Toxicology

The majority of products that you use in your bathroom, your kitchen, garden or for your car, including food products, have been tested on animals at some point to see how much of that product is poisonous (toxic) and what effects it has on the body. These cruel animal tests  can be replaced with advanced technology and also, with predications based on the vast knowledge we already have about the effects of chemicals, from human use.  However, despite the alternatives available, animal tests continue.

NAVS Huntingdon macaque (1)Primates and dogs are used in regulatory tests (toxicology, safety tests), which are required for a licence for a product to be sold on the market. Regulatory testing represents over 50% of the 6,000 primates used in European laboratories each year. Each year in the UK around 3,000 dogs and more than 2,000 monkeys are subjected to painful experiments to test the safety of different chemicals and drugs for human use.

Animal tests have always been used because animals are available, and the animal testing technology is over 100 years old. However, there are no specific legal requirements for the use of primates or dogs in regulatory testing – the regulations specify that two species of mammals are to be used and one must be a non-rodent species.  So the idea is that the tests are started with smaller animals such as rats and mice, and then move on to larger mammals like dogs and monkeys. In theory, dogs and monkeys are used at the end of the testing strategy. But, an analysis of animal toxicity data of over 3,000 drugs concluded that further data from the second species does not solve the problem of extrapolating results to humans.

For example, safety/toxicity testing of a drug is about a key piece of information – the way a drug travels through the body – the rate and route by which it breaks down, before being excreted. This is crucial and influences how the drug affects the body. However, our genes and other factors influence this process. These key genetic differences between humans and other animals are hugely important in drug development and testing – despite the similarities between humans and the other primates such as use of tools, language, emotions and intelligence.

Case Study: Envigo (formerly Huntingdon Life Sciences)

Envigo (formerly Huntingdon Life Sciences) is a major European contract testing laboratory; they perform the standard animal tests required by regulators on behalf of their clients, the manufacturer of the product being tested – drugs, chemicals, and other products (for example things used in the home).

NAVS Huntingdon Life Sciences restraintA case study by ADI campaign partner, the National Anti-Vivisection Society (NAVS) provides an insight into the functioning of a typical European commercial testing laboratory, Huntingdon Life Sciences (HLS). The nature of the experiments conducted  on behalf of their clients was to look for adverse effects or symptoms of test compounds.

During the investigation, the numbers of macaque monkeys observed being used in tests ranged between 4-72; just five studies accounted for the lives of 217 animals. Monkeys arrived from breeding colonies in Vietnam and tests typically involved restraint, being captured from their cages and firmly grasped by their arms, legs and tail. Three monkeys suffered rectal prolapses during one study. Rectal prolapse is known to indicate extreme stress in monkeys and tells us that they suffered terribly – probably as much through fear and anxiety as anything else.

An incontinence drug was given daily for a year, by forcing it down restrained monkeys’ throats with a pipe (gavage dosing). Some of the monkeys vomited every time they were dosed, including ‘control’ monkeys who did not receive the drug, indicating that the procedure itself, not the test substance, was causing vomiting. Gavage is known to be unpleasant for animals; monkeys are observed to “forcefully resist such intervention”.  During this study, several animals suffered prolapses, which appear to be the result of fear due to anticipation of the procedures.

Yet a review of the incontinence drug market found at least 13 other incontinence drugs in development in the US, Europe and Japan. The market for these drugs was set to become “extremely competitive”.

Tests for a blood clotting drug involved 56 monkeys: they were put in restraint chairs and the substance administered through a cannula inserted into the back of their leg over a period of 2-15 minutes. Animals were bled before and during the study and were fasted every night before they were dosed.  Some animals were killed 24 hours after dosing and others were killed two weeks after dosing.

One female was trembling during dosing, indicating distress. It is known that biochemical changes in the body as a result of stress can influence the outcome of a test “which can cause anomalous experimental results”. Almost a decade before these tests on monkeys, a review of animal models of a blood clotting disorder led to the conclusion that differences in the animal and human disorder cannot be avoided, so “…one should be cautious about extrapolating the results from animals to humans” .

Case Study: Inveresk Laboratories

Monkey backpackDocuments and photographs, including reports of commissioned experiments were leaked to ADI campaign partner, the NAVS. They provide a chilling insight into the world of ‘contract research’ – commercial safety testing. The company stated they would help businesses to comply with the EU’s REACH chemicals regulations by carrying out animal experiments on their behalf.

An asthma drug tested on monkeys involved a cannula being inserted into the leg vein of 16 animals where it remained so that they could be dosed daily for 14 days. The animals were then killed. Monkeys were observed for any signs of ill health or reaction to treatment. In order to obtain samples for analysis, the monkeys were deprived of food and water.

From approximately 5 minutes after dosing, all of the animals suffered reddening of the face and lips; this increased with dose levels, in terms of both incidence and length of time. They also experienced a range of symptoms including diarrhoea, swelling in the stomach, redness of feet and hands, white pigmentation on the feet; the males’ testes increased in weight and they suffered red and swollen penises and scrota. In addition, the monkeys were reported to be subdued and hunched on their branches; body tremors were seen in one; another did not use its right leg throughout the test, apparently due to “an injury”; and females suffered abdominal and umbilical hernias.

The use of cynomolgus macaque monkeys has also been criticised as being the most misleading laboratory animal model for the study of human cardiotoxicity (i.e. toxic effects on the heart), yet this is one of the key questions that the test intended to address.

The experimental drug was intended for inhalation administration in people, but the drug was given to the monkeys directly into the bloodstream. Yet it is already known that side effects can differ, dependent upon whether a drug is given through the blood stream, or inhaled. Results obtained on the effects of a drug administered through the vein may be misleading if the drug is intended for inhalation.

Case study: BIA 10-2474 and human tragedy

In January 2016, six volunteers were hospitalised following adverse reactions to a drug that was being tested by French research company, Biotrial, for Portuguese pharmaceutical company Bial. The drug, BIA 10-2474, was being tested as a pain killer among other possible uses for the first time in humans.

Within three days of taking the drug, a volunteer in a high dose group was admitted to hospital after beginning to feel sick. The remaining volunteers in the same group continued to receive the drug, until the hospitalised volunteer’s condition deteriorated and he was diagnosed as brain dead the following day. A week later he died. The other five men were hospitalised, with MRI showing evidence of deep bleeding and tissue death in the brain.

The symptoms experienced by these volunteers in the highest dose group included: headache, problems with their movement and walking, uncontrolled eye movements, slurred speech, dizziness, fatigue, diarrhoea, brain lesions and bleeding on the brain. It has been reported that at least one of the volunteers lost all his fingers and toes. One volunteer also showed signs of amnesia, struggling to remember events two months before taking the drug and one month after.

Ten volunteers in a lower dose group also experienced problems such as dizziness and blurred vision. Almost a year later, four of the volunteers who became ill had not yet fully recovered from their neurological symptoms and continued to suffer memory loss, headaches, motor disorders and tremors.

Animal test results failed to predict dangers

beagle_Toxicol_1993Prior to studies in human volunteers, the drug had been tested extensively on mice, rats, dogs, and monkeys for toxic effects on the heart, kidneys and gastrointestinal tract, and on rabbits and rats (including their foetuses) to determine its reproductive and developmental toxicity effects. It has been estimated that monkeys were given doses of the drug approximately 75 times greater than the highest dose given to patients, with no ill effects. Animals in the preclinical studies would have inevitably suffered during dosing for these tests, as well as from any side effects of the drug.

Despite the fact that fthese animal tests did not predict the tragic outcome in humans, researchers have carried out more animal tests in an attempt to determine the causes of the adverse events. Tests on rats involved injecting the compound into their tails before killing them by cutting off their heads, so that their brain could be removed for analysis. Astonishingly, researchers admit that extrapolation of their results “from rodents to human is fraught with error”.

The reason for the toxic effects of the drug remains unknown, with scientists stating that “precisely how a drug that seemed to be safe in animal testing and other early testing in people turned out to be deadly is still unclear”. A report from an investigative committee concluded that “no toxicity, especially neurological (central or peripheral) comparable to that observed in the accident in Rennes, appears to have been demonstrated in animals, despite the use of 4 different species and high doses administered over long periods”. It is clear that animal testing did not make the human trials safe.

Other failed drug trials

TGN1412

Anti-inflammatory drug TGN1412 was given to healthy volunteers in doses 500 times weaker than that given to lab monkeys, but in an hour the volunteers were so seriously ill that they had to be transferred to intensive care. They suffered multiple organ failure caused by a massive immune reaction. One volunteer spent 147 days in hospital with heart, liver and kidney failure and had all his toes amputated and the tips of several fingers removed.

Vioxx

The anti-inflammatory drug Vioxx had unexpected effects on human patients, after laboratory animal tests. It has been reported that from 88-140,000 extra heart attacks may have been caused by Vioxx in the five years since its introduction with between 38,720 and 61,600 deaths. It was found to increase the risk of heart attack by 34% compared to people on similar drugs. Many of the participants in the trials were at lower risk of cardiovascular disease than the elderly population that would use Vioxx, so the risk to the intended recipients may have been even greater – up to eight times greater.

Eraldin

The heart drug, Eraldin was thoroughly studied in animals and satisfied the regulatory authorities. None of the animal tests warned of the serious side effects in people, such as blindness, growths, stomach troubles, and joint pains.

Opren

Opren, the anti-arthritis drug, was passed safe in animal tests. It was withdrawn after causing more than 70 deaths, and serious side effects in 3,500 other people, including damage to the skin, eyes, circulation, liver and kidneys.

Replacing animals – the alternatives

The alternatives to the use of animals in safety testing include databases of known information, human tissue culture and sophisticated analytical techniques. Many non-animal techniques are already used before tests on animals, but regulations still require animal tests. See more here