Impediments to dialogue about animal research (part 3).

As with yesterday's dialogue blocker (the question of whether animal research is necessary for scientific and medical advancement), today's impediment is another substantial disagreement about the facts. A productive dialogue requires some kind of common ground between its participants, including some shared premises about the current state of affairs. One feature of the current state of affairs is the set of laws and regulations that cover animal use -- but these laws and regulations are a regular source of disagreement:

Current animal welfare regulations are not restrictive enough/are too restrictive.

Those who are against animal research may view the regulations as letting researchers do too much, enabling them to exercise a free hand without taking proper account of animal welfare.

Those who support animal research may view animal welfare regulations as unnecessarily burdensome, impediments to scientific knowledge building imposed at the behest of people who neither understand nor appreciate science.

This is one of those places where people seem able to articulate strong views in the absence of particularly good knowledge about the regulations themselves. It's hard to make a solid case that the regulations are too strict or too loose if you don't know what the regulations actually require. As I've noted before, there are some governments websites that link to fairly comprehensive round ups of the various regulations and information on how they are applied. However, the dense regulatory language can be tough going.

The key regulation from the U.S. federal government started with the Animal Welfare Act of 1966, passed in the wake of a heartbreaking exposé in Life magazine of inhumane conditions in dog dealers' pens. Significant amendments to the Animal Welfare Act were passed in 1970 and 1985, the latter of these (plus the Health Research Extension Act of 1985) establishing the requirement that each institution using animals covered by the AWA establish an Institutional Animal Care and Use Committee (IACUC) charged with assuring the institution's compliance with the regulations. The IACUC must include, at a minimum, three members, at least one of whom is a veterinarian and at least one of whom is not affiliated with the institution (and whose role is to represent the interests of the community). In addition to regulations under federal law, funding agencies like the National Institutes of Health and the Public Heath Service impose further regulations on animal use, and depending on the sorts of animals and the type of research, other regulatory agencies (like the US Fish & Wildlife Service, NOAA, state departments of Fish and Game, etc.) may impose further requirements. Funding agency requirements also influence the composition of the IACUC (e.g. PHS policy requires that the IACUC include at least one practicing scientist experienced with animal research and at least one non-scientist).

The IACUC functions as the local body that ensures that animal use conforms to animal welfare regulations. Among other things, this involves reviewing protocols for animal use, including research, classroom use, training, testing, and exhibition. Animal work cannot commence until protocols are submitted to, and approved by, the IACUC. Further, the IACUC is responsible for monitoring animal use and the institutions animal care facility and for investigating animal welfare concerns.

The principal investigator, of course, is responsible for animal welfare in his or her own research. This involves both assurance that laboratory operations and experimental conditions are compliant with animal welfare regulations and cooperation with the IACUC -- submitting protocols, revising them if needed to address concerns, and then following those protocols or submitting proposed modifications for IACUC approval before implementing those modifications.

The IACUC oversees the use at the institution (or under the auspices of researchers affiliated with the university) of all the animals captured by the federal regulations and regulations from funders. At my university, the standard animal use application forms come in four versions: use of live vertebrate species, use of non-living tissues (from archived sources), use of fertile eggs or invertebrate species, and observational field studies. For the animal use submitted for IACUC review, the PI must submit a protocol which details the study design and rationale, the care and use of the animals involved, the training and experience of the personnel who will be conducting the activities, the planned handling of hazardous materials, and issues of occupational health and safety in conducting the proposed activities. Within these protocols, there are specific content items that regulatory agencies require PIs to include and IACUCs to evaluate, including the species and numbers of animals to be used, the rationale for involving animals in the research and for the appropriateness of the species selected and the number of animals proposed, a complete description of the animal use from acquisition to final disposition, and detailed descriptions of procedures designed to assure that discomfort and pain of the animals is limited to what is unavoidable for the conduct of the work.

Note that any protocol that describes research where animal use falls into the pain and distress category involving management of mild to moderate pain will raise the bar the PI must meet in providing justification for the project. Moreover, any proposal anticipating substantial pain or discomfort must not only detail the plan for alleviating it with analgesics and supportive care but also triggers a requirement for physical documentation of what is actually done to address this pain or discomfort.

At this point, I think it's useful to look at the guidance offered to the IACUC on how to understand their duties in evaluating proposed protocols on the matter of animal pain or distress. Here is how these duties are described in the Institutional Animal Care and Use Committee Guidebook (2nd edition, 2002):

Investigators are required to consider alternatives to painful procedures, and to avoid or minimize discomfort, distress, and pain, consistent with sound scientific practice and the goals of the research. This requires an understanding of the potential of pain or distress in the animals (see Section C.2.d.).

When there is no consensus among IACUC members as to whether a certain procedure actually causes pain or distress in the affected animals, U.S. Government Principle IV should be applied. This Principle states, "Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals."

To assist in this deliberation, the IACUC may need to utilize one or more of the following:

• pilot studies,
• evaluations of clinical signs,
• clinical pathology,
• gross and histological necropsy studies,
• review of comparable literature, and
• consultation with experts.

If there remains any doubt about the presence of pain or distress, the IACUC should err on the side of protecting the animals against the potential of unnecessary pain or distress.

Some refinement opportunities include:

• pain-relieving drugs,
• non-pharmacologic techniques,
• new diagnostic and therapeutic techniques,
• environmental enrichment programs, and
• establishment of more humane endpoints.

Pain-relieving drugs: While it is preferable to design a protocol that prevents pain and distress, when this is not possible the AWRs [animal welfare regulations] require that the AV [attending veterinarian] (or designee) be consulted to develop an appropriate plan for the use of anesthetics, analgesics, or other measures, such as anti-inflammatory agents, antibiotics, or sedatives.

New diagnostic and therapeutic techniques: In addition to the use of pain relieving drugs, new diagnostic and therapeutic techniques may have the capability to dramatically reduce the invasiveness of data collection and thereby refine animal research. These include:

• use of sophisticated imaging equipment to replace invasive procedures, and
• blood and tissue sampling techniques that allow for easier collection and the processing of smaller sample sizes.

Environment: The IACUC should consider that environmental factors, such as noises, odors, infrequent or inexperienced handling, or boredom from lack of environmental stimulation can cause unnecessary distress, and that US Government Principle IV should be applied in this area as well. Aside from the AWR requirement to provide environment enhancement for non-human primates, many institutions have implemented environmental modifications for other species with a view to reducing unnecessary distress.

Humane endpoints: The establishment of the earliest possible humane endpoint consistent with the research design may provide an additional opportunity to significantly reduce pain and distress, thereby refining the experiment. For any study that defines death of the experimental animals as the endpoint, the IACUC should ask if there is an earlier point in the study when the necessary data have been collected and the animal could be euthanized without proceeding through more severe illness and death. Or, alternatively, if death is a necessary endpoint, the IACUC could ask for careful ongoing assessment of the animal, so that, when it is determined that death is inevitable, the animal can be euthanized.

(pp. 99-100)

The upshot here is that animal pain and distress are central to what PIs and IACUCs must consider -- and deal with -- in order to keep animal use compliant with the regulations. And, if IACUCs, PIs, and regulatory agencies are taking the regulations seriously, it is not the case that researchers are given a free hand to do whatever they want with the animals.

At this point, it is worth noting separable issues that often get tangled with the question of whether the regulations are too strong, too weak, or just right. One of these is whether the enforcement by federal agencies is too strong, too weak, or just right. Another is whether the average IACUC's protocol review and oversight is too strong, too weak, or just right. A third is whether the typical PI can be relied upon to make honest and accurate representations in the protocols submitted to the IACUC, and to follow the protocols as actually approved. Each of these questions is distinct from the question of whether the current regulations are reasonable. Moreover, while these related questions can give rise to more disputes over premises that block dialogue, the disputes cannot generally be resolved without something like empirical data that all parties recognize to be credible -- and some of this data might not be available at present, requiring concerted efforts to collect.

There's always the option to say, "We're not sure how good compliance with the regulations is." This might mean agreeing to shift the dialogue to the question of whether perfect compliance with the regulations would result in a good situation for animals or for scientists.

Assuming, of course, the dialogue isn't derailed by other impediments.

Tomorrow, we'll look at one more sort of disputed premise, disagreements around the facts as far as animal discomfort, distress, pain, or torture when animals are used in scientific research.