The ethics of animal experiments in 3 steps Stijn Bruers Bite Back aug-2013

The 3 steps Step 1) Animal experiments are scientifically unreliable: animal models lack predictability for humans Step 2) Animal experiments are ethically unjustifiable: too much loss of well-being Step 3) Animal experiments are ethically unjustifiable : too much violations of basic rights

Step 1: scientifically unreliable Imagine animals were not sentient. Do animal experiments still have value? Applied biomedical research for human purposes: barely Fundamental research: yes Problem 1: too many false positive and false negative test results Too low predictive value for humans Effect humans Yes No Effect animals True positive test False positive test Falss negative test True negative test

Step 1: scientifically unreliable False positive tests Chocolate? Lethal for dogs! Safe medicines harmful for animals. E.g.: aspirin,… Many substances carcinogenic for mice but not for humans Positive predictive value: if there is an observed effect in animals, how big is the probability that the effect will be observed in humans? Often < 50% probability! Delay of development of good products and medicines

Step 1: scientifically unreliable False negative tests No observed effect in animals, but effect in humans E.g.: Softenon (thalidomide), Vioxx, cyclosporin, TGN1412,… Tested safe in animal experiments, dangerous/lethal for humans Smoking: lung cancer in humans, not in mice Epidemiological research instead of animal experiments Negative predictive value: if there is no observed effect in animals, how big is the probability that the effect will not be observed in humans? Often < 50% probability! Allows dangerous products on the market

Step 1: scientifically unreliable Problem 2: which species? Discovery of first antibiotic: penicillin (A. Fleming, 1928) No effect in rabbits (false negative) Good result with dogs (true positive) Dangerous and lethal for rats, hamsters and guinea pigs (false positive)

Step 1: scientifically unreliable How to predict the correct lottery number? Most of the time there is a winner, so look at the collection of all lottery players? No prediction possible Which player?

Step 1: scientifically unreliable Problem 3: how to cause a human disease in healthy animals? E.g. MS, Parkinson,… Procedure is often merely harming animals such that they acquire some symptoms (e.g. shaking) instead of the disease

Step 1: scientifically unreliable No anecdotes! No “cherry picking” of examples But: Statistical analysis of collection of studies (meta-analysis) Blind peer reviewed Critical, impartial Reviews of systematic reviews new (only last decade), increasing recognition of importance

Step 1: scientifically unreliable Reviews of systematic reviews (last decade) Anisimov V.N., Ukraintseva S.V., Yashin A.I. (2005). Cancer in rodents: does it tell us about cancer in humans? Nat Rev Cancer 5:807-819. Greek, R. and Menache, A. (2013). Systematic Reviews of Animal Models: Methodology versus Epistemology. Int J Med Sci 10(3):206-221. Hackam D. G., and D. A. Redelmeier. (2006). Translation of Research Evidence from Animals to Humans. JAMA 296: 1731-1732. Knight A., Bailey J., Balcombe J. (2006) Animal carcinogenicity studies: 1. Poor human predictivity. Altern Lab Anim 34:19-27. Knight, A. (2007). Systematic reviews of animal experiments demonstrate poor human clinical and toxicological utility. ATLA 35:641-659. Knight, A. (2008). Systematic reviews of animal experiments demonstrate poor contributions toward human healthcare. Rev. Recent Clin. Trials 3:89-96. Mestas, J and Hughes, CCW, (2004). Of mice and not men: differences between mouse and human immunology. The Journal of Immunology, 172: 5. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P & Khan KS (2007). Comparison of treatment effects between animal experiments and clinical trials: systematic review. British Medical Journal 334:197-203. Pound P., Ebrahim S., Sandercock P., Bracken M.B., Roberts I. (2004). Where is the evidence that animal research benefits humans? British Medical Journal 328:514-517. Seok, J Shaw Warren, H et al, (2013). Genomic responses in mouse models poorly mimic human inflammatory diseases. PNAS 110(9): 3507–3512. Shanks, N. Greek, R. Greek, J. (2009) Review: Are animal models predictive for humans? Philosophy, Ethics, and Humanities in Medicine, 4(2).

Step 1: scientifically unreliable Human vs animal bioavailability 1. Graph generously provided by James Harris PhD, who presented it at the Center for Business Intelligence conference titled 6th Forum on Predictive ADME/Tox held in Washington, DC September 27–29, 2006 and is adapted from data that appeared in Grass GM, Sinko PJ. Physiologically-based pharmacokinetic simulation modelling. Adv Drug Deliv Rev. 2002 Mar 31;54(3):433–5.

Step 1: scientifically unreliable Why lack of predictive value? Why that many false positive and false negative results? Theory of complexity: small differences can generate big effects Gene regulation, complex interactions E.g. chimpanzees: 98% of genes in common with humans, yet not susceptible for HIV, hepatitis and malaria (false negative tests) Theory of evolution: small and large differences between individuals, populations and species

Step 1: scientifically unreliable Current biomedical research (medicins and toxic substances): very specific, strongly dependent on complex interactions of genes,… At this specific level: differences between species (and populations, sexes, ages, individuals…) become important No longer at a rough (less specific) level (such as e.g. the overall functioning of blood vessels Additional confounding factors: breeding procedure, stress in animals, sickening (infecting) animals

Step 1: scientifically unreliable Alternatives of animal experiments become more and more reliable, because more human-specific and more technological developments Epidemiological research Clinical research Autopsies Human (stem) cells and tissue cultures

Step 1: scientifically unreliable New technologies Computer simulations and mathematical models Microdosing MRI-scanners

Step 1: scientifically unreliable New technologies Gene chips (DNA microarrays) Human-on-a-chip

Step 1: scientifically unreliable Animal testing can be harmful to people: Misleading False positive and negative results: Preventing development of good products Allowing harmful products Alternatives are more reliable, so fewer false positive and false negative results Animal studies are wasting scarce resources (money, time)

Step 1: scientifically unreliable Why are there still animal experiments? Psychological mechanisms of animal researchers Habit Belief Peer pressure Money

Step 1: what if animals were not sentient? Science Step 2: what if animals are sentient? Ethic of well-being

Step 2) ethically irresponsible: welfare loss in animals Animals are too different from humans for contemporary biomedical research But animals are equal to humans in terms of global functions: circulatory, respiratory,… and consciousness (feelings)! So: Concerning what is ethically relevant: strong similarity between humans and animals Concerning what is scientifically important: strong differences between humans and animals According to animal researchers: the opposite!

Step 2) ethically irresponsible: welfare loss in animals Well-being of animals should be taken into account Place yourself in the position of an animal used in experiments, and measure the loss of well-being Increase well-being of everyone, giving priority to the worst-off Loss of well-being due to breeding, confining, testing and premature killing of animals Lab animals are often in the worst-off positions

Step 2) ethically irresponsible: welfare loss in animals Three R’s Refine Reduce Replace Credibility of animal researchers? Regularly violating 3R’s in earlier experiments What do researchers eat? No vegan: researchers violate 3R’s 3 times a day! Animal products are not necessary for healthy diets

Step 3) ethically irresponsible: animal rights violations Humans not only have a right to live and to flourish Also the basic right not to be used as merely a means to someone else’s ends Humans are not tools E.g. slavery No use as property No coerced human experimentation Not even according to 3R’s Not even if well-being of other people would increase more (if human experiments would be beneficial for a vast majority) Not even if seriously mentally disabled orphans would be used

Step 3) ethically irresponsible: animal rights violations Species is not morally relevant Arbitrary: why species instead of population, subspecies, genus, family, order, class,…? Artificial and far-fetsched: how to define a species? Relevance of fertility of potential offspring?

Step 3) ethically irresponsible: animal rights violations Fuzzy boundaries: human-animal hybrids, chimeras, ancestors, genetically modified humans? No merit: we did not choose to be born as humans Comparison with racism: genes not morally relevant

Conclusion Step 1: many experiments should stop Step 2: more experiments should be prohibited (not only for cosmetics) Step 3: nearly all animal experiments should be prohibited