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June 20, 2008

Validation of Animal Tests

Humane Society International/Europe

Although some animal tests in use today were created nearly 80 years ago, most have never been formally validated (i.e., assessed in multiple laboratories to see if they reliably give the correct answers). However, there is a great deal of scientific evidence that some of the most common animal tests may be poor predictors of human effects. For example:

 Eye and skin irritation tests:

  • Among 281 cases of accidental human eye exposure to 14 household products, investigators with the US Food and Drug Administration determined that rabbit test results correctly predicted human responses less than half the time. [1]
  • Animal tests failed to correctly predict human skin reactions for nearly half of 65 consumer products examined. [2]
  • Excessively high variability in test results and interpretation between labs. A comparison of test results across 24 labs documented variability up to 100%. [3]

Acute toxicity tests (often conducted using oral, inhalation and skin routes):

  • Animal tests seriously underestimate human risk, as documented human sensitivity to some chemicals is as much as 2,000-times greater than in animals. [4]
  • Only 65 percent agreement between rat and mouse test results for the same 50 chemicals. [5]
  • “The information obtained from conventional acute toxicity studies is of little or no value in the pharmaceutical development process.” [6]

Birth defect tests (often conducted in both rats and rabbits):

  • Tests in both rats and rabbits failed to detect the developmentally toxic effects of PCBs, ACE-inhibiting drugs, and other substances, and rabbits gave false negative results for toluene, tetracycline, diethylstilboestrol (DES), and other drugs. [7]
  • Less than 74 precent agreement between rat, mouse and rabbit test results for the same chemicals. [8
  • Testing in a second animal species increases the already high rate of false positive results. [9]

Cancer tests (usually conducted in both rats and mice):

  • Failed to detect the hazards of asbestos, benzene, bromodichloromethane, cigarette smoke, dichlorovos, lindane, DDT, selenium sulfide, and many other substances, delaying consumer warnings and worker protection measures by decades in some cases. [10]
  • Only 50-70 percent agreement between rat and mouse test results for the same chemicals. [11]
  • Less than 60 percent agreement in the interpretation test results between labs for the same chemicals. [12]
  • Many biological mechanisms leading to cancer in rodents are irrelevant to humans (e.g., buildup of alpha 2u-globulin in the kidneys of male rats, peroxisome proliferation in rodent livers, calcium phosphate-containing urinary buildup in rats). [13]
  • Rodents possess cancer-prone organs for which there are no human equivalents (e.g., forestomach, Harderian gland, Zymbal’s gland). [14]
  • Animals are sometimes administered 100-times or more the equivalent human intake of a chemical (e.g., to consume the level of the pesticide Alar that was fed to rats and mice in one study would require eating 28,000 pounds of apples daily for 10 years). [15]
  • Commonly used strains of rats and mice are highly prone to spontaneous tumor development—even “control” animals who are not administered a test chemical—which confounds the interpretation of test results. [16]

As a direct consequence of the shortcomings cited above, pharmaceutical regulators have reported that fully 92% of drugs that pass preclinical (animal) testing fail clinical trials because animal studies so often “fail to predict the specific safety problem that ultimately halts development.” [17]

¹ Freeberg FE, Griffith JF, Bruce RD, et al. Correlation of animal test methods with human experience for household products. Journal of Toxicology – Cutaneous and Ocular Toxicology 1, 53-64 (1984). 
² Robinson MK, McFadden JP & Basketter DA. Validity and ethics of the human 4-h parth test as an alternative method to assess acute skin irritation potential. Contact Dermatitis 45, 1-12 (2001).
³ Weil CS & Scala RA. Study of intra- and interlaboratory variability in the results of eye and skin irritation tests. Toxicology and Applied Pharmacology 19, 276-360 (1971). 
4 Müller R. Vergleich der im Tierexperiment und beim Menschen tödlichen Dosen wichtiger Pharmaka. Diss. Univ. Frankfurt/Main (1948).
5 Ekwall B, Barile FA, Castano A, et al. MEIC evaluation of acute systemic toxicity. Part VI. The prediction of human toxicity by rodent LD50 values and results from 61 in vitro methods. Alternatives to Laboratory Animals 26 (Suppl. 2), 617-58 (1998).
6 Chapman K & Robinson S. Challenging the requirement for acute toxicity studies in the development of new medicines.  London: UK National Centre for the 3Rs (2007).
7 Schardein JL. Chemically Induced Birth Defects, 3rd Ed. Rev. New York: Marcel Dekker (2000).
8 Hurtt ME, Cappon GD & Browning A. Proposal for a tiered approach to developmental toxicity testing for veterinary pharmaceutical products for food-producing animals. Food and Chemical Toxicology 41, 611-19 (2003).
9 Bremer S, Pellizzer C, Hoffmann S, Seidle T & Hartung T. The development of new concepts for assessing reproductive toxicity applicable to large scale toxicological programmes. Current Pharmaceutical Design 13, 3047-3058 (2007).
10 Seidle T. Chemicals and Cancer: What the Regulators Won’t Tell You. London: PETA Europe Ltd (2006).
11 Gold LS & Slone TH. Prediction of carcinogenicity from two versus four sex-species groups in the carcinogenic potency database. Journal of Toxicology and Environmental Health 39, 143-57 (1993).
12 Gottmann E, Kramer S, Pfahringer B, et al. Data quality in predictive toxicology: Reproducibility of rodent carcinogenicity experiments. Environmental Health Perspectives 109, 509-14 (2001).
13 Cohen SM. Bioassay bashing is bad science: Cohen’s response. Environmental Health Perspecitves 110, A737 (2002).
14 Cohen SM. Human carcinogenic risk evaluation: an alternative approach to the two-year rodent bioassay. Toxicological Sciences 80, 225-9. (2004).
15 ACSH [American Council on Science and Health]. Of Mice and Mandates: Animal Experiments, Human Cancer Risk and Regulatory Policies. New York: ACSH (1997).
16 Haseman JK, Hailer RJ & Morris RW. Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a National Toxicology Program update. Toxicologic Pathology 26, 428-41 (1998).
17 FDA [Food & Drug Administration]. Challenge and Opportunity on the Critical Path to New Medical Products. Bethesda, MD: FDA (2004).

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