Refinement Issues in Animal Research. Joanne Zurlo, PhD Institute for Laboratory Animal Research National Academy of Sciences

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1 This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License. Your use of this material constitutes acceptance of that license and the conditions of use of materials on this site. Copyright 2010, The Johns Hopkins University and Joanne Zurlo. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided AS IS ; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed.

2 Refinement Issues in Animal Research Joanne Zurlo, PhD Institute for Laboratory Animal Research National Academy of Sciences

3 Introduction to Joanne Zurlo, PhD Paul A. Locke, DrPH, MPH, JD Johns Hopkins University

4 Section A Introduction, Concepts, and Definitions

5 Concept of Animal Welfare It has been proposed that the following three issues should be considered for animal welfare: 1. Ability of the animal to live under conditions natural to its species 2. Health of the animal 3. Avoidance of affective (uncomfortable) states 5

6 Refinement Alternatives Methods that 1. Alleviate or minimize potential pain and distress 2. Enhance animal well-being 6

7 Public Attitudes Toward Research When polled, most members of the public are favorable toward the use of animals in biomedical research, but not when the animals are subjected to pain 7

8 A Prerequisite for Successful Animal Experiments by now it is widely recognized that [the most humane] possible treatment of experimental animals, far from being an obstacle, is actually a prerequisite for successful animal experiments. W.M.S. Russell and R. Burch, The Principles of Humane Experimental Technique (1959) 8

9 Refinement Considerations Pain recognition and alleviation Distress minimization (prevention), recognition, and alleviation Humane endpoints Environmental enrichment 9

10 What Is Pain? Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage International Association for the Study of Pain 10

11 Some Potential Causes of Pain During Experiments Improper or prolonged restraint Experimental infections Chemical-induced toxic effects Surgical and experimental procedures Post-operative complications Chronic inflammation Tumor-induced pain Improper euthanasia techniques Pain research 11

12 Assessment of Pain in Animals Pain can be assessed by evaluating behavioral measures such as eating, socializing, and withdrawal reflexes, and physiological measures such as blood pressure, heart and/or respiration rate Behaviors will be specific to each species and to individuals within a species Some animals may hide signs of pain 12

13 Challenges to Assessing Pain Recognizing a departure from the normal Subjectivity of pain scales Biases of observer Chronic vs. acute pain 13

14 Rodents and Rabbits Indicators of pain in several common laboratory animals Species General behavior Appearance Other Rodents Decreased activity; excessive licking and scratching; selfmutilation; may be unusually aggressive; abnormal locomotion (stumbling, falling); writhing; does not make nest; hiding Piloerection; rough/stained haircoat; abnormal stance or arched back; porphyrin staining (rats) Rapid, shallow respiration; decreased food/ water consumption; tremors Rabbit Head pressing; teeth grinding; may become more aggressive; increased vocalizations; excessive licking and scratching; reluctant to locomote Excessive salivation; hunched posture Rapid, shallow respiration; decreased food/ water consumption Source: NRC. (2003). Guidelines for the care and use of mammals in neuroscience and behavioral research. 14

15 Cats and Dogs Indicators of pain in several common laboratory animals Species General behavior Appearance Other Dog Excessive licking; increased aggression; increased vocalizations, inclusive of whimpering, howling, and growling; excessive scratching; self-mutilation Stiff body movements; reluctant to move; trembling; guarding Decreased food/ water consumption; increased respiration rate/ panting Cat Hiding; increased vocalizations, inclusive of growling and hissing; excessive licking; increased aggression Stiff body movements; reluctant to move; haircoat appearing rough, ungroomed; hunched posture; irritable tail twitching; flattened ears Decreased food/ water consumption Source: NRC. (2003). Guidelines for the care and use of mammals in neuroscience and behavioral research. 15

16 Nonhuman Primates Indicators of pain in several common laboratory animals Species General behavior Appearance Other Nonhuman primate Increased aggression or depression; self-mutilation; often a dramatic change in routine behavior (e.g., decreased locomotion); rubbing or picking at painful location Stiff body movements; reluctant to move; huddled body posture Decreased food/ water consumption Source: NRC. (2003). Guidelines for the care and use of mammals in neuroscience and behavioral research. 16

17 What Is Unacceptable Pain? As a stimulation approaches an animal s pain tolerance level, the animal s behavior will be dominated by attempts to avoid or escape the stimulus This degree of pain must be alleviated, unless scientifically justified 17

18 Alleviation of Pain General anesthesia Local anesthesia and/or analgesia Preemptive analgesia and balanced anesthetic regime Post-surgical analgesics Training of animals to avoid situations that produce pain (behavioral studies) Controlling the intensity of the stimulus 18

19 What Is Distress? Distress is an aversive state in which an animal is unable to adapt completely to stressors and the resulting stress and shows maladaptive behaviors (1992 definition) New report no definition (we can t define it, but we know it when we see it) 19

20 National Research Council, 2008 Recognition and Alleviation of Distress in Laboratory Animals (National Research Council, 2008) 20

21 Model of Stress-to-Distress (Moberg) 21

22 Strategies for Dealing with (Potential) Distress Prevention (by appropriate housing and husbandry) or minimization (incorporation of humane endpoints) Recognition when it occurs (knowledge of species) Alleviation 22

23 Some Potential Causes of Distress These potential causes of distress may or may not be anticipated Prolonged, unrelieved pain Large tumor burden Social deprivation Environmental status, e.g., transportation, boredom, inappropriate housing/husbandry 23

24 Challenges Determining when stress becomes distress Animal s mental state can only be inferred Evaluating the stress of animal husbandry and residence in a research laboratory Assessing the types of stress in the research setting Difficulty in measuring techniques which themselves may cause stress 24

25 Some Potential Signs of Distress Spontaneous self-injurious behavior Severe weight loss Dehydration Hunched posture Stereotypies Labored breathing 25

26 Recognizing Distress In general, it is necessary to know the normal behavior of the animal to be able to recognize abnormal behavior (species and strain dependent) Use of ethograms may help 26

27 Team Approach to Alleviate Distress To ensure the best science and the best animal welfare, decisions regarding the fate of an animal in a study must be made as a team Investigator Veterinarian Animal care staff 27

28 Team Approach to Alleviate Distress SUBJECT ANIMAL New protocol Training animal Breeding colony Recycle back to protocol RECOVERY OBSERVED DISTRESS TEAM DIALOGUE Principal investigator Veterinarian Other staff Stay on protocol with veterinarian approval YES Pull TREAT NO NO RECOVERY VET EUTHANIZE VET 28

Iowa State University Institutional Animal Care and Use Committee (IACUC)

Iowa State University Institutional Animal Care and Use Committee (IACUC) Effective Date: 5-17-2010 Approved Date: 5-17-2010 Revised Date: 5-11-2016 Last Reviewed: 5-11-2016 Institutional Animal Care and Use Committee (IACUC) SOP ID Number: 201.02 SOP Title: Establishing Humane