Autumn 2003 • Volume XII, Number 4

Anything But Routine
By Jonathan Balcombe, Ph.D.

When King Kong grasped Fay Wray in his enormous hand in the 1933 science fiction classic, the victim screamed and struggled in terror. If one could have measured the writhing heroine’s heart rate, blood pressure, and blood levels of corticosterone and glucose, the readings would have been off the charts.

These same physiological responses to acute fear and stress occur in other animals, and studies of rats, mice, rabbits, monkeys, and other species commonly used in laboratory experiments indicate that the experience of being picked up by a human experimenter may be every bit as fearsome as being palmed by King Kong.

PCRM recently reviewed some 80 articles published in scientific journals to examine how animals react to three common procedures performed in the lab: 1) handling (defined as any non-invasive manipulation that is part of routine husbandry, such as picking up the animal and/or cleaning or moving his or her cage), 2) blood collection, and 3) gavage (force-feeding a substance with a tube inserted in the mouth and then into the stomach). In virtually all of the studies we examined, the animals’ stress levels rose quickly and significantly and usually remained high for an hour or more after the animal had been handled, venipunctured, or gavaged.

Here are some examples:

• Heart rate and blood pressure of eight male rats (surgically fitted with transmitters) increased 50 percent and 20 percent, respectively, in response to several routine laboratory procedures, including a cage change.¹
• Handling and weighing 12 male rats caused a quadrupling of plasma corticosterone within 15 minutes, and levels had not fallen significantly 30 to 60 minutes later.²
• Blood glucose rose 30 percent and 24 percent in six male and six female mice, respectively, following handling and transport to an adjoining room.³
• Heart rate increased nearly 50 percent in six rhesus macaques in response to a cage change and remained elevated for two hours after the procedure.⁴
• Corticosterone levels rose more than 500 percent in 14 hens within 45 seconds of being picked up and held against a table.⁵
• Corticosterone levels rose about 240 percent in 10 male rats following the collection of blood from the jugular vein.⁶
• Blood glucose rose 120 percent in six rabbits following venipuncture.
• Blood cortisol rose about 60 percent following venipuncture in eight capuchin monkeys, and all of the animals continued to show elevated levels through six weeks of thrice weekly blood collection.⁸
• Rats gavaged daily for ten days exhibited massive death of liver cells (apoptosis). A “sham” group gavaged with saline responded similarly, suggesting that the pathology was caused by the gavage manipulation itself.⁹
• Corticosterone levels increased to nearly 600 percent in rats gavaged with varying volumes of test substances and caused reflux of stomach acid, leading to injury to the airway and lungs.¹⁰

Studies also reported significant stress responses of animals (rats and monkeys) who witnessed others being subjected to these routine procedures,^{1,11,12,13,14} suggesting that witnesses recognize procedures as painful and stressful whether or not they are being done on them—and/or that they fear they are next in line.

These findings indicate that procedures considered routine by researchers are anything but routine from the animals’ perspective. This is perhaps not surprising, considering that the experimental procedures to which the animals are subjected are nearly always unpleasant and sometimes fatal and that they typically have no idea what is going to be done to them and when. Nor is there likely to be much humane oversight of these and other aversive routines, such as restraint, injections, and food or water deprivation. Institutional Animal Care and Use Committees (IACUCs) rarely scrutinize the day-to-day maintenance of animals when they review experimental protocols. Indeed, these routines are typically absent from the protocols they review.

The ramifications of these findings are two-fold. First, if routine laboratory procedures cause high levels of animal pain and distress (regardless of the expertise and care shown by their handlers), one may conclude that laboratory research on animals is intrinsically inhumane. Second, it is well known that stress can play havoc with an animal’s biology, including behavior, biochemistry, physiology, and immunity. These variables weaken the application of experimental findings to the human condition–an application already compromised by species differences.

What You Can Do

Money talks, and each year many Americans unintentionally say “yes” to animal experimentation by donating to organizations that continue to use or fund it.
Be assured that your contributions are used for ethical, human-centered research, care, and support by visiting www.HumaneSeal.org. There you will find a comprehensive list of charities awarded the Humane Charity Seal of Approval, signifying an organization’s pledge that animals are not harmed in the process of the important work they do on behalf of people.

Most recently, the Seal was presented to Cheyenne Village, which assists the developmentally and physically disabled, and to the Multiple Sclerosis Foundation, which provides comprehensive support and education and fosters research on causes, cures, and treatments.

1Sharp JL, Zammit TG, Azar TA, Lawson DM. Stress-like responses to common procedures in male rats housed alone or with other rats. Contemp Top Lab Anim Sci 2002;41(4):8-14.
2Barrett AM, Stockham MA. The effect of housing conditions and simple experimental procedures upon the corticosterone level in the plasma of rats. J Endocrin 1963;26:97-105.
3Tabata H, Kitamura T, Nagamatsu N. Comparison of effects of restraint, cage transportation, anesthesia and repeated bleeding on plasma glucose levels between mice and rats. Lab Anim 1998;32:143-148.
4Line SW, Morgan N, Markowitz H, Strong S. Heart rate and activity of rhesus monkeys in response to routine events. Lab Primate News 1989;28:9-12.
5Beuving G, Vonder GMA. Effect of stressing factors on corticosterone levels in the plasma of laying hens. Gen Comp Endocrinol 1978;35:153-159.
6Vachon P, Moreau JP. Serum corticosterone and blood glucose in rats after two jugular vein blood sampling methods: comparison of the stress response. Contemp Top Lab Anim Sci 2001;40(5):22-24.
7Drouhault R, Courtes AM, Dufy B. Hyperglycemic effect in the rabbit induced by ACTH4-10. Experientia 1983;39:920-922.
8Dettmer EL, Philips KA, Rager DR, Bernstein IS, Fragaszy DM. Behavioral and cortisol responses to repeated capture and venipuncture in Cebus apella. Am J Primatol 1996;38:357-362.
9Roberts RA, Soames AR, James NH, et al. Dosing-induced stress causes hepatocyte apoptosis in rats primed by the rodent nongenotoxic hepatocarcinogen cyproterone acetate. Toxicol Appl Pharmacol 1995;135:192-199.
10Brown AP, Dinger N, Levine BS. Stress produced by gavage administration in the rat. Contemp Top Lab Anim Sci 2000;39(1):17-21.
11Sharp JL, Zammit TG, Lawson DM. Stress-like responses to common procedures in rats: Effect of the estrous cycle. Contemp Top Lab Anim Sci 2001;41:15-22.
12Sharp JL, Zammit TG, Azar TA, Lawson DM. Does witnessing experimental procedures produce stress in male rats? Contemp Top Lab Anim Sci 2002b;41(5):8-12.
13Sharp JL, Zammit TG, Azar TA, Lawson DM. Are “by-stander” female Sprague-Dawley rats affected by experimental procedures? Contemp Top Lab Anim Sci 2003b;42:19-27.
14Flow BL, Jaques JT. Effect of room arrangement and blood sample collection sequence on serum thyroid hormone and cortisol concentrations in Cynomolgus Macaques (Macaca fascicularis). Contemp Top Lab Anim Sci 1997;36:65-68.

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