ANIMAL TESTING

1
ANIMAL TESTING

• A Placebo for our Conscience?

2

• The case for animal testing is now being
  directly challenged by scientists and doctors and
  their judgement must be taken seriously. Tony
  Benn 2004

3

• Uncritical reliance on the results of animal
  tests can be dangerously misleading and has cost
  the health and lives of tens of thousands of
  humans.
• Handbook of Laboratory Animal Science 1994

4

• The Advertising Standards Agency (ASA) recently
  ruled that the statement Some of the major
  advances in the last century would have been
  impossible without animal research is misleading
  and shouldnt be repeated

5
Structure

• Where did vivisection come from?
• The Law
• Medical Research Explored
• Historical Impact of Animal Experimentation
  Exploding the Myths
• Drug Disasters
• Humans vs Animals Wheres the Difference?
• Scientific Limitations
• Risks of Animal Experimentation
• Introduction to Alternative Methods
• Why does Vivisection Persist?
• Need for an Independent Scientific Evaluation
• EDM 92
• Vivisection at Durham
• Next Meeting Primate research, Alternative
  methods explored

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Where did vivisection come from?

• From a history of misconceptions
• 2nd century AD, papal decree forbade autopsy, so
  animal experiments became the norm
• In the 1600s 1800s we knew little about
  physiology, one could learn basic things from
  animals
• Today our studies are at the molecular level
  where the differences between species are
  greatest

7

• 10.7 million animals used in experiments across
  Europe every year
• 2.9 million animals in the UK

8
The Law

• The 7th amendment of the EU Cosmetics Directive
  bans the testing of cosmetics by 2013, although
  it is already banned in the UK
• REACH (registration, evaluation, authorisation,
  and restriction of chemicals) came into force
  last June, industry to spend 3 billion reviewing
  the safety of over 30 000 chemicals in use across
  Europe (8 million extra animals to endure
  chemicals toxicity testing)
• Ever since Thalidomide drug disaster, medical
  pre-clinical testing on animals has been
  mandatory

9
Medical Research explored

• Some disturbing facts
• Animals predict correctly for humans only 5-25
  of the time
• 92 of new drugs fail in clinical trials, after
  passing all the safety tests in animals (FDA
  2004)
• Over half of the 8 which do gain FDA approval
  must later be withdrawn or relabeled due to
  severe, unexpected side effects (FDA 1990)

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Historical Impact of Animal Experimentation
Exploding the Myths

• Correlation between cigarette smoking and lung
  cancer had already been shown in human patients
  by 1963, experimenters failed to produce lung
  cancer in animals
• Clarence Little concluded The failure of many
  investigators to induce experimental cancers,
  except in a handful of cases, during fifty years
  of trying, casts serious doubt on the validity of
  the cigarette-lung cancer theory (1957133)
• Health warnings delayed for years

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• Correlation between asbestos and cancer shown in
  human clinical investigation by 1940s
• Animal models failed to demonstrate this,
  workplace precautions not instituted in the US
  until decades later
• Correlation between alcohol consumption and
  cirrhosis
• failed in all nonhuman animals except baboons,
  although with inconsistent data

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• Development of surgery to replace clogged
  arteries with patients own veins was impeded by
  dog experiments, indicated that veins couldnt be
  used
• Deep brain stimulation in Parkinsons disease and
  dystonia was pioneered in patients, not monkeys
• Anaesthesia was discovered through
  self-experimentation in the 1800s

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POLIO

• Polio virus discovered in human intestines as
  early as 1912, suggesting entrance through
  digestive tract
• Animal model resulted in misunderstanding of
  mechanism of infection
• Monkeys indicated that the virus was transmitted
  via a respiratory, rather than digestive route
• Delayed development of tissue culture
  methodologies critical to discovery of vaccine
• It was research with human cell cultures which
  first showed that the virus could be cultivated
  on non-neural tissue
• 1941 Dr. Albert Sabin studies of human
  autopsies, made same discoveries as had been made
  30 years earlier, prevention was long delayed
  by the erroneous conception of the nature of the
  human disease based on misleading experimental
  models of the disease in monkeys (1984)
• Still monkey tissue was used to produce the
  vaccine
• Infected 204 people with polio, 11 documented
  deaths, at least one virus jumped the species
  barrier as a result
• Now grown on human diploid-cell culture

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PENICILLIN

• In 1929, Fleming observed penicillin as it killed
  bacteria in a Petri dish when he administered
  the compound to bacteria-infected rabbits it
  didnt happen
• Drug was set aside for a decade
• Years later, he administered the drug to a dying
  patient and it performed a miracle
• Later admitted that misleading results from
  animal testing almost prevented discovery of the
  entire field of antibiotics

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INSULIN

• Insulin harvested from slaughterhouses saved the
  lives of many diabetics true
• BUT, physicians in the late 18th C first linked
  the disease with characteristic changes in the
  pancreas seen at autopsy
• Difficult to reproduce in animals, so many
  scientists disputed the pancreas role in the
  disease
• Animal research led researchers to believe
  diabetes was a liver disease, delaying research
  for decades
• In vitro research had isolated insulin not
  animal experiments

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INSULIN (cont.)

• Insulin from slaughterhouses wasnt without
  complications (allergic reactions etc)
• Insulin is only a treatment, not a cure

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CANCER research

• Number one killer in the UK
• Animal cancer is not the same as human cancer
• Cancer is many diseases, 200 different forms in
  humans alone
• 46 of chemicals found to be carcinogenic in rats
  werent carcinogenic in mice
• 19 out of 20 compounds safe for humans caused
  cancer in animals
• Cancer occurs on the cellular level where we
  differ from animals

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CANCER research (cont.)

• The history of cancer research has been a
  history of curing cancer in the mouse We have
  cured mice of cancer for decades and it simply
  didnt work in humans Dr. Richard Klausner,
  director of the US National Cancer Institute
• Treatments for cancers have come from
  serendipity, clinical observation, computer and
  mathematical modelling etc.
• Dr. Irwin Bross, former Director of the worlds
  largest cancer research institute while
  conflicting animal results have often delayed and
  hampered advances in the war on cancer, they have
  never produced a single substantial advance in
  either the prevention or treatment of human
  cancer

19
AIDS research

• Inability to produce an adequate animal model
  animals do not develop the human AIDS syndrome!
• Blood from HIV-infected patients remains most
  illuminating research material to date
• Through epidemiology and in vitro research,
  scientists have already isolated the human gene
  believed responsible for their immunity, defined
  the diseases natural course and identified risk
  factors
• Aidsvax was tested on 8000 high-risk volunteers,
  had protected chimpanzees from HIV infection, but
  afforded no protection to human patients
• Since 1987, more than 100 clinical trials have
  been funded by the US National Institute of
  Allergy and Infectious Disease but every one of
  the more than 50 preventive vaccines and more
  than 30 therapeutic vaccines that were successful
  against HIV/AIDS in primate studies failed in
  human clinical trials

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Toxicity Testing

• Highly unreliable LD50 test, how much of a drug,
  chemical or household product is needed to kill
  50 of a group of test animals (usually rodents)
• Inconsistencies between species, ages, sex,
  weight etc of the animals
• In vitro tests have been validated to replace
  LD50 (deleted from test guidelines of the OECD in
  2002)
• Draize eye irritancy test humans and rabbits
  differ in structure of eyelids, corneas and
  ability to produce tears
• Differ by factor of 18-250
• In vitro tests would be less expensive and far
  more accurate

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• Rodent carcinogenicity studies, false positive
  rate of rodent testing when applied to human
  cancer causation as high as 95
• Study of 500 rodent carcinogenicity studies
  concluded that rodent cancer assays are
  scientifically invalid and fiscally indefensible
• U.S. National Cancer Institute (NIC) replaced
  animal testing by 1990, using a panel of about
  100 human cell lines to screen compounds for
  carcinogenicity

22

• Teratogens (causing birth defects) - Jarrod
  Bailey et al. study of animal tests of 1396
  different substances
• of those known to cause birth defects in humans,
  animal tests indicated that almost half were
  safe, and of those known to be safe in humans,
  animal tests indicated half were dangerous
• Almost 1/3 of all substances tested yielded
  varying results, depending on the species

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Karnofskys Law

• Any substance can be teratogenic (cause birth
  defects) if given to the right species, at the
  right stage in development, and in the right dose
• The great majority of perinatal toxicological
  studies seems to be intended to convey medical
  and legal protection to the pharmaceutical houses
  and political protection to the official
  regulatory bodies, rather than produce
  information that might be of value in human
  therapeutics. Dr. D.F. Hawkins (1983)

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Genetic Diseases

• Genetic diseases reflect interactions between
  defective gene and other genes of the environment
  
• Nearly all models have failed to reproduce the
  essential features of the analogous human
  conditions Lee T. (1993) Gene Future. New York
  Plenum Press.
• Differences in metabolic pathways between species
  especially important

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DRUG DISASTERS

• Drug related problems caused twice as many
  hospital admissions as motor vehicle accidents in
  the Netherlands (www.bmj.com, 15th Dec. 2006)
• Adverse drug reactions are the UKs fourth
  leading cause of death, killing over 10 000
  people a year, costing the NHS 466 million

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Drug Disasters of the Last Century

• Thalidomide
• Introduced in late 1950s to reduce morning
  sickness in pregnant women
• Caused an estimated 10 000 birth defects and
  thousands of fetal deaths worldwide
• The drug had previously been proven safe in
  animal test, but ironically its failure in
  humans resulted in pre-clinical animal testing
  becoming mandatory
• Tony Benns wife was offered Thalidomide but
  refused, today we have Hilary Benn

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• Vioxx
• Arthritis drug, good for the heart in animal
  tests but cost the lives of 140 000 people, 320
  000 heart attacks, strokes and cases of heart
  failure worldwide in total
• Previously shown to be safe in monkeys at 500
  times the dose
• Withdrawn from the market in 2004
• the single greatest drug safety catastrophe in
  the history of this country or the history of
  this world David Graham (Associate Director
  for Science and Medicine in the Office of Drug
  Safety at the FDA)

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• TGN 1412
• wonder drug, anti-inflammatory, proven safe in
  monkeys at 500 times the dose
• 2006 Northwick Park Hospital disaster, left 6
  young men fighting for their lives, suffered
  terrifying effects on their immune system
• This led Prof. Colin Blakemore (recently denied
  knighthood because of his outspoken support for
  vivisection) to claim that testing on monkeys was
  ever more important
• Some however have concluded that animal tests
  provided a false sense of security and call for
  an overhaul of drug safety testing requirements
  and clinical trial design

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HUMANS vs ANIMALS wheres the difference?

• All animal cells have properties in common but
  smaller idiosyncracies distinguish the way the
  cells of different species react to food,
  environment and medicines
• It is not DNA make-up that is the deciding
  factor, rather it is DNA expression
• Even human monozygotic twins display different
  drug responses!

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Scientific Limitations of Animal Models

• Human clinical investigation is the only way
  hypotheses about human physiology or pathology
  can be tested
• Medical Research Modernization Committees review
  of 10 randomly chosen animal models of human
  diseases didnt reveal any important
  contributions to human health Kaufman, SR.,
  Reines, BP., Casele, H.,Lawson, L., Lurie, J.
  (1991) Animal models of degenerative
  neurological diseases. Perspectives on Medical
  research. 3. 9-48
• Researchers tend to investigate those aspects of
  an animals condition that resemble features of
  the human disease, generally ignoring or
  discounting fundamental anatomical, physiological
  and pathological differences

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• Vivisection involves manipulations of
  artificially induced conditions, laboratory
  environment influenced pulse, blood pressure,
  hormone levels, immunological activities etc
• Many laboratory discoveries reflect mere
  laboratory artefact
• e.g. treatment of stroke Ultimately, the
  answers to many of our questions regarding the
  underlying pathophysiology and treatment of
  stroke do not lie with continued attempts to
  model the human situation more perfectly in
  animals, but rather with the development of
  techniques to enable the study of more basic
  metabolism, pathophysiology and anatomical
  imaging detail in living humans. Wiebers et
  al. 1990.

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Gene Therapy

• Since 1990, several hundred gene therapies that
  were successful in animal studies have been
  tested on thousands of patients worldwide
• Only 1 (for children with the severe immune
  system disorder X-SCID) appears to have succeeded
• However 3/10 of the treated children developed
  leukemia and 1 died
• US FDA halted several gene therapy trials in 2005
  because of these unexpected side effects

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• The Handbook of Laboratory Animal Science
  (19946)
• It is impossible to give reliable general rules
  for the validity of extrapolation from one
  species to another. (This) can often only be
  verified after the first trials in the target
  species (humans). Extrapolation from animal
  models will always remain a matter of
  hindsight.

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Risks of Animal Experimentation

• Through vivisection humans exposed to wide
  variety of deadly nonhuman primate viruses
• 16 lab workers killed by Marburg virus and other
  monkey viruses
• 2 outbreaks of Ebola occurred in American monkey
  colonies
• Polio vaccines grown on monkey kidney cells
  exposed millions to the simian virus 40, found in
  several human cancers
• AIDS epidemic HIV-1 (principal AIDS virus)
  differs markedly from all other viruses found in
  nature, evidence that it originated either
  through polio vaccine production using monkey
  tissues or through manufacture in American labs
  (cancer and bio-weapons research in 1970s) Hooper
  1999 Reinhardt, V. and Roberts, A. 1997
  Horowitz, LG 1996.
• Risks of xenotransplants (from pigs or primates)

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ALTERNATIVES

• In vitro (test tube) research instrumental in
  discovery of antibiotics, the structure of DNA,
  and many modern vaccines (polio, meningitis)
• Epidemiology (population research) revealed
  that folic acid deficiency causes birth defects,
  that smoking causes lung cancer and that lead
  damages childrens brains
• Post-mortem studies
• Genetic research DNA chips allow doctors to
  prescribe the right drug for specific patients
• Clinical studies given us most of our current
  treatments and cures
• Human tissue e.g. Episkin and Epiderm
  sophisticated 3D reconstructions of human skin,
  grown from human cells

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• Computer modelling virtual human organs,
  virtual metabolism programmes
• Technological advances MRI and PET scanners,
  ultrasound, laser surgery, cochlear implants,
  laparascopic surgery, artificial organs,
  pacemakers
• Human stem cells already treated children with
  leukemia
• Microdosing by 2012, 90 of pharmaceutical
  companies plan to use microdosing (Wilkinson
  2007) and the European Medicines Agency (EMEA,
  London 2004) and the US Food and Drug
  Administration (FDA 2006) support its use to
  reduce the time, cost and risks associated with
  developing new drugs
• Alternatives are being developed. And they are
  being properly validated, which is more than can
  be said for animal testing methods!...

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Why does Vivisection Persist?

• The Law
• important legal sanctuary, pre-clinical testing
  is mandatory
• It is easily published
• in academic science it is easier to take an
  animal model, change a variable or species, and
  obtain new interesting findings clinical
  research is more difficult, expensive and
  time-consuming.
• Sheer number of species available and infinite
  possible manipulations allows researchers
  opportunity to prove almost any theory that
  serves their economic, professional or political
  needs (most evident in research on the effects of
  smoking cigarettes)
• It is self-perpetuating
• Scientists are tied to grants, critical in grant
  applications is proof of prior experience and
  expertise

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• It is lucrative
• Respected place in modern medicine resulting in
  secure financial support, esp. at universities
• It appears more scientific than clinical
  research
• Researchers assert that lab experiments are
  controlled because they can change one variable
  at a time completely ignores individual
  physiology and pathology of animal and effect of
  lab setting (stress etc)

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Need for independent Scientific Evaluation

• House of Lords Select Committee report concluded
  (UK 2002) that all sides of the debate on animal
  procedures say that animals are highly imperfect
  models. It will be for the benefit of science,
  and ultimately of human health, if better methods
  of research and testing could be developed
• Toxicology Working Group of the House of Lords
  Select Committee on Animals in Scientific
  Procedures in 2002 recommended that the
  reliability and relevance of all existing animal
  tests should be reviewed as a matter of urgency
• 83 of 500 GPs that were interviewed in an
  independent survey in 2004 would support an
  independent scientific evaluation of the clinical
  relevance of animal experimentation

40

• Last UK Government came to power promising Royal
  Commission on Animal Experimentation
• However UK Gov has not commissioned or evaluated
  any formal research on the efficacy of animal
  experiments and has no plans to do so (Home
  Office Minister Caroline Flint 2004)

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EDM 92

• "That this House, in common with Europeans for
  Medical Progress, expresses its concerns
  regarding the safeguarding of public health
  through data obtained from laboratory animals,
  particularly in light of large numbers of serious
  and fatal adverse drug reactions that were not
  predicted by animal studies is concerned that
  the Government has not commissioned or evaluated
  any formal research on the efficacy of animal
  experiments, and has no plans to do so and, in
  common with 83 per cent of general practitioners
  in a recent survey, calls upon the Government to
  facilitate an independent and transparent
  scientific evaluation of the use of animals as
  surrogate humans in drug safety testing and
  medical research."

42

• Roberta Blackman-Woods has signed EDM 92, along
  with 249 other MPs
• The Research Defence Society opposes an
  independent comparison of animal tests with the
  latest human-based tests for drug safety
• What are they afraid of??

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Vivisection at Durham

• Many of the worlds major medical breakthroughs
  have been thanks to many years of
  scientific work carried out with animals which
  share many genes and diseases with humans. Animal
  testing is usually the only option for testing
  treatments are safe before progressing to
  clinical trials in humans. Professor Chris
  Higgins, Vice Chancellor and Warden, Durham
  University
• http//www.dur.ac.uk/resources/about/AnimalR
  esearchatDurhamUniversity.pdf

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Chris Higgins

• Himself graduated from Durham with degree in
  Botany in 1976 and PhD in 1979
• Previously lead establishment of new research
  laboratories for ICRF (now Cancer Research UK) at
  the Institute of Molecular Medicine, and was
  recruited by the Medical Research Council as
  Director in 1998
• Recently compared Colin Blakemore (scientists
  denied knighthood because of outspokenness in
  favour of animal testing) with Nelson Mandela
  http//news.independent.co.uk/sci_tech/article3289
  238.ece

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• Durham has licences to carry out lab work on
  mice, rats, rabbits, fish, and frogs
• Random science journal search
• The effect of neonatal nerve crush on adult rat
  muscle spindles
• Operant hear-rate conditioning in the curarised
  rat
• Effect of application of carcinogenic substances
  on the epidermal cell populations of mouse skin
• The animals enjoy the highest levels of care
  from a dedicated team of qualified technical
  staff, in modern, hygienic rooms and controlled
  environmental conditions, with regular veterinary
  inspections. - Higgins

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Ethics Committee

• Scrutinises all projects involving animals at
  Durham
• Consists of scientists, people with animal care
  and veterinary expertise, lay members of the
  public
• Based on consensus (only when all are satisfied
  will proposals be approved)
• Duty to conduct all business of the Committee in
  a fair, proper, transparent and ethical manner.
  But chair and vice-chair are appointed in
  consultation with the vice-chancellor.

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Conclusions

• All methods face the difficulty of mimicking a
  whole living system, however the answer is
  unlikely to be found in studying the wrong
  system!
• Cancer Research UK We do trials in people
  because animal models do not predict what will
  happen in humans (Burltes 2006)