Combined Actions and Interactions of Chemicals in Mixtures

c TCTFP = 1,1,2-trichloro-3,3,3-trifluoropropene
d HCBD = hexachloro-1,3-butadiene
e NONEL = No observed nephrotoxic effect level (=LONEL/4)
f LONEL = Lowest observed nephrotoxic effect level
5.4 Mixtures of chemicals affecting the same target organ but with different
target sites
A number of 3-day inhalation studies (6 h/d) were carried out in male rats with
formaldehyde, acetaldehyde, and acrolein and mixtures of two or three of these
toxicants (Table 5.4.1). They all produce the same type of adverse effect (nasal
cytotoxicity) but with different target sites (different regions of the nasal mucosa).
Formaldehyde had no effect on the nasal epithelium at 1 ppm, but produced clear
changes at 3.2 ppm. Acrolein induced marked nasal changes at 0.67 ppm and less
severe changes at 0.25 ppm. Both dose levels of acetaldehyde only produced minor
changes. The nasal changes seen after exposure to mixture 1 and mixture 2 were
very similar in site, type, degree and incidence to those induced by 0.25 ppm
acrolein alone. These changes were therefore considered to be induced by acrolein
and not influenced by co-exposure to 1,0 ppm formaldehyde or to 1.0 ppm
formaldehyde + 750 ppm acetaldehyde. Mixture 3 induced pronounced changes
that were more severe than those found after exposure to the individual compounds
at comparable concentrations. The changes indicated that the combined effect of
formaldehyde and acrolein on the nasal respiratory epithelium was at least additive
and that formaldehyde and/or acrolein probably potentiated the effect of
acetaldehyde on the olfactory epithelium.
The authors conclude that neither effect addition nor potentiating interactions
occur, providing the exposure concentrations of the aldehydes are at NOAELs.
They also state that the type of combined action or interaction found at clearly
toxic effect levels is not very helpful in predicting what will happen at levels that
are not toxic (Feron et al. 1995a, Cassee et al. 1996, 1998).
Table 5.4.1. Exposure concentrations (ppm) used in 3-day (6 h/d) inhalation toxicity studies
in male rats with nasal toxicants
Groups a Formaldehyde Acetaldehyde Acrolein
Formaldehyde/low 1.0
Formaldehyde/high 3.2
Acetaldehyde/low 750
Acetaldehyde/high 1500
Acrolein/low 0.25
Acrolein/high 0.67
Mix 1 1.0 0.25
Mix 2 1.0 750 0.25
Mix 3 3.2 1500 0.67
a Each separate study included a control group exposed to clean air only.
5.5 Conclusions of the Dutch studies
The overall conclusion that the Dutch group draws from their experiments is that
combined exposure to arbitrarily chosen chemicals clearly demonstrated the
absence of full additivity, and provided some evidence of partial additivity when
all chemicals in the mixture were administrated at their own individual NOAELs.
At slightly lower dose levels no clear evidence of toxicity was found. This
conclusion was found valid for combinations of chemicals that have either different
target organs and or different target sites within the same organ (i.e. differ in the
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