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Context - Evaluating the safety of chemicals most often requires the use of tests on animals.
However, there is a strong push, both by regulatory bodies and the public at large, towards the use of alternative methods.
What are these alternatives and are they effective? This is a look at the present situation in the EU in the frame of the ‘Registration, Evaluation, Authorisation and Restriction of Chemicals’ or “REACH” Regulation.
This is a faithful summary of the leading report produced in 2017 by European Chemicals Agency (ECHA): "
In the EU, the use of chemicals is regulated under the Regulation 1907/2006 or REACH Regulation. This Regulation outlines the conditions required for the use of chemicals on the European market, whether they are in consumer products, or used as raw materials or intermediaries in industrial processes, or as substances in research laboratories. Phytosanitary and pharmaceutical products are regulated separately.
In this system, companies have to register within the European Chemicals Agency (ECHA) the chemicals that they import, produce, use or/and sale, and to produce the information needed to determine their human and environmental safety. It is thus up to the user or seller to prove that the product is safe for human health or the environment in the context of its use.
In order to evaluate the intrinsic potential hazard1 of a chemical product, about thirty standard potential toxic effects, also named “endpoints” are evaluated, from skin irritation and acute toxicity, to carcinogenicity and bioaccumulation.
For each of these effects, there are a number of ways that information can be gathered, and in the context of the REACH Regulation, these are called “adaptations”:
Presently, the main source of information originates from experimental in vivo studies, with a high percentage of them having been carried out before the REACH Regulation entered in force.
In case new tests are needed, there are two possible options:
When such option is needed, the company(ies) registering the chemical must, in the application procedure, ask for approval before conducting any such tests on animals.
1 See the short animation video which define and differentiate the notions of hazard, risk and safety : https://www.youtube.com/watch?v=PZmNZi8bon8
In order to know what the potential hazardous effect on human health or the environment of a substance could be, it is necessary to test it to ensure that the conditions in which people will handle and use it will be without significant risk and thus safe.
Some toxic end points, in particular reproductive, immunologic or carcinogenic effects are still difficult to anticipate and evaluate from so-called “in vitro” models using a.o. isolated cells in culture. When for such kind of effects animal tests are necessary however, they must be conducted under close control to ensure that the smallest possible number of animals is used to get meaningful results.
With the increasing number of new registration dossiers submitted to the European Chemicals Agency (ECHA), the absolute number of new experimental studies has increased for all endpoints. This may mean that, although registrants make use of full provisions under REACH to avoid unnecessary animal testing, there is insufficient data available to properly identify the long-term hazardous properties.
However, particularly for chronic toxicity effects (such as reproductive toxicity, immunotoxicity and carcinogenicity) the numbers of new experimental studies or testing proposals are not as high as could be expected from the number of submitted registration dossiers. Globally, only 11 % of REACH information requirements for chemicals analysed in this report (so from 2009 onwards) have been covered by new experimental studies performed on vertebrate animals.
As a matter of fact, the instruments provided by REACH to avoid unnecessary animal testing seem to work well. The main contributing factor is the registrants’ obligation to share their data and register jointly when they use the same substance. This ensures that for each substance the test data are generated, collected, and brought together in one single joint registration dossier.
Besides, alternative experimental options for addressing information requirements, in particular in vitro tests for skin corrosion/irritation, serious eye damage/eye irritation and skin sensitization, have been used extensively by registrants.
Other alternative options include the use of relevant information from analogous substance(s) to predict properties for the ‘target’ substance(s) under consideration (the so-called Read Across Assessment Framework (RAAF) procedure), and computer models that compare substances whose structures are close or similar (“Quantitative Structure-Activity Relationships” or QSAR models).
ECHA’s evaluation shows that many adaptations to alternative methods had quality deficiencies, particularly for human health endpoints such as long-term toxicity or genetic toxicity, and for environmental endpoints such as toxicity to birds and fish.
To increase their robustness and regulatory acceptance, additional data is needed, particularly those related to absorption, distribution, metabolism, and excretion (ADME) properties and to the mechanisms of toxicity of the substances.
The new methodologies have a potential to further substantiate the hypotheses of approaches based on the use of toxicity data from a similar substance (the “Read-across” methodology already mentioned) as these approaches often use starting points which are directly relevant for humans (e.g. human liver cells).
One of the great challenges is currently to compensate the complexity of a higher organism (a.o. the in vivo processes of metabolism and elimination of substances, etc.) when extrapolating from data obtained for instance on cell cultures.
Although the Read-across is a promising methodology, ECHA’s experience is that this approach is still often not substantiated with thorough argumentation and that supporting evidence was frequently lacking.
For some information requirements, ECHA’s focus is promoting the possibilities of a range of appropriate alternative in vitro methods that are already available such as for skin or eye irritation, and to explore how to make better use of the registration data. For complex endpoints, ECHA published a Read-Across Assessment Framework, which allows registrants to improve their toxicity predictions made with this methodology.
The development of these new approach methodologies will bring high throughput assessment methods, which can support current alternative approaches and might potentially provide more human relevant information. A challenge for ECHA is to bring them into regulatory use.
Further, ECHA also gives regulatory input to scientific projects and activities, and contributes to the development and promotion of alternative methods through the activities of the Organisation for Economic Co-operation and Development (OECD).
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