REACH, the European Community Regulation on chemicals, is an apology to society for the thousands of poorly-tested industrial chemicals that now pervade the environment and our bodies. But REACH regulations still allow traditional unquestioned animal experiments.
This article serves two purposes. It is a compte-rendu of the conference presented in Vannes on 21 June 2008 by AndrÃ© MÃ©nache and it is a bugle call to all responsible scientists, regulators and members of the public to help avoid a catastrophe.
REACH is the European Community Regulation on chemicals. It deals with the Registration, Evaluation, Authorisation and Restriction of Chemical substances and entered into force on 1 June 2007. The task of managing this huge program has been assigned to the newly formed European Chemicals Agency (ECHA), located in Helsinki Finland. To re-iterate, the stated aim of REACH is to “improve the protection of human health and the environment through the better and earlier identification of the intrinsic properties of chemical substances”.
It is our view that the REACH program represents an apology and an admission of guilt to society for the thousands of poorly tested industrial chemicals that now pervade our bodies and the environment. It would not be helpful at this stage to engage in a philosophical debate on whether to apportion blame more to industry than to society – or vice versa – for our current predicament, surrounded as we are, by thousands of chemicals – some good, some bad, some very bad. To try to answer the question, “who created the need for so many chemicals in the first place – society or industry?” is like trying to solve the riddle of which came first – the chicken or the egg?
Rats and mice are still being fed to this chemical dinosaur
The concept and framework of REACH are fait accompli. We now have the onerous task of trying to tame a chemical dinosaur—to try to assess the toxic risk of some 30,000 chemicals. Although the REACH regulations allow room for innovation (e.g. Annex XI*), the current test regimen involving traditional animal experiments remains essentially unquestioned with respect to their relevance to human health. In addition, any attempt to introduce a new test method will require the submission of “proof of principle”, followed by a fairly lengthy “validation” procedure, which is usually enough to put most people off, including industry.
Trying to challenge a European Commission (EC) directive to show that the current testing regimen is out of date as well as irrelevant, is by no means an easy feat. In fact, the EC is essentially immune to legal challenge, except in rare instances (e.g. Sweden versus Commission of the European Communities**). However, within the framework of the REACH regulations, there are several ways in which to promote good science and thus eliminate “bad science” (a reference to animal testing, made by the outgoing director of ECVAM). The view of Antidote is that using animals to set “safety limits” for human chemical exposure is meaningless in terms of public health. With more than 250 strains of rats and 330 strains of mice to choose from, it is possible to prove that virtually any chemical is “safe” or the opposite. When talking about safety, the operative phrase should be: “safe for whom (which species)?”
The EU scientists and regulators who are allied with animal testing are willing to consider using non-animal methods, but on condition that these methods first undergo “validation”. Validation of a method implies that it has been scientifically evaluated for a particular purpose (relevance) and, in addition, that it is reliable and reproducible. Although the concept of validation is a sound one, it raises two pivotal questions:
(i) to what extent have animal experiments been validated ? In asking this question, we make the bold assumption that animal tests have all been validated. However, this is in fact a “red herring”, because it detracts from the real issue – the need to validate test data with respect to humans – by testing human biological material, including cells and tissues of human origin, in addition to non-invasive clinical studies of human volunteers and patients. There are no reliable models for the study of humans other than humans themselves.
(ii) why is validation and regulatory acceptance so painfully slow ?
The regulatory system is out of step with scientific facts
These two aspects of validation warrant closer inspection. Incredibly, animal experiments have never undergone formal validation (1), a fact which prompted a former head of ECVAM*** to put forward the concept of “invalidation”, saying that it was clear that many currently accepted animal tests do not, and could never, meet the agreed criteria for validation (2). This initiative – not surprisingly – appears to have been largely ignored both by industry and by regulators. For the authorities to admit that animal experiments don’t work would simply be too big a public embarrassment.
The second problematic aspect of validation is the time taken to develop and validate a non-animal method and then await regulatory approval. A current example to illustrate this point is the replacement of the rabbit pyrogenicity (fever) test by a non-animal method. A non-animal method was developed in 1988 by UK scientists, but was not validated until 2006 (3). Informed sources predict that this method will obtain regulatory approval in 2010, as an official replacement for the rabbit test – a total of 22 years to achieve one single animal test replacement! Many people ask the burning question: “why does this process take so long?” The answer is quite sad. It is due partly to government and industry incompetence and partly because animal experiments have been around for years and both regulators and industry are familiar with the animal data, even if it is irrelevant to human health. Industry knows that in order to develop and introduce a new, non-animal method it will need to spend some money, although that in itself is not a barrier. A much bigger worry, however, is the risk that the method will not be accepted by the regulatory authorities. This is especially likely to happen when a test method developed using human cells and tissues is compared to historical animal data.
A test case: acute toxicity
One of the most basic requirements of any chemical testing program is to determine the amount of a substance that can kill an individual in a single dose (acute toxicity).REACH is no exception to this rule, but will these (animal) tests simply be an exercise in blind information gathering – a stubborn refusal to let go of the “bad science” – ignoring the fact that no animal species is a reliable biological model of humans?
Initially, REACH called for acute systemic (whole body) toxicity data via a single route, and only for chemicals marketed in volumes of more than10 metric tonnes per annum (4). However, amendments tabled by several EU member states have led to acute lethality data being required for all substances covered under REACH (i.e., 30,000 chemicals marketed in volumes greater than 1 tonne per year), plus a further requirement for lethality data via a second exposure route for approximately 10,000 chemicals marketed annually in volumes greater than 10 tonnes (5).
Since virtually every chemical in commerce has been tested using an oral LD50 (lethal dose that kills 50% of the test animals) or reduction/refinement variant thereof, the second route study will either be inhalation or dermal – which consume 30-40 animals per test, according to OECD Test Guidelines 402/403 (6), and for which “alternative tests” have yet to be accepted. In addition, there are many more “alternative tests” yet to be invented, since current regulations still rely largely on animal experiments as their point of reference, rather than test methods that are directly applicable to humans, as pointed out by Antidote in 2005. We are told that these human based methods must first undergo validation – a mission impossible – since ECVAM does not possess animal data against which to compare human cell data! So for the sake of expedience, 10,000 chemicals are going to be tested once more on animals, even though the resulting data will be meaningless in terms of protecting human health and the environment. Although this allows manufacturers to satisfy regulatory requirements, it will not serve the interests of the consumer public.
An admission by the pharmaceutical industry
This situation sounds like a catastrophe in the making. Interestingly, however, a scientific publication that appeared at the beginning of the year may offer a way to challenge animal testing in REACH. A consortium of 18 pharmaceutical companies announced that they were looking to reach an agreement with regulatory authorities to scrap acute toxicity testing, since this category of test was considered redundant. This move has actually opened up a Pandora’s box of shocking news – the admission by industry that these “traditional” toxicity tests actually served no purpose. Although the present discussion refers only to acute toxicity tests, it may herald the beginning of a “domino effect” with respect to all the other regulatory animal test requirements. In addition to acute toxicity, we should also revise testing requirements for cancer, neurological disease, reproductive malformations, foetal damage, and more, for which the animal data is simply unreliable, and for which the traditional studies of epidemiology (study of human populations) may be unsuitable because it may be many years before disease symptoms appear.
This strange turn of events begs the question: how long have industry and the regulatory authorities known about this situation and kept quiet about it? The answer is: about 30 years!! (7).
One has no doubt that it is public pressure and the efforts of the animal welfare lobby that have contributed significantly to this timely expose and raises the suspicion that there are more redundant toxicity tests that the public is not being told about (we would say that all animal toxicity testing is irrelevant and therefore redundant). An opportunity thus presents itself to challenge the REACH chemicals program, in the light of this revelation by the pharmaceutical industry.
Antidote Europe would like to inform its readers and supporters that this line of investigation will now be vigorously pursued by all possible legal avenues in order to ensure that REACH achieves its stated aim – the protection of human health and the environment – through the use of modern toxicological methods and good science.
*Annex XI (General rules for adaptation of the standard testing regime)
Article 1.2. Weight of evidence
“There may be sufficient weight of evidence from the use of newly developed test methods, not yet included in the test methods referred to in Article 13(3) or from an international test method recognised by the Commission or the Agency as being equivalent, leading to the conclusion that a substance has or has not a particular dangerous property.
Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available: – further testing on vertebrate animals for that property shall be omitted”.
- In 2004 the Swedish government brought a case before the Court of First Instance over the Commission’s decision to permit the use of paraquat, a hazardous pesticide, in the EU. The Court of First Instance subsequently banned the use of paraquat in July 2007.
- European Centre for the Validation of Alternative Methods
1. “Most of the animal tests we accept have never been validated. They evolved over the past 20 years and the FDA is comfortable with them.” – Anita O’Connor, Office of Science, Food and Drug Administration (USA). Written communication to Andre Menache in 1998.
2. Balls M, Combes R. Altern Lab Anim. 2005 Jun;33(3):299-308
3. Poole S, et al. Dev Biol Stand. 1988;69:121-3. “Assay of pyrogenic contamination in pharmaceuticals by cytokine release from monocytes”.
7. Robinson S et al. Regulatory Toxicology and Pharmacology 2008 (50): 345- 352. “A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development”.