Combined Actions and Interactions of Chemicals in Mixtures

Thirty percent of the papers reported no interaction (including additive effects),
35% reported antagonistic effects, and the rest of the papers reported synergistic or
rarely potentiative effects. Additivity was defined as 100 ± 20 % of the combined
result of the single-agent effects.
The percent response to combined chemicals showing synergism, according to the
definition of the author, was in the range 120-5300 % with a mean ± SD of 360 ±
589 (n=215 combinations). All dose combinations from the table by Nelson was
included in the calculation. Only 11 combinations gave rise to effects exceeding
1000 %. Almost all of these (n=10) were studies on retinoic acid in combination
with either TCDD or zinc or protein deficiency i.e. studies highly related to
nutrition.
The quality of the papers was highly variable (in general: few animals, few dose
levels, maternal toxicity not considered, time-effect relationships not often
examined, inconsistent use of terms). ‘Potentiation’ was the term misused most
often; frequently the more appropriate term would have been synergism.
7.4.5 Conclusions
Combined exposure of two or more chemical compounds has shown that
interaction may or may not occur, and that it is impossible predicting the outcome
based on experimental conditions alone. However, the published data suggest that
the prevailing outcome of exposure to mixtures deduced from in vivo experiments
is either an antagonistic effect or no interactive effect, including an additive effect.
Frequently, one type of interaction was noted at some doses, while another type of
interaction was noted at other doses. An evaluation of the results suggests that low
doses of combinations often produced either no effect or additive effects, whereas
higher doses produced antagonistic or synergistic effects.
In addition, combinations of chemicals with common features such as similar
structure or similar type of effect on a common target organ probably are more
likely to result in an - at least additive - effect. In such cases, additivity should be
considered in the assessment of the exposure to mixtures. However, when
assessing simultaneous exposure to two or more chemicals in general, the
consideration of consequences of a possible interaction or an additive effect should
be considered on a case-by-case basis.
7.5 Endocrine disrupting chemicals
Prepared by Anne Marie Vinggaard
7.5.1 Introduction
Abnormal sexual development in wildlife, the worldwide rise in the incidence of
testicular cancer, developmental disorders of the male reproductive tract and the
continuing rise in the incidence of female breast cancer are causing widespread
concern. It has been suggested that these effects might be related to environmental
chemicals, which are able to mimic endogenous estrogens. The list of chemicals
reported to show estrogenic activity has grown considerably during the last years
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