Highlights of a report on the toxicity, dangers and risks from exposure to chemical mixtures (“cocktails”)

Highlights by GreenFacts of an opinion of the non Food  EU Scientific Committees

SCHER, SCCS, SCENIHR, Opinion on the Toxicity and Assessment of Chemical Mixtures, 2012, 50 p.

The non-Food scientific committees are[1]

– The Scientific Committee on Health and Environmental Risks -SCHER

– The Scientific Committee on Emerging and Newly Identified Health Risks SCENIHR

– The Scientific Committee on Consumer Safety – SCCS

Since humans and their environments are exposed to a wide variety of substances, there is increasing concern in the general public about the potential adverse effects of the interactions between those substances when present simultaneously in a mixture (in the media often referred to as “cocktail-effects”).

1. The answers to three key questions of the EU Commission

 The non-food committees made an analysis of the available scientific literature on the subject. Among their conclusions from this review, they highlighted several conclusions and answers to the EU Commission questions on basis of the mode of action of these chemicals :

1.1. Is there scientific evidence that, when organisms are exposed to different chemical substances,  these may act jointly in a way (addition, antagonism, potentiation, synergies, etc.) that affects the overall level of toxicity?

Yes, says the report. Under certain conditions, chemicals will act jointly in a way that the overall level of toxicity is influenced:

a. For chemicals with common modes of action, these will act jointly to produce effects that are larger than the effects of each mixture component applied singly. These effects can be described by dose/concentration addition.

b. For chemicals with different modes of action (independently acting), no robust evidence is available that exposure to a mixture of such substances is of health or environmental concern if the individual chemicals are present at or below their zero effect levels. In the examples in which independent action provided a more accurate prediction, dose (concentration) addition slightly overestimated the actual mixture toxicity, which suggests that the use of the dose/concentration concept for risk assessment of chemicals of unknown toxic mechanisms is sufficiently protective.

c. Interactions (including antagonism, potentiation, and synergies) usually occur at medium or high dose levels (relative to the lowest effect levels). At low exposure levels, they are either unlikely to occur or are toxicologically insignificant.

 1.2. Do the current assessment methods take proper account of these joint actions and what are the major gaps regarding such assessments?

No, says the Opinion report.  Indeed at present, risk assessment on the combined effects of chemicals in a mixture is not commonly carried out, nor required by most EU regulations.  Direct toxicity testing is performed with mixtures, for some purposes only.

Currently, there is neither an agreed inventory of mode of actions, nor a defined set of criteria how to characterise or predict a mode of action for data-poor chemicals.

The Opinion highlights that a major knowledge gap at the present time is the lack of exposure information and the rather limited number of chemicals for which there is sufficient information on their mode of action.

If no mode of action information is available, the dose/concentration addition method should be preferred over the independent action approach. Prediction of possible interaction requires expertjudgement and hence needs to be considered on a case-by case basis.

It is noted in the report that the dose-additivity approach relies on a correct grouping of “similar” chemicals. Although guidance on grouping of chemicals has been issued (ECHA, OECD, EFSA), there is currently no general agreement on the scientifically best approach and grouping of chemicals is most often done by expertjudgement on a case-by-case basis. The reports noticed in particular that Kortenkamp et al. (2009) reviewed the literature for deviations from expected additivity and found that – in human and mammalian toxicology studies – such deviations “were observed quite rarely”.

For compounds acting by independent action, the analysis of the four most relevant studies by the working group supports the conclusion that relevant human exposures are very unlikely to produce a biologically relevant increase in response.

It should be noted, underlines also the report, that the REACH Regulation is generating the largest database on chemicals in history, and that this information could be used to reduce some of the current uncertainties.

 1.3. What is the most effective way to target resources on those combinations of chemicals that constitute the highest risk for man and the environment?

In order to prioritize chemical mixtures for possible assessment and given that it is unrealistic to assess every possible combination of chemical substances,  it is first necessary to consider whether there is significant human or environmental exposure to the mixture or its components.

Unless there are indications for a significant interaction, a dose/ concentration addition model could be used if the components of the mixture exert their biological effects via an identical or similar mode/ mechanism of action.

If the mixture components act dissimilarly, the independent action model would be applied. It further appearsjustifiable that a dose/concentration addition approach should be used as default approach in cases where neither mode of action nor dose-response information is available to ensure adequate conservatism in the assessment.

2. Which is the definition of a chemical mixture in this report ?

 For the purposes of this request, 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 processes and consumption or recycling processes;

• Several chemicals that might occur together in various media : environmental (water, soil, air), food items, biota and humans as a result of emission from various sources and via multiple pathways.

 3. Pharmaceuticals were not included in this evaluation(2).

This opinion does not specifically address drug-drug interactions for human health assessment because they are within the remit of the European Medicines Agency (EMA).

Pharmaceuticals have been considered for the environmental assessment and the indirect exposure of the general population. However, this opinion does not address essential metals and nutrients for human health.

4. What are the effects of mixtures on ecosystems?

For ecological effects, states the report, the exposure to mixtures of dissimilarly acting substances at low, but potentially relevant concentrations should be considered as a possible concern, even if all substances are below the individual PNECs. Consequently there is a need for improving the current knowledge and methodologies, and developing holistic approaches for the ecological risk assessment of chemicals under realistic conditions.

[1] About the Scientific Committees: Three independent non-food Scientific Committees provide the Commission with the scientific advice it needs when preparing policy and proposals relating to consumer safety, public health and the environment. The Committees also draw the Commission’s attention to the new or emerging problems which may pose an actual or potential threat.

(2) This is the subject of another report whose “Highlights” will also be proposed by GreenFacts

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