Exposure to potentially toxic substances and their adverse effects

Discussion in 'Health and medical' started by Ilena Rose, May 11, 2004.

  1. Ilena Rose

    Ilena Rose Guest

    ~~~ Excellent. Thanks, Kathi! ~~~

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

    Exposure to potentially toxic substances and their adverse effects
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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) of
    skin. 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.
     
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