Combination effects of chemicals

People and the environment are continuously exposed to many chemicals from several different sources. Exposure to different chemicals may take place simultaneously or at different times. It has been estimated that there are more than 100,000 chemical substances and a large number of mixtures of various substances in different kinds of use. The combination effects of chemicals are a cause for concern, because it is suspected that they cause many of the harmful effects of chemicals. Exposure to chemicals may occur at the place of work and via consumer products, such as food, paint, detergents or cosmetic products, as well as indirectly via the environment (air, water, soil). People can be exposed to chemicals orally, through skin, or through inhalation. The exposure of animals to chemicals in the environment mainly occurs via food and water.
Three forms of the combination effects of two or more substances have been proposed:

  • additive (the combination effect is the same as the sum of individual effects),
  • potentiating (the combination effect is higher than the sum of individual effects), or
  • antagonistic (the combination effect is lower than the sum of individual effects).


The modes of action resulting in the harmful effects of chemicals in an organism can be complex. The harmful effects resulting from a combination effect of chemicals may be due to their similar or different modes of action in the system. While exposure to individual substances may occur at concentrations known to be harmless, the combination of similar or potentiating modes of action can cause harmful effects. It has been suspected that the environmental or health risk due to exposure to several chemicals may be greater than that of exposure to a single substance. The combination effects of chemicals can be studied by testing a mixture to which people and animals are being exposed instead of individual substances, using different kinds of test methods or calculations in order to predict the combination effects. By testing the whole mixture, it is possible to study the mutual effects of the components on how they are absorbed through the skin, for example.
The hazard and risk assessments in accordance with the EU legislation on chemicals are currently done mainly to individual substances and intentionally manufactured mixtures, whose composition is known (e.g. paint, cosmetic products). The assessments of mixtures are usually based on information about the individual ingredients in the mixture, and occasionally on toxicity tests on the mixture as a whole (e.g. acute toxicity). Several EU laws on chemicals require that the available information on the combination effects of substances must be taken into account when assessing the safety of a mixture that has been manufactured, such as a cosmetic product. However, the assessment of combination effects is currently challenging, because there is rarely information available on the modes of action of the substances.
At the moment, EU legislation does not include procedures for a comprehensive assessment of environmental and health risks of exposure to chemicals from several different sources. In such a situation, assessing the risks due to the combination effects of substances is more complicated than when exposed to a mixture, whose composition is known, because people and the environment can be exposed to countless combinations of different substances. Much more information on the exposure of people and the environment to the substances and their modes of action would be required in order to make an assessment possible.
In the EU, the risk assessment and management of the combination effects of chemicals is considered important. Methods of studying the combination effects of chemicals are developed so that they could be used in the risk assessment of chemicals. The aim is also to develop the current legislation on chemicals in a direction, in which the combination effects of chemicals could be taken into account better when making risk assessments and selecting risk management procedures for chemicals.
The European Commission has published the ‘State of the Art Report on Mixture Toxicity’ (2009) and an opinion of scientific committees on the combination effects of chemicals (2011). The reports can be found on the Commission’s website on the combination effects of chemicals.
The International Programme on Chemical Safety (WHO/IPCS, 2011) has prepared a report on the combination effects of chemicals. The report can be found on WHO’s website.