Combined Actions and Interactions of Chemicals in Mixtures

Another in vitro test for ocular irritancy, the HET-CAM Test (Hens Egg Test at the
Chorion Allantois Membrane) has recently been used to investigate combined
action of chemicals. Compounds, which can occur as disinfecting by-products in
swimming pool water, were tested. Previous studies using the rabbit eye test
(Draize test) had shown that the irritating potential of typical concentrations of free
and combined chlorine are insufficient to explain the degree of eye irritation that
can result from exposure to swimming pool water. The compounds tested included
halogenated carboxyl compounds (HCC’s) which act as precursors during the
formation of chloroform. Some of the compounds tested were found to have a
significantly increased irritating effect when compared to a chlorine/chloramine
mixture of the same concentration, several mixtures of HCC’s where even more
active at lower concentrations than single compounds. However, the irritating
effects of individual compounds as well as of mixtures of HCC's were not
sufficiently intense to allow the identification of those compounds specifically
responsible for the overall observed increase in irritation. HCC's were therefore
tested in the presence of aqueous chlorine solution. When combined with aqueous
chlorine, a number of compounds exhibited significantly enhanced effects
(Erdinger et al., 1998).
7.1.4 Irritancy to the respiratory tract
7.1.4.1 Composition of the respiratory tract
The respiratory tract consists of three compartments: the nasopharyngeal, the
tracheobronchial and the pulmonary region. The nasal passages are lined with
vascular ciliated mucous epithelium. The nasopharynx filters out large inhaled
particles, and in this region the temperature of the air is moderated and the relative
humidity is increased. The airways of the tracheobronchial region are lined with
ciliated epithelium and coated with a thin layer of mucus, which is secreted by goblet
cells and mucus secreting cells. The surface of the airways in this region serves as a
mucociliary escalator, moving particles from the lung to the oral cavity. The physical
dimensions and the branching patterns of the airways are critical in determining the
absorption of gases and deposition of particles in the respiratory tract.
More than 40 cell types are present in the respiratory tract, but the cells of greatest
interest are the types that are unique to the region. These are the ciliated bronchial
epithelium, the non-ciliated bronchial epithelium (Clara cells), and various
pneumocytes and alveolar macrophages. The endothelial cells, the interstitial cells
(fibroblasts and fibrocytes), and the cells lining the trachea and bronchi are of interest
since they are extremely susceptible to various types of injury. The Clara cells are
metabolically active, and they are the major sites of injury from xenobiotics, which
are metabolized to reactive substances by the lung cytochrome P-450 enzyme systems
(Boyd et al., 1980).
Irritation of the air passages often results in constriction of the airways. Ammonia and
chlorine are classic examples of irritant gases. They first influence the bronchial
smooth muscle cells, and bronchioconstriction occurs immediately on inhalation.
Ammonia and chlorine are highly water soluble, and thus they are primarily removed
by the upper airways. Unless the concentration is sufficient to cause death, the acute
effects do not result in chronic pulmonary damage (Weill et al., 1969).
Other types of acute cell toxicity moreover cause irritation of the airways. Damage to
the cells lining of the airways may result in necrosis, increased permeability and
oedema. When the cells of the airways and alveoli are damaged, the permeability is
increased and this leads to the release of oedema fluid into the lumen of the airways
and the alveoli. The production of major oedema may take several hours to develop.
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