Lecture Note 2 - Health effects from exposures and mechanisms of effects.ppt

Health effects from exposures
and
mechanisms of effects
LECTURE NOTE 2

Intended Learning Outcomes
The Students should be able to:
By the end of this topic, students should be able to:
a)analyse the various health effects emanating from
exposure to certain environmental chemicals or
toxicants.
b)explain the mechanisms leading to these effects.
Thursday, July 6, 2023
MPH 709: Environmental and Occupational Health 2

Health effects: factors
• Pollutant may cause an adverse effect on a living organism through
a) disruption or destruction of cellular structure;
b) direct chemical combination with a cell constituent;
c) its influence on enzymes; and
d) initiation of a secondary action.
Disruption or destruction of cellular structure
• pollutant may exert its injurious effect on an organ by causing structural damage to its tissues.
• For example, airborne pollutants such as SO2 and O3, NO2, and fluoride are known to be
phytotoxic. Phytotoxicity is the degree to which a chemical or other compound is toxic to
plants.
• Inhalation of quantities of O3 and sulphuric acid mists can cause damage to surface layers of
the respiratory system of animals and humans. Exposure to high levels of ozone leads to
pulmonary oedema
MPH 709: Environmental and Occupational Health
Thursday, July 6,
2023
3

Direct Chemical Combination with a Cellular Constituent
• A pollutant may combine with a cell constituent and form a complex. This often leads to
impaired function.
• For example, carbon monoxide (CO) in the blood readily binds to haemoglobin (Hb), forming
carboxyhaemoglobin (COHb) as shown below:
CO + Hb → COHb
• Since haemoglobin in the body is essential in the carbon dioxide–oxygen exchange system
between the lungs and the tissues, interference with the functioning of haemoglobin as a
result of COHb formation can be detrimental.
Effect on Enzymes
• Enzymes are protein catalysts that speed up the rate of biochemical reactions in cells or the
body. They are protein in nature.
• Coenzymes are organic molecules that are required by certain enzymes to carry out
catalysis.
Thursday, July 6,
2023

• Cofactors are often classified as inorganic substances that are required for, or increase the
rate of, catalysis. E.g. Zn2+, Fe3+, Fe2+, Cu2+, K+ & Mg2+, Mn2+ and Na+.
• The optimum activity of many enzymes depends on the presence of cofactors.
• Enzymes that require a cofactor but are not bound by one are called apoenzymes and
exhibits very low activity or none at all.
• Holoenzymes represent the apoenzyme bound to its necessary cofactors and exhibits
maximal catalytic activity.
• Several ways in which environmental pollutants may inactivate an enzyme system:
a) A pollutant may combine with the active site or sites of an enzyme thus inactivating it. For example, a
heavy metal such as mercury, lead, or cadmium can attach itself to the thiol or sulfhydryl (SH) group
on an enzyme molecule, forming a covalent bond with the sulphur atom. This will lead to inactivation
of the enzyme if the sulfhydryl group happens to be the active site of the enzyme.
Thursday, July 6,
2023

b) Many enzymes require cofactors, often cations, for their activity. These
ions provide electrophilic centres in the active site. A pollutant may
inhibit an enzyme by inactivating the cofactor involved.
• E.g. fluoride is known to be a potent inhibitor of enolase, a glycolytic enzyme that
requires Mg2+ ions for its activity. In the presence of phosphate, fluoride inactivates
the Mg2+ cofactor, presumably by causing the formation of a magnesium
fluorophosphate complex.
c) A pollutant may exert its toxicity through competing with the cofactor
for the active site, thus inactivating the enzyme.
• For example, Be (beryllium) competes with Mg and Mn, and Cd replaces Zn in
some enzymes.
d) The activity of an enzyme may be inhibited by the presence of a
toxic metabolite.
• Metabolism of sodium fluoroacetate results in the formation of a toxic chemical called fluorocitrate.
Thursday, July 6,
2023

• fluorocitrate inhibits aconitase, the enzyme responsible for the conversion of citrate into cis-aconitate and
then into isocitrate in the tricarboxylic acid cycle. Inhibition of aconitase results in citrate accumulation.
The cycle stops for lack of metabolites, leading to disruption of energy metabolism.
Thursday, July 6,
2023

Secondary Action as a Result of the Presence of a Pollutant
• The presence of a pollutant in a living system may cause the release of certain
substances which are injurious to cells.
• Subsequent to inhalation of pollen, allergic response occurs in many individuals, leading to a
common symptom of hay fever. This is due to the release of histamine, a substance formed from
the amino acid histidine.
• Release of histamine is also triggered by certain drugs and chemicals. Histamine is a powerful
vasodilator and causes dilation and increases permeability of blood vessels.
• It stimulates secretion of pepsin; it can reduce the blood pressure and can induce shock, if severe
enough. In excessive concentrations histamine can cause vascular collapse
Thursday, July 6,
2023

Factors affecting the toxic action of Toxicants
• The major factors affecting pollutant toxicity include
a) physicochemical properties of pollutants,
b) mode of exposure,
c) time,
d) environmental factors,
e) interaction,
f) biological factors, and
g) nutritional factors.
Thursday, July 6,
2023

a) Physicochemical Properties of Pollutants
• Membranes are more permeable to a nonionized than an ionized substance. Therefore, a
nonionized substance will generally have a higher toxicity than an ionized substance.
• One of the most important factors affecting pollutant toxicity is the concentration of the
pollutant in question.
• Even a generally highly toxic substance may not be very injurious to a living organism if its
concentrations remain very low.
• On the other hand, a common pollutant such as carbon monoxide can become extremely dangerous if its
concentrations in the environment are high.
Thursday, July 6,
2023

b) Time and Mode of Exposure
• Exposure time is another important determinant of toxic effects.
• Normally, one can expect that for the same pollutant, the longer the exposure time the
more detrimental the effects.
• Also, continuous exposure is more injurious than intermittent exposure, with other
factors being the same.
• The mode of exposure, i.e., continuous or intermittent, is an important influence on
pollutant toxicity because living organisms often can, to a certain degree, repair
injuries caused by environmental agents.
• In addition, organisms may be able to develop tolerance so that they will be able to
withstand otherwise toxic doses of chemical substances.
Thursday, July 6,
2023

Environmental Factors
Environmental factors such as temperature, light, and humidity also influence the toxicity of
pollutants.
• Temperature
• There are two basic types of temperature effects on toxicity:
• either an increase in toxicity at both high and low temperature or an increase in toxicity with an increase in
temperature.
• For example, both warming and cooling increases the toxicity of caffeine to mice, whereas the toxicity of
amphetamine is lower at reduced temperatures and shows a regular increase with increases in temperature.
• Amphetamine stimulates the central nervous system (nerves and brain) by increasing the amount of certain
chemicals in the body. This increases heart rate and blood pressure and decreases appetite, among other
effects.
Thursday, July 6,
2023

• Light
• Many enzymes, including some of those involved with xenobiotic metabolism, show a
diurnal pattern that can be keyed to the light cycle.
• Sensitivity of pinto bean to Peroxyacyl nitrates (PAN) increased with increasing light
intensity.
• Plants exposed to pollutants in the dark are generally not sensitive.
Altitude.
• Altitude can either increase or decrease toxicity.
• Examples of altitude effects include the observations that at altitudes of ≥ 5000 ft, the
lethality of digitalis (a medication prescribed to certain heart patients) to mice is decreased,
whereas that of amphetamine is increased.
Thursday, July 6,
2023

• Humidity
• Generally, the sensitivity of plants to air pollutants increases as relative humidity increases.
• Some studies have found certain plants to be more sensitive to fluoride as relative humidity
increased from 50 to 80%.
• Interaction of Pollutants
• Synergism
• Potentiation
• Antagonism
• Additive
Thursday, July 6,
2023

INTERACTION OF POLLUTANTS
• Potentiation - Potentiation of toxicity occurs when the toxic effect of one chemical is
enhanced in the presence of a toxicologically unrelated agent.
 The situation can be described numerically as 0 + 2 > 2, where a relatively non-toxic chemical alone
has little or no effect (0) on a target organ, but may enhance the toxicity of another co-administered
chemical (2).
 The hepatotoxicity of carbon tetrachloride, for instance, is greatly enhanced in the presence of
isopropanol.
• Additive - Two or more chemicals whose combined effects are equal to the sum of the
individual effects is described as an additive interaction.
 Numerically this is summarized as 2 + 2 = 4.
 This happens when the chemicals in question exert their effects in a similar manner, as when a person is
exposed to several organophosphate pesticides at a time: each inhibits the activity of a specific enzyme.
The chemicals do not interact.
Thursday, July 6,
2023
15

INTERACTION OF POLLUTANTS (cont.d)
• In synergism the combined effect of two chemicals are greater,
sometimes much greater than additive.
 i.e., one plus one equals much more than two (1 + 1 > 2).
Carbon tetrachloride and ethyl alcohol are both toxic to the liver, but
exposure to both at the same time leads to much greater injury than the
sum of their individual effects.
• In antagonism one chemical interferes with the action of another –
it acts as an antidote.
Exposure to one chemical results in the reduction in the effect of the other
chemical.
Thursday, July 6,
2023
16

• Variation among species
• A chemical that harms one species at a given dose may not be toxic to another species.
• Silicosis is a lung disease that was commonly found in human miners exposed to silica dust,
but their similarly exposed mules were not affected.
• Dioxin” or TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is one of the most toxic chemicals
known. Although formed naturally in very tiny amounts, most is generated by human
activities. Dioxin toxicity varies greatly by species.
• The politician Yushchenko was fortunate that humans are not as sensitive as are a number of
other species.
• Variation within a species
• Within a given species, individuals may vary greatly in their sensitivity to a toxicant, some
very sensitive, others resistant. Consider aspirin or the sulphites (widely used in wine and food
preservation).
• Some humans are hypersensitive to these chemicals but, at levels commonly used, there is no
indication of adverse effects in most people.
Thursday, July 6,
2023

• Gender
• The sex hormones, androgens and oestrogens, affect animal anatomy, physiology, and
metabolism in many ways.
• Thus, it is not surprising that the two genders can react differently to xenobiotics.
• Women, for example, have less alcohol dehydrogenase (an enzyme involved in
metabolizing alcohol) than do men.
• Thus, a woman can become intoxicated more rapidly than a man of the same weight.
• Age
• The immune system in babies and small children is less well developed than in adults.
They often – but not always – are more sensitive to toxicants than adults.
• Likewise, the immune systems of elderly persons function less efficiently than in
younger adults.
• Thus, they may react more strongly to a drug or pollutant than younger adults.
Thursday, July 6,
2023

• Nutrition
• Good nutrition helps to maintain a healthy immune system, which
provides protection against xenobiotics and infectious (pathogenic)
microorganisms.
• Alcoholics are an example of a poorly nourished population more likely to
be affected by xenobiotics and pathogens.
• Other susceptible populations are people whose diets have insufficient
calories or insufficient nutrients.
• Overweight rats and other animals develop more cancers than do animals
fed a well-balanced, but low-calorie diet.
• Obese people have a greater risk of cardiovascular diseases and of a
number of cancers.
• Individuals who consume high-fat diets have a greater risk of colon and
skin cancer. Thursday, July 6,
2023

BIOTRANSFORMATION
• Biotransformation is the sum of several processes by which the structure
of a chemical is changed during passage through the organism.
• The metabolites formed from the parent chemical are usually more water
soluble.
• The increased water solubility lowers the ability of the metabolites to
move across membranes, restricts renal and intestinal reabsorption, and
thus facilitates excretion with urine or bile.
• Biotransformation occurs in any of several tissues and organs such as the
intestine, lung, kidney, skin, and liver.
• The liver is the site for most biotransformation processes.
Thursday, July 6,
2023
20

BIOTRANSFORMATION (cont.d)
• It occurs in 2 phases: Phase I and Phase II.
• Phase I and II reactions result in the breakdown and synthesis of compounds that
are generally less toxic, H2O soluble and, therefore, easier to excrete.
• Phase I involves catabolic reactions that break down the toxicant into various
components.
• The catabolic reactions include oxidation, reduction and hydrolysis.
• Phase II involves anabolic reactions that combine molecules into either the
original toxic molecule or the toxic molecule metabolite derived from Phase I
reactions.
• The Phase II reactions include glucuronidation, sulfation, acetylation, methylation,
conjugation with glutathione, and conjugation with amino acids.
Thursday, July 6,
2023
21

• Oxidation reaction: this occurs when a molecule combines with oxygen, loses hydrogen or loses one or
more electrons. E.g. conversion of parathion to paraoxon.
• Parathion is one of the most extremely acutely toxic organophosphate pesticides. It is notorious for the
number and severity of human poisonings it causes each year. There is evidence that parathion is a
chronic neurotoxin, carcinogen, mutagen, reproductive toxin, immunotoxin, and can cause birth defects.
• The toxicity of parathion is caused by its metabolite, paraoxon, which is 50 times as toxic as the parent
compound.
MPH 709: Environmental and Occupational Health Thursday, July 6, 2023 22

• Reduction: occurs when a molecule combines with hydrogen, loses oxygen, or gain one or more
electrons . E.g. conversion of nitrobenzene to aniline.
• Acute and chronic inhalation, oral, and dermal exposure of humans to nitrobenzene result in effects on
the blood (i.e., methaemoglobinemia). At low nitrobenzene concentrations, symptoms include fatigue,
weakness, shortness of breath, headache, and dizziness. At higher concentrations, depressed
respiration, bluish-gray skin, disturbed vision, and coma may occur.
• Aniline is irritating to the skin, eyes, and respiratory tract. Effects can result from all routes of
exposure. Aniline induces methaemoglobinemia, which impairs the delivery of oxygen to tissues.

• Methylation is the addition of one or more methyl group (CH3-) to a toxic molecule
undergoing metabolism.
• The methyl group is transferred from the nucleotide S-adenosyl-l-methionine (SAM) by
means of a methyltransferase.
• Methylation, and to some degree acetylation decrease water solubility.
• Toxic substances that undergo these reactions are retained in the body for longer
periods of time.
• Metals can undergo methylation. E.g. methylation of mercury.
• Methyl mercury is highly toxic and soluble in lipids.
• It affects the immune system, alters genetic and enzyme systems, and damages the nervous system.
• Methylmercury is particularly damaging to developing embryos, which are five to ten times more
sensitive than adults.

Lecture Note 2 - Health effects from exposures and mechanisms of effects.ppt

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