Fluent Essays

read the instructions write around900 words there are two word document down stair, read the instructions choose one docunment and write about it Journal of Nursing Law, Volume 12, Number 4, 2008 Copyright  2008 Springer Publishing Company • 147 DOI: 10.1891/1073-7472.12.4.147 Drug Safety: An Argument to Ban Animal Testing Sheree Stachura, RN, BSN The U.S. Food and Drug Administration (FDA) mandates that drugs under development go through a preclinical testing phase that includes animal testing. Unfortunately, animals and humans differ greatly biologically. Many drugs are safe for animals but not safe for humans. Therefore, when the drugs are placed on the market and used by humans, many times those drugs harm people. In addition, courts are reluctant to allow the admittance of animal testing as evidence, stating that the tests are not reliable. People rely on FDA approval of drugs to their detriment. They assume that if the FDA approved the drug, it is safe for use. In many documented incidences, this is not the case. There are many alternative methods available other then animal testing that can make drugs more efficient and safe for human use. Therefore, the FDA should not mandate animal testing and should look to the alternative methods for evidence that supports drug approval. Keywords: animal testing; drug safety; medications; Daubert standard The statistics are staggering. Every year, thou-sands of people are hurt or killed as a result of using prescription drugs that were approved by the U.S. Food and Drug Administration (FDA); 5.34% of newly approved drugs were pulled from the market by the FDA from 1997 to 2000. 1 Approximately 125,000 Americans have died from FDA-approved medica- tions. 2 Just recently, Vioxx, a medication manufactured by Merck and approved by the FDA, was pulled from the market. The medication caused 25% of 239 patients taking it to have heart attacks within 13 days of starting the drug. 3 How does this happen? How does a drug that goes through the process mandated by the FDA injure or kill people as soon as it is released to the public? Because the method by which the drugs are declared safe for human consumption is outdated and obviously detrimental to humans. Animal testing is mandated by the FDA for certain drugs to receive approval for distribution to the public: 4 Scientists have to test those compounds that have shown at least some desired effects in living animals. In animal test- ing, drug companies make every effort to use as few ani- mals as possible and to ensure their humane and proper care. Two or more species are typically tested because a drug may affect one differently from another. Such tests show whether a potential drug has toxic side effects and what its safety is at different doses. 5 If animal testing is an accurate indicator that medi- cations are safe, why are so many drugs pulled from the shelves once humans start taking them? There is a much evidence that animal tests are not reliable. The results are sometimes discarded if the desired effect is not achieved. 6 In fact, 95% of drugs that pass the ani- mal testing stage are immediately discarded because they are useless or harmful to humans. 7 Human con- sumers need drugs that are proven to be safe and effec- tive before they are prescribed. Because animal testing is unreliable and not indicative to human response, ani- mal testing should be banned and alternatives utilized so that drugs are safer and useful. HISTORY OF ANIMAL TESTING AND ITS REGULATING LAW The first record of animal testing can be traced back to early Greece. Aristotle was the first person to dissect animals to reveal internal differences. 8 But it was not until the 19th century that animal testing gained wide- spread popularity. This movement was made popular by the leading scholars of that time. For example, in 1865, the so-called father of experimental science, Claude Bernard, a French physiologist, published An Introduction to the Study of Experimental Medicine, which in essence stated that information gleaned 148 • Journal of Nursing Law • Vol. 12, No. 4 from laboratory studies far exceeded that gained in human clinical trials and investigation. 9 He concluded, “Experiments on animals, with deleterious substances or in harmful circumstances, are very useful and entirely conclusive for the toxicity and hygiene of man. Investigations of medicinal or of toxic substances also are wholly applicable to man from the therapeutic point of view.” 10 He also “succeeded in persuading the scientific community that if any disease could not be reproduced on animals in the laboratory, it simply did not exist—despite accumulated clinical (human) data to the contrary.” 11 Other key 19th-century figures in the popularization of animal studies included the renowned microbiologist Louis Pasteur and the noted German physician Robert Koch. Both had limited successes with animal studies that can be attributed to other causal factors. 12 Pasteur was studying rabies and was able to infect the brains of animals and inject this “vaccine” into humans who were bit by a rabid animal. Many of these people did not develop rabies, but clinically, very few humans ever develop the disease after being bitten. Therefore, the people that “recovered” were more than likely never infected in the first place. 13 Koch had similar limited success. He was studying cholera. Previous animal studies he had conducted consisted of giving diseases to animal models. He stated that the microbe reproduced the same in this animal model as in humans. Unfortunately, he had to discredit himself when he was unable to produce cholera in any animal model. 14 Because he had to give up on the animal study and focus solely on human investigation, he was able to isolate the microbe and determine its mode of transmission. This information led to preven- tive actions to help stop the spread of the devastating disease. 15 His work and study led to the credibility of animal testing despite his reversal later in his career. Despite dubious laboratory results of the past, animal testing has continued on through the years and is now a mandatory process for drug approval by the FDA. Con- gress granted authority to the FDA under the federal Food, Drug and Cosmetic Act (FDCA) and the Public Health Service Act. 16 Over the years, many changes have occurred in the FDCA that increased the govern- ment’s control over medications, labeling, and develop- ment processes. 17 One of the requirements of any drug before premarket approval is that the manufacturer has to show that the drug has had proper preclinical inves- tigation. 18 This includes animal studies 19 “before any clinical testing of a new drug is undertaken, of reports, by the manufacturer or the sponsor of the investigation of such drug, of preclinical tests (including tests on animals) of such drug adequate to justify the proposed clinical testing.” 20 Therefore, regardless of the rocky beginnings of such science, the government mandates that all drugs go through animal testing to demonstrate a basis for safety and efficiency of the drug. ANIMALS ARE BIOLOGICALLY AND PHYSIOLOGICALLY DIFFERENT FROM HUMANS Animals are biologically different from human beings. Animal bodies and their systems react very differently from humans. In fact, animal tests and human results are the same only 5% to 25% of the time. 21 Eighty-eight percent of doctors agreed that animal experiments can be misleading “because of anatomical and physiologi- cal differences between animals and humans.” 22 When comparing certain drugs and their different effects on humans and then on animals, the results are startling. For example, the drug Thalidomide was found safe in mice and approved for distribution from the German government. It was later found to cause severe birth defects in humans after thousands of babies were born with debilitating defects. Many of those children died before the age of 1. 23 When the manufacturer was sued, it ultimately settled, and there was no judgment made. Many of the experts testifying agreed that the animal tests could not be relied on. 24 More recently, the drug Vioxx was withdrawn from the market. It was manufactured to be an anti- inflammatory medication. It passed animal studies on mice, rats, and African green monkeys. 25 The medication was with- drawn in the fall of 2004. The drug caused cardiac and vascular disease when used in humans. 26 It is estimated that as many as 60,000 Americans have died from the drug and that more than 100,000 Americans have been injured. 27 After an investigation, William G. Bowen, the chairman of the Special Committee of Merck & Co., Inc., concluded “that management acted with integrity and had legitimate reasons for making the decisions that it made, in light of the knowledge available at the time.” 28 There are many other drugs that also have had devas- tating effects on humans after they had been found safe in animal testing. Arsenic is safe in large quantities when given to sheep but is fatal in humans. 29 Chlorampheni- col, an antibiotic, was safe in animal testing but caused irreversible damage to the bone marrow of humans. 30 Encainide and flecainide were found safe when tested on animals, and when given to humans, they caused heart attack and death. 31 It is estimated that as many as Stachura • An Argument to Ban Animal Testing • 149 3,000 people died from using the drugs. It was withdrawn in 1989. 32 Ibufenac, an anti-inflammatory, caused no liver damage to animal subjects but caused liver damage and death in humans. It was also withdrawn from the mar- ket. 33 Domperidone, a drug that was used to help with nausea and vomiting associated with anticancer drugs, caused no heart rhythm changes in animals but caused serious heart arrhythmias in human. 34 These are just a handful of documented drugs that showed safe adminis- tration in animals and serious side effects in humans. In contrast, there are plenty of drugs that are unsafe or deadly to animals while having a beneficial effect on humans. For example, aspirin is deadly in cats and can cause birth defects in dogs, monkeys, and rats. In humans ,it is an analgesic and a therapeutic blood thin- ner. 35 Penicillin, a great antibiotic for humans, kills guinea pigs. 36 Depo-Provera, a long-acting contracep- tive in humans, causes cancer in animals and breast and uterine infections in dogs. 37 Lasix, a common and effective diuretic, causes liver damage in mice but does not affect the human liver. 38 Digitalis, a drug that is used for heart failure and arrhythmias, causes high blood pressure in dogs but does not raise blood pressure when given to human patients. 39 Iron sorbitol, which is used for anemia, causes cancer at the injections site when given to animal subjects but does not when given to humans. 40 If animal tests were reliable and relied on, none of these beneficial drugs would be available for human use. The FDA claims that they also use animal testing to determine the metabolism of the drugs. “In animal test- ing, scientists measure how much of a drug is absorbed into the blood, how it is broken down chemically in the body, the toxicity of its breakdown products (metabo- lites), and how quickly the drug and its metabolites are excreted from the body.” 41 Because the systems of animals and humans are different, there is little to be gained from these tests. For example, the drug Digoxin is metabolized in 44 hours in a human and in only 9 hours in rats. 42 Demerol is metabolized in 1.2 hours in rhesus monkeys, 0.9 hours in dogs, and 5.5 hours in humans. 43 It takes Digitoxin 216 hours to be metabolized by humans and only 14 hours in dogs and 18 hours in rats. 44 Not only does the absorption rate needed to metabo- lize drugs differ between humans and animal subjects, but the lethal doses are also significantly different. Amytal causes death in humans when the concentration reaches 42 mg/kg. In rats, the dose that would cause death is 560 mg/kg. 45 Boric acid is lethal to humans when the dose is 640 mg/kg. In rats, the number rises to 2,660 mg/kg, and the number rises still when given to mice, 3,450 mg/kg. 46 For Lindane, a human lethal dose would be 840 mg/kg, while a rat’s lethal dose is signifi- cantly smaller, 125 mg/kg. 47 All animals differ from humans when it comes to basic physiological functions. Basic human physiology is as follows: normal breaths per minute are 12 to 20, respiratory tidal volume is 500 ml, heart rate is 60 to 100 beats per minute, and normal body temperature is 98.6 degrees Fahrenheit. Normal breaths per minute for a guinea pig is 120, a mouse 180, a primate 35, and a rat 90. 48 Tidal volumes are also very different. The normal tidal volume in a cat is 30 ml, a guinea pig 2.5 ml, a rat 1.6 ml, and a mouse 0.15 ml. 49 A normal heart rate for a guinea pig is 155 beats per minute, a mouse 570, a gerbil anywhere from 260 to 600, and a normal rat 350. 50 Body temperature also varies. For a gerbil, the normal body temperature is 102.2 degrees Fahrenheit. A mouse’s nor- mal body temperature is 99.3 degrees Fahrenheit, and a rat’s is 100.4 degrees Fahrenheit. 51 Given all the basic differences, it is impossible to see how a drug meant for a specific body system can be accurately tested when each body system is so different. Rodents are the most commonly used animals for experiments, but they differ drastically from humans biologically. In humans, plaque is deposited in blood vessels, and this leads to heart attacks and strokes. In rodents, plaque is deposited in the liver. 52 A rodent’s life span is only 3 years, while a human has a life span of 72 years. Therefore, a rodent must be given massive doses of drugs to make comparisons, much more then a human will ever use. 53 A rodent can manufacture vitamin C in its body, while a human cannot. A human must obtain vitamin C through diet. 54 A rodent can eliminate drugs from its body in 3 hours; a human eliminates the drug in 72 hours. This increases the danger of a drug when given to the elderly because the elderly take even longer to eliminate drugs because of the aging process of the kidneys and livers. Therefore, the drug stays in their bodies even longer. 55 Rats do not have a gallbladder; humans do. Therefore, the metabo- lism of fats is completely different. 56 Looking at such varying data, it is hard to imagine what knowledge can be gained about human safety when testing drug effects on these animals. In addition to biological differences leading to incon- sistent data, the environment the animals are kept in affects the way they react to medications and disease processes: Routine handling, venipuncture, and gavage (the admin- istration of test compounds through an oral tube) elicit striking elevations in pulse, blood pressure, and steroid hormone release that can persist for an hour or more after the event. Similarly, routine features of the laboratory 150 • Journal of Nursing Law • Vol. 12, No. 4 environment—isolation, confinement, social disruption, noise, and restrictions on physical movement—have been shown to be noxious for animals. Together, these bodies of evidence indicate that even routine experiments that appear to be minimally invasive can be highly stressful for the animal subjects, and this finding applies to commonly used rodent species as well as larger and less frequently used animals. Stress effects are relevant to humane con- cerns as well as to the interpretation of scientific findings. Research on immune function, endocrine and cardiovas- cular disorders, neoplasms, developmental defects, and psychological phenomena are particularly vulnerable to stress effects. 57 Being that stress itself exerts such an effect on ani- mals, the results of any test performed in this arena are skewed at best. Sometimes simple environment changes, such as bedding and diet changes, have affected disease processes in animals. 58 And yet these are the results that are being relied on for human safety. ANIMALS DO NOT HAVE THE SAME DISEASES AS HUMANS When producing drugs, manufacturers are trying to cure a certain disease or aliment. The fact remains that animals do not get the same diseases that humans have. Only 1.16% of human illnesses are seen in animals. 59 “Different species have different biological reactions to disease, viruses, compounds, and so on. Experimen- tal results between dogs and cats differ, as do some results between different strains of mice; therefore it is not practical to apply nonhuman animal results to humans.” 60 Animal models for diseases are created by the re- searcher to be as close to the human disease process as possible. But this can rarely be done. For example, arteriosclerosis is a disease process in which plaque is deposited on blood vessel walls. In humans, this is the main cause for heart attacks and strokes. One of the most widely used animals for these studies are rabbits. They are fed a high-cholesterol diet, and their vessels become blocked. The difference between humans and rabbits is that the rabbit’s plaque lesions do not develop fibrosis, hemorrhaging ulceration, or thrombosis. The primary reason for the study is to study these proper- ties. These are the properties that cause complications in humans, and they cannot be replicated in animal models. 61 Cancer is another disease that cannot be replicated in animal studies. Animals are given artificial tumors that differ greatly from spontaneous ones that arise in humans: Indeed the Lancet (1972) warned that, since no animal tumour is closely related to a cancer in human beings, an agent which is active in the laboratory may well prove useless clinically. This was certainly the case with the US National Cancer Institute’s 25-year screening programme in which 40,000 plant species were tested for antitumour activity. As a result of the programme several materials proved sufficiently safe and effective on the basis of ani- mal tests to be considered for clinical trials. 62 Some of the agents produced showed promising results with animal testing, but they were ineffective in humans or too exotic for use. After 25 years of this expansive and expensive program, not one antitumor drug emerged. 63 The National Cancer Institute now uses human cancer cells to accurately screen new drugs. 64 The world of psychotropic drugs gives rise to a com- pletely different issue. There are no animal models for schizophrenia, mania, depression, and other mental ill- nesses. The drugs that are used to treat these disorders are created from drugs that have had a particular side effect. For example, when trying to find a drug that increases a certain neurotransmitter, they test for the drugs that have that as a side effect. The result is that the drugs are made with serious known built-in side effects from the beginning. Many of the drugs used for mental disorders to block dopamine receptors have side effects such as catalepsy, Parkinsonism, and tardive dyskinesia. 65 Therefore, the medications for these indi- viduals are already set up with devastating, life-altering side effects. Because animals cannot “catch” human diseases, testing effectiveness of medications is impossible. The results are naturally not able to be transferred to humans suffering from the disorder. These models are set up for failure, and humans who rely on drugs that are tested in this manner are taking risks with their own lives. THERE IS A LACK OF INTEREST IN DEVELOPING ALTERNATIVE METHODS Animal testing is big business. It is estimated that tril- lions of taxpayer dollars along with charity donations fund animal testing. 66 The subjects are relatively cheap and the regulations for their welfare quite broad: Private institutions, such as facilities that breed animals for research and those companies that make equipment and caging for animals, depend on animal research in order to stay in business. Finally, many of the people who receive federal funding and perform research depend on that money for a living, and for the future success of their career. With all of this money at stake, there is not much incentive for finding alternatives to animal research. 67 Stachura • An Argument to Ban Animal Testing • 151 And, not surprisingly, the funds needed to develop alternatives are minimal. 68 Government grants, which are essential for research institutions, are influenced by the amount of publishing a researcher can do. Animal testing is quick because animals have a shorter life span than humans, and they can also be euthanized to obtain results. Researchers also find it easier to control the test subjects, unlike clinical testing, where the subjects are human: 69 The more animal experiments the researcher does, the more articles get published. The more articles he gets published, the more grant money he receives. The more grant money he receives, the more money the university receives. The more money the university receives, the better its reputation. The better its reputation, the less liable big business is when the university safely tests its new product and hence the more products they can sell. The more big business sells the more money for adver- tising and hence the more compliant is the media. And on the other side of this cabal is the unwitting American consumer, paying through the nose for, at best, nothing and worse, ill health. 70 There are many individuals who profit from animal testing and they will not willingly allow the money wheel stop. In addition to funding issues, the FDA mandates that animal testing be completed prior to approval. 71 Interestingly enough, a new bill, the ICCVAM, has been passed that has looked into alternatives: An important stride in the use of alternative methods occurred at the end of 2000, when a bill known as the ICCVAM Authorization Act was passed. This bill made the Interagency Coordinating Committee for the Validation of Alternative Methods ( ICCVAM ) an official standing body of the government. ICCVAM validates alternative methods and subsequently recommends these validated alternatives to government agencies (such as the Food and Drug Adminis- tration). It is then the responsibility of the government agen- cies to strongly recommend that the alternatives be used by the institutions that receive funding from that agency. It is important to point out that animal tests have never under- gone the vigorous validation process that alternatives must go through. Furthermore, the results of alternative methods are most often compared to animal results. 72 It is hoped that, with the passage of this new bill, alternatives will be seen more seriously and that safer methods can be developed. The next hurdle is whether institutions that do research will embrace the change, which historically has not been the case. 73 ANIMAL TESTING IS DANGEROUS TO HUMANS Animal testing is relied on to the detriment of humans. Drugs are being produced and given to humans without being truly tested for humans. Therefore, real testing is occurring in human subjects who are given the medi- cation as if it were safe. The FDA approval for safety is a facade. It gives the allusion that the manufacturer has produced a safe product that works the way it was intended to work and that the government agrees. The public accepts that approval as truth and rely on it. When humans are used for experimentation, the FDA requires they be given an extensive informed con- sent form that outlines the risks involved in participa- tion. 74 Patients who died from taking Vioxx were never given that consideration, but they were, in essence, being experimented on, as are all humans who take a new drug. The researchers do not really know for sure what the human reaction to a drug is until humans start taking it. When humans start taking the drug, the manufacturer really learns if the drug is effective and safe. The people taking the drug do not know that they are being tested on. They do not know the risks associ- ated with the drug because the manufacturer does not even know. When animal testing is the basis for safety and effi- ciency, the humans are the one’s truly being experi- mented on. Their reactions to the “safe” drug are the true side effects and toxicity levels. PROPONENTS FOR ANIMAL TESTING There are many who, even after seeing the evidence, still believe that animal testing is necessary and essen- tial to human medical innovation. 75 One argument is that animal studies have saved thousands of human lives. 76 The believers look to the advances made in medicine and attribute them to animal research. But the research has indicated that misleading information acquired and relied on from animal studies has injured and killed humans. And there are alternative methods to animal testing that are more accurate in determin- ing efficiency and safety of drugs. 77 These alternative methods can save many more lives. Proponents also argue that there has been medical knowledge gained through animal testing. But the fact remains that it is impossible to say that those gains would not have been made without animal studies. In fact, the innovation may have occurred more quickly if animal testing were not utilized to mislead the researcher. 78 For example, the researcher who devel- oped the polio vaccine won the Nobel Peace Prize based on his work with in vitro studies on the virus, not the animal studies. “Nobel Laureate Arthur Kornberg noted that for 40 years, experiments on monkeys who had 152 • Journal of Nursing Law • Vol. 12, No. 4 been infected with polio generated ‘limited progress’ toward a cure. The breakthrough came when scientists learned how to grow the virus from human and mon- key cells.” 79 Another argument is that testing on animals will show how safe a drug is. This is clearly erroneous. There is an abundance of research that shows that animal testing does not ensure that a drug is safe for human consumption. 80 Many people have died or have been seriously injured after they took a drug that had passed animal testing. The evidence presented here, along with the statistics of medications that are with- drawn from the market, clearly show that animal stud- ies do not guarantee that a drug is safe. Proponents also argue that if testing is not done on animals, then the drugs have to be tested on humans and that testing on humans is unethical. 81 This reason- ing is simply untrue. Because the drugs are not being tested on animals does not mean that they will be test- ed on humans either. There are not just two options. There are many others. In vitro studies examine study cells in a test tube to see the reaction that the cells have to a chemical. Computers can also be used as models to determine safety. 82 These are just a few of the options that are available. COMMON-LAW ISSUES AND ANIMAL TESTING The case law regarding animal testing admittance in trials is shrouded by discussion regarding the rules of evidence and the Daubert standards. The first stan- dard used when looking whether to admit evidence in a trial was made in 1923 in Frye v. United States, the Supreme Court held that as to scientific evidence, the method must be generally accepted in the field where it has come from. 83 This standard was changed in Daubert v. Merrell Dow Pharmaceuticals, Inc. in some jurisdictions. 84 The Court looked to Rule 702 of the Federal Rules of Evidence (FRE 702) and concluded that FRE 702 superseded the Frye standard. 85 The Court stated that FRE 702 was not meant to allow the admit- tance of all scientific evidence. Thus, the Daubert stan- dard was developed. The Court held that the trial court is the gatekeeper in regard to expert testimony. All scientific testimony that is admitted as evidence should be both reliable and relevant. 86 To be reliable, the testimony must be “based on recognized methodology and supported by appropri- ate validation based on what is known.” 87 The Supreme Court laid out five factors that are considered when determining the reliability of testimony. These factors are: (1) whether the theory has been tested; (2) whether the theory has been subject to peer review and publication; (3) the known or potential rate of error; (4) whether standards and controls exist and have been maintained with respect to the technique; and (5) the general acceptance of the methodology in the scientific community. 88 The facts of the case determine which of these fac- tors apply. In addition to these, there are other factors that a court can consider when assessing the reliability of expert testimony: (1) whether the expert’s opinion is based on incomplete or inaccurate dosage or duration data; (2) whether the expert has identified the specific mechanism by which the drug supposedly causes the alleged disease; (3) whether the expert has … Animals 2014, 4, 729-741; doi:10.3390/ani4040729 animals ISSN 2076-2615 www.mdpi.com/journal/animals Article Ethical and Animal Welfare Considerations in Relation to Species Selection for Animal Experimentation John Webster Emeritus, University of Bristol, Old Sock Cottage, Mudford Sock, Yeovil, Somerset BA22 8EA, UK; E-Mail: [email protected] Received: 12 March 2014; in revised form: 14 August 2014 / Accepted: 11 November 2014 / Published: 3 December 2014 Simple Summary: When making a choice of species for animal experimentation we must balance its suitability as a model for human medicine against the potential harms to the animals both from the procedures and the quality of their lifetime experience. The capacity to experience pain may be similar in mammals, birds and fish. The capacity to suffer from fear is governed more by sentience than cognitive ability, so it cannot be assumed that rodents or farm animals suffer less than dogs or primates. I suggest that it is unethical to base the choice of species for animal experimentation simply on the basis that it will cause less distress within society. Abstract: Ethical principles governing the conduct of experiments with animals are reviewed, especially those relating to the choice of species. Legislation requires that the potential harm to animals arising from any procedure should be assessed in advance and justified in terms of its possible benefit to society. Potential harms may arise both from the procedures and the quality of the animals’ lifetime experience. The conventional approach to species selection is to use animals with the “lowest degree of neurophysiological sensitivity”. However; this concept should be applied with extreme caution in the light of new knowledge. The capacity to experience pain may be similar in mammals, birds and fish. The capacity to suffer from fear is governed more by sentience than cognitive ability, so it cannot be assumed that rodents or farm animals suffer less than dogs or primates. I suggest that it is unethical to base the choice of species for animal experimentation simply on the basis that it will cause less distress within society. A set of responsibilities is outlined for each category of moral agent. These include regulators, operators directly concerned with the conduct of scientific experiments and toxicology trials, veterinarians and animal care staff; and society at large. OPEN ACCESS Animals 2014, 4 730 Keywords: reduction; replacement; refinement; utilitarianism; autonomy; justice; ethical matrix; moral agents; sentience 1. Introduction “The great fault of all ethics hitherto has been that they believed themselves to have to deal only with the relations of man to man. In reality, however, the question is what is his attitude to the world and all life that comes within his reach.” —Albert Schweitzer The ethical and legislative principles by which to justify and define good practice with regard to scientific procedures with animals “calculated to cause pain, distress, suffering or lasting harm” have been established within international treaties such as the Amsterdam Treaty Protocol [1], international legislative provisions including the Council of the European Union Convention ETS123 [2], national legislation such as the UK Animals (Scientific Procedures) Act [3] and the European Directive on the protection of animals used for scientific purposes [4]. They require that the potential harms to animals under experiment should be assessed in advance and justified in terms of their possible benefit to the society of humans or (more rarely) other animals. Of course, the harms and benefits do not accrue to the same species and the species to which the harm is done cannot contribute to the decision-making process. These unfortunate facts create a major ethical dilemma, but not one that comes within the remit of this article. The principles that govern the need to minimise harm are encapsulated within the classic triad of Russel and Burch [5], namely “reduction, replacement, and refinement”; the three R’s. Briefly stated, reduction means using the smallest possible number of living animals to achieve the desired objective. Replacement refers to the use of non-sentient organisms, or direct studies with humans, as an alternative to the use of protected animals for experiments. Refinement has two applications. It refers to any changes in protocol that can reduce the incidence or severity of distress experienced by living vertebrate animals in consequence of scientific procedures. It also refers to any changes in husbandry that can improve their welfare assessed in terms of their lifetime experience. ASPA (1986) interprets the principles of the three R’s as follows: “When an experiment has to be performed, the choice of species shall be carefully considered and, where necessary, explained to the authority. In a choice between experiments, those which use the minimum number of animals, involve animals with the lowest degree of neurophysiological sensitivity, cause the least pain, suffering, distress or lasting harm and which are most likely to provide satisfactory results shall be selected”. The broad aim of my paper is to contribute to the discussion as to how best we may apply ethical principles to the conduct of scientific procedures with animals. Of course, one fundamental principle of moral philosophy is that some harms are unacceptable in any circumstances. However, this paper starts from the premise that the use of animals for procedures necessary to advance science and protect human health and safety does not fall into this category. My specific aim is to examine the ethical and welfare issues that should govern the choice of species within the orders of sentient animals for Animals 2014, 4 731 scientific procedures that may cause pain, suffering distress or lasting harm. The first step should always be to explore alternatives to the use of sentient animals. However, when there is no realistic alternative we need to ask: “How do the potential benefits accruing from the choice of a particular species rank against any changes, for better or worse, in the harm done to the test animals?” This paper will examine the question within the context of key principles and theories of moral philosophy and good husbandry, namely the educated and compassionate care of animals used in scientific procedures. This paper will explore these questions within a formal ethical matrix that seeks to achieve justice for all creatures involved directly or indirectly in scientific procedures with sentient animals. Many of the views expressed in this paper emerged from productive discussion with my colleagues Peter Bollen, Herwig Grimm and Maggie Jennings during the preparation of an earlier paper on the ethical implications of using the minipig in regulatory toxicology studies [6]. 2. Ethics Ethics, synonymous with moral philosophy, is a structured approach to examining and understanding the moral life. Classical, or “top down” ethics asks the question “Which general moral norms for the evaluation and guidance of conduct should we accept and why?” Olsson et al. [7] discuss this on the basis of three ethical theories, Contractarianism, Utilitarianism and Animal Rights. Briefly, contractarianism requires humans, as moral agents, to afford an appropriate degree of protection to animals within our care, the moral patients. The morality of this approach is limited by the fact that it is us, not them who decides how much protection is appropriate; e.g., pets are liable to be given more protection than farm animals. Singer [8] has profoundly explored the application to non-human species of the theory of utilitarianism, namely the practice of beneficence and non- maleficence to achieve the greatest good for the greatest number. The extent to which we may do good or harm will be defined by the capacity of the recipient animal (human or non-human) to experience pleasure or suffering. The third theory, that of Animal Rights [9] is typically applied to define boundaries that should not be crossed, e.g., the conferring to primates of the right not to be used in experimentation. It should be clear by the end of my argument that I do not believe this to be a useful argument, not least because the animals to which we seek to confer rights have not contributed to the discussion. This “top-down” approach makes for good philosophy but can have difficulty dealing with the complexities and uncertainties of real life. Moreover the ethical arguments that we use to justify our actions are of absolutely no concern to the animals. It is what we do that counts. An alternative “bottom-up” approach to the ethical evaluation of real-life situations in which we may do both good and harm is first to identify the specific practical issues, then proceed to a step-by step analysis of the relevant moral issues. Beauchamp and Childress [10] have used this approach to address problems in Biomedical Ethics. It is built upon three pillars of common morality defined as “promoting well-being”, utilitarianism (the greatest good for the greatest number), “autonomy”, respect for the individual (“do as you would be done by”); and “justice” which incorporates principles of equality and fairness. I suggest that it is helpful to think of utilitarianism and autonomy as inputs to moral action and justice as a moral outcome. The notion of justice for individual animals used in scientific procedures is illogical since they can derive no direct benefit to offset the harms done. In this context therefore, Animals 2014, 4 732 the concept of justice places the onus entirely on us, the moral agents to do the best we can for our moral patients. It demands, obviously, that we should seek a fair and humane compromise between the likely benefits to humans of specific procedures and their potential to cause pain, suffering, distress or lasting harm to the test animals. Our second, maybe less obvious but equally important aim should be to do all we can to ensure that the animals enjoy the best possible quality of life at all times when not directly involved in experiments. This is consistent with the principle of autonomy, which implies much more than the absence of suffering and pain. Rollin [11] states: “Not only will welfare mean control of pain and suffering, it will also entail nurturing and fulfilment of the animals’ natures, which I call telos,” (as did Aristotle) “the unique, evolutionarily determined, genetically encoded, environmentally shaped set of needs and interests which characterize the animal in question—the ‘pigness’ of the pig, the ‘dogness’ of the dog, and so on”. There are those, including philosophers [12] who argue that the concept of telos is not well defined and that it is possible to deal satisfactorily with the issues in response to which the concept was evoked without giving up the idea that welfare is all that matters from a moral point of view in our dealings with animals. Personally, I find telos to be a useful concept. However, I agree with Sandoe that it may be more useful simply to state that our aim should be to provide animals with a physical and social environment as satisfactory as possible in terms of their phenotype and experience [13]. 3. Moral Agents and Moral Patients: The Ethical Matrix The balancing of harms to animals against benefits to society is the central question in the analysis of experiments with animals but it is not the only one. The ethical approach must be to seek a fair and just compromise between the reasonable expectations of all concerned parties, whether directly or indirectly involved. Table 1 sets out the principles and identifies the concerned parties in the form of an ethical matrix [14]. The three columns identify the three ethical principles, wellbeing, autonomy and justice. The five concerned groups are: 1. Human society at large: the beneficiaries of new science, pharmaceuticals and other substances tested on animals 2. Regulators: those regulating procedures designed for the advancement of science and statutory testing for product safety. 3. Operators: those licensed to carry out scientific procedures with animals, controllers of pharmaceutical and testing companies, suppliers of test animals. 4. Animal care staff: technicians and veterinarians directly concerned with animal care 5. Experimental and breeding animals � Animals 2014, 4 733 Table 1. Application of the ethical matrix to the use of animals in scientific procedures, regulatory toxicology and drug testing. Wellbeing Autonomy Justice Human society at large Improved health Product safety Freedom of choice among available therapies and products Compassionate and informed recognition of the harms to the test animals Regulators of products Regulators of animal experiments Responsibility to society (health and safety) Responsibility to animals (minimise harms) Open-minded approach to new developments (e.g., testing methods) Respect for animal welfare enshrined in legislation and codes of practice Operators (Scientists, pharmaceutical industry, animal breeders) Financial reward Informed and sympathetic regulation of procedures Open-minded approach to new developments (e.g., testing methods). Compassionate interpretation of legislation. Apply three R’s Animal care staff Pride and security in work Control over decisions: e.g., animal husbandry and end-points Input into animal welfare policy Experimental animals Minimal harm from procedures Physical and emotional well-being through good husbandry Environmental enrichment Just interpretation of harm:benefit equation The first four groups are all moral agents, the animals are the moral patients. The Ethical Matrix as set out in Table 1 presents a structure for discussion of the ethical issues. The phrases within each of the boxes are simply headlines. It is not possible within the scope of this paper to consider all the responsibilities of the various moral agents. However, I offer a few examples to illustrate how the matrix can be made to work. It is (for example) self-evident that improved scientific knowledge, health and product safety contribute to the well-being of society at large (Group 1) and, of course, to the welfare of other domestic animals. It is generally, though not universally accepted that the properly regulated practice of scientific procedures with animals is essential to this aim (Groups 2 and 3). Equally we recognise that financial success and pride in work are proper elements of wellbeing. This applies both to scientists and staff with day-to-day responsibility for animal care (Groups 3 and 4). However, these “rights” bring responsibilities. The utilitarian principle of respect for animal wellbeing relates, of course, to the principle of minimising harm directly associated with scientific procedures, whether for the advancement of knowledge or for toxicity testing. This applies not only to the physical effects of the procedures themselves but also to any emotional effects of the procedures (including handling and restraint) and other aspects of the animals’ lifetime experience. It therefore requires that proper attention should be given to the physical and emotional welfare of all laboratory animals from their birth to death. Utilitarian principles dictate that the general wellbeing of society depends on scientists who seek new knowledge and regulators who demand product testing and trials with animals to ensure public health and safety. The principle of justice requires that the regulators ensure that Animals 2014, 4 734 proper respect for the test animals is enshrined in legislation and codes of practice, and that licensed experimenters and animal care staff ensure that these principles are implemented in practice. Two practical expressions of the principle of autonomy, as it applies to society at large, are competition and freedom of choice, both of which are encouraged through the development of new, desirable drugs and chemicals. The principle of autonomy, as applied to regulators and operators of animal experiments implies that both parties should be open-minded to new ideas. This is particularly important in the case of toxicology testing where it can be too easy to stick to long-standing methods and choice of species, because “we have always done it this way”. Any discussion of the ethics of animal experimentation must include the application of the three principles to the animal care staff. They have the right to enjoy pride and security in their work. To this end they should be given every encouragement to ensure the best possible welfare for the animals in their care, not only on a day-to-day basis but also through opportunities to contribute to strategic decisions, e.g., in regard to housing and environmental enrichment and setting end-points for procedures calculated to cause chronic suffering or lasting harm. Application of the utilitarian principle to the experimental animals requires the need to minimise harm from the procedures themselves and to promote physical and emotional well-being through good husbandry on a lifetime basis. Autonomy can be encouraged through the design and provision of enriched environments that provide freedom of choice for individuals without compromising the welfare of others. The outcome, justice for the animals, requires that all who work with experimental animals, who commission work with experimental animals, or who benefit from the outcome of such work, should promote their welfare and minimise harms through policies based upon the principle of respect for all life. 4. Species Selection: Ethical Issues and Practical Questions The ethical matrix provides a framework upon which to identify and explore issues raised by the moral imperative to seek a fair compromise between the differing needs of the different interest groups (Table 1). We should seek the most humane solution to the harm/benefit assessment for every class of experimental animal and every procedure. In the specific context of species selection we are faced with four key questions. 1. How do species compare as models for the physiological, psychological or medical function in humans that the experimental procedure seeks to reproduce? 2. To what extent may different classes of sentient animal (e.g., fishes, birds and mammals) or different species within the class mammalia (e.g., rodents, farm animals, dogs and primates) differ (or not) in their capacity for pain and suffering? 3. To what extent may the choice of species reduce the harm associated directly or indirectly with a specific scientific or testing procedure? 4. To what extent is, or should the choice of species be encouraged or constrained by human values that are unsupported by scientific evidence? Questions 1 and 2 are matters of science and practical expediency. This implies that the answers are not fixed and should always be subject to further questioning and revised in the light of new Animals 2014, 4 735 understanding. Question 3 arises from the moral need to minimise harms and involves both science and ethics. Question 4 is entirely a matter of ethics. 5. Species Suitability as Models for Human Physiology and Medicine Considered simply in terms of human self-interest, the suitability of a species for procedures regulated by the EU Directive 2010/63 [4 ] is likely to be determined by its assumed similarity to human physiology, pathophysiology, psychology or behaviour. Other important considerations include convenience and cost, and the predictability and consistency of the outcome measures of the trial, based on past experience and the genetic uniformity of the test animals. Genetically similar or cloned rats and mice have obvious advantages in all these respects. It is not possible to come to any general conclusions regarding the relative suitability of different non-rodent species as models for humans. Webster et al. [6] have reviewed factors affecting choice between minipigs, dogs and primates. For example, in some toxicological or immunological studies, a valid case can be made for the use of the minipig because its skin is similar to humans. The dog has been chosen as the preferred species in the development of anti-ulcer drugs, since dogs have a similar gastric mucosal membrane to that of humans. A consensus is emerging within the scientific community that the use of primates should be restricted to those experiments for which there is, at this time, no known alternative [15,16]. This could restrict the choice of primates to certain studies in neuroscience and brain function and communicable diseases common to man and other primates (e.g., HIV/AIDS and tuberculosis). Some important questions, e.g., many studies of the immune system, are so species-specific that no non-human species can serve as an ideal predictive model. However, the problem is being addressed by new science. For example, Geertje et al. [17] have demonstrated that minipigs are no less effective than primates as a model for human immunogenicity testing. All the arguments outlined above can and should be incorporated into the decision as to the selection of the most suitable species for a specific procedure. However, choice of species should never be made on the basis of conservatism. The continued use of dogs and primate species as non-rodent subjects in regulatory toxicology is often justified by the preamble “the species has been used in the past, there is a substantial library of knowledge and it is acceptable to the regulators”. Obviously the decision as to whether or not use dogs or primates for scientific and regulatory procedures will involve factors other than their suitability as models for human function. These other factors are discussed later. At this stage it is sufficient to say that the continued use of these two species must be justified by state-of-the-art science, not by tradition. 6. Sentience and “Neurophysiological Sensitivity” ASPA defines the rules of engagement for the protection of “any living vertebrate other than man” when used in procedures likely to cause “pain, suffering, distress or lasting harm”. EU Directive 2010/63/EU states “in addition to vertebrates, including cyclostomes, cephalopods should also be included in the scope of this Directive, as there is scientific evidence of their ability to experience pain, suffering, distress and lasting harm”. However, ASPA, while affording protection to all these animals, then proceeds to state that the aim should be to “involve animals with the lowest degree of Animals 2014, 4 736 neurophysiological sensitivity”. This begs the question ‘Can we be sure of our assumptions as to differences in neurophysiological sensitivity between classes of vertebrates (e.g., mammals, birds and fish), still less between species of mammals (e.g., mice, rats, pigs, dogs and primates)?”. Let us consider first the matter of pain. It is now beyond cavil that, for all mammals, pain is a physical and emotional experience. It is much more than just an unpleasant sensation; it also induces changes in behaviour and mood broadly similar to those seen in humans [18]. Evidence is accumulating to indicate that similar responses to pain are seen in birds [19] and fish [20]. In respect to procedures calculated to cause pain it would appear to be unjust to distinguish between these three classes of sentient animal in terms of neurophysiological sensitivity. It is valid, however, to ask whether different classes of sentient animal, or different species with the class mammalia differ in their response to scientific and husbandry procedures in elements of suffering other than pain, especially those elements with the potential to cause long-term psychological distress (e.g., anxiety). I have previously defined a sentient animal as one that has “feelings that matter” [13]. To expand this definition: sentient animals interpret sensations and experiences primarily in emotional terms and are motivated to behaviour designed to make them feel good and avoid feeling bad. This emotional basis to motivation may, or may not, be modified by cognition (or reason). Having behaved in a way designed to achieve a favourable physical and emotional state, the animal reviews the consequences of its actions. If these are successful, it will achieve a sense of well- being because it has learned to cope. If it fails to cope it is liable to suffer distress. It follows from this that all sentient mammals can suffer distress not only from consequences of scientific procedures, such as pain, fear and malaise, but also from the emotional consequences of failure to cope; i.e., failure to achieve their physiological and behavioural needs within the constraints of their environment. Such long-term consequences cover a spectrum of distress that ranges from chronic anxiety to learned helplessness. Thus means that the capacity of a sentient animal to suffer is defined by its emotional potential, and not necessarily by its cognitive ability. Cognitive understanding of causes and consequences can make things either better or worse. Consider, for example, the effect of human consciousness on the interpretation of pain from dental surgery or stomach cancer. Webster et al. [6] have argued on this basis that it cannot be assumed that a rat or pig is less (or more) capable of suffering in any form than a primate simply on the basis that it appears to be “less like us” in terms of neurophysiological sensitivity. 7. Minimising Harms The responsibility of those who work with animals used for scientific purposes, toxicology and drug testing is directed, in the first instance, to minimising harms associated with all scientific procedures calculated to cause pain, suffering, distress or lasting harm, e.g., infections, induced fractures, genetic modifications known to be associated with significant abnormalities. However, our responsibility should also embrace a proper concern for the lifetime welfare of the animals based on a professional understanding of the special physiological, behavioural and emotional needs of the species concerned. These include: � Animals 2014, 4 737 � Comparison of harms, both physical and emotional, associated with direct interference with the animals in the course of scientific procedures: e.g., blood sampling, gavage etc. and the restraint involved with such procedures. � Adequacy of knowledge and procedures for assessment of pain and distress and identification of humane end points. � Quality of housing and husbandry for test, stock and breeding animals based, wherever possible on the principle of environmental enrichment. � Quality of animal care based on a competent and compassionate understanding of the human/animal bond as it applies to the different species. In all these cases, the effectiveness of practical steps to reduce harm and to enrich lifetime experience, will depend on the professional competence and compassionate understanding of those responsible for day-to-day care of the animals and those responsible for the design and strategic management of the laboratory. Moreover, much of this will need to be species-specific. For example, it may be less stressful to handle a dog than a pig during experimental procedures, but a dog may well display greater anxiety either in anticipation of future procedures or during separation from the animal care staff. The behavioural indices of pain are also very species-specific. Recognition of pain in sheep, a stoic, stone-faced species, requires knowledge of some very subtle signals [21]. 8. Application of the Three R’s Refinement: Substituting a “lower” species (phylogenetic reduction), is often considered to be refinement. Indeed it is encapsulated in the guidance to ASPA (1986) namely to choose animals with the “lowest degree of neurophysiological sensitivity”. However, it should be clear by now that I believe this cannot be assumed simply on phylogenetic grounds. Such a judgement can only be made if assessment of the available scientific evidence suggests that the lower species is less sentient and therefore less likely to suffer. In most cases the scientific evidence does not exist, but where it does, e.g., pain in fish [20] it indicates that we should not act on such assumptions in the absence of definitive proof. Indeed the more evidence we accumulate, the more we should be aware of the limits of our understanding and the need to give the “lower” species the benefit of the doubt. Judgements about whether it is more humane to use one species over another are particularly difficult where the species are closely related phylogenetically (e.g., species within the class Mammalia or order Primates). I contend that it is not possible to distinguish a priori between sentient mammalian species in terms of their capacity to suffer physical or emotional harm. It is however, possible to make …