5 August 2024
Why Toxicity Testing on Macaques Must End: Superior Alternatives for Safer Drug Testing
Learn why toxicology testing on macaques is outdated, inhumane, and unreliable. Discover superior animal-free alternatives for drug safety testing.
This article was originally published in French in Week-End weekly newspaper in Mauritius and https://www.lemauricien.com/week-end/monkey-business-savita-nutan-le-macaque-a-longue-queue-est-la-principale-espece-utilisee-pour-les-tests-de-toxicite/644728/
The Ineffectiveness of Animal Testing in Toxicology
Animal experimentation should have been abolished long ago. It has long thwarted medical and scientific progress but, despite this known fact, the number of animals used in research and testing annually (more than a 100 million globally) has not shown clear signs of stopping. These numbers include not only animals cruelly experimented on but also the surplus bred specifically for this purpose and killed when no longer needed. Thus, these animals face two horrific constraints: either to live a life of brutal torture through experimentation or to live a life under incredible duress within the confines of a cage, watching their fellow animals undergo painful procedures till they face their own death.
What is even more unbelievable is that we subject our closest relatives, our primate comrades, (ranging from monkeys to lemurs) to this undeniable torture and pain. Primates (both human and non-human) are characterised by a highly developed brain, use of hands and complex behaviour. These animals, much like us, understand complex social behaviours key to survival. Behaviours such as communication, cooperation, sharing and parental care. They know and appreciate the true value of family and depend on each other to survive.
Approximately 200,000 non-human primates are used across the world for research and testing every year. These primates are tortured, abused and killed in experiments which cannot be justified and lacks real human benefit.
Most non-human primates are used in toxicology, a field of science that helps to understand the damaging effects of chemicals, such as new medicines, can have on the human body. Whilst we need to understand whether new pharmaceutical drugs have an adverse reaction to people, it is completely unfathomable why animals are needed for this purpose when we have superior alternatives.
The long-tailed macaque is the primary species for the purpose of toxicity testing in the biomedical industry. In the US alone, more than 30,000 long-tailed macaques are imported from countries such as Mauritius annually for laboratory use.
Scientific Reasons Why Macaques Should Not Be Used for Toxicity Testing
Darwin’s theory of evolution has long been held as justification of animal testing, that all species share a common ancestor and shared genetic similarity was reason enough to use these animals as “models” of humans.
Because nonhuman primates are closely related to humans, they are often considered in research and testing. The most common primate species used in science are the rhesus and cynomolgus (or long-tailed) macaques. They are 90-93% genetically similar to humans however that remaining 7-10% difference creates many fundamental biological distinctions completely distorting their suitability in science. The similarity between monkeys and humans are therefore superficial, because what is key to species differences is the way in which DNA is expressed in the body.
There is a myriad of papers which have highlighted how animal testing of potential new drugs for humans do not sufficiently predict human safety and toxicity. A recent study showed that only 5% of animal-tested medical therapies are approved for human benefit.
This poor translation (from animal testing to human drug development) is supported by the significant biological variation not only between animals and humans but even within each species. For example, populations of macaques within different regions vary so greatly that it can have significant differences in their vulnerability to disease and even in the way they metabolise drugs.
Macaque Monkeys in Research and Testing: The Ethical and Scientific Concerns
These long-tailed macaques have been used to test on a broad range of drugs; from testing the effects of the popular weight loss drug Ozempic, to COVID-19 vaccines to long-acting HIV drugs. [29]
History has shown us the mounting evidence of the ineffectiveness and proven human harm that can come from animal testing of human medicines. A notable example is the drug TGN1412 which was originally intended of the treatment of leukaemia. Long-tailed macaques showed this potential drug to be safe, even at a dose 500 times higher than the dose given to humans, that almost killed six healthy clinical trial volunteers.
The devastating truth is that our fellow primates, accustomed to tropical rainforests, are subjected to heavy restraint in a laboratory, such as a “primate chair”, to immobilise their neck and given different doses of the drug. These drugs are either injected directly into the bloodstream or forcibly ingested into their mouths via a tube to reach the stomach. The dose of the drug varies, it could be given over a hundred times more than a human dose, to see any visible effect. Effects of these drugs in primates range from difficulty breathing, vomiting, seizures to internal bleeding, organ failure and even outright death. All of this can occur even at low doses of a drug.
When it comes to drug toxicity testing, is this the best we can do? Subject our closest living non-human relative to a life behind metal cages, necks pinned in a chair, suffering from the plethora of drugs and doses administered to them?
The life of a laboratory monkey
Long-tailed macaques typically have an average lifespan of 15-30 years in the wild and the maximum recorded is 40 years when living in captivity. Bear in mind that being in captivity and being in a laboratory are two distinct experiences for animals. Living in captivity such as a wildlife sanctuary means that animals live in an environment closely resembling their natural home and effort is made to remove potential threats such as predators, disease and food scarcity. They therefore are likely to live longer.
Laboratory life, however, is a stark contrast to an animal’s natural way of living; they’re subjected to an incredibly stressful life due to the nature of research activities. This ranges from the restraint used (see “primate chair” in the previous question), the lack of social interaction due to captivity, the handling and, of course, the harsh treatments they are subjected to.
All animals experience stress in their own way, from mice to macaques, which range from pain, stress and distress, and/or depression and anxiety. This will cause changes in the mental and physical health of the animal. Psychological effects can involve repetitive pacing, obsessive-compulsive disorder (OCD) and even self-harm (much like animal behaviour seen in zoos). Physical effects include severe changes to the immune system, metabolism and being more vulnerable to illness. Some of these effects can potentially be passed down through generations. For example, macaques who were wild caught and/or who have experienced the stress and duress of laboratory life can pass on these genetic changes causing an altered biology in their infants. It has been argued that all of this is strongly likely to influence the reliability of scientific data.
It is not clear how many monkeys die each year because of the torture they suffer during testing. The number of failed experiments is not disclosed to the public, but it should be public knowledge. This is especially important given the poor human benefit of animal testing.
If we review the data in the United Kingdom, animal project licence information is summarised and provided to the public annually. This shows how many animals are approved for each project. In 2023, the number of macaques (cynomolgus) ranged from 200 to 5300 per project involved in the testing of medicinal products. The number of animals required for toxicity testing therefore varies widely and is likely dependent on the type of product and specifics of testing as well as regulatory requirement.
Organ-on-Chip and AI: The Future of Toxicology Testing
There are several alternative tests outperforming animal testing, providing more reliable and accurate testing. The problem is threefold – academia, industry and government. Scientists may feel pressured into using animals as highlighted in a workshop conducted to investigate ‘animal methods bias’ in scientific publishing. In this workshop, Don Ingber, inventor of Organ-on-Chip technology, argued that animal studies in clinical drug development and toxicity testing are often not reproducible, subject to high variability and do not reliably predict clinical responses. Thus, requests to add animal studies to validate non-animal testing is completely misguided.
Human organ-on-chip models – engineered microchips containing living human cells which work together to create organ-level function – may be the most relevant tool to confirm clinical testing. There is ample evidence showing it can surpass current animal testing. A notable example was seen when human liver-on-chips were used to identify the likelihood of drug-induced-liver-injury (DILI). DILI is one of the leading causes of failure of new drugs in clinical trials. Human liver-on-chips were used to evaluate toxic and non-toxic drugs and highlighted its capability to be a superior predictive tool. Tools like the Liver-Chip do have a substantial initial cost, for example CN Bio Innovations offer this technology at a starting price of approximately $22,000. However, compared to traditional animal studies, organ-on-chips possesses faster and more reliable results. Hence, the long-term economic advantages outweigh the initial investment of these organ-chips.
It is worth bearing in mind that the poor translation of animal studies into human therapies means that much of the cost in research and development (R&D) – is the cost of failure. That is, the money spent on projects initially deemed safe by animal testing but later proven ineffective or unsafe in human trials. Estimates of the cost of failure are approximately 75% of the total R&D cost. If you compare cell-based assays (also known as in vitro testing), animal tests can range from 1.5 times to > 30 times as expensive.
A review at the beginning of this year highlighted the rapid progress of AI in the field of toxicology. Areas where AI is expected to take over traditional animal testing include but are not limited to:
· Prediction of toxicity of new chemicals
· Generating synthetic datasets such as a virtual control group
AI can thereby remove the reliance on animal testing through its suitability to handle large and complex volumes of data.
The end of 2022 saw the United States Food and Drug Administration (FDA) pass the FDA Modernisation Act giving drug manufacturers and sponsors the option to use scientifically rigorous, proven non-animal test methods. [28] If the US government acknowledges this bright future, we need other countries to follow suit. They must recognise the countless breakthroughs that non-animal technologies are capable of for the ultimate benefit of humans.
Savita Nutan
Founder of Medicine Without Cruelty
