Quotes from Doctors & Researchers:
It is often claimed that scientists and doctors are united in their belief in the value of, and necessity for, animal experiments to protect human health. This stream of quotes from scientists and doctors, stretching from as far back as the early 20th Century right up to today, shows that there has been a long tradition of scepticism about this issue. Many of the quotes are from scientists who support or conduct animal research; far from diminishing the impact of their words, this fact ought to give them extra weight.
Note: FDA stands for Food and Drug Administration, the US drug regulatory body.
Teratogenicity and thalidomide
The rapid and fatal approval of thalidomide at that time ultimately was a consequence of the sole use of thalidomide-insensitive species in animal toxicity tests.
Molecular Pharmaceutics, 1st December 2008.
It appears that humans & animal (rodent or non-rodent) models have some differences in the process of implantation, in addition to the well-known variabilities with regard to the uptake & metabolism of drugs & chemicals. These data suggest there is a high uncertainty with regard to the validity of a risk assessment based on reliance only on animal studies. Therefore, new in vitro models based on human tissues (cell & tissue culture, uterus perfusion, etc.) can provide mechanistic information to address the problem of inter-species variation, & such information can facilitate reliable predictions which are relevant for human hazard identification. Bremer and colleagues, Alternatives to Laboratory , 35, 421-439.
All the parties involved, both in testing for reproductive toxicity & in the regulatory authorities, are aware of problems in assessing the meaning of results such as teratogenicity in animal tests. An important consideration is whether any observed malformation in animal embryo studies is relevant for risk assessment in relation to human embryos. Bremer and colleagues, Alternatives to Laboratory Animals, 35, 421-439.
Birth defects induced by maternal exposure to exogenous agents during pregnancy are preventable, if the agents themselves can be identified and avoided. Billions of dollars and man-hours have been dedicated to animal-based discovery and characterisation methods over decades. We show here, via a comprehensive systematic review and analysis of this data, that these methods constitute questionable science and pose a hazard to humans. Mean positive and negative predictivities barely exceed 50%; discordance among the species used is substantial; reliable extrapolation from animal data to humans is impossible, and virtually all known human teratogens have so far been identified in spite of, rather than because of, animal-based methods. Bailey and colleagues, Biogenic Amines, vol.19, N° 2, pp 97-146.
Because most human teratogens have been discovered by alert physicians or epidemiology studies, not animal studies, animal studies play a minor role in discovering teratogens... Well-performed epidemiology studies are still the best method for determining the human risk and the effects of environmental toxicants. Brent, Pediatrics, 113(4 Suppl):984-95.
The following comments & recommendations of the National Academy of Sciences/ National Research Council (1997) concerning teratogenicity testing are equally pertinent to in utero studies of potential carcinogenicity: “The ideal animal for teratological testing would have the following characteristics: (1) the ability to absorb, metabolize, & eliminate the test substance in a manner similar to that of man, (2) the ability to transmit the substance & its metabolite across the placenta as does man, and (3) embryos & fetuses that have developmental schedules & metabolic pathways similar to those in the human conceptus. Existing comparative data are too limited for a judgement as to which animal is most like man in any of these regards; but it is already apparent that no presently used species, including simians, resembles man in all of these respects. Furthermore, it is evident that the degree of similarity to man exhibited by a given species varies from 1 test substance to another.
What is noxious or ineffective in nonhuman species can be innoxious or effective in humans. For example, penicillin is fatal for guinea pigs but generally well tolerated by human beings; aspirin is teratogenic in cats, dogs, guinea pigs, rats, mice, and monkeys but obviously not in pregnant women despite frequent consumption. Handbook of Laboratory Animal Science Volume II Animal Models, p4, Svendensen and Hau (Eds.) (CRC Press).
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 Volume II Animal Models, p4, Svendensen and Hau (Eds) (CRC Press).
Drugs known to damage the human foetus are found to be safe in 70% of cases when tried on primates. Developmental Toxicology: Mechanisms and Risk, p313, McLachlan, Pratt, and Markert (Eds).
"...there is no ideal animal model to extrapolate teratogenicity results to human exposure because of species sensitivity and species difference. Dr Lin, In Vitro Toxicology, vol 1.
More than 800 chemicals have been defined as teratogens in laboratory animals, but only a few of these, approximately 20, have been shown to be teratogenic in humans. This discrepancy can be attributed to differences in metabolism, sensitivity and exposure time. Schmid, Trends in Pharmacological Sciences, vol 8, p 133.
It is the actual results of teratogenicity testing in primates which have been most disappointing in consideration of these animals’ possible use as a predictive model. While some nine subhuman primates (all but the bushbaby) have demonstrated the characteristic limb defects observed in humans when administered thalidomide, the results with 83 other agents with which primates have been tested are less than perfect. Of the 15 listed putative human teratogens tested in nonhuman primates, only eight were also teratogenic in one or more of the various species…. Schardein, Chemically Induced Birth Defects (publ. Marcel Decker).
A number of different animal species have been used in teratological research in an attempt to determine the most satisfactory model for predicting the hazard to humans…No single species thus far evaluated, however fulfills all criteria. Schardein, Chemically Induced Birth Defects (publ. Marcel Decker).
The great majority of perinatal toxicological studies seem to be intended to convey medico-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. Prof Hawkins, Drugs and Pregnancy: Human Teratogenesis and Related Problems, p 41-49 (publ. Churchill Livingstone).
Unfortunately species variation in the sensitivity to drug teratogenicity is very widespread. Even within a species considerable variation can be demonstrated between different animal strains... Faced with such complexity it is not surprising that teratological testing based on animal tests has a poor predictive power and is thought to do little more than exclude grossly toxic substances. Dr Lewis, Archives of Toxicology, suppl 5, p 195-196.
What is the value of routine tests in animals for prediction of chemical teratogens? The correlation between known effects in laboratory animals and clinical adverse effects is very low. Dr Larsson and colleagues, in a letter to The Lancet, p 439, 21st August.
There is at present no hard evidence to show the value of more extensive and more prolonged laboratory testing as a method of reducing eventual risk in human patients. In other words the predictive value of studies carried out in animals is uncertain. The statutory bodies such as the Committee on Safety of Medicines that require these tests do so largely as an act of faith rather than on hard scientific grounds. With thalidomide, for example, it is only possible to produce specific deformities in a very small number of species of animal. In this particular case, therefore, it is unlikely that specific tests in pregnant animals would have given the necessary warning: the right species would probably never have been used. Prof George Teeling‑Smith, A Question of Balance; the benefits and risks of pharmaceutical innovation, p 29, publ. Office of Health Economics.
The extensive animal reproductive studies to which all new drugs are now subjected are more in ...the nature of a public relations exercise than a serious contribution to drug safety. Prof R W Smithells, Monitoring for Drug Safety, ed. Inman, p 306-313.
In the absence of useful tests for teratogenicity clinicians have to accept responsibility for drug exposures in early pregnancy... if clinicians were more aware of the shortcomings of animal teratogenicity testing they might take this responsibility more seriously. Dr Peter Lewis, senior lecturer in clinical pharmacology at Hammersmith Hospital, London, Monitoring for Drug Safety, ed. Inman, 1980.
There is a fundamental lack of knowledge of pathogenesis of most malformations and, therefore, extrapolation to man has to be done with reservation and care. Negative results cannot be used to predict that an agent will lack teratogenic effect in man. Dr Ralph Heywood, Journal of the Royal Society of Medicine, vol 71, p 686-689, 1978.
In approximately 10 strains of rats, 15 strains of mice, 11 breeds of rabbits, 2 breeds of dogs, 3 strains of hamsters, 8 species of primates and in other such varied species as cats, armadillos, guinea pigs, swine and ferrets in which thalidomide has been tested, teratogenic effects have been induced only occasionally. Schardein, J.L., Drugs as Teratogens, 1976 and Schardein, J.L., Chemically Induced Birth Defects, 1985.
Any chemical can cause birth defects in humans and/or animals if given at the right time in pregnancy and in the right amount. Common table salt and even water are teratogens in some species if given at the right time in the right dose. Acta Anat Nippon 1969; 74:121-4 and Teratology 1971; 4:427-32.
Numerous attempts to reproduce the malformations which occurred in human babies from Thalidomide-treated mothers have met with only limited success. Although many representatives of aves [birds] and mammalian experimental species have been investigated for this purpose, the results fall short of paralleling the effect of the drug on the human foetus. Hendrickx, Axelrod, Clayborn, Nature, 210:958-959.
The factors influencing the response of an embryo to a drug interact in such complicated ways that one cannot predict whether a drug will be teratogenic in man from results obtained in animals…The results are interpreted to cast doubt upon the reliability of the use of the rat as an adequate laboratory test for possible teratogenic agents in man. McColl, Globus and Robinson, Effect of some therapeutic agents on the developing rat foetus. Toxicology and Applied Pharmacology, 7, 409-417.
We chose a dose of thalidomide close to the estimated amount required to produce human anomalies. This dose had no detectable toxic effects in the monkey... Science 1963; 139:1294-95.
Grünenthal has tried to reproduce phocomelia in rats, mice, and rabbits and has failed, In Keil the drug was fed to hens and the chicks were normal. Taussig, Journal of the American Medical Association, 180: 1106–14.