Exposure to potentially toxic substances and their adverse effect

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" Perhaps the most difficult adverse effects to detect

are those that follow years after exposure in the

womb; "

http://www.bio.hw.ac.uk/edintox/Exposure.htm

Exposure to potentially toxic substances and their

adverse effect

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OBJECTIVE

You should know the routes of human exposure to

potentially toxic chemicals and the ways in which

resultant effects may depend upon these routes,

exposure pattern and the properties of the chemicals.

You should know about allergy and its possible

consequences.

You should know about idiosyncratic reactions, delayed

effects and irreversible effects.

You should know about the complexities of possible

interactions between chemicals and their effects.

Introduction

Injury can be caused by chemicals only if they reach

sensitive parts of a person or other living organism

at a sufficiently high concentration and for a

sufficient length of time.

Thus, injury depends upon the physicochemical

properties of the potentially toxic substances, the

exact nature of the exposure circumstances, and the

health and developmental state of the person or

organism at risk.

Major routes of exposure are through the skin

(topical), through the lungs (inhalation), or through

the gastrointestinal tract (ingestion). In general,

for exposure to any given concentration of a substance

for a given time, inhalation is likely to cause more

harm than ingestion which, in turn, will be more

harmful than topical exposure.

Skin (dermal or percutaneous) absorption

Many people do not realise that chemicals can

penetrate healthy intact skin and so this fact should

be emphasized.

Amongst the chemicals that are absorbed through the

skin are aniline, hydrogen cyanide, some steroid

hormones, organic mercury compounds, nitrobenzene,

organophosphate compounds and phenol.

Some chemicals, such as phenol, can be lethal if

absorbed for a sufficient time from a fairly small

area (a few square centimetres) ofskin. If protective

clothing is being worn, it must be remembered that

absorption through the skin of any chemical which gets

inside the clothing will be even faster.

Inhalation

Gases and vapours are easily inhaled but inhalation of

particles depends upon their size and shape. The

smaller the particle, the further into the respiratory

tract it can go.

Dusts with an effective aerodynamic diameter of

between 0.5 and 10 micrometres (the respirable

fraction, the PM10 fraction) can persist in the

alveoli and respiratory bronchioles after deposition

there.

Peak retention depends upon aerodynamic shape but

seems to be mainly of those particles with an

effective aerodynamic diameter of between 1 and 2

micrometers. Particles of effective aerodynamic

diameter less than 1 micrometre tend to be breathed

out again and do not persist either in the alveoli or

enter the gut (see below).

Remember: The effective aerodynamic diameter is

defined as the diameter in micrometers of a spherical

particle of unit density which falls at the same speed

as the particle under consideration.

Dusts of larger diameter either do not penetrate the

lungs or lodge further up in the bronchioles and

bronchi where cilia (the mucociliary clearance

mechanism) can return them to the pharynx and from

there to the oesophagus.

From the oesophagus dusts are excreted through the gut

in the normal way: it is possible that particles

entering the gut in this way may cause poisoning as

though they had been ingested in the food.

A large proportion of dust breathed in will enter the

gut directly and may affect the gut directly by

reacting with it chemically or indirectly from

contamination with micro-organisms. As already

mentioned, some constituents of dust may be absorbed

from the gut and cause systemic effects.

Physical irritation by dust particles or fibres can

cause very serious adverse health effects but most

effects depend upon the solids being dissolved.

Special consideration should be given to asbestos

fibres which may lodge in the lung and cause fibrosis

and cancer even though they are insoluble and

therefore not classical toxicants: similar care should

also be taken with manmade mineral fibres.

Insoluble particles may be taken in by the macrophage

cells in the lung which normally remove invading

bacteria (phagocytosis).

If phagocytic cells are adversely affected by

ingestion of insoluble particles, their ability to

protect against infectious organisms may be reduced

and infectious diseases may follow. Note: Phagocytosis

is the process whereby certain body cells, notably

macrophages and neutrophils engulf and destroy

invading foreign particles. The cell membrane of the

phagocytosing cell (phagocyte) invaginates to capture

and engulf the particle. Hydrolytic and oxidative

enzymes are released around the particle to cause its

destruction: these enzymes may leak from the phagocyte

and cause local tissue damage. Tissue damage may

release biologically active substances which cause

further adverse effects.

Some insoluble particles such as coal dust and silica

dust will readily cause fibrosis of the lung. Others,

such as asbestos, may or may not cause fibrosis

depending on the exposure conditions.

Remember that tidal volume (the volume of air inspired

and expired with each normal breath) increases with

physical exertion; thus absorption of a chemical as a

result of inhalation is directly related to the rate

of physical work. This is why jogging and other active

exercise has been discouraged in certain cities during

periods of severe air pollution.

Ingestion Airborne particles breathed through the

mouth or cleared by the cilia of the lungs will be

ingested. Otherwise, ingestion of potentially toxic

substances in the work, domestic, or natural

environment is likely to be accidental and commonsense

precautions should minimize this.

The nature of the absorption processes following

ingestion is discussed elsewhere.

The importance of concentration and time of exposure

has already been pointed out.

It should be remembered that exposure may be

continuous or repeated at intervals over a period of

time; the consequences of different patterns of

exposure to the same amount of a potentially toxic

substance may vary considerably in their seriousness.

In most cases, the consequences of continuous exposure

to a given concentration of a chemical will be worse

than those of intermittent exposures to the same

concentration of the chemical at intervals separated

by sufficient time to permit a degree of recovery.

Repeated or continuous exposure to very small amounts

of potentially toxic chemicals may be a matter for

serious concern if either the chemical or its effects

have a tendency to accumulate in the person or

organism at risk.

A chemical may accumulate if absorption exceeds

excretion; this may happen with substances that

combine a fairly high degree of lipid solubility with

stability.

Adverse Effects

Adverse effects may be local or systemic.

Local effects occur at the site of exposure of the

organism to the potentially toxic substance.

Corrosives always act locally.

Irritants frequently act locally. Most substances

which are not highly reactive are absorbed and

distributed around the affected organism causing

systemic injury at a target organ or tissue distinct

from the absorption site.

The target organ is not necessarily the organ of

greatest accumulation.

Adipose (fatty) tissue accumulates organochlorine

pesticides to very high levels but does not appear to

be harmed by them.

Some substances produce both local and systemic

effects; for example, tetraethyl lead damages the skin

on contact and is then absorbed and transported to the

central nervous system where it causes further damage.

Effects of a chemical can accumulate even if the

chemical itself does not. There is evidence that this

is true of the effects of organophosphate pesticides

on the nervous system.

A particularly harmful effect that may accumulate is

death of nerve cells, since nerve cells cannot be

replaced though damaged nerve fibres can be

regenerated.

It will be clear that the balances between absorption

and excretion of a potentially toxic substance and

between injury produced and repair are the key factors

in determining whether any injury follows exposure.

All of the possible adverse effects cannot be

discussed here but some aspects should be mentioned

specifically.

Production of mutations, tumours and cancer, and

defects of embryonic and fetal development have been

referred to in Descriptive terms.

Adverse effects related to allergies are a cause of

increasing concern.

Allergy (hypersensitivity) is the name given to

disease symptoms following exposure to a previously

encountered substance (allergen) which would otherwise

be classified as harmless.

Essentially, an allergy is an adverse reaction of the

altered immune system.

The process which leads to the disease response on

subsequent exposure to the allergen is called

sensitization.

Allergic reactions may be very severe and even fatal.

To produce an allergic reaction, most chemicals must

act as haptens, that is - combine with proteins to

form antigens.

Antigens entering the human body or produced within it

cause the production of antibodies; usually at least a

week is needed before appreciable amounts of

antibodies can be detected and further exposure to the

allergen can produce disease symptoms.

Most common symptoms are skin ailments such as

dermatitis and urticaria, or eye problems such as

conjunctivitis; the worst possibility is death

resulting from anaphylactic shock.

Of particular importance in considering the safety of

individuals is the possibility of idiosyncratic

reactions.

An idiosyncratic reaction is an excessive reactivity

of an individual to a chemical, for example - an

extreme sensitivity to low doses as compared with the

average member of the population. There is also the

possibility of an abnormally low reactivity to high

doses.

An example of a group of people with an idiosyncrasy

is the group which has a deficiency in the enzyme

required to convert methaemoglobin (which cannot carry

oxygen) back to haemoglobin; this group is

exceptionally sensitive to chemicals like nitrites

which produce methaemoglobin.

Another factor to be considered is whether the adverse

effects produced by a potentially toxic chemical are

likely to be immediate or delayed.

Immediate effects appear rapidly after exposure to a

chemical while delayed effects appear only after a

considerable lapse of time.

Amongst the most serious delayed effects are cancers;

carcinogenesis may take 20 or more years before

tumours are seen in humans.

Perhaps the most difficult adverse effects to detect

are those that follow years after exposure in the

womb; a well established example of such an effect is

the vaginal cancer produced in young women whose

mothers have been exposed to diethylstilbestrol during

pregnancy.

Another important aspect of adverse effects to be

considered is whether they are reversible or

irreversible.

For the liver, which has a great capacity for

regeneration, many adverse effects are reversible and

complete recovery can occur.

For the central nervous system, in which regeneration

of tissue is severely limited, most adverse effects

leading to morphological changes are irreversible and

recovery is, at best, limited.

Carcinogenic and teratogenic effects are also

irreversible, but suitable treatment may reduce the

severity of effects.

A major problem in assessing the likely effect of

exposure to a chemical is making allowance for

possible interactions. The simplest interaction is an

additive effect; this is an effect which is the result

of two or more chemicals acting together and which is

the simple sum of their effects when acting

independently,. In mathematical terms: 1 + 1 = 2, 1 +

5 = 6 etc.

The effects of organophosphate pesticides are usually

additive.

More complex is a synergistic (multiplicative) effect:

this is an effect of two chemicals acting together

which is greater than the simple sum of their effects

when acting alone; it may be called synergism. In

mathematical terms: 1 + 1 = 4, 1 + 5 = 10 etc.

Asbestos fibres and cigarette smoking act together to

increase the risk of lung cancer by a factor of forty,

taking it well beyond the risk associated with

independent exposure to either of these agents.

Another possible form of interaction is potentiation.

In potentiation, a substance which on its own causes

no harm makes the effects of another chemical much

worse. This may be considered to be a form of

synergism. In mathematical terms: 0 + 1 = 5, 0 + 5 =

20 etc.

For example - isopropanol, at concentrations which are

not harmful to the liver, increases (potentiates)

liver damage caused by a given concentration of carbon

tetrachloride.

The opposite of synergism is antagonism: an

antagonistic effect is the result of a chemical

counteracting the adverse effect of another; in other

words, the situation where exposure to 2 chemicals

together has less effect than the simple sum of their

independent effects; such chemicals are said to show

antagonism. In mathematical terms: 1 + 1 = 0, 1 + 5 =

2 etc.

Tolerance is a decrease in sensitivity to a chemical

following exposure to it or a structurally related

substance.

For example - cadmium causes tolerance to itself in

some tissues by inducing the synthesis of the

metal-binding protein, metallothionein. However, it

should be noted that cadmium-metallothionein sticks in

the kidney causing nephrotoxicity.

Resistance is almost complete insensitivity to a

chemical. It usually reflects metabolic capacity to

inactivate and eliminate the chemical and its

metabolites rapidly.

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SUMMARY

You have now learnt about routes of human exposure to

potentially toxic chemicals and how effects depend

upon exposure pattern and the properties of the

chemicals involved.

You have also learned about allergy (hypersensitivity)

and possible allergic reactions.

You should know what an idiosyncratic reaction is,

what a delayed toxic effect is and what may constitute

an irreversible effect.

Local and systemic injuries have been discussed.

Definitions and examples have been given of possible

interactions between potentially toxic chemicals.

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SELF ASSESSMENT QUESTIONS

What are the routes of human exposure to potentially

toxic chemicals?

Name 5 chemicals that are readily absorbed through the

skin.

What diameter of particle can reach the alveoli?

What are phagocytosis and tidal volume and why are

they important in human toxicology?

How are inhalation and ingestion related?

What combinations of exposure pattern and chemical

properties are likely to be the most harmful?

What are the key factors in determining whether injury

follows exposure to a potentially toxic chemical?

What is hypersensitivity (allergy)?

What are the most common symptoms of allergy?

Define " idiosyncratic reaction and give an example.

Give an example of a delayed toxic effect and name the

potentially toxic chemical that causes it.

Name 3 adverse effects that are essentially

irreversible.

What is systemic injury and what is a target organ?

What is the importance of body fat in relation to

potentially toxic substances?

What are the possibilities for interactions between

potentially toxic substances in causing injury? Give

examples.