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 protection products;
• 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 realistic mixtures.

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 levels.

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 action approach.

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 separately.

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 synergy.

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 toxicology.

REFERENCE:
SCHER, SCCS, SCENIHR,  Opinion on the Toxicity and Assessment of Chemical Mixtures, 2012