Why animal studies are often poor predictors of human reactions to exposure

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746847/

 

The concept that animal research, particularly that relating to pharmaceuticals and environmental agents, may be a poor predictor of human experience is not new. A thousand years ago, Ibn Sina commented on the need to study humans rather than animals,1 and Alexander Pope's dictum ‘The proper study of mankind is man’ is well known and has been widely cited.2 Pharmacologists, in particular, have long recognized the difficulties inherent in extrapolating drug data from animals to man.3,4 Given the large number of animal studies conducted, it would be expected that some animal experiments do predict human reactions. For example, penicillin was observed to protect both mice and humans from staphylococcal infections,5 and isotretinoin (‘Acutane’) causes birth defects in rabbits and monkeys as well as in humans (although not in mice or rats).6 By contrast, corticosteroids are widely teratogenic in animals but not in humans,7 and thalidomide is not a teratogen in many animal species but it is in humans.8 Recent experience in a phase 1 study of the monoclonal antibody TGN 1412 resulted in life-threatening morbidity in all six healthy volunteers, reflecting inadequate prediction even in non-human primates of the human response.9

 

One reason why animal experiments often do not translate into replications in human trials10,11 or into cancer chemoprevention12–14 is that many animal experiments are poorly designed, conducted and analysed. Another possible contribution to failure to replicate the results of animal research in humans is that reviews and summaries of evidence from animal research are methodologically inadequate.15 In one survey, only 1/10,000 Medline records of animal studies were tagged as being meta-analyses compared with 1/1000 human studies.16 In recent reports, the poor quality of research synthesis was documented by a comprehensive search of Medline which found only 25 systematic reviews of animal research.17 Other recent studies similarly found only 3015 and 5718 systematic reviews of any type of animal research. These deficiencies are important because animal research often provides the rationale for hypotheses studied by epidemiologists and clinical researchers.....

 

 

See full study by clicking on the link above.

 

_____________________________________

 

And here's a related study:

 

"Extrapolating from Animals to Humans"

 

http://stm.sciencemag.org/content/4/151/151ps15

 

Abstract

 

Because of a variety of caveats, the safety and effectiveness of interventions in human subjects can only be speculated from animal studies. Careful synthesis of data from multiple animal studies is needed to begin to assess the likelihood of successful cross-species translation (Fay et al., this issue).

 

A perusal of PubMed (search date: 21 July 2012) with the search term “animal” yields 4,993,350 papers—almost a quarter of the biomedical literature—a number that exceeds that obtained by searching with the term “patient” (N = 4,337,985 hits). Mice and rats are king in the biomedical literature (N = 1,193,679 and N = 753,612 hits, respectively), although these rodents are arguably distant relatives of Homo sapiens sapiens. Other animals are also well represented; for example, the search term “rabbit” yields 354,561 hits, and “rhesus monkey” yields 35,558 hits. The phrase “animal model” yields almost a half million papers (N = 495,339).

 

Although some research is performed purely for the sake of studying the physiology and pathophysiology of animals, the goal of the majority of animal studies is to gain knowledge and insights that are useful for understanding human biology, the response of humans to treatments or other interventions, or both. But how successful is this cross-species translation (Fig. 1)? In this issue, Fay et al. (1) present a careful synthesis of mortality data from 21 animal studies on the new recombinant protective antigen (rPA) vaccines and the already-licensed anthrax vaccine adsorbed (AVA).

 

Thanks for posting.  It’s all the more important when it comes to drugs that affect the brain.

 

They’ve known about many of these differences with corticosteroids for several decades.

 

“...in contrast, corticosteroids are widely teratogenic in animals but not in humans,7 and thalidomide is not a teratogen in many animal species but it is in humans.”

Much agreed, cs123. That's why I posted it. The idea that they would extrapolate from a study on a mouse to a human with regards to psychiatric meds makes no sense to me. Every time I read about the "forced swim test", which they use on mice in trials for antidepressants, it makes me so angry. The human brain is complex in a way that no other animal's is. I understand the role of animals in research, but there's obviously a limit to their usefulness.

In the pharmaceutical industry, animal studies are mainly used as a tool to determine the safety profile of a drug before (and during) studies of the drug in humans. The animal studies hopefully determine what is a safe dose to give to people, so that it won't kill them.

 

As the example of monoclonal antibody TGN 1412 shows, however, it doesn't always work well.

 

The "mechanism of action" of drugs is usually left to researchers in academia or government. Companies are not interested. The only thing companies want to know is, does the drug provide a benefit that is worth more than the risk of taking the drug. 

 

And as we all know, usually those risks are not known.

Here's a bit of info on the forced swim test:

 

https://en.wikipedia.org/wiki/Behavioural_despair_test 

 

Apparently, it's not quite clear how to interpret the results, which obviously has major implications when it comes to antidepressants.

 

There's also this one:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401172/

 

Suffice to say, depression is a complex human experience, and using a "forced swim test" on mice in order to approximate depressive behaviour in human beings seems to be a stretch. There are so many ways that depression can manifest in humans -- way more diverse than a mouse refusing to swim across a container of water.

Here's a bit of info on the forced swim test:

 

https://en.wikipedia.org/wiki/Behavioural_despair_test 

 

Apparently, it's not quite clear how to interpret the results, which obviously has major implications when it comes to antidepressants.

 

There's also this one:

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401172/

 

Suffice to say, depression is a complex human experience, and using a "forced swim test" on mice in order to approximate depressive behaviour in human beings seems to be a stretch. There are so many ways that depression can manifest in humans -- way more diverse than a mouse refusing to swim across a container of water.

 

 

Yes, exactly!  Here's one I posted this in the News section:

 

 

A very interesting read!  Includes cancer research, AIDS research, toxicity tests, the scientific limitations of animal models, as well as the morality of animal experimentation.

 

A Critical Look at Animal Experimentation

© Medical Research Modernization Committee, 2018

This booklet was revised by Stephen R. Kaufman, M.D. The prior version of this booklet was prepared by Christopher Anderegg, M.D., Ph.D., Kathy Archibald, B.Sc., Jarrod Bailey, Ph.D., Murry J. Cohen, M.D., Stephen R. Kaufman, M.D., and John J. Pippin, M.D., F.A.C.C.

 

The Medical Research Modernization Committee is a non-profit health advocacy organization composed of medical professionals and scientists who identify and promote efficient, reliable, and cost-effective research methods.

 

"Increasing numbers of scientists and clinicians are challenging animal experimentation on scientific grounds.^1-2 Considerable evidence demonstrates that animal experimentation is inefficient and unreliable, while newly developed methodologies are more valid and less expensive than animal studies. People should not have their tax dollars spent on activities to which they object on scientific and/or ethical grounds unless there is clear benefit to the general public. Does animal experimentation meet this standard?

"Conclusion

The value of animal experimentation has been grossly exaggerated by those with vested interests in its preservation. Because animal experimentation focuses on artificially created pathology, involves confounding variables, and is undermined by fundamental differences between human and nonhuman anatomy, physiology and pathology, it is an inherently unsound method to investigate human disease processes. Further the tens of millions of animals used and killed each year in American laboratories generally suffer enormously, often from fear and physical pain, and nearly always from the deprivation inflicted by their confinement, which denies their most basic psychological and behavioral needs. Consequently, the general public is uneasy about animal experimentation, and 50% of surveyed Americans oppose it.¹⁷¹

 

We conclude that the billions of dollars invested annually in animal experimentation would be put to much more efficient, effective, and humane use if redirected to clinical and epidemiological research and public health programs. Those who believe that substantially reducing or eliminating animal experimentation would impede medical progress can take comfort in knowing that, if it were valuable, it would be generously supported by pharmaceutical companies and other private industries that stand to benefit. Taxpayers should not be forced to sponsor activities they reasonably oppose."

 

 

http://www.mrmcmed.org/critcv.html

http://www.mrmcmed.org/Critical_Look_Booklet.pdf - (pdf format)

 

http://www.benzobuddies.org/forum/index.php?topic=207361.msg2681162#msg2681162