The Nuremberg Code subverts human health and safety by requiring animal modeling

BMC Medical Ethics

Lawrence A Hansen¹  Annalea Pippus²  Ray Greek² 

[1] Department of Neurosciences and Pathology, University of California, San Diego, Mail Code 062, 9500 Gilman Drive (MTF 351), La Jolla, CA, 92093-0624, USA;Americans For Medical Advancement, 2251 Refugio Rd, Goleta, CA 93117, USA

关键词: Species variation;    Nuremberg code;    Law;    Evolution;    Ethics;    Biological complexity;    Animal;   

Others  :  800038
DOI  :  10.1186/1472-6939-13-16

 received in 2012-02-12, accepted in 2012-05-14,  发布年份 2012

【 摘 要 】

Background

The requirement that animals be used in research and testing in order to protect humans was formalized in the Nuremberg Code and subsequent national and international laws, codes, and declarations.

Discussion

We review the history of these requirements and contrast what was known via science about animal models then with what is known now. We further analyze the predictive value of animal models when used as test subjects for human response to drugs and disease. We explore the use of animals for models in toxicity testing as an example of the problem with using animal models.

Summary

We conclude that the requirements for animal testing found in the Nuremberg Code were based on scientifically outdated principles, compromised by people with a vested interest in animal experimentation, serve no useful function, increase the cost of drug development, and prevent otherwise safe and efficacious drugs and therapies from being implemented.

【 授权许可】

   
2012 Greek et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Maehle A-H, Trohler U: Vivisection In Historical Perspective. edn. In Animal Experimentation from Antiquity to the End of the Eighteenth Century: Attitudes and Arguments. Edited by Rupke N. Croom Helm, London; 1987:14-47.
• [2]Elliot P: Vivisection in Historical Perspective. edn. In Vivisection and the Emergence of Experimental Medicine in Nineteenth Century France. Edited by Rupke N. Croom Helm, New York; 1987:48-77.
• [3]Wax PM: Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med 1995, 122(6):456-461.
• [4]Nuremberg Trial: United States v. Karl Brandt et al., "The Medical Case, Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10". U.S. Government Printing Office, Washington, D.C; 1949.
• [5]Taylor T: The Anatomy of the Nuremberg Trials: A Personal Memoir. Knopf, New York; 1992.
• [6]Annas GJ, Grodin MA: The Nazi Doctors and the Nuremberg Code. Oxford University Press, Inc., New York; 1992.
• [7]Harvard Law School Library: Nuremberg Trials Project. A Digital Document Collection. Introduction to NMT Case 1, U.S.A. v. Karl Brandt et al; [ http://nuremberg.law.harvard.edu/php/docs_swi.php?DI=1&text=medical - persons webcite]
• [8]American Medical Association: American Medical Association, Board of Trustees. In Minutes of the May 1946 meeting, (ACHRE No. IND-072595-A), 156–157. AMA Archive, Chicago, Illinois; 1946.
• [9]Moreno JD: Reassessing the Influence of the Nuremberg Code on American Medical Ethics. Journal of Contemporary Health Law and Policy 1997, 13(2):347-360.
• [10]American Medical Association: American Medical Association, Board of Trustees: 1946. In Minutes of the 19 September 1946 meeting, AMA Archive, Chicago, Illinois (ACHRE No. IND-072595-A), 51–52. AMA Archives, Chicago, IL; 1946.
• [11]Ivy AC: Report on War Crimes of a Medical Nature Committed in Germany and Elsewhere on German Nationals and the Nationals of Occupied Countries by the Nazi Regime during World War II," 1946. This report was not published, but it is available at the National Library of Medicine. A copy also exists in the AMA Archive (ACHRE No. DOD-063094-A). 1946.
• [12]Chapter 2: The American Expert, the American Medical Association, and the Nuremburg Medical Trial. [ http://www.hss.energy.gov/HealthSafety/ohre/roadmap/achre/chap2_2.html webcite]
• [13]WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. [ http://www.wma.net/en/30publications/10policies/b3/ webcite]
• [14]LaFrance AB: Bioethics and Animal Experimentation. Animal Law 1996, 2:157.
• [15]NIH: Regulations and Ethical Guidelines. Reprinted from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Vol. 2. U.S. Government Printing Office, Washington, D.C; 1949:181-182. [ http://ohsr.od.nih.gov/guidelines/nuremberg.html webcite]
• [16]The Law Pertaining to the Protection of Animals JAMA 1934, 102(7):551-552.
• [17]New Regulations Concerning Vivisection JAMA 1933, 101(14):1087-1088.
• [18]Fritzsche U: Animal experimentation in Nazi Germany. Hosp Pract (Off Ed) 1990, 16(4A):18.
• [19]Fritzsche U: Nazis and animal protection. Anthrozoös 1992, 5(4):218-219.
• [20]Kenny MG: A darker shade of green: medical botany, homeopathy, and cultural politics in interwar Germany. Soc Hist Med 2002, 15(3):481-504.
• [21]Orlowski V: Promising Protection Through Internationally Derived Duties. Cornell International Law Journal 2004, 36:381.
• [22]Food and Drugs Act (R.S.C., 1985, c. F-27). [ http://laws.justice.gc.ca/eng/acts/F-27/page-7.html - h-12 webcite]
• [23]Food and Drug Regulations (C.R.C., c. 870). [ http://laws-lois.justice.gc.ca/eng/regulations/C.R.C.,_c._870/page-296.html?term=regulations+drugs+food+drug - s-G.01.001 webcite]
• [24]Statutory Instruments Act (R.S.C., 1985, c. S-22). [ http://laws-lois.justice.gc.ca/eng/acts/S%2D22/ webcite]
• [25]Table IV: Number of Animals Used in 2009 by Participants in the CCAC Program according to Purpose of Animal Use and the Category of Invasiveness. http://www.ccac.ca/en_/publications/audf/stats-aud/table-IV/2009 webcite]
• [26]US Food and Drug Administration: International Conference on Harmonisation; Draft Guidance on M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Fed Regist 73(ed. HHSs):51491-2. [ http://www.fda.gov/cder/guidance/8500dft.htm webcite]
• [27]Paul JR: A History of Poliomyelitis. Yale University Press, New Haven; 1971.
• [28]Ehrlich P, Hata S: Die experimentalle Chemotherapie der Spirillosen. Springer, Berlin; 1910.
• [29]Mayr E: What evolution Is. Basic Books 2002.
• [30]LaFollette H, Shanks N: Animal Experimentation: The Legacy of Claude Bernard. Int Stud Philos Sci 1994, 8(3):195-210.
• [31]Bernard C: An Introduction to the Study of Experimental Medicine. Dover, New York; 1957. (1865)
• [32]Cheung DS, Warman ML, Mulliken JB: Hemangioma in twins. Ann Plast Surg 1997, 38(3):269-274.
• [33]Couzin J: Cancer research. Probing the roots of race and cancer. Science 2007, 315(5812):592-594.
• [34]Gregor Z, Joffe L: Senile macular changes in the black African. Br J Ophthalmol 1978, 62(8):547-550.
• [35]Haiman CA, Stram DO, Wilkens LR, Pike MC, Kolonel LN, Henderson BE, Le Marchand L: Ethnic and racial differences in the smoking-related risk of lung cancer. N Engl J Med 2006, 354(4):333-342.
• [36]Spielman RS, Bastone LA, Burdick JT, Morley M, Ewens WJ, Cheung VG: Common genetic variants account for differences in gene expression among ethnic groups. Nat Genet 2007, 39(2):226-231.
• [37]Stamer UM, Stuber F: The pharmacogenetics of analgesia. Expert Opin Pharmacother 2007, 8(14):2235-2245.
• [38]Wilke RA, Dolan ME: Genetics and variable drug response. JAMA: The Journal of the American Medical Association 2011, 306(3):306-307.
• [39]Holden C: Sex and the suffering brain. Science 2005, 308(5728):1574.
• [40]Kaiser J: Gender in the pharmacy: does it matter? Science 2005, 308(5728):1572.
• [41]Simon V: Wanted: women in clinical trials. Science 2005, 308(5728):1517.
• [42]Wald C, Wu C: Of Mice and Women: The Bias in Animal Models. Science 2010, 327(5973):1571-1572.
• [43]Willyard C: HIV gender clues emerge. Nat Med 2009, 15(8):830.
• [44]LaFollette H, Shanks N: Animal models in biomedical research: some epistemological worries. Public Aff Q 1993, 7(2):113-130.
• [45]LaFollette H, Shanks N: Brute Science: Dilemmas of animal experimentation. Routledge, London and New York; 1996.
• [46]Shanks N, Greek R: Animal Models in Light of Evolution. Brown Walker, Boca Raton; 2009.
• [47]Shanks N, Greek R, Greek J: Are animal models predictive for humans? Philos Ethics Humanit Med 2009, 4(1):2. BioMed Central Full Text
• [48]Greek R, Greek J: Is the use of sentient animals in basic research justifiable? Philos Ethics Humanit Med 2010, 5:14. BioMed Central Full Text
• [49]Greek R, Shanks N, Rice MJ: The History and Implications of Testing Thalidomide on Animals. The Journal of Philosophy, Science & Law 2011., 11
• [50]Lewis EB: A gene complex controlling segmentation in Drosophila. Nature 1978, 276(5688):565-570.
• [51]McGinnis W, Hart CP, Gehring WJ, Ruddle FH: Molecular cloning and chromosome mapping of a mouse DNA sequence homologous to homeotic genes of Drosophila. Cell 1984, 38(3):675-680.
• [52]Gellon G, McGinnis W: Shaping animal body plans in development and evolution by modulation of Hox expression patterns. Bioessays 1998, 20(2):116-125.
• [53]Slack JM, Holland PW, Graham CF: The zootype and the phylotypic stage. Nature 1993, 361(6412):490-492.
• [54]McPherson JD, Marra M, Hillier L, Waterston RH, Chinwalla A, Wallis J, Sekhon M, Wylie K, Mardis ER, Wilson RK, et al.: A physical map of the human genome. Nature 2001, 409(6822):934-941.
• [55]Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, et al.: The sequence of the human genome. Science 2001, 291(5507):1304-1351.
• [56]King MC, Wilson AC: Evolution at two levels in humans and chimpanzees. Science 1975, 188(4184):107-116.
• [57]Caccia S, Garattini S, Pasina L, Nobili A: Predicting the clinical relevance of drug interactions from pre-approval studies. Drug Saf 2009, 32(11):1017-1039.
• [58]Martignoni M, Groothuis GM, de Kanter R: Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2006, 2(6):875-894.
• [59]Donato MT, Castell JV: Strategies and molecular probes to investigate the role of cytochrome P450 in drug metabolism: focus on in vitro studies. Clin Pharmacokinet 2003, 42(2):153-178.
• [60]Gonzalez-Angulo AM, Hortobagyi GN, Esteva FJ: Adjuvant Therapy with Trastuzumab for HER-2/neu-Positive Breast Cancer. Oncologist 2006, 11(8):857-867.
• [61]Wagner GP, Amemiya C, Ruddle F: Hox cluster duplications and the opportunity for evolutionary novelties. Proc Natl Acad Sci U S A 2003, 100(25):14603-14606.
• [62]Amores A, Force A, Yan YL, Joly L, Amemiya C, Fritz A, Ho RK, Langeland J, Prince V, Wang YL, et al.: Zebrafish hox clusters and vertebrate genome evolution. Science 1998, 282(5394):1711-1714.
• [63]Garcia-Fernandez J: Hox, ParaHox, ProtoHox: facts and guesses. Heredity 2005, 94(2):145-152.
• [64]Paracelsus: Der Buecher und Schriften. VII(1590):172.
• [65]Goldstein BD, Henifin MS: Reference Manual on Scientific Evidence. In Reference Guide on Toxicology. Third Edition edition. Edited by Kassirer JP, Kessler G. National Academy of Sciences, Washington DC; 2011:633-685.
• [66]Roses AD: Pharmacogenetics and the practice of medicine. Nature 2000, 405(6788):857-865.
• [67]Bruder CE, Piotrowski A, Gijsbers AA, Andersson R, Erickson S, de Stahl TD, Menzel U, Sandgren J, von Tell D, Poplawski A, et al.: Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 2008, 82(3):763-771.
• [68]Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, et al.: Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 2005, 102(30):10604-10609.
• [69]Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O'Hanlon TP, Rider LG, et al.: Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 2010, 20(2):170-179.
• [70]Wong AH, Gottesman II, Petronis A: Phenotypic differences in genetically identical organisms: the epigenetic perspective. Hum Mol Genet 2005, 14(1):R11-18.
• [71]Blair E: Predictive tests and personalised medicine. Drug Discovery World 2009, 10(4):27-31.
• [72]Dolgin E: Big pharma moves from 'blockbusters' to 'niche busters'. Nat Med 2010, 16(8):837-837.
• [73]Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, et al.: Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010, 363(9):809-819.
• [74]Hudson KL: Genomics, health care, and society. N Engl J Med 2011, 365(11):1033-1041.
• [75]Hughes AR, Spreen WR, Mosteller M, Warren LL, Lai EH, Brothers CH, Cox C, Nelsen AJ, Hughes S, Thorborn DE, et al.: Pharmacogenetics of hypersensitivity to abacavir: from PGx hypothesis to confirmation to clinical utility. Pharmacogenomics J 2008, 8(6):365-374.
• [76]Serrano D, Lazzeroni M, Zambon CF, Macis D, Maisonneuve P, Johansson H, Guerrieri-Gonzaga A, Plebani M, Basso D, Gjerde J, et al.: Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial. Pharmacogenomics J 2011, 11(2):100-107.
• [77]Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W: Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011, 11(4):274-86.
• [78]Lyman GH, Cosler LE, Kuderer NM, Hornberger J: Impact of a 21-gene RT-PCR assay on treatment decisions in early-stage breast cancer: an economic analysis based on prognostic and predictive validation studies. Cancer 2007, 109(6):1011-1018.
• [79]Smalley KS, Sondak VK: Melanoma–an unlikely poster child for personalized cancer therapy. N Engl J Med 2010, 363(9):876-878.
• [80]Thomas H: Cancer Treatments get Personal. New Scientist 2009, 2704:48-50.
• [81]Weiss ST, McLeod HL, Flockhart DA, Dolan ME, Benowitz NL, Johnson JA, Ratain MJ, Giacomini KM: Creating and evaluating genetic tests predictive of drug response. Nat Rev Drug Discov 2008, 7(7):568-574.
• [82]Gad S: Animal Models in Toxicology. In Preface. Edited by Gad S. CRC Press, Boca Rotan; 2007:1-18.
• [83]Hau J: Handbook of Laboratory Animal Science Second Edition Animal Models. Volume II. In Animal Models. 2nd edition. Edited by Hau J, Hoosier GK Jr. CRC Press, Boca Rotan; 2003:1-9.
• [84]Longer Tests on Lab Animals Urged for Potential Carcinogens. [ http://www.cspinet.org/new/200811172.html webcite]
• [85]Huff J, Jacobson MF, Davis DL: The limits of two-year bioassay exposure regimens for identifying chemical carcinogens. Environ Health Perspect 2008, 116(11):1439-1442.
• [86]Litchfield JT Jr: Symposium on clinical drug evaluation and human pharmacology. XVI. Evaluation of the safety of new drugs by means of tests in animals. Clin Pharmacol Ther 1962, 3:665-672.
• [87]Collins JM, McDevitt DG, Shanks RG, Swanton JG: The cardio-toxicity of isoprenaline during hypoxia. Br J Pharmacol 1969, 36(1):35-45.
• [88]Inman WH: Monitoring for Drug Safety. 1980.
• [89]Stolley PD: Asthma mortality. Why the United States was spared an epidemic of deaths due to asthma. Am Rev Respir Dis 1972, 105(6):883-890.
• [90]Stolley PD, Schinnar R: Fatal asthma. Lancet 1979, 2(8148):897.
• [91]Rosenblum I, Wohl A, Stein AA: Studies in Cardiac Necrosis. 3. Metabolic Effects of Sympathomimetic Amines Producing Cardiac Lesions. Toxicol Appl Pharmacol 1965, 7:344-351.
• [92]Rosenblum I, Wohl A, Stein AA: Studies in Cardiac Necrosis. Ii. Cardiovascular Effects of Sympathomimetic Amines Producing Cardiac Lesions. Toxicol Appl Pharmacol 1965, 7:9-17.
• [93]Rosenblum I, Wohl A, Stein AA: Studies in Cardiac Necrosis. I. Production of Cardiac Lesions with Sympathomimetic Amines. Toxicol Appl Pharmacol 1965, 7:1-8.
• [94]Fletcher AP: Drug safety tests and subsequent clinical experience. J R Soc Med 1978, 71(9):693-696.
• [95]Heywood R: Target organ toxicity. Toxicol Lett 1981, 8(6):349-358.
• [96]Heywood R: Target organ toxicity II. Toxicol Lett 1983, 18(1–2):83-88.
• [97]Salsburg D: The lifetime feeding study in mice and rats–an examination of its validity as a bioassay for human carcinogens. Fundam Appl Toxicol 1983, 3(1):63-67.
• [98]Garattini S: Toxic effects of chemicals: difficulties in extrapolating data from animals to man. Crit Rev Toxicol 1985, 16(1):1-29.
• [99]Heywood R: Animal Toxicity Studies: Their Relevance for Man. In Clinical Toxicity--Could it have been predicted? Post-marketing experience. Edited by Lumley CE, Walker S. Quay, Lancaster; 1990:57-67.
• [100]Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, et al.: Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000, 32(1):56-67.
• [101]Suter K: Animal Toxicity Studies: Their Relevance for Man. In What can be learned from case studies? The company approach. Edited by Lumley C, Walker S. Quay, Lancaster; 1990:71-78.
• [102]Lumley C: Animal Toxicity Studies: Their Relevance for Man. In Clinical toxicity: could it have been predicted? Premarketing experience. Edited by Lumley C, Walker S. Quay, London; 1990:49-56.
• [103]Spriet-Pourra C, Auriche M: SCRIP Reports. PJB; 1994.
• [104]Eason CT, Bonner FW, Parke DV: The importance of pharmacokinetic and receptor studies in drug safety evaluation. Regul Toxicol Pharmacol 1990, 11(3):288-307.
• [105]Igarashi T: CMR Workshop: The Timing of Toxicological Studies to Support Clinical Trials. In The duration of toxicity studies required to support repeated dosing in clinical investigation—A toxicologists opinion. Edited by Parkinson NM C, Lumley C, Walker SR. Kluwer, Boston/UK; 1994:67-74.
• [106]Igarashi T, Nakane S, Kitagawa T: Predictability of clinical adverse reactions of drugs by general pharmacology studies. J Toxicol Sci 1995, 20(2):77-92.
• [107]Igarashi T, Yabe T, Noda K: Study design and statistical analysis of toxicokinetics: a report of JPMA investigation of case studies. J Toxicol Sci 1996, 21(5):497-504.
• [108]Weaver JL, Staten D, Swann J, Armstrong G, Bates M, Hastings KL: Detection of systemic hypersensitivity to drugs using standard guinea pig assays. Toxicology 2003, 193(3):203-217.
• [109]Willis RC: The Virtual Patient. Modern Drug Discovery 2003, 6(2):35-40.
• [110]Sankar U: The Delicate Toxicity Balance in Drug Discovery. Scientist 2005, 19(15):32.
• [111]Lin JH: Species similarities and differences in pharmacokinetics. Drug Metab Dispos 1995, 23(10):1008-1021.
• [112]Ekwall B: Overview of the Final MEIC Results: II. The In Vitro--In Vivo Evaluation, Including the Selection of a Practical Battery of Cell Tests for Prediction of Acute Lethal Blood Concentrations in Humans. Toxicol In Vitro 1999, 13(4–5):665-673.
• [113]Roggeband R, York M, Pericoi M, Braun W: Eye irritation responses in rabbit and man after single applications of equal volumes of undiluted model liquid detergent products. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2000, 38(8):727-734.
• [114]Miller M, Bhalla K: An urgent need to restrict access to pesticides based on human lethality. PLoS Med 2010, 7(10):e1000358.
• [115]Dawson AH, Eddleston M, Senarathna L, Mohamed F, Gawarammana I, Bowe SJ, Manuweera G, Buckley NA: Acute human lethal toxicity of agricultural pesticides: a prospective cohort study. PLoS Med 2010, 7(10):e1000357.
• [116]Sietsema WK: The absolute oral bioavailability of selected drugs. Int J Clin Pharmacol Ther Toxicol 1989, 27(4):179-211.
• [117]Giri S, Bader A: Foundation review: Improved preclinical safety assessment using micro-BAL devices: the potential impact on human discovery and drug attrition. Drug Discovery Today 2011, 16(9/10):382-397.
• [118]Browne LJ, Taylor LL: Predictive chemoinformatics: applications to the pharmaceutical industry. Drug Discovery World 2002, 71-77. Fall
• [119]Gura T: Cancer Models: Systems for identifying new drugs are often faulty. Science 1997, 278(5340):1041-1042.
• [120]Wang L, McLeod HL, Weinshilboum RM: Genomics and drug response. N Engl J Med 2011, 364(12):1144-1153.
• [121]Mann R, Andrews E: Pharmacovigilance. 2nd edition. John Wiley and Sons, Chichester; 2006.
• [122]Kaplowitz N: Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005, 4(6):489-499.
• [123]Fourches D, Barnes JC, Day NC, Bradley P, Reed JZ, Tropsha A: Cheminformatics analysis of assertions mined from literature that describe drug-induced liver injury in different species. Chem Res Toxicol 2010, 23(1):171-183.
• [124]Koppanyi T, Avery MA: Species differences and the clinical trial of new drugs: a review. Clin Pharmacol Ther 1966, 7(2):250-270.
• [125]Collins JM: Inter-species differences in drug properties. Chem Biol Interact 2001, 134(3):237-242.
• [126]Knight A, Bailey J, Balcombe J: Animal carcinogenicity studies: 1. Poor human predictivity. Altern Lab Anim 2006, 34(1):19-27.
• [127]Oser BL: The rat as a model for human toxicological evaluation. J Toxicol Environ Health 1981, 8(4):521-542.
• [128]Calabrese EJ: Suitability of animal models for predictive toxicology: theoretical and practical considerations. Drug Metab Rev 1984, 15(3):505-523.
• [129]Calabrese EJ: Principles of Animal Extrapolation. CRC Press, Boca Rotan; 1991.
• [130]Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS: Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 2007, 334(7586):197.
• [131]Testing Treatment on Animals: Relevance to Humans. [ http://www.pcpoh.bham.ac.uk/publichealth/methodology/docs/invitations/JH18_Final_Report_April_2006.pdf webcite]
• [132]Lindl T, Voelkel M, Kolar R: [Animal experiments in biomedical research. An evaluation of the clinical relevance of approved animal experimental projects]. ALTEX 2005, 22(3):143-151.
• [133]Lindl T, Völkel M, Kolar R: Animal experiments in biomedical research. An evaluation of the clinical relevance of approved animal experimental projects: No evident implementation in human medicine within more than 10 years. [Lecture abstract.]. ALTEX 2006, 23:111.
• [134]Tolman KG: The liver and lovastatin. Am J Cardiol 2002, 89(12):1374-1380.
• [135]Navarro VJ, Senior JR: Drug-related hepatotoxicity. N Engl J Med 2006, 354(7):731-739.
• [136]Dixit R, Boelsterli U: Healthy animals and animal models of human disease(s) in safety assessment of human pharmaceuticals, including therapeutic antibodies. Drug Discovery Today 2007, 12(7–8):336-342.
• [137]Toxicity Testing in the 21st Century. [ http://www.alttox.org/ttrc/overarching-challenges/way-forward/andersen/ webcite]
• [138]Hartung T: Toxicology for the twenty-first century. Nature 2009, 460(7252):208-212.
• [139]Force T, Kolaja KL: Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat Rev Drug Discov 2011, 10(2):111-126.
• [140]Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N: Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006, 355(10):1018-1028.
• [141]Dayan CM, Wraith DC: Preparing for first-in-man studies: the challenges for translational immunology post-TGN1412. Clin Exp Immunol 2008, 151(2):231-234.
• [142]Chapman AR: Addressing the Ethical Challenges of First-in-Human Trials. J Clinic Res Bioeth 2011, 2(4):113.
• [143]Marshall E: Gene therapy on trial. Science 2000, 288(5468):951-957.
• [144]Horstmann E, McCabe MS, Grochow L, Yamamoto S, Rubinstein L, Budd T, Shoemaker D, Emanuel EJ, Grady C: Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med 2005, 352(9):895-904.
• [145]Lavery JV: How can institutional review boards best interpret preclinical data? PLoS medicine 2011, 8(3):e1001011.
• [146]Anderson J, Kimmelman J: Extending Clinical Equipoise to Phase I Trials Involving Patients: Unresolved Problems. Kennedy Inst Ethics J 2010, 20:79-81.
• [147]Enna SJ, Williams M: Defining the role of pharmacology in the emerging world of translational research. Adv Pharmacol 2009, 57:1-30.
• [148]Shapiro SD: Transgenic and gene-targeted mice as models for chronic obstructive pulmonary disease. Eur Respir J 2007, 29(2):375-378.
• [149]Rangarajan A, Weinberg RA: Opinion: Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 2003, 3(12):952-959.
• [150]Leaf C: Why we are losing the war on cancer. Fortune 2004, 77-92. March 9
• [151]Greek R, Shanks N: FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed. University Press of America, Lanham; 2009.
• [152]Lappin G, Garner RC: Big physics, small doses: the use of AMS and PET in human microdosing of development drugs. Nat Rev Drug Discov 2003, 2(3):233-240.
• [153]Lappin G, Garner RC: The utility of microdosing over the past 5 years. Expert Opinion on Drug Metabolism & Toxicology 2008, 4(12):1499-1506.
• [154]Lappin G, Kuhnz W, Jochemsen R, Kneer J, Chaudhary A, Oosterhuis B, Drijfhout WJ, Rowland M, Garner RC: Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. Clin Pharmacol Ther 2006, 80(3):203-215.
• [155]Abadie R: The Professional Guinea Pig: Big Pharma and the Risky World of Human Subjects. Duke University Press Books, Durham; 2010.
• [156]Rice MJ: The institutional review board is an impediment to human research: the result is more animal-based research. Philosophy, ethics, and humanities in medicine : PEHM 2011, 6:12. BioMed Central Full Text
• [157]Rothwell PM: Funding for practice-oriented clinical research. Lancet 2006, 368(9532):262-266.
• [158]Scientific Achievements Less Prominent Than a Decade Ago. Public praises science; scientists fault public, media. [ http://people-press.org/report/528/ webcite]
• [159]Aldhous P, Coghlan A, Copley J: Let the people speak. New Scientist 1999., (2187) May 22
• [160]Special Eurobarometer: Social values, Science and Technology. [ http://ec.europa.eu/public_opinion/archives/ebs/ebs_225_report_en.pdf webcite]
• [161]Four Moral Issues Sharply Divide Americans. [ http://www.gallup.com/poll/137357/Four-Moral-Issues-Sharply-Divide-Americans.aspx?utm_source=alert&utm_medium=email&utm_campaign=syndication&utm_content=morelink&utm_term=Moral Issues webcite]
• [162]Giles J: Animal experiments under fire for poor design. Nature 2006, 444(7122):981.
• [163]U.S. Investment In Health Research. 2009. [ http://www.researchamerica.org/uploads/healthdollar09.pdf webcite]
• [164]Ioannidis JPA: Contradicted and Initially Stronger Effects in Highly Cited Clinical Research. JAMA: The Journal of the American Medical Association 2005, 294(2):218-228.
• [165]Crowley WF Jr: Translation of basic research into useful treatments: how often does it occur? Am J Med 2003, 114(6):503-505.
• [166]Daubert v. Merrell Dow Pharms., 509 U.S. 579, 584 (U.S., 1993). In
• [167]Viterbo v. Dow Chemical Co., 826 F.2d 420 (5th Cir. 1987). In
• [168]Selwood v. Oxford Chemicals, Inc., No. 90–1048 (M.D. Pa. June 28, 1991). In
• [169]Joiner v. General Elec. Co., 864 F. Supp. 1310, 1323 (N.D. Ga. 1994). In
• [170]Bourne v. E.I.DuPont de Nemours and Company, 189 F Supp. 2d 482 (S.D. W.Va. 2002).
• [171]Fliri AF, Loging WT, Thadeio PF, Volkmann RA: Biological spectra analysis: Linking biological activity profiles to molecular structure. Proc Natl Acad Sci U S A 2005, 102(2):261-266.
• [172]Borman S: Drugs by Design. Chemical & Engineering News 2005., 28
• [173]Models Predict Toxicity of Compounds[ http://www.dddmag.com/product-Models-Predict-Toxicity-of-Compounds-052611.aspx?et_cid=1799359&et_rid=45518461&linkid=http%3a%2f%2fwww.dddmag.com%2fproduct-Models-Predict-Toxicity-of-Compounds-052611.aspx webcite]
• [174]Hoffman LM, Carpenter MK: Characterization and culture of human embryonic stem cells. Nat Biotechnol 2005, 23(6):699-708.
• [175]Sinha G: Cell biology. Human embryonic stem cells may be toxicology's new best friends. Science 2005, 308(5728):1538.
• [176]Geerts H: Of mice and men: bridging the translational disconnect in CNS drug discovery. CNS Drugs 2009, 23(11):915-926.
• [177]Altman L: Who Goes First? The Story of Self-Experimentation in Medicine. University of California Press; 1998.
• [178]Greek J, Greek R: What Will We Do if We Don't Experiment on Animals? Trafford 2004.
• [179]Regenberg A, Mathews DJ, Blass DM, Bok H, Coyle JT, Duggan P, Faden R, Finkel J, Gearhart JD, Hillis A, et al.: The role of animal models in evaluating reasonable safety and efficacy for human trials of cell-based interventions for neurologic conditions. J Cereb Blood Flow Metab 2009, 29(1):1-9.
• [180]Littman BH, Williams SA: The ultimate model organism: progress in experimental medicine. Nat Rev Drug Discov 2005, 4(8):631-638.