Combined Actions and Interactions of Chemicals in Mixtures

lipid peroxidation was observed, while at higher concentrations the combined effect
was less than additive (Goldstein, 1976).
In several well-conducted human clinical experiments on the interaction between
ozone and nitrogen dioxide there is insufficient evidence to conclude that an
interactive effect on pulmonary function occurs. Both the animal studies and the in
vitro experiment suggest, however, an interaction between ozone and nitrogen dioxide
of at least an additive nature for several cellular parameters. It still has to be
established if the biochemical effects of the combined exposure to the gasses are
occurring in humans (Calabrese, 1991). However, based on the animal experiments, a
simple additive model for the interaction between ozone and nitrogen dioxide may be
established (Larsen et al., 1997).
Contradictory results have been obtained concerning possible synergistic effects in
humans due to co-exposure to low levels of sulphur dioxide and ozone, and no
convincing evidence exists that nitrogen dioxide and sulphur dioxide interact to cause
enhanced acute respiratory irritancy in humans. A study with human volunteers
suggests that ozone and peroxyacetylnitrate (PAN) may interact to enhance
respiratory symptoms (Calabrese, 1991).
Various aldehydes are also established as critical irritants in urban air, and the
combined effects of exposure to formaldehyde and acrolein have been studied a
couple of animal experiments. These aldehydes have shown similar effects concerning
effects on pulmonary function in animal experiments, induction of increased epithelial
cell proliferation, induction of DNA-protein cross-binding and of DNA strand-breaks.
Acrolein appears to be more cytotoxic than formaldehyde, but the latter is the most
DNA damaging agent (Roemer et al., 1993; Leikauft, 1992; Grafström, 1990). In two
studies with rats, the animals were exposed to combinations of formaldehyde,
acetaldehyde and acrolein. Cassee et al. (1995) measured the reduction of breathing
frequency as an indicator for the irritative response, and found that the combined
effect of the aldehydes was 20% lower than the sum of the responses on the single
substances. In another study, the irritancy was monitored by measurements of changes
in the tissue of the nasal epithelium. At low exposures no potentiated effects of the
combined exposure was observed, but a more than additive effect was observed at the
highest exposure level (Feron et al., 1995). Based on these observations, a simple
additive model for the interaction between the aldehydes has been suggested (Larsen
et al., 1997).
7.1.5 Conclusions
Many studies have been performed on skin, eye and respiratory tract irritation
mediated by complex mixtures, but only few studies allows a quantitative evaluation
of the modulating effects of the combination of single chemicals.
Effects on several types of endpoints may serve as a basis for combination effects,
including:
• Damage to biological barriers against exposure of the cells to xenobiotics, like the
stratum corneum of the skin.
• Impairment of defence mechanisms such as the ocular blinking and tearing
reflexes or the function of the mucociliary escalator of the upper airways.
• Induction or depletion of the capacity of the xenobiotic metabolising enzymes of
the tissues.
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