The Animal Welfare Division of OPRR was renamed Office of Laboratory Animal Welfare (OLAW) in 2000.
November 17, 1997
Subject: Production of Monoclonal Antibodies Using Mouse Ascites Method
This letter provides guidance to Public Health Service (PHS) awardee institutions and Institutional Animal Care and Use Committees (IACUCs) on avoiding or minimizing discomfort, distress, and pain in the care and use of animals for the production of monoclonal antibodies using mouse ascites antibody production. The Public Health Service Act, the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training, the PHS Policy on Humane Care and Use of Laboratory Animals, the Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act provide statutory and policy bases for the expectations in these areas (see enclosure for citations).
There is evidence that the mouse ascites method of monoclonal antibody production causes discomfort, distress, or pain. Practical in vitro methods exist which can replace the ascites method in many experimental applications without compromising the aims of the study.
Accordingly, IACUCs are expected to critically evaluate the proposed use of the mouse ascites method. Prior to approval of proposals which include the mouse ascites method, IACUCs must determine that (i) the proposed use is scientifically justified, (ii) methods that avoid or minimize discomfort, distress, and pain (including in vitro methods) have been considered, and (iii) the latter have been found unsuitable. Fulfillment of this three-part IACUC responsibility, with appropriate documentation, is considered central to an institution's compliance with its Animal Welfare Assurance and the PHS Policy.
The federal mandate to avoid or minimize discomfort, pain, and distress in experimental animals, consistent with sound scientific practices, is, for all practical purposes, synonymous with a requirement to consider alternative methods that reduce, refine, or replace the use of animals. Consideration of these issues should be incorporated into IACUC review, investigator training, research proposals, and ongoing monitoring of the institutional animal care and use program. IACUCs, acting as agents of institutions, are expected to implement and routinely evaluate these aspects of the institutional animal care and use program to ensure compliance with the PHS Policy.
Because these longstanding requirements are central to the federal oversight of all animal-related activities in research, testing, and training, this guidance may also be applied more generally to other PHS-supported and nonPHS-supported activities involving animals. Additional references to resources relevant to this issue are enclosed for your information.
Thank you for your attention to these matters. As always, please feel free to contact OPRR at 301-496-7163 if you have questions regarding this correspondence.
Gary B. Ellis, Ph.D.
Office for Protection from Research RisksNelson L. Garnett, D.V.M.
Director, Division of Animal Welfare
Office for Protection from Research Risks
Director, Office of Laboratory Animal Welfare
Office of Extramural Research,
Office of the Director, National Institutes of Health
RKL 1, Suite 360
6705 Rockledge Dr .
Bethesda , MD 20892-7982
(For express or hand-delivered mail use zip code 20817)
Telephone (301) 496-7163
STATUTORY AND POLICY BASES FOR CONSIDERATION OF ALTERNATIVES
Health Research Extension Act of 1985, Public Law 99-158, at Sec. 495(c):
"The Director of NIH shall require each applicant for a grant, contract, or cooperative agreement involving research on animals which is administered by the National Institutes of Health ...to include in its application...
"(1)...assurances satisfactory to the Director, NIH that..."(B) scientists, animal technicians, and other personnel involved with animal care, treatment, and use...have available to them instruction or training in the...concept, availability, and use of research or testing methods that limit the use of animals or limit animal distress; and
"(2) a statement of the reasons for the use of animals in research to be conducted with funds provided under such grant or contract."
U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training, Principles III, IV, and V:
"III. The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid results. Methods such as mathematical models, computer simulation, and in vitro biological systems should be considered.
IV. Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative....
V. Procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia..."
PHS Policy on Humane Care and Use of Laboratory Animals, IV.A.1.g:
[The Assurance shall fully describe...] "a synopsis of training or instruction in the humane practice of animal care and use, as well as training or instruction in research or testing methods that minimize the number of animals required to obtain valid results and minimize animal distress, offered to scientists, animal technicians, and other personnel involving in animal care, treatment, or use;"
PHS Policy on Humane Care and Use of Laboratory Animals, IV.C.1.a.:
[In order to approve proposed research...the IACUC shall determine that...] "Procedures with animals will avoid or minimize discomfort, distress, and pain to the animals, consistent with sound research design."
Guide for the Care and Use of Laboratory Animals, 1996, National Academy of Sciences:
"Although scientists have also developed nonanimal models for research, teaching, and testing...these models often cannot completely mimic the complex human or animal body, and continued progress in human and animal health and well-being requires the use of living animals. Nevertheless, efforts to develop and use scientifically valid alternatives, adjuncts, and refinements to animal research should continue." (page 1)
"The following topics should be considered in the preparation and review of animal care and use protocols...Availability or appropriateness of the use of less-invasive procedures, other species, isolated organ preparation, cell or tissue culture, or computer simulation..." (page 10)
Animal Welfare Act, as amended by the Food Security Act of 1985, Public Law 99-198:
"[The Secretary shall promulgate...requirements]...for animal care, treatment, and practices in experimental procedures to ensure that animal pain and distress are minimized... that the principal investigator considers alternatives to any procedure likely to produce pain to or distress in an experimental animal..." (Section 13(a)(3)(A)&(B))
"Each research facility shall provide for the training of scientists, animal technicians, and other personnel...training shall include instruction on--(1) the humane practice of animal maintenance and experimentation; (2) research or testing methods that minimize or eliminate the use of animals or limit animal pain or distress;" (Section 13(d))
CFR, Title 9, Chapter 1, Subchapter A - Animal Welfare, Sec. 231(d):
"In order to approve...activities...the IACUC shall determine that...(i) Procedures involving animals will avoid or minimize discomfort, distress, and pain to the animals; (ii) The principal investigator has considered alternatives to procedures that may cause more than momentary or slight pain or distress to the animals, and has provided a written narrative description of the methods and sources...used to determine that alternatives were not available."
CFR, Title 9, Chapter 1, Subchapter A - Animal Welfare, Sec. 232(c):
"Training and instruction of personnel must include guidance in...(2) The concept, availability, and use of research or testing methods that limit the use of animals or minimize animal distress;"
RESOURCES FOR ALTERNATIVES IN ANIMAL CARE AND USE
Adjuvants and Antibody Production, ILAR Journal, National Research Council, Institute of Laboratory Animal Resources, Volume 37, Number 3, pp. 92-152, 1995.
Alternatives to the Use of Live Vertebrates in Biomedical Research and Testing. A bibliography with abstracts prepared by the Toxicology and Environmental Health Information Program, Specialized Information Service, National Library of Medicine, NIH. This document is updated quarterly. To receive the latest copy or be placed on the mailing list call 301-496-1131. Also available on-line at: http://toxnet.nlm.nih.gov/altbib.html
Altweb is a world wide web site devoted to replacement, reduction and refinement alternatives for research and testing, maintained by the Johns Hopkins Center for Alternatives to Animal Testing (CAAT). The site is: http://altweb.jhsph.edu/
Information Resources for Adjuvants and Antibody Production: Comparisons and Alternative Technologies, Resource Series No. 3, March 1997, available from the Animal Welfare Information Center (AWIC), NAL, USDA, 10301 Baltimore Boulevard, Beltsville, MD 20705. Also available on-line at: http://www.nal.usda.gov/awic/pubs/antibody
NIH Plan for the Use of Animals In Research, October 1993. Copies available from the Office of Laboratory Animal Research, OER, NIH, 9000 Rockville Pike, Building 1, Room 252, Bethesda, MD 20892. http://altweb.jhsph.edu/science/regs/nihplan.htm --->
Office for Protection from Research Risks (OPRR) laboratory animal welfare web page available at: OLAW
A Report on Validation and Regulatory Acceptance of Toxicological Test Methods, NIH Publication No. 97-3981, available from the Center for Evaluation of Alternative Toxicological Methods, NIEHS, P.O. Box 12233, Research Triangle Park, North Carolina 27709-12233. Also available on-line at: http://ntp-.niehs.nih.gov/ntpweb/