Context - There is increasing concern in the general public about the potential toxic effects of chemical substance mixtures (in the media often referred to as “cocktail-effects”).
Humans and ecosystems are indeed continually exposed to a very complex mixture of chemical substances, the composition of which is always changing.
However, in the great majority of risk assessments, only a single chemical is considered and there are no generally applicable guidelines as to when and how assessment of combinations of chemical substances should be carried out.
Are there combined adverse human health effects produced by exposure to a mixture of different chemical products?
Mixtures of chemicals are considered to be:
- Substances that are mixtures themselves (multi-constituent substances:
MCS; materials of unknown or variable composition, complex reaction products
or biological materials: UVCB);
- Products that contain more than one chemical e.g. cosmetics, plant
- Chemicals jointly emitted from production sites, during transport, and
consumption or recycling processes;
- Several chemicals that might occur together in environmental media
(water, soil, air), food items, biota and humans as a result of emission
from various sources and via multiple pathways.
Two cases should be considered:
Are specific assessment of risks for human related to exposure to mixtures possible and necessary?
Substances that have a similar mode of action
When substances have a similar mode of action – which means that their adverse
effects are cause by similar chain of events –, their concentration can be added
together to predict their combined effect. The additivity of doses is assumed
over the entire range of concentrations, including those below the level at
which each substance has no observed effect. In some rare specific cases,
antagonistic (lower than the sum of
the parts) or synergistic (greater than the
sum of the parts) effects have been observed, but in general, dose addition is a
reasonable conservative (protective) default approach.
Substances that have different modes of action
With mixtures composed of chemical substances with various modes of action,
there is good evidence that the effects are higher than those of the individual
components. At present, the safety margins that are used in
risk assessment of single chemical
substances could be insufficient to allow room for the effects for all possible
However, the Opinion of the Scientific Committees is that, for chemical
substances that act independently, no robust evidence is available and it is
very unlikely that exposure to a mixture of such substances is of health concern
if the individual chemical substances are present at or below their no effect
If the mode of action is not known, as is the case for many substances, the
dose/concentration addition method should be preferred over the independent
What about synergic effects between oestradiol and “endocrine disruptor” substances potentially reacting with its cellular receptor?
Specific mixture risk assessment is
indeed necessary, in order to avoid underestimations of risks that might occur
under the classical current approach that takes each chemical substance
Except for mixtures composed of chemical substances with a similar mode of
action, current evidence does not show significant mixture toxicity at exposures
at or below zero-effect levels of the individual components.
Endocrine disrupting chemical substances (specifically those that are
affecting sex hormones) are often mentioned in the context of chemical mixtures,
since they have effects at relatively low concentrations, although larger than
the concentration of the hormones that they are affecting. Since concentrations
that are found in people are very low, it is unlikely that there is an effect of
chemical mixtures on these hormones.
Is the assessment of mixture of chemicals applicable in ecotoxicology?
The general principles of the risk
assessment of chemical substances mixtures is also applicable in the
context of environmental toxicology, for
predicting effects at population level, although the concepts of “independent
action”, “dose additions” and “synergistic
action” still need to be understood at the population level. At the level of
communities, an additional concept of “synergism” is also possible. It requires
an approach based on the understanding of ecology, of interactions between
species and their environment, and of indirect effects. Consequently there is a
need for improving the current knowledge and methodologies for the ecological
risk assessment of chemical substances under realistic conditions.
Where are the major knowledge gaps with regard to the assessment of the toxicity of chemical mixtures?
One major gap is the lack of knowledge on where, how often and to what extent
humans and the environment are exposed to certain chemical mixtures and how
exposure may change over a person’s lifetime.
For many chemical substances, there is no good information on mode of action.
Interactions of chemical substances in mixtures are also difficult to foresee,
particularly for long-term effects. Research is needed to define criteria that
could predict potentiation or
In ecotoxicology, the problem is even more complex. A knowledge of all
possible modes of action in complex biological communities is difficult (if not
impossible) to be attained and ecologically relevant endpoints are generally
broader and not so specific (e.g. toxicity on specific organs, etc.) as in human
SCHER, SCCS, SCENIHR, Opinion on the Toxicity and
Assessment of Chemical Mixtures, 2012