Regulatory Toxicology and Pharmacology 70 (2014) 575–576
Contents lists available at ScienceDirect
Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph
Editorial
Animals and ethical research During the last two centuries, a few fortunate societies became prosperous, healthy, and long-lived as never before. Such novel affluence fostered an anxious protection mindset, which soon fragmented into the assertiveness of many advocacy groups. Their reach has been restrained only by the certainty that protection has limits, that limits are different for each protected target, and that favoring one target usually means reducing protection for another. A case in point is the efforts to protect animals in biomedical research, at times extending to calls for halting altogether the use of animals for those ends. The reaction of most scientists has been halfhearted and dismissive, while animal rights activists have secured enough public support to make significant political and legislative inroads. Presently, key animal experimentations – long considered necessary to advance therapies and welfare – are seriously threatened with extinction at the hands of activists. Central to the animal rights movement is that certain animals are sentient in ways similar to humans, and therefore deserving of similar protections. Still, wary of being seen as utopians, activists have been selective with their targets by following cultural trends. In a society that quietly benefits from the annual slaughter of millions of raised and wild animals, even the minor harming of cats, dogs, horses, monkeys, and other familiar animals is taboo. The prospect that those animals and pets may be forced into painful experiments has been used to gain support in limiting those experiments. The countervailing argument is that animal experiments have made possible key medical advances: as it is for drugs, antibiotics, foods and vaccines, which have been responsible for exceptional gains in health and longevity. Jonas Salk – my earlier mentor – first injected himself and his children with his polio vaccine, but not before safety had been tested in monkeys, at that time the only susceptible animals close to humans. Indeed, it has been long socially accepted that a few thousand Rhesus and other small primates had to be sacrificed, so that hundreds of millions of children would not contract polio to die or end up paralyzed for life. A core justification of the animal rights message stresses that animal experiments have become obsolete because in vitro, in silico, and other ‘‘omic’’ approaches by now are proven substitutes of animal experimentation. This dangerous misconception is being sold to the media, the public, and to naïve politicians, and is even sustained by over enthusiastic technicians who make a living of ‘‘omic’’ tests, which should remain as a most speculative research topic. It is clearly erroneous to affirm that the complex homeostatic responses of trillions of very differentiated cells over the lifetimes of live animal organisms – humans included – could be predicted by short-lived and sketchy signals of in vitro micro-cultures of single cell types, from smears of isolated biological samples, or other similarly rapid and extremely reductionist assays. http://dx.doi.org/10.1016/j.yrtph.2014.10.001 0273-2300/Ó 2014 Elsevier Inc. All rights reserved.
Because the future progress of human and animal health is at play, this quandary needs a factual and not an emotional resolution, which could possibly be achieved by discounting some of the inconsistencies of both activism and biomedical research. If it became sensible again to agree that human suffering, health, and safety remain significant priorities, activists and politicians should first concur that advances in animal and human health require animal experiments, however well monitored. On this premise, the biomedical community would then outline desirable animal research, preferably divided in two broad categories: experiments needed for regulations to determine the safety of marketed products, and experiments needed in research to advance therapy and prevention. The former group should be limited to animal experiments capable of results that are objectively relevant to human experiences. Anything short of this standard is bound to cause irrelevant and therefore unnecessary animal tests, and to encourage arbitrary and capricious regulations and policies, as standing history shows. Gori (2013) Such standard would exclude long term chronic animal studies, whose outcomes are known to diverge over the lifetimes of different species. The reasons are divergent variables such as dosing and exposure conditions, genetic, somatic, behavioral, nutritional, environmental, and many other determinants, which end up yielding results that are irrelevant to human experiences. For different reasons but parallel conclusions, in silico, in vitro, and other conjectural ‘‘omic’’ screening tests should not have a place in directing policy and regulation. As noted, such tests generate facile signals that are posited or presumed to be adverse, but that are irrelevant to long-term responses of complex organisms. Those signals could only be forced into regulation after filtering their massive data sets through new collections of arbitrary default assumptions – an exercise devoid of testable relevance to humans, and a sham pretext for arbitrary and capricious regulations and policies. As a singular example of wasteful animal use, during the last 70 years many millions of mice and rats have been abused and killed in thousands of futile lifetime tests, attempting to identify and measure hypothetical human cancer risks presumably posed by natural and synthetic agents. Such tests continue today at government and industrial facilities, each test taking several hundred mice and rats and about 5 years and over $5M to complete. Tests are subject to protocols of execution and interpretation dictated by official default assumptions that are admittedly arbitrary, and which belie the insinuations that such tests produce scientifically unbiased evidence of human risk. This wasteful and deceptive operation is not newly discovered. During congressional hearings in 1980, the late Dr. David Rall – first director of the National Toxicology Program set up for such cancer tests – testified to a young and astonished congressman
576
Editorial / Regulatory Toxicology and Pharmacology 70 (2014) 575–576
Albert Gore that cancer tests could not be run and interpreted on a scientific basis. Dr. Rall demanded that faith and trust should be granted to the ‘‘experts’’ who – like ancient augurs – guess the meaning of animal entrails at public expense. Rall (1981) Simply stated, there is no way that such tests could provide factually valid estimates of human cancer risk. So much so that government agencies set up committees of ‘‘experts’’ who examine animal test results and vote personal opinions of their presumed meaning. Insecure even of this ballot, government agencies further massage animal data and expert opinions by applying arbitrary ‘‘safety factors’’ in multiples of ten and up to several hundred or more. Contrary to all protestations of ethical governance, this fabricated nonsense ends up in the Federal Register as official regulations, which are enforced to exact $trillions of wasteful economic and litigation activity in the US and worldwide; to levy massive fines, and even to criminally convict and detain hapless transgressors. Oblivious of the colorless rats and mice of carcinogen testing, the animal right movement has focused on the more visible and glamorous academic and pharmaceutical research. Here, an implicit premise of activists is that researchers – in a free organized society and whether publicly, privately, or self-funded – do not have a natural right to conduct whatever research comes to mind, with or without animals. Constraints of moral, political, legal, social and financial import should be expected to permit or deny topics of study, experimental modalities, and whether and how animals and humans should be involved. Long privileged scientists would be initially reluctant to accept such restraints to their traditional freedom of inquiry, but most could eventually agree to the reality of tradeoffs between the promises and costs of research; the budgets and projected time to success; who and how many in society might benefit; and in general the societal valuations of projected benefits. In fact, scientists could point out that such negotiations have forever if implicitly guided the planning and execution of research. The crux of contention would rather be to what extent current social tolerance should accommodate research and experiments on people and animals. Scientists should agree to negotiate and accept reasonable regulations for humane animal treatment. At the same time they
should forcefully sustain the undeniable achievements of research with animals, the promises of current and projected research, and how senseless and dangerous it would be to dismiss the real life complexity of animal homeostasis in favor of a few lonesome and hypothetical signals from artificial in vitro, in silico and other omics tests. Scientists especially would be irresponsible to think of this challenge as unscientific, irrational or emotional, for an unbalanced outcome would have serious and far reaching consequences. Apart from the loss of science and medical advances, should pharmaceutical progress become too difficult for efficacy and safety evaluations that require animals, a migration of people and means to more hospitable shores would be inevitable. To be unprepared is unwise, and it is time to engage the good will of national academies, universities, professional societies, individual scientists, the media, and the animal rights movement in reaffirming societal and political support for the humane handling of research animals, and for the undeniable achievements and promises of animals in biomedical research. References Gori, G.B., 2013. Regulatory forum opinion piece, long-term animal bioassays: is the end near? Toxicol. Pathol. 66, 163–165. http://dx.doi.org/10.1177/ 0192623312467524. Rall, D.P., 1981. National Toxicology Program: Hearing before the Subcommittee on Investigations and Oversight of the Committee on Science and Technology, U.S. House of Representatives, Ninety-seventh Congress, first session, July 15. U.S. Government Printing Office, Washington, DC, pp. 52–57, (accessed 21.09.14).
Editor-in-chief Gio Batta Gori Regulatory Toxicology and Pharmacology, United States E-mail address: [email protected] Available online 19 October 2014
Contents lists available at ScienceDirect
Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph
Editorial
Animals and ethical research During the last two centuries, a few fortunate societies became prosperous, healthy, and long-lived as never before. Such novel affluence fostered an anxious protection mindset, which soon fragmented into the assertiveness of many advocacy groups. Their reach has been restrained only by the certainty that protection has limits, that limits are different for each protected target, and that favoring one target usually means reducing protection for another. A case in point is the efforts to protect animals in biomedical research, at times extending to calls for halting altogether the use of animals for those ends. The reaction of most scientists has been halfhearted and dismissive, while animal rights activists have secured enough public support to make significant political and legislative inroads. Presently, key animal experimentations – long considered necessary to advance therapies and welfare – are seriously threatened with extinction at the hands of activists. Central to the animal rights movement is that certain animals are sentient in ways similar to humans, and therefore deserving of similar protections. Still, wary of being seen as utopians, activists have been selective with their targets by following cultural trends. In a society that quietly benefits from the annual slaughter of millions of raised and wild animals, even the minor harming of cats, dogs, horses, monkeys, and other familiar animals is taboo. The prospect that those animals and pets may be forced into painful experiments has been used to gain support in limiting those experiments. The countervailing argument is that animal experiments have made possible key medical advances: as it is for drugs, antibiotics, foods and vaccines, which have been responsible for exceptional gains in health and longevity. Jonas Salk – my earlier mentor – first injected himself and his children with his polio vaccine, but not before safety had been tested in monkeys, at that time the only susceptible animals close to humans. Indeed, it has been long socially accepted that a few thousand Rhesus and other small primates had to be sacrificed, so that hundreds of millions of children would not contract polio to die or end up paralyzed for life. A core justification of the animal rights message stresses that animal experiments have become obsolete because in vitro, in silico, and other ‘‘omic’’ approaches by now are proven substitutes of animal experimentation. This dangerous misconception is being sold to the media, the public, and to naïve politicians, and is even sustained by over enthusiastic technicians who make a living of ‘‘omic’’ tests, which should remain as a most speculative research topic. It is clearly erroneous to affirm that the complex homeostatic responses of trillions of very differentiated cells over the lifetimes of live animal organisms – humans included – could be predicted by short-lived and sketchy signals of in vitro micro-cultures of single cell types, from smears of isolated biological samples, or other similarly rapid and extremely reductionist assays. http://dx.doi.org/10.1016/j.yrtph.2014.10.001 0273-2300/Ó 2014 Elsevier Inc. All rights reserved.
Because the future progress of human and animal health is at play, this quandary needs a factual and not an emotional resolution, which could possibly be achieved by discounting some of the inconsistencies of both activism and biomedical research. If it became sensible again to agree that human suffering, health, and safety remain significant priorities, activists and politicians should first concur that advances in animal and human health require animal experiments, however well monitored. On this premise, the biomedical community would then outline desirable animal research, preferably divided in two broad categories: experiments needed for regulations to determine the safety of marketed products, and experiments needed in research to advance therapy and prevention. The former group should be limited to animal experiments capable of results that are objectively relevant to human experiences. Anything short of this standard is bound to cause irrelevant and therefore unnecessary animal tests, and to encourage arbitrary and capricious regulations and policies, as standing history shows. Gori (2013) Such standard would exclude long term chronic animal studies, whose outcomes are known to diverge over the lifetimes of different species. The reasons are divergent variables such as dosing and exposure conditions, genetic, somatic, behavioral, nutritional, environmental, and many other determinants, which end up yielding results that are irrelevant to human experiences. For different reasons but parallel conclusions, in silico, in vitro, and other conjectural ‘‘omic’’ screening tests should not have a place in directing policy and regulation. As noted, such tests generate facile signals that are posited or presumed to be adverse, but that are irrelevant to long-term responses of complex organisms. Those signals could only be forced into regulation after filtering their massive data sets through new collections of arbitrary default assumptions – an exercise devoid of testable relevance to humans, and a sham pretext for arbitrary and capricious regulations and policies. As a singular example of wasteful animal use, during the last 70 years many millions of mice and rats have been abused and killed in thousands of futile lifetime tests, attempting to identify and measure hypothetical human cancer risks presumably posed by natural and synthetic agents. Such tests continue today at government and industrial facilities, each test taking several hundred mice and rats and about 5 years and over $5M to complete. Tests are subject to protocols of execution and interpretation dictated by official default assumptions that are admittedly arbitrary, and which belie the insinuations that such tests produce scientifically unbiased evidence of human risk. This wasteful and deceptive operation is not newly discovered. During congressional hearings in 1980, the late Dr. David Rall – first director of the National Toxicology Program set up for such cancer tests – testified to a young and astonished congressman
576
Editorial / Regulatory Toxicology and Pharmacology 70 (2014) 575–576
Albert Gore that cancer tests could not be run and interpreted on a scientific basis. Dr. Rall demanded that faith and trust should be granted to the ‘‘experts’’ who – like ancient augurs – guess the meaning of animal entrails at public expense. Rall (1981) Simply stated, there is no way that such tests could provide factually valid estimates of human cancer risk. So much so that government agencies set up committees of ‘‘experts’’ who examine animal test results and vote personal opinions of their presumed meaning. Insecure even of this ballot, government agencies further massage animal data and expert opinions by applying arbitrary ‘‘safety factors’’ in multiples of ten and up to several hundred or more. Contrary to all protestations of ethical governance, this fabricated nonsense ends up in the Federal Register as official regulations, which are enforced to exact $trillions of wasteful economic and litigation activity in the US and worldwide; to levy massive fines, and even to criminally convict and detain hapless transgressors. Oblivious of the colorless rats and mice of carcinogen testing, the animal right movement has focused on the more visible and glamorous academic and pharmaceutical research. Here, an implicit premise of activists is that researchers – in a free organized society and whether publicly, privately, or self-funded – do not have a natural right to conduct whatever research comes to mind, with or without animals. Constraints of moral, political, legal, social and financial import should be expected to permit or deny topics of study, experimental modalities, and whether and how animals and humans should be involved. Long privileged scientists would be initially reluctant to accept such restraints to their traditional freedom of inquiry, but most could eventually agree to the reality of tradeoffs between the promises and costs of research; the budgets and projected time to success; who and how many in society might benefit; and in general the societal valuations of projected benefits. In fact, scientists could point out that such negotiations have forever if implicitly guided the planning and execution of research. The crux of contention would rather be to what extent current social tolerance should accommodate research and experiments on people and animals. Scientists should agree to negotiate and accept reasonable regulations for humane animal treatment. At the same time they
should forcefully sustain the undeniable achievements of research with animals, the promises of current and projected research, and how senseless and dangerous it would be to dismiss the real life complexity of animal homeostasis in favor of a few lonesome and hypothetical signals from artificial in vitro, in silico and other omics tests. Scientists especially would be irresponsible to think of this challenge as unscientific, irrational or emotional, for an unbalanced outcome would have serious and far reaching consequences. Apart from the loss of science and medical advances, should pharmaceutical progress become too difficult for efficacy and safety evaluations that require animals, a migration of people and means to more hospitable shores would be inevitable. To be unprepared is unwise, and it is time to engage the good will of national academies, universities, professional societies, individual scientists, the media, and the animal rights movement in reaffirming societal and political support for the humane handling of research animals, and for the undeniable achievements and promises of animals in biomedical research. References Gori, G.B., 2013. Regulatory forum opinion piece, long-term animal bioassays: is the end near? Toxicol. Pathol. 66, 163–165. http://dx.doi.org/10.1177/ 0192623312467524. Rall, D.P., 1981. National Toxicology Program: Hearing before the Subcommittee on Investigations and Oversight of the Committee on Science and Technology, U.S. House of Representatives, Ninety-seventh Congress, first session, July 15. U.S. Government Printing Office, Washington, DC, pp. 52–57, (accessed 21.09.14).
Editor-in-chief Gio Batta Gori Regulatory Toxicology and Pharmacology, United States E-mail address: [email protected] Available online 19 October 2014
