Thursday, March 3, 2016

Dying for Better Warning Labels: The Short and Lonely Life of the Laboratory Research Dog

Additional Note: The EPA continues to adjust its metaldehyde regulations, though it is not clear that any additional dog experiments have been conducted in doing so. 81 Fed. Reg. 71633 (October 18, 2016)

In Kazuo Ishiguro’s 2005 novel, Never Let Me Go (made into a movie in 2010), children at an isolated English boarding school do not have parents but rather guardians who continually encourage them to remain healthy. Three students learn that this emphasis on health is not for their own good, but because they have a special function. They are clones created for only one purpose, to provide healthy organs for members of the society outside the school who need to replace parts of their bodies. After the organs of these clones have been harvested, they will die, a step referred to as completion. The school and the students come from a novelist’s imagination, but for laboratory animals such a world is not fictional. 

As Lynda Birke wrote in a 2012 article in Body & Society, the “edifice of what we call scientific, medical, knowledge is built upon animal corpses.” Dogs have been specifically bred for laboratory experimentation as commercial products for over a hundred years (Asdal 2008), but this segment of the canine breeding industry, unlike all other dog breeders, strives to remain as inconspicuous to the general public as possible. The scientists who perform research on animals also avoid describing how those animals were used in their experiments, perhaps 45% of the time do not indicate how the animals were killed, and frequently do not even acknowledge that the animals in fact died (Smith et al. 2005). One seminal analysis of animal research papers found that of 98 papers describing “procedures which must have involved the death of the animals involved,” only 44 of the papers mentioned that the animals in the experiments had died (Smith et al. 1997).

Killing Snails and Slugs

Laboratory Research Dog (courtesy Peta)
When I go through the Federal Register every morning, I look for certain topics, including terrorism financing and anti-money laundering regulation, as well as references to dogs, wolves, and other terms relevant to interests of mine.  Many, perhaps most, of the federal government releases that refer to dogs are of only passing interest, including items about drugs that are being approved for veterinary use with dogs, food additives that are being found safe for use in dog food, or sometimes not safe, and occasionally references to pesticides and other chemicals that may put dogs at risk if ingested.  Such references are usually brief, often contained only in tables that summarize research findings, and rarely draw my attention.  These findings sometimes mean that dogs were used in experiments, that is, that dogs were laboratory animals being given food or undergoing procedures to see what the effects of administering a chemical might be. 

Somewhere in the back of my mind, when I encounter such references, is an image of a dog in a cage in a sterile room, looking at other dogs in cages, none ever having any name beyond  numbers on their cages, perhaps allowed a brief period of exercise each day in a small room with a concrete floor and windows too high to look out, perhaps not even allowed to play with other dogs if companionship might violate somebody’s requirements for the research being conducted on them, often maimed or killed in the interest of science and human welfare, autopsied with organs weighed and then biopsied to establish variance from a control population (which may also be killed, but here it is sometimes possible to use legacy statistics from other laboratories), and finally disposed of as laboratory waste rather than given any dignity in a burial or individual cremation.    

Recently I saw a document that gave more information than is usually available, more than I really wanted to know because it forced me think about what the animals’ lives were like, something I try not to think about, until I can’t avoid it.  The Federal Register for March 4, 2015, contained a release of the Environmental Protection Agency that provided tolerances for residues of metaldehyde in parts per million (ppm) on certain commodities including ginseng (0.25 ppm), pea and bean (succulent shelled, subgroup 6B, 0.20 ppm), vegetable, foliage of legume (except soybean, 1.5 ppm), clover (forage and hay, each 0.60 ppm).  Metaldehyde is a molluscicide that is used by growers and gardeners to kill snails and slugs and the EPA was doing some fine tuning to its regulation (40 CFR 180.522) on how much can be present in certain food items for human and animal consumption, such as for cattle that are slaughtered for meat markets.

Metaldehyde (National Center for Biotechnology Information)
This Federal Register release was almost certainly of no interest to anyone outside of a relatively small set of farming and agricultural production facilities, and of only slightly more interest to manufacturers of metaldehydeKnown more technically as 2,4,6,8-tetramethyl-1,3,5,7-tetroxocane, metaldehyde is sold, according to the National Center for Biotechnology Information, under at least 65 trade names, including Antimilice, Ariotox, Blitzem (in Australia), Cekumeta, Deadline, Defender (in Australia), Halizan, Limatox, Limeol, Meta, Metason, Mifaslug, Namekil, Slug Fest Colloidel 25, and Slugit. A UC Davis website concerning pests in gardens and landscapes states that this is the most common snail and slug bait product available, but adds the following warning:

[M]etaldehyde baits are particularly poisonous to dogs and cats, and the pelleted form is especially attractive to dogs. Don’t use metaldehyde snail baits where children and pets could encounter them. Metaldehyde baits containing 4% active ingredient are more effective than those containing only 2%; however, they also are more toxic to dogs and wildlife. Avoid getting metaldehyde bait on plants, especially vegetables.

The entry in the Federal Register came about because a research group at Rutgers University, the IR-4 Project, had recommended in 2013 that tolerance levels for metaldehyde on certain crops be established, and recommended changes to tolerance levels previously set by the EPA for certain other crops.  This is a case where a university research program was filling in certain gaps in industrial research that would not be cost-effective for chemical manufacturers to conduct.  The crops with new tolerance levels included ginseng, certain peas, beans, and tomatoes, forage clover and hay

The EPA’s release effectively finalized some of the proposals previously made by IR-4.

Toxicological Profile

The March 4 Federal Register release contained the following sentences in the description of the toxicological profile of metaldehyde:

The principal toxic effects for metaldehyde are clinical signs of neurotoxicity, as well as changes in the liver and testes/prostate following repeated oral dosing. The dog is the most sensitive species for neurotoxic effects. Nervous system effects observed in the subchronic and chronic oral toxicity studies include: Ataxia and tremors; twitching; salivation; emesis; rapid respiration in dogs and maternal rats; and limb paralysis, spinal cord necrosis, and hemorrhage in maternal rats. Liver effects include increased liver weight, increased incidence of liver lesions (hepatocellular necrosis, hepatocellular hypertrophy and inflammation), and an increased incidence of hepatocellular adenomas in female rats and in both sexes of mice. In dogs, atrophy of the testes and prostate was observed following subchronic and chronic exposure.

Summary of Toxicological Doses and Endpoints for Metaldehyde Use in Human Health Risk Assessment (EPA 2013)
Things like liver weights and prostate size could not have been precisely determined without killing the dogs and extracting their organs.  This got me wondering where the information on metaldehyde’s effects came from, but the EPA gave no citation to support its short description.  In 2013, however, in an earlier release setting limits on residues for metaldehyde on various commodities (78 Fed. Reg. 70864, November 27, 2013), the EPA again did not name the original studies on toxicity of metaldehyde, but did include a table of “toxicological doses and endpoints for metaldehyde for use in human health risk assessment.”  Note that although the table is intended to provide a human health risk assessment, the recommendations for limits are based, as indicated in the fourth column, on a “chronic dog oral toxicity study.”  Some acronyms need defining: 

NOAEL = no-observed-adverse-effect-level
LOAEL = lowest-observed-adverse-effect-level
LOC = level of concern
MOE = margin of exposure
UF = uncertainty factor
UFA = uncertainty factor extrapolated from the study on dogs to humans because humans, of course, are not available to be put in cages and administered poisons to undertake such tests.  UFH = potential variation among humans, i.e., once the dosage limit is extrapolated from dogs to humans, how much variation in that estimate there might be in the human population. 
RID = reference dogs

The 2013 release added some detail to the information about the dog studies on which the various limits for metaldehyde were determined, stating that clinical “signs (ataxia, tremors, twitching, salivation) in the chronic dog study, which occurred within the first week of explosure and persisted through week 19 (other signs included lateral position, reduced mobility, convulsions, and vocalization in one female, and agitation in another).” Thus, some of the dogs had been given doses of metaldehyde over at least 19 weeks, almost five months, and one female dog protested her unfair lot by barking while another may have begun to lose her mind. 

Metaldehyde Dog Experiments

The U.S. Environmental Protection Agency publishes a manual, Recognition and Management of Pesticide Poisonings (Roberts and Reigart 2013), which gives sources that were not provided by the agency in its Federal Register releases.  Prior to 1986 there had only been two metaldehyde pharmacology studies, both of which used mice, that had found (1) a significant decrease in the brain concentration of γ-aminobutyric acid, (2) and increase in monoamine oxidase activity, and (3) a significant decrease in brain levals of noradrenaline, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid.  The LD50 for rats (the dosage level that would kill 50% of a population of test animals) was determined to be between 420 and 690 mg/kg (milligrams per kilogram of body weight). 

Then in 1986, Booze and Oehme used dogs instead of rats. They chose 15 “healthy mixed-breed male dogs” weighing between 8 and 19 kilograms (18 and 42 pounds), from six months to two years old.  Using young dogs is preferred so that measures such as organ weight and damage can largely exclude effects of aging. The animals came from Kansas State University’s Animal Resources Facility (renamed the Comparative Medicine Group in 2009).  Dogs were “housed individually in large metabolism cages, two to a room.”  (Metabolism, or metabolic cages, have themselves been the subject of research.  Sabchuk et al. (2012) found that “dogs kept in metabolic cages eliminate drier feces and spend more time inactive than those kept in kennels.” The dogs in this study also slept more in cages than kennels.) 

The dogs were given dry dog food and free access to water.  Eight dogs were orally dosed with 600 mg of metaldehyde (or 600 mg of acetaldehyde) per kg of body weight. An arterial catheter was surgically placed in the left carotid artery under anesthesia, “and brought to the surface on the left side of the neck, where it was kept in place by a Velcro-fastened enclosure.”  Dogs were dosed at 8 a.m., with blood samples obtained after 15 minutes, 45 minutes, and then hourly for 12 hours after the dose was administered.  Urine samples were collected in a stainless steel pan under the cage until the drugs were no longer detected.

Tremors were graded into four categories: none, slight, moderate, severe; respiration as normal, panting, or labored; salivation as normal, increased, or thick; coordination as normal or abnormal; hyperesthesia (increased sensitivity to stimulation) as absent or present; vomiting as absent or present; and diarrhea as absent or present.  One dog had tonic-clinic convulsions, profuse and thick salivation, hyperesthesia, and ataxia, and died 4.5 hours after dosing.  The remaining dogs appeared normal a day after dosing.  The clinical signs occurred in the following numbers of the eight dogs dosed with metaldehyde:

Slight tremors
8
Moderate tremors
3
Severe tremors
2
Ataxia
4
Hyperesthesia
4
Increased salivation
2
Death
1

The authors concluded that the LD50 of metaldehyde for dogs is greater than 600 milligrams per kilogram of the dog’s body weight, refining a previous estimate of the same authors (1985), based on poisoning cases, of between 100 and 1,000 mg/kg of body weight.

More recent dog research on metaldehyde was conducted in England.  A 1996 British government report by the Department of Environment, Food and Rural Affairs, Pesticides Safety Directorate, describes an unpublished German study (Neumann 1980) using smaller doses of metaldehyde (20, 60, or 90 mg/kg body weight/day) where there were “no clinical or ophthalmological signs of toxicity and no deaths” over six months of dosing.  The research also found that “clinical chemistry, haematology and urinalysis were unaffected by treatment.”  All of which makes the study sound relatively harmless to the dogs except for the observation that “post-mortem organ weights were not affected by the treatment.”  The animals were killed at the end of the study to verify internal effects resulting from the administration of the pesticide.   The NOEL level (no observed effect level) for metaldehyde, from this study was determined to be 20 mg/kg body weight/ day.  It is on the basis of this finding that some of the minimum levels of metaldehyde in agricultural products were established. 

Laboratory Animal Welfare Act

The fate of laboratory dogs is all quite legal, of course, though Congress has taken occasional interest in laboratory animals, often because of stories disturbing to the public about escaped pets that ended up as subjects in research facilities (National Research Council 2009).  This generally happens in states that permit pounds to sell pets, usually after a short period, to research facilities as an alternative to euthanizing them.  (The connections between pounds and research facilities could itself be an extensive study.) 

Number of Animals Covered by AWA Used in Research 2001-2007 (NRC 2009)
The number of animals over a seven-year period from 2001 to 2007 that were used as research subjects is indicated in a table provided in the NRC’s 2009 report, taking statistics from an earlier USDA report.  Fortunately, sporadic statistics for later years indicate that the number of dogs used in experiments continues to decline.   

Section 13 of the Animal Welfare Act of 1966 (PL 89-544, August 24, 1966) provides that the Secretary of Agriculture is to “establish and promulgate standards to govern the humane handling, care, treatment, and transportation of animals by dealers and research facilities.”  Standards are to include requirements on “housing, feeding, watering, sanitation, ventilation, shelter from extremes of weather and temperature, separation by species, and adequate veterinary care.” 

Under 9 CFR 3.7, which concerns the humane handling, care, treatment, and transportation of dogs and cats by “dealers, exhibitors, and research facilities,” specifies that if “a dog is housed, held, or maintained at a facility without sensory contact with another dog, it must be provided with positive physical contact with humans at least daily.” Thus, the research facility has a choice between giving dogs contact with each other or contact with people. 

The National Research Council of the National Academies publishes a Guide for the Care and Use of Laboratory Animals (8th ed. 2011), which accepts that dogs, cats, rabbits, and other animals benefit from “positive human interaction.”  Dogs are singled out as regards human attention: “Dogs can be given additional opportunities for activity by being walked on a leash, having access to a run, or being moved into areas for social contact, play, or exploration.” 

Cage Height Table (NRC 2011)
Dogs have an advantage over most experimental species, according to the NRC’s Guide, in that they can be “trained, through use of positive reinforcement techniques, to cooperate with research procedures or remain immobile for brief periods.”   (See also Meunier 2006.) Dogs, because they are “noisy animals,” should be housed away from where research is being done.  When possible, they should be given “manipulable toys.” However, their noisiness, according to the Guide, makes them useful in research where pain thresholds are being measured.  (See, e.g., Devitt et al. 2005; Holton et al. 1998.)

Dogs have the disadvantage of needing more space in cages that cats and rabbits, so the fact that dogs are used less extensively than some other species is not wholly due to the reluctance of researchers to use animals that their children might think of as pets.  Cage size also determines why certain breeds, such as beagles, are more common in research settings (Andersen 1970). 

Various organization, including Peta and the Humane Society, have launched campaigns to improve the lot of laboratory animals, in some cases attempting to force the USDA’s Animal & Plant Inspection Service to investigate complaints about how some laboratories care for animals on which they are experimenting.  Of course, this goes only to the more superficial trappings of what happens to these animals, insuring that cages are cleaned, vermin are removed from the environment, wounds are treated, etc.  The fact that there is often a horror to the overall fate of these animals is not something that the present law or rules will do anything to alleviate.

Sociological Research on Researchers Who Use Dogs in Lethal Experiments

Lynda Birke of the University of Chester, already quoted, must be read if one wants to delve into the nether world of the use of animals in biomedical research. In a 2012 paper she gets as close to the core of anyone I have read as to why we find the use of animals in experiments to be acceptable:

We inherit a long history of cultural beliefs that animals, unlike humans, do not have souls/consciousness, and that other species cannot perceive pain or perceive it less than we do. Thus we can justify producing sick animals as models, and we can accept probing into their bodies in the search for understanding what bodies do. Indeed, it is precisely because of that history of human exceptionalism that probing into animals’ living bodies in pursuit of knowledge becomes acceptable. Animal bodies, whether alive or dead, thus stand in for human ones, representing our diseases – so much so, that lab animals can be said to represent our salvation from the terror of our own mortality.

Arnold Arluke of Northeastern University, who has also studied how researchers relate to laboratory animals and is a sometime collaborator with Birke, notes (Arluke 1988) that researchers often prefer to avoid eye contact with the dogs on which they experiment. 

A laboratory that transported conscious dogs kept them in a private hallway outside the laboratory until moments before an experiment was to get under way. Another laboratory, which had no such hallway, would turn the dogs' cages to face a wall and sometimes drape surgical sheets over the cages as well.

Laboratory Research Beagle (courtesy Peta)
Arluke reports that laboratory technicians often prefer purpose-bred dogs—dogs that have never known anything but cages in breeding facilities and experimental environments—because these dogs are less likely to behave like pets, to extend a paw for contact, to whine, to sit on command, in other words to behave like an animal that should be cared for.  Shapiro (1989) concludes that researchers attempt to view an animal they are dealing with not as an individual, not even as a member of a species, but rather as an organic process, a biological organism, a physiological system, or, as Birke (2012) says, “a specific local accomplishment of the organization of laboratories and their associated infrastructure.”  She elaborates:

Once lab animals are thus perceived, it becomes more difficult to see them in the same way as ‘naturalistic’ animals elsewhere. They are different: they would not exist were it not for the demands of experimental science. As such, we can learn to justify intrusion into their bodies for a putative greater good, and we can learn (if somewhat ambivalently) to see their bodies as sums of parts.

As someone who once did research to determine if intertidal crabs could orient toward the nearest shore by the position of the sun or, at night, the moon, I am aware of how easily the objective of the research, and its importance to the advancement of science (or at least to one’s career), can become an excuse for ignoring the effects of the experiments on the animal subjects that are producing the raw data.  Yet it sometimes moves to the macabre, and must make us question our humanity, as with a technician described by Arluke (1988) who amused his colleagues by addressing a dog he was about to anesthetize by saying to it, “Okay Fido, let’s boogie!”

Birke (2012) also notes that because of an animal’s species-specific biology, its ability to stand in for humans and provide relevant conclusions may often be questionable.  This, of course, opens up yet another issue that could fill volumes. 

Conclusion

If it could be shown that some research directed towards human health requires validation through experiments on medium-sized mammals (National Research Council 2009 accepts that this is the case), and admitting that some core element of our humanity requires that we not use members of our own species as research subjects, then insisting that dogs not be used while pigs or rabbits can be used seems arbitrary, as if we must heed the advice of the Chick-fil-A cows and EAT MOR CHIKIN.  Birke et al. (2006) cite one scientist who did not have a problem experimenting on certain species, but could not see working with dogs, cats, or monkeys. 

Yet perhaps there should be a social contract in the human-canine relationship, as if the fact their varied and complex assistance to us throughout the long history of their domestication creates an obligation on us to excuse them from the more horrific burdens of domesticated status.  Certainly, as I shall argue elsewhere in much greater detail, the law of domestication as it applies to dogs is often more nuanced than the law applied to our relationship with other domesticates, though this does not prove that we move onto moral high ground if we insist that dogs not be used in painful and fatal experiments yet accept that pigs can be. 

Scientists should indicate in published research when and how animals are used, and when they are killed for experimental purposes.  Federal and state agencies relying on such research for setting standards should at least refer to the research, in the Federal Register or elsewhere, when indicating the justification for a standard being set. Steps should be taken to lift the veil of secrecy that has been built to protect the industry that produces animals for research.  Efforts by various groups, such as the Humane Society, to find out about conditions of laboratory animals often require filing of Freedom of Information Act requests with the USDA and other inspection services.  Such reports should be publicly available, without advocates having to figure out where information and statistics may have been hidden by government bureaucracies to avoid the possibility of public outrage.  

Finally, although efforts should continue to be made to regulate the transfer of animals from pounds and general dealer markets into research markets, the use of purpose-bred dogs by laboratories should not create a façade that allows us to ignore the horror faced by such dogs just because they were never pets or around other dogs that were to become pets. Purpose-bred dogs are as horrifying as purpose-bred people. Like the children in Ishiguro’s novel, such dogs have only one purpose, and often one fate, and many, in the few short years they are allowed to live, will never be able to stand tall enough to look out to any other world. We cannot absolve ourselves, even if we can justify our research.   

This blog was written by John Ensminger and L.E. Papet.
Sources:
  1. Andersen, A.C. (1970).  The Beagle as an Experimental Dog.  Ames: Iowa State University Press.
  2. Arluke, A.B. (1988). Sacrificial Symbolism in Animal Experimentation: Object or Pet? Anthrozoos, 2(2), 98-116 (discussing how researchers avoid the term “kill” when referring to what happens to laboratory animals, preferring “sacrifice,” “sack,” “terminate,” or just putting an X on a form.  “Sacrifice” is no longer used in scientific contexts because of a desire to avoid any religious connotations.
  3. Asdal, K. (2008).  Subjected to Parliament: The Laboratory Experimental Medicine and the Animal Body. Social Studies of Science, 38, 899-917.
  4. Austrian Agency for Health and Food Safety (AGES) (2012).  CLH Report for Metaldehyde.
  5. Barber, A.L.A., Randi, D., Muller, C.A., and Huber, L. (2016). The Processing of Human Emotional Faces by Pet and Lab Dogs: Evidence for Lateralization and Experience Effects.  PLoS/One, DOI:10.1371/journal.pone.0152393 (April 13, 2016) (finding that lab dogs pay less attention to the mouths of humans, perhaps because they are not anticipating verbal commands as pet dogs do; pet dogs also look at faces more quickly perhaps because the lab dogs here "live in packs and are therefore surrounded by other dogs but not humans, [so] human faces are not salient enough to elicit a fast response.").
  6. Bates, N. S., Sutton, N. M., & Campbell, A. (2012). Suspected Metaldehyde Slug Bait Poisoning in Dogs: a Retrospective Analysis of Cases Reported to the Veterinary Poisons Information Service. Veterinary Record: Journal of the British Veterinary Association, 171(13), 324 (“A retrospective analysis of telephone enquiries to the Veterinary Poisons Information Service found 772 cases with follow-up concerning suspected metaldehyde slug bait ingestion in dogs between 1985 and 2010. Half the enquiries occurred in the summer months. The amount and strength of the slug bait ingested was rarely known. In 56, cases the quantity consumed was estimated and was on average 229.6 grams of bait. Clinical signs developed in 77.3 per cent of dogs; common signs were convulsions, hypersalivation, twitching, hyperaesthesia, tremor, vomiting, hyperthermia and ataxia. Only 4.6 per cent of dogs developed hepatic changes, and only one developed renal impairment. The average time to onset of signs was 2.9 hours post-ingestion, with 50.3 per cent of dogs developing effects within one hour. Increased muscle activity (twitching, convulsions) lasted on average 15.2 hours. Recovery time was reported in 61 cases and occurred on average at 39.3 hours. Common treatments were gut decontamination, anticonvulsants, anaesthetics and intravenous fluids. Of the dogs that were treated with sedatives, 45.8 per cent required more than one sedative or anaesthetic agent. Methocarbamol was rarely used, probably due to unavailability. The outcome was reported in 762 dogs; 21.7 per cent remained asymptomatic, 61.7 per cent recovered and 16 per cent of dogs died or were euthanased. Where known (only six cases), the fatal dose of bait ranged from 4.2 to 26.7 g/kg (average 11.8 g/kg).”).
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