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Combination effects/cocktail effects

When we are exposed to a number of different chemical substances simultaneously, combination effects, also known as 'cocktail effects', can occur.

Combination effects might change the risk of adverse effects. This means that even though exposure to a particular dose of a single chemical does not in itself constitute a risk of effects, there could be a risk if there is simultaneous exposure to other substances at the same time.

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The issue is very complex. We know little about the possible combination effects of all the chemicals to which we are exposed in our everyday lives. In view of all the different chemicals on the market which can be mixed in innumerable different ways, it is incredibly difficult to establish rules that take into account all combinations and all the possible environmental and health effects.

Indeed, there is still much to be learned about the effects of individual chemicals and part of the reason for introducing the new chemicals regulation in the EU (REACH) was to increase our knowledge in this field. The lack of knowledge about how combination effects work is an added challenge.

How should we approach combination effects?

Existing chemicals legislation is in general based on our knowledge of the effects of individual substances. In cases where combination effects are understood, this understanding is where possible taken into consideration when evaluating the risk of chemical substances. When we carry out risk assessments of chemical substances, we also use safety factors in order to ensure a high level of protection. These safety factors can to some extent provide protection against combination effects.

In view of our current level of knowledge, it is difficult to incorporate combination effects in an entirely general way into the legislation at national, EU or international level. It is equally difficult to establish requirements in the legislation concerning such a complex problem. Much of our work is therefore aimed at increasing our level of knowledge. For example, the Danish Environmental Protection Agency supports research into substances with endocrine-disrupting properties and combination effects at DTU Food - the National Food Institute.

The EU has also begun three major new research projects, collectively known as 'NECTAR'. These projects include studies of the endocrine-disrupting effects of mixtures of chemicals in the quantities to which we are exposed every day. In January 2009, the Danish Environmental Protection Agency held an international Expert workshop on ways of formulating legislation to deal with the problems of combination effects. The message from the experts is clear: although we still have large gaps in our knowledge, information learned in recent years on the combination effects of endocrine-disruptors is such that we can and should take combination effects into consideration.

Read more (in Danish)

As a follow-up to the Expert workshop, the Danish Environmental Protection Agency carried out a study in 2009 of the total daily exposure of two-year-old children to multiple substances with endocrine-disrupting properties which showed that there was cause for concern.

The Expert report and the Danish Environmental Protection Agency's report on the total daily exposure of two-year-old children to combinations of endocrine disruptors led Denmark to raise the issue of combination effects at EU level. The initiative resulted in the Council (environment) adopting the Council's conclusions concerning the combination effects of chemicals .

As a follow-up to the Council's conclusions, the European Commission has begun a study into whether, and if so, how, existing legislation takes combination effects into consideration and has begun the preparation of a proposal for the way in which combination effects can be incorporated into relevant legislation in the future. As part of the work relating to combination effects, the European Commission has also commissioned a report on the scientific status of combination effects . This report has been assessed by the EU's three scientific committees. A draft of the opinion is available here .

Three types of combination effects

Different types of combination effects occur:

  • Additive effect
  • Antagonistic effect
  • Synergistic effect

Additive effect means that the quantity of the substances in the mixture can essentially be added together. This would cause the same effects that would be expected based on the same quantity of the individual substances. In the event of exposure to four substances, for example, the mixture would have the same effects as a four-fold increase in the quantity of the individual substance. In other words, 1+1+1+1=4. However it cannot be assumed that the effect will always increase four-fold. This is partly because there is an upper limit for effects.

There is also a lower limit for effects. We are continually being exposed to small quantities of substances without suffering effects. However, the combined effect could be significant if we are simultaneously exposed to other substances with the same types of effects. If, for example, a person is exposed to four substances which individually would not have any effect, the total quantity of the substances could result in effects. In other words, 0+0+0+0 could = 3, when we consider effect.

The latest studies indicate that it is additive effects in particular that we see as combination effects.

Antagonistic effect means that the substances cancel out or reduce each other's effect. Being exposed to the two substances simultaneously is in this case less dangerous than would be expected on the basis of our existing knowledge of the effects of either single substance. In other words, 2+2=3.

Synergistic effect means that the substances reinforce each other's effect. This means that the effect of the substances when mixed is greater than expected. In this case, the risk of effects is greater for simultaneous exposure than for exposure to the substances as such. In other words, 2+2=7.

More information

Conclusions from the Expert workshop on combination effects, January 2009 (in Danish)

Study of the exposure of two-year-old children to substances with endocrine-disrupting properties , 2009

Combined Actions and Interactions of Chemicals in Mixtures (pdf)
Danish Environmental Protection Agency and Danish Veterinary and Food Administration, 2003

Combination effects of pesticides
Pesticide research from the Danish Environmental Protection Agency, 98, 2006

Endocrine-disrupting effects of combinations of pesticides
Pesticide research from the Danish Environmental Protection Agency, 88, 2004