New psychoactive substances laws require manufacturers to provide evidence that their product poses a ‘low risk’ to consumers before they can market it. Can they do it without animal testing?
In the debate over the current legal status of novel psychoactive substances, questions have been raised over the ethics of using animal testing to prove the safety of new “legal highs”.
New legislation will be introduced under urgency when Parliament convenes on 8 May to revoke the transitional interim approvals granted to a number of psychoactive products. Following the establishment of regulations later this year, manufacturers will only be able to sell a novel psychoactive product if proven ‘low risk’ under a testing regime stipulated by the government.
The Science Media Centre approached New Zealand experts with the question: ‘Would it be possible to show a substance presents a low risk to human health without animal testing?‘.
Professor Nick Holford, Department of Pharmacology & Clinical Pharmacology, University of Auckland, comments:
“It is certainly possible to show a substance presents low risk to humans without testing in non-human animals. This would however be on a case by case basis. If a new molecule from a well established and acceptably safe class was proposed for use in humans then it would be reasonable to go directly to humans for further testing of effectiveness and safety.”
Dr Malcolm Tingle, Associate Professor in Toxicology, University of Auckland comments:
NB: The author states that the following constitutes his personal opinion.
“The (Interim) Psychoactive Substances Expert Advisory Committee — of which I am a member — was established in 2013 and tasked with advising on a suitable testing regimen capable of demonstrating ‘low risk of harm’. Intrinsic to that were two key questions:
- What is an acceptable low risk of harm? and
- Is there an existing internationally-recognised system for other products (e.g. medicines, food or cosmetics) that could be used as a basis for psychoactive substances?
“The answers to these questions were broadly that for a compound to be considered to have a low risk of harm it should:
- Be unlikely to cause death after a low single dose
- Have no cumulative effect on repeated exposure
- Not be genotoxic (potential for cancer many years later)
- Not be teratogenic (no harm to unborn child: NOT a user by choice!)
- Have a low addiction potential: indirect toxicity through modification of behaviour
“The Psychoactive Substances Act 2013 details the duty of the advisory committee relating to the use of animals in assessing a low risk of harm. This Act establishes in law that alternatives to animal tests must be used if they exist and are suitable.
“So, do ‘alternative’ tests exist that have been validated? Yes; the OECD has ~80 guidelines for the testing of chemicals and there are in vitro (‘alternative’) tests for: genotoxicity; skin irritation; corrosion; sensitisation; absorption; estrogenic activity; photosensitivity. There are NO VALIDATED alternatives for systemic toxicity or teratogenesis.
“Would it be possible to show a substance presents a low risk to human health without animal testing? If we accept that a limited battery of the biological end points above is sufficient — for example, genotoxicity (but not cancer, for which there are no in vitro alternatives), irritation and photosensitivity — then YES, we may avoid animal testing.
“If, however, we accept that low risk of harm should cover systemic toxicity (e.g. toxicity after oral or inhalation exposure) and teratogenesis, then the answer is NO.
“Will that always be the case? Possibly, BUT if a new alternative test becomes available that is suitable, under the existing legislation, it must be used and any animal data for that endpoint becomes redundant.
“Putting my toxicology hat on, for the testing regimen proposed by the Psychoactive Substances Expert Advisory Committee, it is highly likely that substances/products must pass all animal testing in order to demonstrate a low risk of harm and thus gain approval. of dose. Given that no manufacturer/sponsor would wish to have a negative result, their desire will be driven by the use of doses that do not produce adverse effects in any animal, thus the animal welfare impact will be as low as possible under test conditions.
“Another current issue is that of which species. Putting my animal ethics hat on — for historical reasons, mice and rats have been used most frequently and are the major species for many safety pharmacology testing, with rabbits, dogs and some lower primates being other common species used. HOWEVER, the Psychoactive Substances Act 2013 requires that for any animal test ‘the trial is based on the relevant International Conference on Harmonisation Guidelines‘. The guidelines state that ‘In choosing an animal species and strain for reproductive toxicity testing should be given care to select a relevant model‘. This means decisions must be made on scientific, not current political grounds. Undertaking a test in an inappropriate species merely because of political pressure would also be a breach of the Animal Welfare Act, if an Animal Ethics Committee were to approve it.
“Finally, to the argument that ‘if people want to test these compounds they should just do it on themselves’. Fair enough: human in vivo is the most appropriate of any model. However, any submission under the Psychoactive Substances Act must contain testing data conducted to the highest standard, and should be conducted under Good Clinical Practice. In New Zealand, this would require ethical approval from a Health and Disability Ethics Committee. If this is to be first time in human study, then an HDEC is highly likely to want to see some pre-clinical evaluation to assure them that volunteers will not suffer adverse effects. Without that assurance, the absence of animal testing shifts the ethical dilemma to human ethics committees and they are thus unlikely to approve any such study. If a manufacturer tries to circumvent ethical approval (either at the level of animal or human) then no regulatory committee is going to accept their data.”
Declared interests: Member of the (Interim) Psychoactive Substances Expert Advisory Committee; Member of the National Animal Ethics Advisory Committee; Active researcher in the field of drug safety for ~30 years, including the use of in vitro and in vivo (experimental animal and human studies, including myself); prior member of University of Auckland Animal Ethics committee, including 6 years as chairperson; Most importantly, father of 16 & 18 year old children.
These comments are abridged, a full copy of Dr Tingle’s commentary is available on request or can be downloaded from the SMC Resource Library.