Combined Actions and Interactions of Chemicals in Mixtures

stannous chloride and cadmium chloride resulting in a lower ASAT activity than
expected on the basis of additivity.
As expected, the carboxyhaemoglobin formation was mainly due to
dichloromethane and no interactions with other compounds were observed.
Aspirin, DEHP, and surprisingly stannous chloride increased the incidence of
hepatocellular hypertrophy and there were no significant cases of interaction in the
liver. The factorial analysis revealed a slightly increased incidence of epithelial
hyperplasia in the nasal cavity in rats exposed to dichloromethane in the absence of
formaldehyde. However, in the presence of formaldehyde most of the rats showed
epithelial hyperplasia independent of the presence or absence of dichloromethane.
In the main study the only treatment related effects observed in the NOAEL group
were decreased alkaline phosphatase activity and triglyceride concentration and
slight and infrequent hypertrophy of liver cells and epithelial cells of the nasal
cavity. Liver changes had previously been observed after administration of DEHP,
aspirin or spermine at higher doses, and changes in the nasal cavity is characteristic
for the effect of formaldehyde. Relative kidney weights were increased in rats of
the NOAEL and one-third the NOAEL groups. The satellite part of the study
revealed that BHA, aspirin, or stannous chloride might increase the kidney weight.
The effect on kidney weight at the LOAEL could well be explained by summation
of the effects of BHA, aspirin and stannous chloride and a similar joint (additive)
action of these compounds might also explain the in crease in kidney weight at the
NOAEL.
It was concluded that simultaneous exposure to these nine chemicals did not
constitute an evidently increased hazard compared to exposure to each of the
chemicals separately, provided the exposure level of each chemical in the mixture
was at most similar to or lower than its own NOAEL (Groten et al. 1997).
In comparison with the adverse effects produced by the individual compounds,
both more severe and less severe effects were observed at the LOAEL of the
combined compounds, indicating interactions of effects at this exposure level.
Several of the effects (growth retardation, reduced food intake, and liver damage)
were more severe than seen with the individual compounds.
5.2.1 Other studies
Ito et al. (1995) examined the combined dietary administration to rats of 19
organophosphorus compounds and one organochlorine pesticide, all permitted for
use in Japan, each at its acceptable daily intake (ADI) level. The dietary exposure
at this level did not enhance the development of rat liver preneoplastic lesions
initiated by diethylnitrosamine. However, a mixture administered at 100 times the
ADI levels of the pesticides significantly increased the number and area of lesions.
The authors concluded that the study provided direct support for the present use of
the safety factor approach in the quantitative hazard evaluation of pesticides.
Swiss albino male rats were treated orally by gavage with 100- and 1000-fold the
ADI of endosulfan, dimethoate and carbaryl (Akay et al., 1999). The authors had
previously reported that endosulfan, dimethoate and carbaryl, either alone or in
mixture at 1- and 10-fold the ADIs, did not cause significant effects on
immunological and haematological parameters of rats. No effects were reported on
immunoglobulin concentrations or blood parameters at the 100-fold ADI level as
well as after treatment with the individual pesticides. It was concluded that the
mixtures acted like the single compounds and that no synergistic or antagonistic
effects were observed. However, the authors ignored elevations in the red blood
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