Introduction to Toxicity Testing

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Introduction to Toxicity Testing

• Emily McIvor
• EU Policy Co-ordinator
• European Coalition to End Animal Experiments
• ECEAE.org

Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels
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Safety Testing Integral to wide range of EU
legislation, including

• Cosmetics
• Detergents
• Chemicals
• Pesticides
• Biocides
• Novel foods
• Food additives
• Vitamins and food supplements
• Traditional and herbal medicines
• Veterinary medicines
• Pharmaceuticals

Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels
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Chemicals Testing in Context EU Animal
Experiments in 2002

• Total number 10.7 million
• Diagnosis of disease 2.12
• Production and control of veterinary medicine
  2.42
• Education and training 3.2
• Other 5.7
• Toxicological and other safety evaluation 9.93
• Production and control of human medicine 13.6
• RD pharmaceutical/veterinary medicine 28.4
• Fundamental biology studies 34.7

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Human Health Effects

• Skin corrosion (in vitro)
• Skin irritation (rabbit14 days)
• Eye irritation (rabbit 21 days)
• Skin sensitisation (guinea pig)
• Mutagenicity (rodent)
• Acute toxicity (oral/dermal/inhalation
  rodents)
• Repeat dose toxicity (rodent oral/dermal/inhalatio
  n28 day)
• Sub-chronic toxicity (oral/dermal/inhalation/roden
  t/non-rodent
• 90 day)
• Chronic toxicity (rodent minimum 12 months)
• Developmental toxicity (rodent/non-rodent)
• Two generation repro-tox (rodent)
• Carcinogenicity (rodent life-time)
• Toxicokinetics (rodent)

Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels
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How many vertebrate animals?(human health
and ecotoxicity testing)REACH Commission
estimate 1.3 - 3.9 million 3,000 HPV chemicals
full animal test data set 27.1 millionEach
HPV chemical (full animal test data set) 1,500
7,000 Based on the worst case scenario
assumptions that1. No existing information is
brought forward, resulting in new testing for
each required endpoint.2. Testing is performed
according to conventional OECD guidelines.3. All
chemicals are tested individually rather than in
groups of structurally similar compounds.
Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels
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Test methods Overview

• Toxicity tests are classified according to
• The length of dosing from acute studies lasting
  up to a few days to chronic studies spanning the
  lifetime of a test species.
• The route of administration ingested,
  intravenous, oral, dermal, ocular or inhaled.
• The end-point being studied which may be death,
  appearance of a tumour, effects on reproduction
  or development, allergic sensitisation, or a
  neurotoxic or behavioural effect.
• Animals are exposed via gavage (tube to
  stomach)/injection to stomach or under
  skin/application to eye or skin/inhalation.
• No pain relief is given.

Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels
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Problems with animal tests . . .

• Outdated rooted in 19th century science
• Slow US National Toxicology Program 36 years
  to achieve results for only 500 chemicals in
  rodent cancer study
• EU Existing Substances Regulation 2 years to
  complete dossier evaluation.
• Expensive animal cancer study around 2m
• Frequently irrelevant extrapolation animals to
  people and lab doses to real life exposure can be
  used to call for more information rather than
  regulatory action.
• Typically do not measure effects of mixtures.
• Not validated would animal tests satisfy modern
  validation standards?

Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels
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Single chemical tests / multiple chemical exposure

• Animal based toxicity tests are carried out on
  single test chemicals but exposure is rarely to a
  single substance.
• Chemicals can act together in different ways, but
  these variations are not predicted using animal
  tests
• Independent produce different effects or have
  different modes of action.
• Additive the chemicals behave in similar ways,
  so that the effects or responses produced by the
  chemicals add to each other in a simple way.
• Synergistic the mode of action might enhance
  the effect of the other.
• Antagonistic the result of a chemical
  counteracting the adverse effect of another.

Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels
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Size/doses/length of real-life exposure

• Lab animals are small and have short life-spans.
• Lab doses are usually large (for test animal body
  weight), and applied over short periods, whereas
  real-life exposure in people is small, over long
  periods.
• Species frequently have different ways of
  metabolising and excreting chemicals.

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Case Study Bisphenol A

• Animal tests have been conduced on Bisphenol A
  since the 1940s. Hundreds of studies exist.
• In 1986, on the basis of 90 day repeat dose
  tests in rats, a safe daily intake was
  calculated.
• Bisphenol A is currently suspected of causing
  endocrine disrupting effects, but animal tests
  are failing to clarify the situation three
  different breeds of rats react differently to the
  chemical
• The evidence is that there can be as much as a
  1,000 fold, or greater range of responses to
  these chemicals in different strains of mice.
  The regulatory default assumption of a ten-fold
  correction or safety factor for genetic
  variability is completely out of touch with the
  data. (Professor Frederick vom Saal. Nature,
  409274.)

Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels
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Case study two brominated flame retardants

• PBDEs have widely contaminated the environment,
  are persistent and readily accumulate in animal
  tissues.
• Levels of PBDEs in human breast milk have risen
  exponentially since 1972, doubling every five
  years.
• Human occupational studies indicate effects on
  the thyroid and on neurological function.
• PBDEs have been subjected to several animal tests
  which suggest thyroid toxicity, cancers and
  neurodevelopmental effects but the Swedish
  National Food Administration said it is not
  known what these observations of altered
  spontaneous activity in neonatal mice means in
  terms of human risk assessment.
• Precautionary action needed animal tests have
  failed.

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Regulatory use of animal toxicity tests

• Animal testing seems at present to be the best
  approach to answering some questions about
  toxicity, but it seems to stand in the way of
  reasonable progress. Ways of avoiding animal
  testing must be sought.
• (UK) Royal Commission on Environmental Pollution
• 24th Report Chemicals in Products, June 2003.

Roundtable on Alternatives to Animal Testing
28 February 2005 European Parliament, Brussels