally occurring hormone

define endocrine disruptors

Example of chemical/substance on endocrine disruptor: DDT, polychlorinated biphenyls,

plasticizers

4.