Keep in mind OLAW may need to issue some position statements like AAALAC has done regarding some of the more controversial issues contained in the Guide.

Comment 2:
This sounds like a reasonable time frame.

Finally what alternative does PHS have to accepting the 8th Edition?

I offer only two recommendations relating to past tragedies at my own institution:

Requirements for automated environmental monitoring must be updated given the increasing availability of low-cost technological solutions. Automated temperature monitoring and alerting must by now become mandatory for most facilities rather than merely recommended. As stated in OLAW’s FAQ, “Sole reliance on employees to identify changes in animal room conditions or the use of high-low thermometers to track changes in temperature may not be sufficient to allow timely intervention and prevent catastrophic loss.”

In addition, video surveillance should be considered not only for building security, but also to facilitate independent oversight of animal housing conditions and help ensure that experimental procedures follow approved protocols.

Comment 2:
NIH extramural research programs are themselves institutional programs receiving Public Health Service support for activities involving animals, and must comply with the same federal principles expected of individual grantees.

NIH has placed the burden of applying the “Three Rs” squarely upon individual researchers, while neglecting these principles entirely in decisions of funding. Given multiple proposals of comparable merit as scored by expert scientific review groups, NIH currently gives zero weight to differences in the numbers and types of animals used, or the relative levels of pain and distress that would be caused by the proposed experimental methods.

No implementation plan will be adequate that exempts the NIH administration itself from its responsibility to apply the ethical principles described in the Guide to all decisions determining which animal experiments or alternative studies will be supported by taxpayer funds.

Our Institutional Animal Care and Use Committee has reviewed the pre-publication version of the 2010 “Guide” and would like to express our concerns on only two changes. One change we feel will adversely impact the biomedical research community, and on the other hand proposes something that is at odds with experts in human medicine.

The first issue pertains to the need to provide a female mouse with litter 50 sq. in. of cage floor space (page 62). Currently the most common type of mouse caging at our institution is a small shoebox that has a floor space of 75 sq. in. allowing housing five adult mice similar, I’m certain, to many other institutions. The caging industry has built the small shoebox cage to this floor size standard based upon the 1996 “Guide.” The most common mouse breeding scheme at our institution is the polygamous trio harem of one male and two females established to maximize rodent production by taking advantage of the post-partum estrus and the cross-fostering of litters by two resident lactating females. Our IACUC’s concern regarding overcrowding in harem breeding cages led to our policy that states “no more than 12 pups when the older of two litters reaches 12 days of age”.1 This requires one pregnant prepartum female be removed when large litters are the result of this mating. But given that the vast majority of our mouse colonies are genetically-engineered mice (GEMs) with a propensity to have small litters, similar to many inbred strains of mice, we have anecdotal evidence that the presence of two lactating females increases the probability of offspring maturing to weaning; the reproductive success at weaning being our measure of the well-being of the offspring. To our knowledge there is little evidence in the literature of GEM offspring well-being adversely impacted by trio breeding. If this requirement is implemented it would cause a substantial increase in the number of shoebox cages we currently would have to maintain and impact the mouse space available to support our current research programs.

However, given the current language in Table 3.2 of the new “Guide” all trios would be required to be separated precluding the possibility of cross-fostering of small litters. I ask that you consider removing this space requirement for female mice with litters from the 2010 “Guide” and allow each institution to develop a policy similar to our own (attached).

The other issue our IACUC feels should be re-examined is the requirement for oxygen sensors in animal magnetic resonance imaging areas where cryogenic gases are used (page 157). The literature sited for this requirement appears in the ILAR Journal.2 We respect the opinion of the authors but find them at odds with the American College of Radiologists (ACR) Guidance Document for Safe MR Practices: 2007.3 The ACR guidance document specifies cryogen emergency vent locations and pathways, and specifically states on page 12, “It should be pointed out that room oxygen monitoring was discussed by the MR Blue Ribbon Panel and rejected at this time because the present oxygen monitoring technology was considered by industry experts not to be sufficiently reliable to allow continued operation during situations of power outages, etc.” When a significant cryogen quench occurs that would decrease room oxygenation the room rapidly fills with fog, the location of the exhaust vent away from the exit door, signage stating to exit the room when this occurs and appropriate vent piping and placement of the discharge point are the most important safety factors according to the ACR. Our IACUC further feels that specifying the use of non-ferrous compressed gas tanks around MR scanners rather than remote storage would seem prudent.

I hope the committee will consider our IACUCs collective opinion with regard to these two new requirements of the 2010 “Guide.” We feel it our responsibility to inform the Committee to Update the Guide for the Care and Use of Laboratory Animals of our sentiments.

Sincerely yours, William Sutherland, PhD Professor of Cell Biology Chair, Institutional Animal Care and Use Committee University of Virginia

1. ReebWhittaker et al. 2001. Laboratory Animals 35:5873 2. Klaunberg BA, Davis JA. 2008. ILAR J 49:4-16. 3. E. Kanal et al. 2007. AJR 188:1–27

Comment 2:
POLICY ON BREEDING AND WEANING OF RATS AND MICE Federal regulations establish the density of animals permitted in rodent cages. Breeder rats and mice and their litters can occupy considerable cage space, produce large amounts of fecal and urinary material, and increase cage temperature, humidity, and ammonia levels, all of which can create unhealthy conditions. When litters of two different ages are present in the same box, the younger litter often receives insufficient milk. Finally, the presence of more than one male in a breeding cage often results in aggression between competing males and fetal resorption (Bruce effect).

The following standards provide allowable densities and age/sex combinations to be applied to mouse breeding cages. Special exemptions to these standards can be made that improve animal well-being, such as to accommodate weanlings of low birth weight, slow growth rates, or insufficient mothering; a typical solution might be to cross-foster to other females in the cage. Requests for ongoing exceptions for particular strains should be submitted to the ACUC by revision of your animal use protocol, in the Main Procedure section under a heading “Request for Exception to the Breeding and Weaning Policy”. Exceptions must be justified by providing published citations or PI data demonstrating post-natal failure-to-thrive of the strain in question. Potential reasons for exemption(s) include: 1) Experimental design (e.g. studying psychological imprinting of pups); 2) Need to extend suckling in strains that fail to thrive (requires supporting data); 3) Need to prevent cannibalism diminished by cross-fostering (requires data).

BREEDING SCHEMES AND LITTER NUMBERS ALLOWED: •No more than one adult male is allowed in a breeding cage. •Female rodents must be at least 6 weeks old before they are placed in a breeding cage with a male who is greater than 10 weeks of age. The only exception to this is superovulation of 3-4 week old female mice for collection of zygotes or embryos. •A cage is considered overcrowded if a new litter is born before the older litter from the same female is weaned, or if the older litter remains with the female beyond 23 days of age. Litters with ? 4 pups do not require weaning separation if the male is removed during pregnancy. •Weaning beyond 23 days (25 days of age if CCM does it) is reserved for strains that have litters that routinely fail-to-thrive. In such cases, the male, or even better the pregnant female must be removed from the cage when either female is obviously pregnant (e.g. by 12 days gestational age). Note: Late weaning of this sort requires a special exemption as defined below to avoid ACUC censure.

Animal caretakers are responsible for recording birth dates for litters on cage cards, however they may be recorded by research staff as well. A. One male x one female: Litters should be weaned by post-natal Day 23, or before birth of another litter, whichever is first. Animal care technicians will automatically wean each litter by post-partum Day 25, or whenever a new litter is born, if investigators have not already done so. Investigators will be charged for this service. If there is no prior arrangement with the CCM staff to wean for the PI, it will be considered a non-compliance issue by the ACUC. B. One male x two females: If breeding is conducted in a 1:2 ratio, it is recommended that one of the two females be removed to a separate cage when observed to be pregnant*. Alternatively, it is permissible to keep the male, two females, and the pups together provided that when the oldest litter reaches 12 days of age there are no more than 12 pups in the cage (combined). This is based upon standards used at the Jackson Laboratory (Reeb-Whittaker et al, 2001, Laboratory Animals 35:58-73). Weaning must still be accomplished by Day 23. The animal care technicians will wean litters at Day 25 if not already done by the investigators, and investigators will be charged for this service. If there is no prior arrangement with the CCM staff to wean for the PI, it will be considered a non-compliance issue by the ACUC. C. One male x three or more females: If more than two females are housed with a male for breeding, pregnant females (e. g. 12 days gestational age*) must be separated into boxes containing no more than two pregnant females before any delivery, and the 1:2 policy above (“B.”) is then followed. If removal of obviously pregnant females in this breeding scheme is not done by the research staff, the animal care technicians will perform this function and investigators will be charged for this service. If there is no prior arrangement with the CCM staff to wean for the PI, it will be considered a non-compliance issue by the ACUC.

The accepted procedure for post-Day 25 day weaning: Occasionally, litters (or individuals in a litter) do not thrive or there may be other extenuating circumstances to justify delayed weaning. If you feel a litter (as defined in this policy) is not ready to be weaned, consult your vivarium supervisor. Each supervisor has the authority to provide a one-time exemption (one cage, or for concurrent cages of a new strain) delaying weaning up to 9 days in length for any specific litter (normally weaned on Day 23, extension to 32 days maximum). If a new litter is born to another female in the cage during the exemption period, it must be removed with that dam to another cage, if the original exempted litter cannot be weaned. Permission for ongoing weaning age exemptions for a particular breeding line must be obtained from the ACUC by submitting a protocol modification for that strain. Note: during any delayed weaning situation, the male must be removed from the cage when either female is obviously pregnant (e.g. by 12 days of gestation) to avoid post-partum estrus breeding.

the lab animals never end up alive. they are always killed. i find that unacceptable. the secrecy in how these grants are awarded is beyond belief. the public never never ever finds out whare their tax dollars are going. this is undemocratic. this is secret corruption and needs to be changed. all grants for any research of any kind needs to be totally open to the publc. pictures must be taken to show care and treatment of any animal. the pbulic must be allowed inside the labs to view the animals being abused in labs. jall animals used in any lab experiment needs to be put on the web with the followin ginformation on the lab where it is taking place. each animal individually must be listed. for example dog, white age 5 years test - skin duration - expected result validity NO ANIMAL SHOULD BE USED WITHOUT THIS NIFORMATION BEING QUICKLY AVAILABLE TO THE PUBLIC. THE NAME OF THE PUBLIC MEMBER OF THE IACUS MUST BE CLEARLY PUT ON LINE SO THAT THEY CAN BE QUICKLY FOUND AND COMMUNICATED WITH. ANY ANIMAL USED IN RESEARCH WORK THAT IS KEPT ALIVE NEEDS TO HAVE A RETIREMENT SUM OF MONEY PUT ASIDE TO CARE FOR THAT ANIMAL FOR THE REST OF ITS LIFE. IN FACT, EVERY RESEARCH ANIMAL SHOULD HAVE A TAX PUT ON IT TO ESTABLISH SUCH RETIREMENT FUNDS. I SUGGEST AN INITIAL TAX OF $1,000 ON EACH ANIMAL USED IN RESEARCH TO GO INTO THE FUND TO TAKE CARE OF ANIMALS THAT LIVE AFTER RESEARCH TESTS. ALSO, I PROPOSE THAT ALL LAB ANIMAL TESTS BE DISCONTINUED AND BANNED HENCEFORTH. I DO NOT BELIEVE THE TESTS THAT ARE GOING ON ARE VALID IN ANY WAY TO BE INTERPRETED FOR ANY HUMAN BENEFIT. THIS IS ALL ABOUT GREED AND MONEY. TESTING ON ANIMALS STARTED IN 1500 AND WE HAVE MUCH MORE MODERN, MORE ACCURATE METHODS THAN THIS TO USE TODAY. JEAN PUBLIC ADDRESS IF REQUIRED.

Comment 2:
I do not believe that institutions will be able to even determine proper procedures and protocols for reviewing facilities under the new guide within a year. Several organizations such as AAALAC and AALAS have been struggling to make comparisons and develop guidelines for compliance since last summer. There are not any training programs scheduled to train institutions in compliance issues with the new standards.

On page 57 of "The Guide", Table 3.2 lists recommended minimum cage floor space per mouse. The only change from the 7th edition is that breeding triads are not allowed in standard shoebox (77sq. inches) cages because a single female with a litter should have at least 51 sq. inches of space. The maximum recommended number of adult (>25 g) mice per shoebox cage remains at 5.

However, I could find no scientific basis for these recommendations. In fact, the references cited on p. 58 with regard to cage space argue, if anything, that for many strains, more mice can be housed per cage than the minimum currently recommended by the 7th edition (Davidson Comp. Med. 57:355, 2007; Smith et al. Comp. Med. 54:656, 2004; Gonder and Laber ILAR J 48:29, 2007; Smith et al. Comp. Med. 55:368, 2005.

One of these shows that C57BL/6 mice, housed at 10 per shoebox cage, are as healthy as those at 5 per cage. Another reference provides evidence of anxiety disorder in mice that are not sufficiently crowed.

Therefore, on the basis of the science cited by the authors of "The Guide", I believe that breeding traids should be allowed and that the minimum amount of space per mouse should be doubled over the current space specified by the 7th edition, with the usual footnote that more space may be required for some strains or in special circumstances.

Comment 2:
The prescribed once/week weighing frequency for food-restricted animals is not suitable and may be unnecessary, even risky in some situations. For example, non-human primates (and other larger species) often must be anesthetized (with attendant risks) for weighing. Experience shows that frequent weighing is useful to the point that stable feeding/weight conditions are established. After that point, the frequency of weighing can be decreased

The cost of keeping a mouse colony has already reached an appalling level. I have a relatively small lab (6 people in total), and my research is based on genetically engineered mice. I routinely pay $5,000 to $7,000 a month for the mice. This is quite an absurd amount if you compare it to the average salary in the US. Implementing the space restriction recommended by the 8th Edition of the Guide would further increase the cost for mouse husbandry. The current NIH pay line for grant applications, in addition, is already significantly reducing the funds available to investigators with the risk that the scientific community is soon going to lose many genetically engineered mouse strains.

I consider myself a very sensitive person regarding animal welfare issues. However, I really do not see any justification in the space limit recommendations of the 8th or even the 7th edition of the Guide.

Thus, I recommend OLAW and AAALAC, and the scientific community not to implement the 8th Edition of the Guide.

The space constraints set forth in the new edition of the Guide appear to be specifically intended to disallow trio mating in a standard “shoebox” cage (http://books.nap.edu/openbook.php?record_id=12910&page=57) -- 67 sq in. (floor space of standard cage) - 51 sq in (space requirement for dam plus litter) - 15 sq in (space requirement for sire) = 1 sq in remaining. According to the Jackson Laboratory’s Breeding Strategies for Maintaining Colonies of Laboratory Mice in the “Simple Breeding Schemes” section, “Most strains produce more progeny per cage if mated as trios because all adult cage mates generally help care for the young” (http://www.scribd.com/doc/48964381/breeding-strategies-manual). If the intention is to end trio mating, what institution has the expertise in mouse husbandry to outright discount Jackson Laboratory’s 82 years of research in the field?

Given these issues of revised housing recommendations without scientific backing, the NIH must not adopt the eight edition of the Guide for the Care and Use of Laboratory Animals as a basis for evaluation of institutional programs receiving or proposing to receive Public Health Service support for activities involving animals.

Fullwood S, Hicks TA, Brown JC, Norman RL, McClone JJ. 1998. Floor space needs for laboratory mice: C57BL/6 males in solid-bottom cages with bedding. ILAR J 39:29-36.

Gonder JC, Laber K. 2007. A renewed look at laboratory rodent housing and management. ILAR J 48:29-36.

Institute of Laboratory Animal Resources. 1996. Guide for the care and use of laboratory animals. National Academy Press, Washington, D.C.

Institute of Laboratory Animal Resources. 2011. Guide for the care and use of laboratory animals. National Academy Press, Washington, D.C.

Jackson Laboratory. 2009. Breeding strategies for maintaining colonies of laboratory mice.

McGlone JJ, Anderson DL, Norman RL. 2001. Floor space needs for laboratory mice: BALB/cJ males or females in solid-bottom cages with bedding. Contemp Top Lab Anim Sci 40:21-25

Smith AL, Mabus SL, Stockwell JD, Muir C. 2004. Effects of housing density and cage floor space on C57BL/6J mice. Comp Med 54:656-663.

Comment 2:
The current literature (published since the 1996 revision of the Guide) suggests that mice should actually be housed at higher densities in standard “shoebox” cages than recommended in the 1996 revision of the Guide for increased immune function, decreased mortality, and decreased fighting (Fullwood 1998, Gonder 2007, McGlone 2001, Smith 2004). If modern science suggests that higher housing densities are necessary for the health and welfare of mice, why would the Guide recommend lower housing densities?

The space constraints set forth in the new edition of the Guide appear to be specifically intended to disallow trio mating in a standard “shoebox” cage (http://books.nap.edu/openbook.php?record_id=12910&page=57) -- 67 sq in. (floor space of standard cage) - 51 sq in (space requirement for dam plus litter) - 15 sq in (space requirement for sire) = 1 sq in remaining. According to the Jackson Laboratory’s Breeding Strategies for Maintaining Colonies of Laboratory Mice in the “Simple Breeding Schemes” section, “Most strains produce more progeny per cage if mated as trios because all adult cage mates generally help care for the young” (http://www.scribd.com/doc/48964381/breeding-strategies-manual). If the intention is to end trio mating, what institution has the expertise in mouse husbandry to outright discount Jackson Laboratory’s 82 years of research in the field?

Given these issues of revised housing recommendations without scientific backing, the NIH must not adopt the eight edition of the Guide for the Care and Use of Laboratory Animals as a basis for evaluation of institutional programs receiving or proposing to receive Public Health Service support for activities involving animals.

Fullwood S, Hicks TA, Brown JC, Norman RL, McClone JJ. 1998. Floor space needs for laboratory mice: C57BL/6 males in solid-bottom cages with bedding. ILAR J 39:29-36.

Gonder JC, Laber K. 2007. A renewed look at laboratory rodent housing and management. ILAR J 48:29-36.

Institute of Laboratory Animal Resources. 1996. Guide for the care and use of laboratory animals. National Academy Press, Washington, D.C.

Institute of Laboratory Animal Resources. 2011. Guide for the care and use of laboratory animals. National Academy Press, Washington, D.C.

Jackson Laboratory. 2009. Breeding strategies for maintaining colonies of laboratory mice.

McGlone JJ, Anderson DL, Norman RL. 2001. Floor space needs for laboratory mice: BALB/cJ males or females in solid-bottom cages with bedding. Contemp Top Lab Anim Sci 40:21-25

Smith AL, Mabus SL, Stockwell JD, Muir C. 2004. Effects of housing density and cage floor space on C57BL/6J mice. Comp Med 54:656-663.

The paragraph above is just a sample of the tenor my review of the new edition of the Guide would have were I asked to do so for a reporting agency or a journal. I would conclude my review by saying: The new edition of the Guide, like its predecessor, falls flat as a guidebook. It lacks specific recommendations for investigators and IACUC members, relying instead on general statements that can be left to interpretation. In some cases, it makes statements that are inappropriate with regard to the regulations in question. This so-called guide is a recommendation for a blind-folded walk through the maze of regulations imposed by PHS and USDA.

As an IACUC member and as an investigator I have found it much more productive to refer to the Institutional Animal Care and Use Committee Guidebook published by ARENA and OLAW (the Guidebook). This text offers clear descriptions of the federal regulations, compares requirements of PHS and USDA, and gives clear examples of how to proceed on specific questions that often arise. My best recommendation is to scrap the use of the Guide as the basis for designing an animal use program and instead refer to the Guidebook.

Comment 2:
Stop the implementation plan.

Do not use the Guide as the basis for evaluation. The Guide presents cogent arguments for setting ethical standards for the use of animals in research, but it does little to guide the individual in specific steps needed in devising schemes that meet the regulatory standards set by the Federal agencies. The regulations set forth by the AWA, as interpreted by OLAW and ARENA in the Institutional Animal Care and Use Committee Guidebook published by ARENA and OLAW (the Guidebook), require specific actions. The Guide most often offers generalizations that may be left to interpretation that can lead to non-compliance. Instead, refer individuals and animal use program directors to the Guidebook as the basis for program/protocol design.

Comment 2:
I support the proposed implementation plan.

I sincerely hope that this requirement will be reconsidered.

Comment 2:
At least one semiannual program and facility evaluation using the eighth edition of the Guide as the basis for evaluation is appropriate. I support implementation of such an in inspection.

Francis S. Collins, MD, PhD Director, National Institutes of Health Building One, 126 Shannon 1 Center Drive Bethesda, MD 20892

RE: Request for Extension to Comment Period for Proposed Adoption and Implementation of the Guide for the Care and Use of Laboratory Animals: Eighth Edition

Sent via electronic and U.S. Mail

Dear Dr. Collins:

On behalf of its more than 300 member institutions, many of which are affected Public Health Service (PHS)-assured institutions, the National Association for Biomedical Research (NABR) respectfully requests at least a thirty-day extension to the comment period provided by the NIH Notice, Laboratory Animal Welfare: Proposed Adoption and Implementation of the Eighth Edition of the Guide for the Care and Use of Laboratory Animals, published on February 24, 2011 (76 Federal Register 10379-80).

In order for institutions to adequately assess the substantive changes and additions to the Guide for the Care and Use of Laboratory Animals (Guide) and provide meaningful feedback regarding its impact on their animal care and use programs as requested, additional time is needed. The current timeframe set forth in the Notice is insufficient to accurately evaluate the consequences of NIH’s potential adoption and implementation of the Eighth Edition of the Guide as a basis for evaluation of institutional programs receiving or proposing to receive Public Health Service support for activities involving animals.

Furthermore, Executive Order 13563, issued January 18, 2011 (76 Federal Register 3821-23), states that in order to promote participation each agency “shall afford the public a meaningful opportunity to comment through the Internet on any proposed regulation, with a comment period that should generally be at least 60 days.” We believe that limiting the public comment period to thirty days is not in keeping with the spirit of OMB’s stated intentions to allow for meaningful public input. Therefore, NABR requests that the comment period for the subject Notice be extended at least until April 24, 2011, which would provide a more commonly accepted 60-day comment period.

I hope that the NIH will agree to our request to extend the deadline for comments. Thank you for your consideration and please contact me if you have any questions.

Sincerely, Frankie L. Trull President National Association for Biomedical Research

Comment 2:
I support the proposed implementation plan as being reasonable and sufficient to ensure proper protection of animals.

Comment 2:
I also support the proposed implementation plan which would require that institutions complete at least one semiannual program and facility evaluation using the eighth edition of the Guide as the basis for evaluation by March 31, 2012.

Comment 2:
Yes, this seems appropiate.

Comment 2:
Indeed the sooner a review is completed with the new guide, the sooner appropriate modifcations to individual programs can be made to remove any detrimental conditions or procedures.

The Council on Governmental Relations (COGR) is an association of 184 research universities and affiliated academic medical centers and research institutes. Our members and the research community generally need more than 30 days to assess the impact of the implementation of the Eighth Edition on the operation of facilities and the conduct of research using animals. The Eighth Edition introduces new standards in a number of areas including aquatic species and sets new standards for the environment, housing and physical plant including new minimum cage requirements for rodents and rabbits. The research community needs sufficient time to assess these standards and their related costs to offer thoughtful and thorough comments to NIH. Additional time will not compromise the care and use of animals used in PHS-supported research because we remain responsible for compliance with the earlier 1996 version of the Guide. The Health Research Extension Act of 1985 requires notice and comment on the policy and we appreciate the opportunity. In the spirit of the call for a “meaningful opportunity to comment” on new regulations articulated in EO 13563, we request an extension of the deadline.

Comment 2:
See above

Patricia Brown, VMD, MS NIH Office of Laboratory Animal Welfare Office of Extramural Research RKL1, Suite 360 6705 Rockledge Drive Bethesda, MD 20892-7982

Dear Dr. Brown:

On behalf of the Association for American Universities (AAU) and the Association of Public and Land-grant Universities (APLU), please accept this request for an extension of the deadline for submission of comments in response to the National Institutes of Health notice (FR Doc. 2011–4172) concerning the Proposed Adoption and Implementation of the Guide for the Care and Use of Laboratory Animals: Eighth Edition (“The Guide”). We request an additional 30 days with a suggested new comment deadline of April 25, 2011.

AAU and APLU’s combined memberships include most of the major public and private research universities in the United States. We greatly appreciate the opportunity to comment on whether NIH should adopt The Guide, as well as on the proposed implementation plan, and applaud NIH for exploring the potential impact of this policy change. However, in order to provide “insight from institutions on the impact of changes to the Guide on their animal care and use programs” as requested, our members and the research community need more than 30 days. As noted in the Federal Register notice, the Eighth Edition “contains substantive changes and additions from the previous additions.” The research community needs sufficient time to assess the consequences of these changes and their related costs in order to offer thoughtful and thorough comments to NIH. Additional time will not compromise the care and use of animals used in PHS-supported research because we remain responsible for compliance with the earlier 1996 version of the Guide.

Therefore, we respectfully request that you extend the comment period to April 25, 2011. Thank you for consideration of this request. Sincerely,

Respectfully,

Robert M. Berdahl President Association of American Universities

Peter McPherson President Association of Public and Land-grant Universities

Comment 2:
I support the proposed implementation of the Guide for the Care and Use of Laboratory Animals: Eighth Edition (Guide)

Comment 2:
YES, require that institutions complete at least one semiannual program and facility evaluation using the eighth edition of the Guide as the basis for evaluation by March 31, 2012.

Comment 2:
This question assumes that the first question will be answered in the affirmative. This is very poor survey construction. My comment: NO = There should be NO implementation plan until the 8th edition can be re-written to be less burdensome and then properly routed for reviewed according to standard Federal government procedures.

Go back to the drawing board, make the 8th edition LESS burdensome rather than MORE burdensome, and then go through the proper procedures to get it accepted by all before even considering adopting it.

Do it right or don't do it at all!

Comment 2:
Already, some of the requirements for cleanliness and safety, as well as the semiannual program and evaluations, especially for rodent facilities, exceed those for similar facilities used to house or operate on humans. Daily census for rodents far exceeds the human census done only every 10 years.

Comment 2:
Please adopt the new Guide. It is a necessary step forward.

In my opinion as a relatively senior biomedical researcher, there are no important deficiencies in the currently used 7th Edition of the Guide. Its continued use fully supports and prioritizes animal welfare, is based upon "best practices", and thus facilitates humane, high-quality biomedical research. The proposed changes to the Guide in the 8th Edition are not supported by any credible scientific data. They are very unlikely to improve the scientific quality of the research, or improve animal welfare. As such the very expensive and complicated proposed changes would impose a large and wholely unjustifiable fiscal and logistical burden on the national research enterprise, with no expected "return on investment". Well intentioned, but VERY BAD POLICY.

Comment 2:
It is wholely unrealistic to expect the entire research enterprise of the United States to re-tool completely in one year!

Thank you.

Comment 2:
Two areas of the proposed implementation plan require further modification, in my opinion. Both are on pp 30-32 of the draft guide.

First, the proposed language would require purchase of “pharmaceutical grade” chemicals for all studies with animals. The intent here is laudable - none of us who work with animals wants to administer poor quality compounds that might contain contaminants that might have undesirable side effects. However, the realities of research has taught us that chemicals that are purified to “pharmaceutical grade” are nearly always much more expensive than simply “analytical grade” or other non-pharmaceutical grade products. The further reality is, for many compounds, there is absolutely no safety risk to the animal. The requirement as currently proposed is backwards. It should be acceptable to use compounds of any reasonable purity unless there is reason to believe, for that specific compound, that to do so might be unsafe for the animals. The result of adopting a “pharmaceutical-grade” requirement will, quite simply, be that for nearly all compounds I will seek exemption to use a lesser quality in my protocols, and will waste a lot of my time and my IACUC’s time.

The other issue that should be discussed further is the apparent proposal that use of preferred foods as reinforcers should be preferable to the use of very mild food restriction in behavioral protocols. There is a very extensive published literature in the animal learning area that demonstrates quite clearly that these two sources of motivation are not behaviorally equivalent for animals. Mild food deprivation protocols that have no detrimental physiological consequences for the animals are well-understood. There is a large literature that even much more significant food restriction on a permanent basis has health benefits. So, making a default requirement that preferred foods should be used is unreasonable scientifically and will not protect or improve animal health.

*****

Comment 2:
It is certainly possible to put institutions through a semi-annual under the new "Guide" by March 2012, but there is not sufficient time to ensure compliance particularly in the way of rabbit socialized housing, the essential outlawing of trio mouse mating (and its ramifications for more caging and expanded animal facilities), the intensive training of personnel involved in surgery, and the relocation of rodent surgery procedures from laboratories to dedicated procedure space.

Page 25 Topic: Frequency of Program Review and Facilities Inspections The new Guide states “Program review and facilities inspections should occur at least annually or more often as required (e.g., by the Animal Welfare Act and PHS Policy).” While the Animal Welfare Act and PHS Policy both require semiannual program review and facility inspection, not all research entities, even in the United States, are subject to these regulatory requirements. This will lead to a disparity in requirements for those research entities who utilize the Guide as a guidance document but not the other documents cited. The IACUC is a mechanism of self-regulation and conducting annual reviews of the animal care and use program and facilities is not of a sufficient frequency to identify and resolve program and facility issues in a timely manner.

Page 26 Topic: Protocol Review A new requirement for protocol review states that the protocol should include a “method of euthanasia or disposition of animals, including planning for care of long-lived species after study completion.” The latter part of this statement is very ambiguous and should be clearly defined as to what constitutes ”care” and what are considered “long-lived species.” This could easily be interpreted by oversight agencies as the need to establish retirement funds designed to maintain animals in sanctuaries for the remainder of their natural life. While this is currently done for chimpanzees, this would result in a phenomenal increase in the cost for research if the intent of this guidance was to include more commonly used nonhuman primates such as Old World macaques.

Page 26 Topic: Protocol Review While the new Guide advises that the responsibility for scientific merit review normally lies outside the IACUC, it states “in the absence of evidence of a formal scientific merit review, the IACUC may consider conducting or requesting such a review (Mann and Prentice 2004).” This statement has considerable implications for programs not utilizing the NIH grant review system and leaves the question of “formal review” open to interpretation by oversight agencies. Clarification should be provided as to whether a formal scientific merit review can be performed internally or if the expectation is that it be performed by an external, independent group of scientists.

Pages 59 and 61 Topic: Minimum Space Tables 3.3 and 3.5 The title of the tables prescribing minimum space requirements for rabbits, cats, and dogs (Table 3.3) and nonhuman primates (Table 3.5) changed from “minimum space requirements for individual animals” in the old Guide to “individual space requirements for animals housed in pairs or groups” in the new Guide. While there are some differences in floor space and height requirements, the space requirements are similar in both versions of the Guide. The change with the greatest impact involves the addition of the statement to both tables that states “singly housed animals may require more space per animal than recommended for pair- or group-housed animals.” Caging manufacturers have produced cages with dimensions based on the minimum space required for individually housed animals as specified in the 7th edition of the Guide. An implication, and possible expectation, that individually housed animals should now have more space will cause confusion not only to the cage manufacturers on how large to make cages for these species, but could result in all the existing cages in use for these species to now be unusable when housing animals individually, which is often needed due to veterinary care or experimental requirements (e.g., quarantine, infectious disease research). Depending on how this new requirement is interpreted by regulatory agencies, this could have a huge economic impact if new caging must now be procured whenever the single housing of animals is required. Without solid scientific evidence that single housed animals benefit from having larger amounts of space over the stated individual space requirement for group housed animals, this requirement will result in the unnecessary diversion of funds from science and confusion among animal care and use programs.

Page 139 Topic: Heating, Ventilation, and Air Conditioning (HVAC) With regard to animal room humidification, the new Guide states “Ideally relative humidity should be maintained within ±10% of set point; however, this may not be achievable under some circumstances.” While the Guide recognizes that this may not be achievable, the sentence sets a standard that is unachievable by most all older facilities and many new ones. Even with the caveat, the stated preference of no more than a 10% variation of humidity levels from set point will be used by regulators and oversight agencies as an engineering standard. It should be made clear by regulatory and oversight agencies that this is an unrealistic goal and that as long as humidification levels remain between Guide recommended parameters (i.e., 30-70%), and there are no adverse health effects, that the 10% variation requirement will not be used as a standard when evaluating animal facilities.

Comment 2:
The implementation plan is reasonable and provides sufficient time for programs to incorporate changes to the Guide.

Comment 2:
all use of lab animals should be stopped immediately. i think mice and rats are the only animals i would allow to be used in experiments. no other animal should ever be used. the fact is that there are other testing methods that are more accurate, cheaper and more relevant to people than this stupid use of animals which dates from l500 a.d. it is amazing that just becuase profiteers make money from this disgusting industry that scientific minds continue to allow it to continue. that shows a real problem with scientific minds these days. they have no common sense at all.

Comment 2:
I support institutions evaluating their compliance to the Guide, and would like to see an evaluation of the personnel's treatment of animals; plus animal conditions such as room temperature, water and food, comfort, room to move around; and safety issues, every 6 months. And wouldn't it be better to have an outside agent do the evaluation for an objective view of all of this?

I would like to highlight the concerns I have of the Eighth Edition of the Guide for the Care and Use of Laboratory Animals. The University of Maryland, School of Medicine and a small business located in my district, Spring Valley Laboratories, have contacted me regarding the proposed new laboratory guidelines. Addressing the complete set of guidelines Louis DeTolla, V.M.D.,Ph.D.,DACLAM of the University of Maryland, School of Medicine states that, “There are no deficiencies in the currently used 7th Edition of the Guide, so its continued use fully supports animal welfare, best practices, and quality biomedical research. The proposed changes to the Guide in the 8th Edition are not supported by data that demonstrate any improvement in scientific outcome of animal studies or benefits in animal welfare as a result of these changes.”

Specifically, I am concerned that the costs to academia and small businesses do not justify the negligible benefits to the laboratory animals regarding cage sizes. The additional size requirements (i.e. increasing the height requirement for rabbit cages from 14” to 16”) will be very costly to labs and small businesses. For example, the cost to the University of Maryland would be $230,000 to replace existing caging. The impact to Spring Valley Laboratories will be more profound. The dollar cost could be as much as $400,000 but final result of these regulations could drive them out of business.

As you grapple with developing new guidelines, please consider the following: 1. The Regulatory Flexibility Act of 1980 (amended in 1996) requires that the rulemaking process include cost/benefit analysis of new regulation to small businesses. In this case, the cage size increases compared to the reductions in the amount of money available for advances in medical research and the cost of jobs; 2. The size of the animal in relation to the newly proposed cage size (for example all rabbits are not the same size); 3. A plan to grant exemptions to the Eight Edition guidelines for institutions and businesses with existing cages which meet the specifications of the Seventh Edition of the Guide for the Care and Use of Laboratory Animals.

***

Comment 2:
*REVISED* Comments on Laboratory Animal Welfare: Proposed Adoption and Implementation of the Eighth Edition of the Guide for the Care and Use of Laboratory Animals Submitted for the record by Roscoe G. Bartlett Member of Congress Sixth District of Maryland

I would like to highlight the concerns I have of the Eighth Edition of the Guide for the Care and Use of Laboratory Animals. The University of Maryland, School of Medicine and a small business located in my district, Spring Valley Laboratories, have contacted me regarding the proposed new laboratory guidelines. Addressing the complete set of guidelines Louis DeTolla, V.M.D.,Ph.D.,DACLAM of the University of Maryland, School of Medicine states that, “There are no deficiencies in the currently used 7th Edition of the Guide, so its continued use fully supports animal welfare, best practices, and quality biomedical research. The proposed changes to the Guide in the 8th Edition are not supported by data that demonstrate any improvement in scientific outcome of animal studies or benefits in animal welfare as a result of these changes.”

Specifically, I am concerned that the costs to academia and small businesses do not justify the negligible benefits to the laboratory animals regarding cage sizes. The additional size requirements (i.e. increasing the height requirement for rabbit cages from 14” to 16”) will be very costly to labs and small businesses. For example, the cost to the University of Maryland would be $230,000 to replace existing caging. The impact to Spring Valley Laboratories will be more profound. The dollar cost could be as much as $400,000 but final result of these regulations could drive them out of business.

As you grapple with developing new guidelines, please consider the following: 1. The Regulatory Flexibility Act of 1980 (amended in 1996) requires that the rulemaking process include cost/benefit analysis of new regulation to small businesses. In this case, the cage size increases compared to the reductions in the amount of money available for advances in medical research and the cost of jobs; 2. The size of the animal in relation to the newly proposed cage size (for example all rabbits are not the same size); 3. A plan to grant exemptions to the Eight Edition guidelines for institutions and businesses with existing cages which meet the specifications of the Seventh Edition of the Guide for the Care and Use of Laboratory Animals.

***

Comment 2:
Under normal conditions, implementation of this proposal would have been ideal. However, it is important to note that many research and organizations are under a continuous pressure of budget cuts imposed by the Federal, state and local governments. Many support personnel have been either laid off or working part time to cope up with these changes. The adoption of the proposed actions will result in additional price raises by the veterinary services at different universities. Ultimately, the PI of NIH funded grants or other types grants will not be able to deliver results with increased charges for animal welfare. The current laws sufficiently address many concerns. Thus, it is important the NIH not adopt this new policy and should not implement at this stage.

March 25, 2010

Office of Laboratory Animal Welfare Office of Extramural Research National Institutes of Health RKL1, Suite 360 6705 Rockledge Drive, Bethesda, MD

Re: Proposed Adoption and Implementation of the Eighth Edition of the Guide for the Care and Use of Laboratory Animals

As the organization representing the largest number of American livestock, dairy and poultry producers, the American Farm Bureau Federation has a deeply vested interest in ensuring that science-based principles are available to guide the proper care and treatment of animals in agricultural production. We appreciate the opportunity to comment on the proposed adoption and implementation of the January 2011 eighth edition of the Institute for Laboratory Animal Research (ILAR) Guide for the Care and Use of Laboratory Animals (ILAR Guide) as a basis for evaluation of institutional programs receiving Public Health Service support involving animals. After reviewing the updated guide, it has come to our attention that the document has many technical flaws related to agricultural animal care.

Farm Bureau opposes the adoption by the National Institutes of Health (NIH) of the ILAR Guide as currently published. As we discussed with NIH representatives on Feb. 1, we agree with numerous scientific experts and animal science researchers that the ILAR Guide is flawed in its ethical position. Many of its elements are inconsistent with scientific recommendations for the care of farm animals.

Perhaps most important, strict use of the guide would negatively impact animal care. Scientists that work in the field of large animal welfare have pointed out specific deficiencies in the requirements listed in the ILAR Guide for these animals’ needs.

Unscientific animal care guidelines pose a threat to animals as well as the producers and researchers responsible for their well-being. We are concerned that the adoption of inaccurate standards by NIH would harm agricultural animals in the care of the Public Health Service, and by precedent, animals in academic research and the private sector. This precedent is not only confusing but potentially dangerous, as it starts down the slippery slope of basing care standards on something other than science.

In January 2010, the Federation of Animal Science Societies (FASS) published an updated Guide for the Care and Use of Agricultural Animals in Teaching and Research (Ag Guide). This document was written by 64 professionals with expertise in farm animal care and contains a wealth of substantive technical information about the care of farm animals in teaching or research (agricultural or biomedical). Unlike the ILAR Guide, the Ag Guide contains appropriate, tested and practical protocols for such criteria as sanitation protocols, air temperatures and floor space, to name just a few. All recommendations in the Ag Guide are based upon peer-reviewed research.

The Ag Guide is the most scientifically valid, current resource document for agricultural animal care. We strongly urge NIH to adopt and recognize it as the sole reference for farm animal care.

Sincerely,

Mark Maslyn Executive Director Public Policy

The 16” criteria may be suitable for very large rabbits but requiring the height for all animals seems questionable. The use of performance criteria based on animal weight or age should be considered. The economic impact of changing all caging will be significant. We presently inventory approximately 200 rabbit cages which conform to the 14” criteria. Replacing these cages will result in a large financial burden.

I suggest that NIH consider instituting performance standards based on animal weight.

Comment 2:
Current requirements are sufficient. No additional regulatory requirements should be imposed on institutions.

In the case of non-human primates we understand and appreciate the need for increased cage height to meet the conformational and behavioral needs of the animals. The recommended cage size for non-human primates in The Guide will make some caging obsolete and will require major engineering changes in animal housing buildings, rooms and cages. This will result in substantial cost without providing a mechanism for re-capturing those costs through granting programs since the G-20 process has been discontinued.

Because of these financial constraints, it may not be possible for us to perform a semiannual inspection using the new standards by the recommended date of March 25, 2012.

Comment 2:
"Single housing of social species should be the exception and justified based on experimental requirements or veterinary-related concerns about animal well-being." It would be very beneficial to readers if the Guide could indicate to which commonly used species this applies - provide examples.

This is in direct conflict with 21 CFR 58.33 The study director has overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of results, and represents the single point of study control.

In addition, 9 CFR 2.31 empowers the IACUC committee to resolve differences in opinion between SD and Veterinarian.

It would be a violation of the USDA regulations for the Veterinarian to act unilaterally and intervene against SD opinion, without IACUC consideration and approval. Endpoints and pain/morbidity level plans are a required part of the IACUC protocol approval process. If the Veterinarian is concerned about endpoints or pain management plans, the time to voice those concerns are prior to start of study. Interference can result in biased data and skew endpoints required for FDA decision making and ultimately endanger human health where such endpoints are ignored in favor of animal comfort. Critical data can be lost or obscured under the guise of protecting the test subject.

FDA regulations are designed to create studies which per 21 CFR 58.120 reduce bias and per 21 CFR 58.33 capture all data including unanticipated results which may point to future human safety issues thereby saving lives in future clinical trials.

The Veterinarian having the authority to act unilaterally without IACUC consideration and approval is unacceptable and violates FFDCA and the regulatory authority of the FDA.

Currently the Federal Register Vol 76 March 29, 2011 list April 24, 2011 as the final date for comment.

In addition to the problem with the Study Director – Vet conflict there are a number of revisions of cage dimensions which are virtually unavailable in the market making cage sizes obsolete and creating a rather unreasonable financial burden on all research organizations.

Comment 2:
The recommendations about the use of pharmaceutical grade drugs for pharmacology research are not simply cumbersome, they promote bad science. Also of note is the complete absence of any evidence whatsoever that health and welfare of animals have been compromised by the use of research grade drugs (i.e., pure and in a known vehicle that is usually without effects of its own).

Comment 2:
I believe that the implementation time needs to be extended at least one year. It will be very difficult for institutions to make the changes necessary to be in compliance with the new quidelines by March 31, 2012.

Finally, I wish to comment on the proposed modification on the use of "nonpharmaceutical grade" drugs. THere is virtually no evidence whatsoever, that using pharmaceutical grade drugs would improve animal welfare or science. This is another instance of an attempt to implement a strategy that, on the surface may sound reasonable but, in reality, is completely without benefit to animal welfare. Moreover, the costs incurred are substantial - again, reducing funds available for meaningful research, delaying productivity and increasing the burden of extraneous activity to our investigators.

Comment 2:
OLAW should require any institutional compliance with the new Guide not sooner than 2015.

Comment 2:
Yearly inspections are entirely adequate. Do not fix something that is not broken. Again spoken as a cynic: is this initiative meant to provide jobs for inspectors?? What other purpose could there be?

The intended guide will result in the following: · No more than 4 (not the 5 currently allowed) adult mice per cage – this represents a 20% increase in cages needed over current standards · A female with litter would have to be housed individually, since there would only be 12 sq. in. remaining (63 sq in/cage – 51 sq in for mom with litter) – not “enough” space for a second adult mouse (which needs 15 sq in per these requirements). For a “standard” 2 female, one male breeding cage (which can currently remain together in a single cage as the females deliver pups and nurse them) this represents a >200% increase in cages needed over current standards.

Therefore, to increase research costs without justification or scientific validity is a waste of resources, especially in such a budget restricted time.

J Am Assoc Lab Anim Sci. 2009 Nov;48(6):740-53. The response of C57BL/6J and BALB/cJ mice to increased housing density.

Nicholson A, Malcolm RD, Russ PL, Cough K, Touma C, Palme R, Wiles MV.

The Jackson Laboratory, Bar Harbor, Maine, USA.

Abstract

Increased numbers of mice housed per cage (that is, increased housing density) is seen as 1 way to reduce the costs of conducting biomedical research. Current empirically derived guidelines are based on the area provided per mouse depending on body weight as documented in the Guide for the Care and Use of Laboratory Animals. The current study aimed to provide a more scientific basis for housing density by examining the response of C57BL/6J and BALB/cJ mice to increased housing density from weaning to 5 mo of age, to determine those parameters most useful for future larger-scale studies. A wide range of phenotypic characteristics--including growth rate, body composition, hematology, serum biochemistry, hormone and metabolite measurements, in-cage telemetry, behavior, and cage microenvironment--was examined at various time points. The parameters showing greatest changes were: growth rate, which was significantly reduced in animals at the highest density; adrenal gland size, the proportion of adrenal cortex, and concentration of fecal corticosterone metabolites, all of which were increased at higher densities; and anxiety and barbering, which were more pronounced at higher densities. Cage microenvironment deteriorated with increasing density, but the increases in measured parameters were small, and their biologic impact, if any, was not apparent. The current findings indicate that mouse housing density can be increased 50% to 100% above the current recommendations (as floor area per mouse) with no or few apparent affects on mouse overall wellbeing. However, weight gain, fecal corticosterone metabolite levels, and barbering differed significantly with housing density and therefore are suggested as good measures of the response to alterations in housing.

Comment 2:
This new caging policy for rodents is arbitrarily defined and is not correct according to recent studies. For example, the article given below finds that "The current findings indicate that mouse housing density can be increased 50% to 100% above the current recommendations (as floor area per mouse) with no or few apparent affects on mouse overall wellbeing."

The intended guide will result in the following: · No more than 4 (not the 5 currently allowed) adult mice per cage – this represents a 20% increase in cages needed over current standards · A female with litter would have to be housed individually, since there would only be 12 sq. in. remaining (63 sq in/cage – 51 sq in for mom with litter) – not “enough” space for a second adult mouse (which needs 15 sq in per these requirements). For a “standard” 2 female, one male breeding cage (which can currently remain together in a single cage as the females deliver pups and nurse them) this represents a >200% increase in cages needed over current standards.

Therefore, to increase research costs without justification or scientific validity is a waste of resources, especially in such a budget restricted time.

J Am Assoc Lab Anim Sci. 2009 Nov;48(6):740-53. The response of C57BL/6J and BALB/cJ mice to increased housing density.

Nicholson A, Malcolm RD, Russ PL, Cough K, Touma C, Palme R, Wiles MV.

The Jackson Laboratory, Bar Harbor, Maine, USA.

Abstract

Increased numbers of mice housed per cage (that is, increased housing density) is seen as 1 way to reduce the costs of conducting biomedical research. Current empirically derived guidelines are based on the area provided per mouse depending on body weight as documented in the Guide for the Care and Use of Laboratory Animals. The current study aimed to provide a more scientific basis for housing density by examining the response of C57BL/6J and BALB/cJ mice to increased housing density from weaning to 5 mo of age, to determine those parameters most useful for future larger-scale studies. A wide range of phenotypic characteristics--including growth rate, body composition, hematology, serum biochemistry, hormone and metabolite measurements, in-cage telemetry, behavior, and cage microenvironment--was examined at various time points. The parameters showing greatest changes were: growth rate, which was significantly reduced in animals at the highest density; adrenal gland size, the proportion of adrenal cortex, and concentration of fecal corticosterone metabolites, all of which were increased at higher densities; and anxiety and barbering, which were more pronounced at higher densities. Cage microenvironment deteriorated with increasing density, but the increases in measured parameters were small, and their biologic impact, if any, was not apparent. The current findings indicate that mouse housing density can be increased 50% to 100% above the current recommendations (as floor area per mouse) with no or few apparent affects on mouse overall wellbeing. However, weight gain, fecal corticosterone metabolite levels, and barbering differed significantly with housing density and therefore are suggested as good measures of the response to alterations in housing.

Comment 2:
Retain the 1996 Guide as is. Restrictive policies on science and innovation should be based on valid scientific evidence. The requirement to use only pharmaceutical grade chemicals for all species is particularly absurd.

My rationale for this recommendation is based on multiple factors that include:

-the financial and administrative cost of complying with new regulations and the resulting disruption in research

-the burden of guidance to either use pharmaceutical grade chemicals or to justify not using them, despite a lack of evidence to suggest that pharmaceutical grade chemicals improve animal welfare or science

-vague language subject to multiple interpretations on many issues such cage sizes, use of restraint, and use of food restriction

Comment 2:
Implementation should be delayed until at least March 2015.

My rationale for this recommendation is based on my view of the extensive revisions promulgated by the New Guide and the extensive changes in research procedures, administrative procedures and infrastructure that will be required to comply with the New Guide.

Comment 2:
It is unlikely that institutions can implement all of the major changes (the 'musts') outlined by the guide by March 2012. It is recommended that NIH implement instead a 'evaluation period' in which institutions are encouraged to begin using the guide for evaulations and give feedback to NIH. During this time the current guide should be the basis for the official semiannual IACUC evaluation. As stated above, new policies based on the 8th edition would force major changes to experimental design, caging and/or the physical plant. Any implementation deadlines should be set with full consideration of the time needed to make these major changes.

Comment 2:
NO to adoption of the new 8th edition!

Leave current guidelines in place as they stand; veterinary staff at the local level are more than well qualified to make additional recommendations!

Comment 2:
I do not favor adopting new requirements. The current requirements are sufficient to ensure appropriate care and use of laboratory animals.

My rationale for this recommendation is based on multiple factors that include:

-the financial and administrative cost of complying with new regulations and the resulting disruption in research

-the burden of guidance to either use pharmaceutical grade chemicals or to justify not using them, despite a lack of evidence to suggest that pharmaceutical grade chemicals improve animal welfare or science

-vague language subject to multiple interpretations on many issues such cage sizes, use of restraint, and use of food restriction

Comment 2:
Implementation should be delayed until at least March 2015.

My rationale for this recommendation is based on my view of the extensive revisions promulgated by the New Guide and the extensive changes in research procedures, administrative procedures and infrastructure that will be required to comply with the New Guide.

Comment 2:
All active researchers are concerned that: (1) the 2011 Guide contains many recommendations that will, in effect, function like regulations, rather than the “guidelines” for the care and use of research animals authorized by the Health Research Extension Act of 1985; (2) there is insufficient scientific evidence for some revisions reflected in the new Guide; and (3) the additional provisions of the 2011 Guide will have a significant economic impact on all PHS-assured institutions as well as the Contract Research Organizations that conduct such research on behalf of pharmaceutical industry sponsors. We do NOT want these guidelines finalized or adopted by the USDA or OLAW.

Comment 2:
I am strongly opposed to the recommendations which are not based on good science, are not peer reviewed, and will result in a vast increase in costs without benefit. This is a waste of research money and will have significant effects on the research infrastructure of the USA and further erode the productivity and preeminence of the USA research investment and competitiveness.

Biomedical researchers who use animals in their research are already suffocating in a litany of regulations that range from practical to absurd. Many of these regulations are attributable to animal rights extremists who misrepresent animal research as torture. To move in the direction of abolishing all animal research, they have been able to promulgate their falsehoods to a sufficiently large number of activists who have lobbied congress successfully to impose regulations that cripple the ability of biomedical researchers to develop cures for diseases that afflict both humans and animals.

More enlightened countries such as Singapore are capable of discerning truth from hyperbole. This is why they are becoming a Mecca for biomedical researchers and we are beginning to see a brain drain from the United States.

Several years ago Philip Zimbardo conducted the infamous "Stanford Prison Experiment" which had to be stopped prematurely after only 6 days because of the sadistic abuse of "prisoners" by their "guards". I submit that today's IACUC committees by virtue of the unrestricted powers they have been given, have become the 21st century "guards" and that biomedical researchers have become the "prisoners". Clearly IACUCs are not working as intended and their powers to subject biomedical researchers to their irresponsible whims should be severely curtailed if not completely abolished.

Comment 2:
I oppose this additional regulation because it adds an unreasonable, disabling burden to institutions that are working for the common good.

Comment 2:
There is insufficient scientific evidence for some revisions reflected in the new Guide. Scientific evidence is lacking for changes in at least one major subject, the “recommended minimum space” for animals by species (Tables 3.2 - 3.6). In the Preface of the 8th Edition, the Committee acknowledges that scientific information is insufficient when it comes to space and housing needs of laboratory species, yet still includes new recommendations that will have significant impact on the research community. While acknowledging that many variables must be considered when housing animals in the laboratory, the new Guide offers no justification from the scientific literature as to why minimum space recommendations have been changed and why specific increases in dimensions were selected. Because the minimum cage sizes are expressed in exact dimensions by species in the Guide, they amount to fixed engineering standards with which PHS-assured institutions must comply. While the 2 inch increase in the height of rabbit cages (Table 3.3) and several changes in non-human primate caging (Table 3.5) are a problem for some NABR members, it is the revision of minimum space for laboratory rodents (Table 3.2) that is causing the greatest concern. For the first time the new Guide indicates recommended space for a “Female + litter” for both rats and mice, specifying a floor area of 51 in2 (330 cm2) for the former housing group and 124 in2 (800 cm2) for the latter. This designation would exclude the current practice of housing rodent pairs (male and female) and trios (one male, 2 females) together continuously for breeding purposes in the standard cage used by most facilities. The new European Directive for the Protection of Animals Used in Scientific Procedures (2010/63/EU) indicates the same floor space requirements, but uses the term “breeding” cages for rodent pair/trio housing, thus permitting the practice of housing breeding pairs and trios in existing cages (See Attachment 1). Because the new Guide will require larger caging for standard breeding practices, PHS-assured institutions and NIH contractors will be faced with the prospect of replacing existing cages for breeding pairs and trios with larger cages. Further complicating the situation is the fact that the 2011 Guide states (p 60-61), “Floor space taken up by food bowls, water containers, litter boxes and enrichment devices (e.g. novel objects, toys, foraging devices) should not be considered part of the floor space.” There are significant operational, logistical, physical plant and financial issues associated with these recommendations, which will be commented upon in more detail by individual institutions and commercial laboratory animal breeders. This rodent breeding cage issue was raised in comments on the pre-publication version of the Guide released in June 2010. The final version of the Eighth Edition published in January of this year, only added an asterisk to the title of Table 3.2 with the related note: “* The interpretation of this table should take into consideration the performance indices described in the text beginning on page 55.” OLAW currently has a “frequently asked question” published on its website that leads us to believe that the flexibility of institutions to use performance based standards in determining a policy on cage size will be more limited than implied by the language beginning on page 55 of the Guide. The text of that posting appears below: May the IACUC approve deviations from the Guide for rodent (mice and rats) cage density? - OLAW supports the Guide’s approach to applying performance standards to achieve specified outcomes, and expects institutions to use the Guide’s engineering standards as a baseline. The Guide clearly states that the need for adjustments to the recommendations for primary space enclosures should be made at the institutional level by the Institutional Animal Care and Use Committee (IACUC) and should be based on performance outcomes. The Guide further identifies examples of performance indices to assess adequacy of housing, including health, reproduction, growth, behavior, activity, and use of space (Guide, pages 25-26). IACUC determinations of the need for adjustments in the space recommendations should be based on veterinary considerations or scientific justification relative to the nature of the protocol and its requirements. Blanket, program-wide deviations from the Guide for reasons of convenience, cost, facility capacity, and other non-animal welfare considerations are not acceptable. IACUC approved deviations from the Guide must be clearly documented and reflect the scientific or veterinary justification relevant to the action. For example, the Guide notes that space allocations should be reviewed and modified as necessary to address individual housing situations and animal needs such as prenatal and postnatal care. One way to address housing for maternally dependent litters of mice and rats is to consider them as single entities with their parent(s) until the pups begin actively moving about the cage, at which point multiple parental/litter groups should then be housed according to housing conditions recommended in the Guide. Adoption of the new Guide as planned by OLAW is likely to have a significant economic impact on PHS-assured institutions. Given the fact that research institutions are already under extreme financial strain and NIH faces the possibility of a significant budget reduction in FY 2011 and beyond, this economic impact must be carefully assessed. Since rats and mice are utilized as a research model by the tens of millions, the proposed change in breeding cage size is likely to have a significant economic impact that may be reasonably anticipated to lead to an annual effect on the economy of $100 million or more and would also materially alter the budgetary impact of NIH grants.

Comment 2:
No, implementation should be delayed until at least March 2015

I would also want to add some my personal note. For many years, I am confused by the fact that living expense on those mice in my lab is more than that for any person working in my lab including myself. My monthly animal bill is greater than my mortgage bill for the house where I live. And now, we are told that we did not treat mice well enough and we should offer more. As a human being, I want to stay in a luxury home and work in a luxury lab every day. However, the limiting factor is whether I can afford or not. The question is --- Can NIH afford the increasing costs while maintaining the same productivity? I think the priority for NIH right now should be helping researchers to cut down the costs while maintaining productivity, rather than further increasing their financial responsibility in research.

I have bred and cared for mice for over 20 years as a researcher. There is no basis for the increased area demanded by these new regulations.

Comment 2:
In addition to the added per cage costs, the additional administrative oversight will also add to research costs by necessitating increases in overhead budgets. While this is negotiated by OMB, the costs come from the increasingly strained NIH budget. This means less money for research and more for bureaucracy--another poor decision.

Comment 2:
See above. The new rules are much too severe and will deter important health-related research.

However, they certainly will induce an unnecessary financial burden on everyone who uses or cares for rodents in research. In the current funding environment, available tax-payer money should be spent on advancing research, not buying new cages for a perceived (but scientifically unproven) increase in animal wellbeing.

Comment 2:
The NIH should NOT adopt the implementation plan using the eighth edition of the Guide. This edition of the Guide contains new guidelines for the housing of animals that are highly controversial. These changes, especially for the housing of mice, have not been proven to increase animal health and well being and will needlessly waste tax payer money.

They certainly will induce an unnecessary financial burden on everyone who uses or cares for rodents in research. In the current funding environment, available tax-payer money should be spent on advancing research, not buying new cages for a perceived (but scientifically unproven) increase in animal wellbeing.

FASEB strongly supports deferring to the professional judgment of animal care staff in developing performance based standards that provide the best welfare for laboratory animals. Performance based standards are guiding principles that, while describing a desired outcome, provide flexibility in achieving that outcome by granting discretion to those responsible for managing the animal care and use program. Flexibility is important for providing optimal care to laboratory animals and ensuring the integrity of scientific research as it allows researchers, veterinarians, and animal care staff to take into consideration information on the species, individual animal, and research goals that may impact animal care and use. FASEB encourages NIH to follow the suggestions in the Guide and promote performance based standards and professional judgment.

Our specific comments concern two points: 1) Should NIH adopt the Guide as a basis for evaluation of institutional programs receiving or proposing to receive Public Health Service (PHS) support for activities involving animals? and 2) If NIH decides to adopt the eighth edition of the Guide, should NIH use it as the basis for evaluation by March 31, 2012?

1. FASEB recommends that NIH adopt the eighth edition of the Guide as a basis for evaluation of institutional programs receiving or proposing to receive PHS support for activities involving animals with the following caveats:

a. FASEB appreciates the importance of housing animals in cages appropriate for their physical, physiologic, and behavioral needs. In evaluating social housing needs for laboratory animals, we, again, strongly encourage NIH to place greater emphasis on performance based standards rather than engineering standards. Engineering standards are prescriptive and provide limited flexibility for implementation. For example, logistical barriers sometimes prevent social housing of animals. Odd numbers of animals needed for a particular experiment would leave one animal not pair-housed. In order to ensure all animals are socially housed, more animals than necessary would be utilized, which is inconsistent with the goal of reducing the number of animals used for research.

b. FASEB is particularly concerned about the new cage size requirements for rabbits and rodents. For example, FASEB finds that the change to a two-inch higher cage size for rabbits is especially troublesome. We suggest that the current rabbit cage sizes of 14 inches in height as defined in the 1996 Guide be maintained as opposed to the 16-inch standard in the 2011 Guide unless animals cannot make postural adjustments in the cages. In those cases, performance standards dictate that larger caging should be used. The rationale for increasing the height two inches is unclear, and it is uncertain whether this change would improve the quality of care for laboratory rabbits. Moreover, the current Animal Welfare Act standard is 14 inches in height. In the absence of a clear rationale, congruency between NIH and the United States Department of Agriculture should be maintained. This is consistent with President Obama’s Executive Order 13563 and would reduce confusion and maintain efficient work-flow among researchers and institutions. In addition, imposing the new 16-inch standard will render current rabbit caging systems obsolete and necessitate a significant expenditure of funds by research facilities to replace this caging. The resulting expense in both equipment and administrative costs is not balanced by improvements in animal welfare.

In a change to rat caging standards, the 2011 Guide now requires that when the weight of paired rats increases to a point that they no longer meet the engineering standards of the Guide, they must be separated or moved to a larger cage. Individually housing these animals would conflict with the guidelines on social housing, yet meeting the new engineering standards set forth in the Guide would require a larger cage size, which is potentially problematic in terms of additional cost. Again, the fiscal constraints that institutions are under due to reduced NIH grant funding and reduced state support may make it difficult for institutions to implement the changes. It is important for NIH to provide clear guidance about what should be done in these cases. In addition, the 2011 Guide spells out specific cage size requirements for female rodents plus their litters, as well as other breeding configurations. Implementing these changes would add huge costs and reduce breeding capacity for many institutions. Again, performance standards should be paramount when evaluating cage spacing requirements.

Comment 2:
2. FASEB recommends that: 1) NIH delay the implementation of the Guide, and 2) NIH allow institutions time to develop a comprehensive plan that outlines implementation of new Guide regulations over a predefined period of time, if needed.

In order for institutions to implement the changes outlined in the new Guide, a concrete plan must be devised, which may include consultation with experts, hiring new staff, training existing staff, developing new standard operating procedures, and ordering and purchasing caging to meet new social housing and caging requirements. It will take a substantial amount of time to devise this plan, have it approved by the Institutional Animal Care and Use Committee (IACUC), and complete at least one semiannual program and facility evaluation. This process alone could take well over a year. Additionally, the budgetary constraints faced by research institutions and NIH may make it difficult for some institutions to implement the changes recommended in the new Guide by March 31, 2012. Therefore, FASEB recommends that the implementation date be March 31, 2013.

For institutions unable to implement all the changes at once in order to be in compliance with the new Guide, FASEB recommends they be allowed to develop and submit a plan to implement the necessary changes over a predefined period of time. This plan, for example, could state that an institution would replace all non-compliant cages over the period of four years (25% per year). As long as the institution meets the milestones outlined in the implementation plan, they would be considered in compliance with IACUC and the Office of Laboratory Animal Welfare. This strategy would allow institutions to prepare better for the financial challenges and infrastructural changes that would need to take place in order to be in compliance with the new Guide. This plan would need to be in place by March 31, 2013.

FASEB recognizes that humane animal care and high-quality science go hand-in-hand, and the biomedical researchers represented by FASEB take humane care very seriously. FASEB also appreciates NIH’s commitment to providing guidelines that ensure the optimal care and welfare for research animals, and we thank you for this opportunity to provide comments. If you have questions or need additional information, please do not hesitate to contact us.

Comment 2:
NIH should not adopt the 8th edition of The Guide. If implemented, facilities should not be required to use it in their semiannual inspections prior to March 31, 2015. It will take substantial time and effort to revise internal policies and procedures to meet the recommendation of the 8th edition of The Guide. This would be a multi-year process.

Comment 2:
Institutions are already under tremendous scrutiny and reporting demands for their use of animals and no beneficial purpose would be served by additional reporting, this would be a waste of taxpayers dollars.

1) Of great concern is where the wording of must (defined by the guide as a requirement) is followed by something vague and subjective such as ensure the "well-being" of the animal or "provide a high quality of care and ethical standards" that could expose Universities and investigators to frivolous litigation from groups that would like to entirely eliminate animal research.

2) Under surgery it states that, "Careful monitoring increases the likelihood of successful surgical outcomes. Monitoring includes routine evaluation of anesthetic depth and physiologic functions and conditions, such as body temperature, cardiac and respiratory rates and pattern (Flegal et al. 2009), and blood pressure (Kuhlman 2008), and should be appropriately documented." I completely disagree with this statement. In rodents, successful surgical outcomes are best assured by clean, efficient surgeries that do not require supplemental anesthetic or longer exposure to gas anesthesia than necessary. Not only is it difficult to measure these physiological symptoms in rodents, doing so requires distraction from the surgery that increases anesthetic exposure and encourages breaks from aseptic technique.

3) The new mechanical standards do not appear to allow for a breeder male mouse to stay in the cage with the female and litter and appear to prevent harem breeding in most standard cages; hence they are in conflict with requirements elsewhere in the guide indicated that social animals should not be individually housed. They also state that environmental enrichment (e.g. a paper cup) is to be subtracted from available floor space without taking into consideration that the animal can walk or climb on it or carry it around. The new mechanical standards could greatly restrict research where space is at a premium and will require the employ of personnel who police this. It was better to have standards, e.g. the animal should be able to turn around in its cage and not touch the lid when situated in a normal position.

4) Under food restrictions the guide requires "the least restriction necessary to achieve the scientific objective." This is counter to studies which show rodents are healthier and live longer under food restriction (more than the least necessary to perform a task) than they do under ad libitum schedules. The guide again mandates that the “well-being” of the animals be monitored. This is vague and subjective. In addition, this section is written in a way that could be interpreted as though both food and fluid intake have to be monitored daily even if only one or the other is regimented. This could require a significant increase in personnel effort without increasing the safe monitoring of the health of the animals.

5) “Disaster plans should be established in conjunction with the respon¬sible investigator(s), taking into consideration both the priorities for triaging animal populations and the institutional needs and resources. Animals that cannot be relocated or protected from the consequences of the disaster must be humanely euthanized.” This could be interpreted to mean in an impending disaster supporting the unnecessary death of animals and is in conflict with the 3Rs.

6) A good addition in the surgery section is that craniotomy could be considered a minor surgery where most have previously considered it opening a body cavity and classified it as major surgery. This makes sense given how quickly rodents recover from this type of surgery.