Combined Actions and Interactions of Chemicals in Mixtures

analysis was used to predict the high dose for each agent causing a pup weight loss
of 2 g on postnatal days 6-8. The other doses were equally spaced between the top
dose and the 0-level. Combination of TCE and DEHP caused synergism, appearing
as a negative effect on the parameters: maternal weight gain, prenatal loss, and full
litter resorption and pup weights on day 6. Combination of DEHP and HEPT had a
synergistic effect on maternal death and antagonised main effects on the
parameters: maternal weight gain, full litter loss, pup weights on day 1 and pup
weights on day 6. However, the authors discussed that this antagonistic effect may
be due to a ceiling effect of combining high responses or due to biased exclusion of
susceptible dams as a consequence of the synergistic interaction of these agents
towards maternal mortality. HEPT potentiated the effect of TCE and DEHP on
prenatal loss and full litter resorption. TCE-HEPT interaction was antagonistic
concerning adverse effects on full litter loss (Narotsky et al. 1995). The authors
conclude that assumption of additive toxicity may be inadequate in some risk
assessment situations. Thus, at the doses used in this study several mechanisms of
interaction are involved, when these compounds are administered simultaneously.
However, the mechanism of action was not elucidated and therefore it is not
possible to classify the kind of interaction as being either complex similar or
dissimilar action. However, if lower doses close to NOAEL were used the
assumption of additivity would have been more appropriate.
The second approach is illustrated by a study on interaction between chemicals
with similar chemical structure. Halogenated aromatic hydrocarbons are among the
most persistent chemicals in the environment. They have been detected in blood,
milk and adipose tissue of wild life animals and humans. When TCCD (20 µg /kg
bw) was administrated to pregnant C57BL/6J mice, 62% of the foetuses developed
cleft palate, without any observable maternal toxicity. Aroclor 1254 (244mg/kg
bw), which is a commercial mixture of polychlorinated biphenyls (PCB), did not
induce cleft palate. Co-treatment of the pregnant mice with Aroclor 1254 (244
mg/kg bw) and TCDD (20 µg/kg bw) resulted in an 8.2% incidence of cleft palate.
These results demonstrate that Aroclor 1254 antagonised 2,3,7,8-TCDD-mediated
teratogenicity in this strain of mice (Haake et al. 1987). Data is insufficient to
evaluate the mechanism of action of the chemicals. However, we suggest that the
interaction demonstrated here may indicate a result of complex dissimilar action, as
aroclor 1254 is a known inducer of liver enzymes thereby increasing the
metabolism of TCDD.
Another example of an antagonistic effect is the interaction between cadmium and
selenium. Cadmium is a well-known toxicant of the male reproductive system.
Wlodarczyk et al. (1995) tested the protective capacity of selenium in acute
cadmium intoxication in male golden hamsters. Selenium alone caused a
significant increase in epididymis weight after 1 and 4 weeks of dosing, whereas
cadmium alone decreased the weight of testes, epididymis and accessory sex
organs compared to the control group. In addition, a decrease in sperm number and
azospermia was observed. Selenium completely reversed the damaging effect of
cadmium on the male reproductive system, when the agents were mixed in a ratio
of 1:1 at a dose-level of 0.5 mg/kg. This kind of interaction is interpreted as
complex dissimilar action.
Mixtures of 2,4-dichlorophenoxyacetic, 2,4,5-trichlorophenoxyacetic and 2,3,7,8tetrachlorodibenzo-p-dioxin
were examined in mice for reproductive disorders and
sister chromatid exchange in bone marrow cells. Fertility, sperm number, motility
and morphology were among the evaluated parameters. No significant dose-related
effects were observed (Lamb et al. 1981). The doses used in this study did not
induce any combined effect.
106