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Animal Experiments and Alternatives

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Justifications for invasive experiments on animals rely on claims that such research is essential for the advancement of biomedical knowledge, for the development of cures to human diseases, or for the evaluation of the toxicity of compounds to which humans are exposed. Until recently, critical evaluations of the accuracy of such claims have been rare. However, a growing body of large-scale systematic reviews have now been published in scientific and medical journals. The outcomes have been consistent: animal experiments have contributed far less than advocates would have us believe.

This presentation summarises these recent results, and comprehensively reviews the alternatives to invasive animal use with biomedical research, toxicity testing, and education.

Published studies are available at www.AnimalExperiments.info.

Published in: Education

Animal Experiments and Alternatives

  1. 1. THE COSTS AND BENEFITS O F ANIMAL EXPERIMENTS Andrew Knight 90101 9 780230 243927 I S B N 9 7 8 - 0 - 2 3 0 - 2 4 3 9 2 - 7 www.palgrave.com PrintedinGreatBritain Leonid Yastremskiy/dream- ssuescreateasmuch controversy asinvasiveexperimentson mescientistsclaim they areessential for combating major ses,or detecting human toxins.Othersclaim thecontrary, ousandsof patientsharmed by pharmaceuticals developed tests.Someclaim all experimentsare umanely,to high scientificstandards.Yet,awealth of recently revealedthat laboratory animalssuffer significant may distort experimental results. eaking scientificresearch,analysisand experienceto provide sed answersto akey question:isanimal ght of animal experimentsto humanhealthcare,whichhave THECOSTSANDBENEFITSOFANIMALEXPERIMENTS AndrewKnight Animal Experiments and Alternatives      ANDREW KNIGHTANDREW KNIGHT DipECAWBM (AWSEL), DACAW,DipECAWBM (AWSEL), DACAW, PhD, MANZCVS, MRCVS, SFHEAPhD, MANZCVS, MRCVS, SFHEA
  2. 2. Scientific resistance to alternatives Non-compliance of US researchers with the alternatives regulations of the Animal Welfare Act:  Most common: inadequate consideration of alternatives (600 - 800 research facilities).  Fourth most common: unnecessary experimental duplication (~ 250 facilities).  Others: inadequate justification for animal numbers, alleged uncertainty of research personnel about signs indicative of pain and/or distress (USDA-APHIS-AC, 2000).
  3. 3.  Chemical companies submitting test plans often failed to follow minimal EPA guidance about 3Rs alternatives:  failed to use existing published data  failed to avoid duplicative or otherwise unnecessary animal testing  proposed irrelevant or unnecessary tests (such as acute fish toxicity tests on water-insoluble chemicals)  Ignored opportunities to use non-animal tests  failed to utilise opportunities to combine protocols, sometimes doubling the number of animals killed  In its responses to test plan proposals, the EPA frequently failed to encourage companies to follow basic animal welfare principles (Sandusky et al., 2006). High Production Volume (HPV) test program
  4. 4. Scientific support for animal experimentation  Animal experimentation is vital for preventing, curing or alleviating human diseases (e.g. Brom 2002, Festing 2004).  The greatest achievements of medicine have been possible only due to the use of animals (e.g. Pawlik 1998).  The complexity of humans requires nothing less than the complexity of laboratory animals to effectively model during biomedical investigations (e.g. Kjellmer 2002).  Medical progress would be “severely maimed by prohibition or severe curtailing of animal experiments,” and “catastrophic consequences would ensue” (Osswald 1992).
  5. 5. Concordance or discordance? Drugs causing serious side effects or death in some laboratory animal species that are harmless to humans:  Penicillin  Morphine  Aspirin  …
  6. 6. Drugs released onto the market after passing more rigorous testing in animals, and very limited testing in humans, that have caused serious human side effects:  TGN1412 (UK, 2006)  Vioxx  Thalidomide, Eraldin, Chloramphenid, Ibufenac, Flosint, Zipeprol, Zomax, Accutane, Benedectin, Phenformin  Many, many more… Such adverse drug reactions have been recorded as the 4-6th leading cause of death in US hospitals, and kill over 10,000 people annually in the UK.
  7. 7. Calls for systematic reviews Clinicians and the public often consider it axiomatic that animal research has contributed to human clinical knowledge, on the basis of anecdotes or unsupported claims. These constitute an inadequate form of evidence for such a controversial area of research, particularly given increasing competition for scarce research resources. Hence, formal evaluation of existing and future animal research is urgently required, e.g., via systematic reviews of existing animal experiments. - Pound et al. Brit Med J, 2004.
  8. 8. Systematic reviews: ‘gold standard’ evidence  Critically examine human clinical or toxicological utility of animal experiments  Examine large numbers of experiments, usually sourced via multiple bibliographic databases  Any subsets of experiments must be selected without bias, via randomisation or similarly methodical and impartial means  Studies published in peer-reviewed biomedical journals
  9. 9. - Altern Lab Anim, 2007. - Rev Recent Clin Trials, 2008. - Palgrave Macmillan, 2011.
  10. 10. 27 systematic reviews of the utility of animal studies in advancing human clinical outcomes (20), or in deriving human toxicity classifications (7) Three different approaches sought to determine the maximum clinical utility that may be achieved by animal studies…
  11. 11. 1. Experiments expected to lead to medical advances Lindl et al. (2005 & 2006) examined animal experiments conducted at three German universities between 1991 and 1993, that had been approved by animal ethics committees partly on the basis of researcher claims that the experiments might lead to concrete advances towards the cure of human diseases. For 17 experiments meeting the inclusion criteria, citations were analysed for at least 12 years. 1,183 citations were evident. However …
  12. 12. Only 8.2% of all citations (97) were in clinical publications. Of these, only 0.3% of all citations (4 publications) demonstrated a direct correlation between the results of animal experiments and human outcomes. However, even in these four cases the hypotheses that had been successfully verified in animals failed when applied to humans. None of these 17 experiments led to any new therapies, or any beneficial clinical impact during the period studied.
  13. 13. 2. Clinical utility of highly cited animal experiments Animal studies with > 500 citations Published in the 7 leading scientific journals when ranked by journal impact factor 76 animal studies were located with a median citation count of 889 (range: 639 - 2,233) However…
  14. 14. Only 36.8% (28/76) were replicated in human randomised trials. 18.4% (14/76) were contradicted by randomised trials, and 44.7% (34/76) had not translated to clinical trials Ultimately, only 10.5% (8/76) of these medical interventions were subsequently approved for use in patients - Hackam & Redelmeier. J Am Med Assoc, 2006.
  15. 15. Even in these cases human benefit cannot be assumed, because adverse reactions to approved interventions are the 4th - 6th leading cause of death in US hospitals - Lazarou & Pomeranz. J Am Med Assoc, 1998.
  16. 16. Translation rates of most animal experiments are much lower Most experiments are neither highly cited nor published in leading journals. Many experiments are not published at all. The selective focusing on positive animal data while ignoring negative results (optimism bias) is one of several factors identified that may have increased the likelihood of translation beyond that scientifically warranted. Rigorous meta-analysis of all relevant animal experimental data would probably significantly decrease the translation rate to clinical trials (Hackam, 2007).
  17. 17. Only 48.7% (37/76) of these highly cited animal studies published in leading journals were of good methodological quality Common deficiences: lack of random allocation of animals blinded assessment of outcomes - Hackam & Redelmeier. J Am Med Assoc, 2006. Poor methodological quality
  18. 18. 3. Invasive chimpanzee research Passionate calls for increased funding of such research, e.g. VandeBerg et al. (Nature 2005): Such research has been of critical importance during struggles against major human diseases such as AIDS, hepatitis and cancer The genetic similarities between humans and chimpanzees — our closest living relatives — makes them ideal biomedical research models
  19. 19. J Appl Amim Welf Sci, 2007 Philos, Ethics, Humanit Med, 2008
  20. 20. Contributions to biomedical knowledge 749 studies of captive chimpanzees or chimpanzee tissues, from 1995-2004: Figure 1: Chimpanzee experiments 1995-2004 (total 749) 48% 42% 3% 3% 2% 2% Biology (363) Diseases: virology (311) Therapeutic investigations (26) Diseases: parasitology (23) Miscellaneous (14) Diseases: other (12)
  21. 21. Figure 2: Biology experiments (363 of 749) 37% 21% 10% 9% 7% 7% 6% 2% 1% Cognition/Neuroanato my/Neurology (133) Behavior/Communicati on (75) Immunology (37) Biochemistry (34) Reproduction/Endocri nology (27) Genetics (25) Anatomy/Histology (20) Physiology (9) Microbiology (3)
  22. 22. 21 others: Six: FV. Four: HAV. Two each: GBV – B, HIV & HV, IV, PIV, Noroviuses. One each: Bacteriophages, Dengue v., Ebola v., HCMV, HGV, HMPV, H/S TLV, LCV, Papillomaviruses, RV2, Rhinovirus, VZV, WMHBV, Unspecified. Figure 3: Virology experiments (311 of 749) 31% 31% 9% 4% 4% 3% 3% 2% 2% 11% HCV (97) HIV (97) HBV (29) RSV (12) HEV (11) STLV (9) HIV & SIV (8) SIV (7) TTV (7) 21 others (34) HCV = hepatitis C v., HIV = human immunodeficiency v., HBV = hepatitis B v., RSV = respiratory syncytial v., HEV = hepatitis E v., STLV = simian T-cell lymphotropic v., SIV = simian immunodeficiency v., TTV = transfusion- transmitted v., FV = foamy v (human and simian FV), HAV = hepatitis A v., GBV-B = GB virus B, HV = herpes v., IV = influenza v., PIV = parainfluenza v., HCMV = human cytomegalovirus, HGV = hepatitis G v., HMPV = human metapneumovirus, H/S TLV = human/simian T-cell leukemia v., LCV = lymphocryptoviruses, RV2 = rhadinovirus (or gamma-2-herpesvirus) genogroup 2, VZV = varicella-zoster v., WMHBV = woolly monkey hepatitis B v.
  23. 23. Remaining chimpanzee studies pharmacological and toxicological studies of various compounds testing of surgical techniques or prostheses, and anaesthesiology experiments investigations of laboratory/husbandry techniques radiation studies various disease studies, including endotoxaemia and eight parasitic species
  24. 24. Implications? Research on captive chimpanzees or chimpanzee tissue appears to have contributed towards a large array of biomedical disciplines. However, not all knowledge has significant value, nor is worth the costs that may be incurred.
  25. 25. Figure 4: Citations of 95 randomly selected published chimpanzee studies 47 34 14 0 10 20 30 40 50 Not subsequently cited Cited by other paper Cited by medical paper
  26. 26. Citations by medical papers 63% (17/27) of these medical papers were wide-ranging reviews of 26 - 300 (median 104) references, to which the cited chimpanzee study made only a small contribution No chimpanzee study demonstrated an essential contribution, or ― in a clear majority of cases ― a significant contribution of any kind, towards papers describing well-developed prophylactic, diagnostic or therapeutic methods for combating human diseases!
  27. 27. 27 systematic reviews: overall results The authors concluded that the animal models were useful in advancing human clinical outcomes, or substantially consistent with human outcomes, in only 2 of 20 studies, and the conclusion in 1 case was contentious 7 reviews failed to demonstrate reliable predictivity of human toxicological outcomes such as carcinogenicity and teratogenicity - Knight.- Knight. Altern Lab Anim,Altern Lab Anim, 2007.2007. - Knight.- Knight. Rev Recent Clin Trials,Rev Recent Clin Trials, 2008.2008.
  28. 28. Causes: 1. Interspecies differences  Altered susceptibility to and progression of diseases  Differing absorption, tissue distribution, metabolism, and excretion of pharmaceutical agents and toxins  Differences in the toxicity and efficacy of pharmaceuticals
  29. 29.  Loss of biological variability or predictivity resulting from the use of in-bred strains, young animals, restriction to single genders, and inadequate group sizes.  Lack of comorbidities (concurrent illnesses) or other human risk factors.  Physiological or immunological distortions resulting from stressful environments and procedures.
  30. 30. 2. Stressful environments and protocols Most laboratory animals spend most of their lives in small, relatively barren cages. A review of 110 studies from the biomedical literature revealed the outcomes: - Balcombe- Balcombe et al. Lab Animet al. Lab Anim 20062006 Impacts of laboratory housing
  31. 31.  Deleterious neuroanatomical, psychological (eg, stereotypical behaviour) and physiological effects  Distortion of many subsequent scientific results  Even so-called ‘enriched’ environments fail to ameliorate most of these deficits - Balcombe- Balcombe et al. Lab Animet al. Lab Anim 20062006
  32. 32. Impacts of common procedures All common laboratory species suffer marked stress, fear and possibly distress (indicated by the distortion of a broad range of physiological parameters) when subjected to:  Handling  Blood sampling  Gavaging (insertion of an esophageal tube for the oral administration of test compounds — a common procedure in toxicity studies) - Balcombe- Balcombe et al. Contemporary Topics Lab Anim Sciet al. Contemporary Topics Lab Anim Sci 20042004
  33. 33. Animals do not readily habituate to these procedures over time. This stressful alteration of normal physiological parameters also predisposes to a range of pathologies and distorts scientific results. - Balcombe- Balcombe et al. Contemporary Topics Lab Anim Sciet al. Contemporary Topics Lab Anim Sci 20042004
  34. 34. 3. False positive results of chronic high dose rodent studies  Overwhelming of natural physiological defences such as epithelial shedding, inducible enzymes, DNA and tissue repair mechanisms, which effectively protect against many naturally occurring toxins at environmentally relevant levels  Differences in rodent physiology when compared to humans, e.g.: increased metabolic and decreased DNA excision repair rates
  35. 35.  Unnatural elevation of cell division rates during ad libitum (‘at will’) feeding studies  Variable, yet substantial, stresses caused by handling and restraint, and frequently stressful routes of administration, and subsequent effects on hormonal regulation, immune status and disease predisposition
  36. 36. 4. Poor methodological quality of animal experiments  At least 11 systematic reviews demonstrated the poor methodological quality of many of the animal experiments examined  None demonstrated good methodological quality of a majority of experiments
  37. 37. Common deficiences Lack of: sample size calculations sufficient sample sizes randomised treatment allocation blinded drug administration blinded induction of injury (ischaemia in the case of stroke models) blinded outcome assessment conflict of interest statements
  38. 38. Conclusions  Historical and contemporary paradigm:  Animal models are fairly predictive of human outcomes.  Provides the basis for their widespread use in toxicity testing and biomedical research aimed at developing cures for human diseases.  However, their use persists for historical and cultural reasons, rather than because they have been demonstrated to be scientifically valid.  E.g., many regulatory officials “feel more comfortable” with animal data (O’Connor 1997).  Some even believe animal tests are inherently valid, simply because they are conducted in animals (Balls 2004).
  39. 39.  However, most systematic reviews have demonstrated that animal models are insufficiently predictive of human outcomes to offer substantial benefit during the development of clinical interventions, or during human toxicity assessment.  Consequently, animal data may not be generally assumed to be useful for these purposes.
  40. 40. 3Rs alternatives  Replacement  Reduction  Refinement  (Recycling?)  (Rehabilitation)
  41. 41. Replacement alternatives Mechanisms to enhance sharing and assessment of existing data, prior to conducting further studies.
  42. 42. Physicochemical evaluation and computerized modelling, including the use of structure-activity relationships, and expert systems. Allow predictions about toxicity and related biological outcomes, such as metabolic fate.
  43. 43. Minimally-sentient animals from lower phylogenetic orders, or early developmental vertebral stages, as well as microorganisms and higher plants.
  44. 44. A variety of tissue cultures, including immortalised cell lines, embryonic and adult stem cells, and organotypic cultures.
  45. 45.  In vitro assays (tests) utilising bacterial, yeast, protozoal, mammalian or human cell cultures exist for a wide range of toxic and other endpoints. These may be static, or perfused, and used individually, or combined within test batteries.  Human hepatocyte (liver cell) cultures and metabolic activation systems offer potential assessment of metabolite (a product of metabolism, usually by the liver) activity — a very important consideration when assessing toxicity.
  46. 46. cDNA microarrays (‘gene chips’) allow assessment of large numbers of genes simultaneously. This may allow genetic expression profiling (detection of up- or down-regulation of genes, caused by exposure to test compounds). This can increase the speed of toxin detection, well prior to more invasive endpoints.
  47. 47. The safety profile and predictivity for diverse human patient populations of clinical trials should be improved using microdosing, biomarkers, staggered dosing, more representative test populations, and longer exposure periods
  48. 48.  Surrogate human tissues and advanced imaging modalities  Human epidemiological, psychological and sociological studies  Particularly when human tissues are used, non-animal models may generate faster, cheaper results, more reliably predictive for humans, yielding greater insights into human biochemical processes
  49. 49. Reduction alternatives  Improvements in experimental design and statistical analysis; particularly, adequate sample sizes.  Minimising animal numbers without unacceptably compromising statistical power, through decreasing data variability:  Environmental enrichment, aimed at decreasing physiological, psychological or behavioural variation resulting from barren laboratory housing and stressful procedures.  Choosing, where possible, to measure variables with low inherent variability.  Genetically homogeneous (isogenic or inbred) or specified pathogen-free animal strains.  Screening raw data for obvious errors or outliers.
  50. 50.  Meta-analysis (aggregation and statistical analysis of suitable data from multiple experiments). For some purposes, treatment and control groups can be combined, permitting group numbers to be minimised.
  51. 51. Refinement alternatives  Analgesics and anaesthetics. (Around 60% of UK procedures are conducted without anaesthetics). While such drugs undoubtedly alter normal physiology, claims that such alterations are sufficiently important to hypotheses under investigation, to warrant their exclusion, require careful scrutiny.
  52. 52.  Non-invasive imaging modalities.  Telemetric devices to obtain information remotely.  Faecal analysis (e.g. faecal cortisol monitoring).  Training animals (especially primates) to participate (e.g. presenting arms for blood-sampling), rather than using physical or chemical restraint.  Environmental enrichment.  Socialisation opportunities.
  53. 53. Increasing 3Rs compliance  Technology reproducibility and transfer: increased methodology description, e.g., via publicly-accessible databases, linked to scientific articles.  Redirection of public funds from animal modelling to alternatives development/implementation.
  54. 54.  Increased 3Rs compliance should be necessary for research funding, ethics committee approval, and publication of results. Would require education and cooperation of funding agencies, ethics committees and journal editors about the limitations of animal models, and the potential of alternatives.  National centres for the development of alternative methods.  Scientific recognition: awards, career options.
  55. 55.  Greater selection of test models more predictive of human outcomes  Increased safety of people exposed to chemicals that have passed toxicity tests  Increased efficiency during the development of human pharmaceuticals and other therapeutic interventions  Decreased wastage of animal, personnel and financial resources. Likely benefits
  56. 56. The scientific and logistical limitations incurred by the use of animal models of humans within biomedical research and toxicity testing are substantial, and increasingly recognized. So is social concern about, and consequent regulatory restriction of, laboratory animal use. In defiance of these factors, such use remains enormous. Increased use of GM animals, and the implementation of large-scale chemical testing programs, are increasing laboratory animal use internationally. Conclusions
  57. 57. These trends clearly demonstrate the need for considerably greater awareness of, and compliance with, the principles of the 3Rs. These principles are universally recognized as essential to good laboratory animal practice, for animal welfare-related and ethical reasons, and also, to increase the quality of the research, and the robustness of subsequent results.
  58. 58. Policy reforms: 1. Animals protected Regulatory protection should be based on current scientific knowledge about: neuroanatomical architecture cognitive, psychological, and social characteristics consequent capacity for suffering in laboratory environments and protocols.
  59. 59. Sufficient scientific evidence exists to warrant the protection of: all living vertebrates advanced larval forms and foetal developmental stages certain invertebrates such as cephalopods
  60. 60. Similar protection is warranted for: animals used to develop or maintain GM strains bred for organ or tissue harvesting bred or intended for laboratory use, including those killed when surplus to requirements
  61. 61. 2. Species and procedures associated with high welfare risks Primate sourcing and use Terminal or surgical procedures Major physiological challenges The production of GM animals Procedures resulting in pain, suffering, or distress likely to be severe or long-lasting
  62. 62. 3. Scrutiny of animal use Independent scientific and public scrutiny of proposed protocols Independent ethical review
  63. 63. Directive 2010/63/EU on the protection of animals used for scientific purposes ‘It is essential, both on moral and scientific grounds, to ensure that each use of an animal is carefully evaluated as to the scientific or educational validity, usefulness and relevance of the expected result of that use.’ ‘The likely harm to the animal should be balanced against the expected benefits of the project.’
  64. 64. Thorough searches for replacement, reduction, and refinement methodologies Where scientifically suitable alternatives are identified, they should be used
  65. 65. 4. Retrospective evaluation To assess the degree to which experimental objectives were successfully met The extent to which animals suffered To inform future research strategy Future experimental licensing decisions Minimise unwarranted experimental duplication
  66. 66. Cited studies: www.AnimalExperiments.info Thank you for your attention! www.Palgrave.com

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