[Federal Register Volume 61, Number 13 (Friday, January 19, 1996)]
[Notices]
[Pages 1482-1490]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-689]



      

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Part III





Department of Health and Human Services





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National Institutes of Health



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Recombinant DNA Research: Actions Under the Guidelines; Notice

  Federal Register / Vol. 61, No. 13 / Friday, January 19, 1996 / 
Notices  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Recombinant DNA Research: Actions Under the Guidelines

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice of Actions under the NIH Guidelines for Research 
Involving Recombinant DNA Molecules (59 FR 34496, 59 FR 40170, 60 FR 
20726).

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SUMMARY: This notice sets forth an action to be taken by the Director, 
National Institutes of Health (NIH), under the NIH Guidelines for 
Research Involving Recombinant DNA Molecules.

FOR FURTHER INFORMATION CONTACT:
Additional information can be obtained from Dr. Nelson A. Wivel, 
Director, Office of Recombinant DNA Activities (ORDA), Office of 
Science Policy and Technology Transfer, National Institutes of Health, 
Suite 302, 6000 Executive Boulevard, MSC 7010, Bethesda, Maryland 
20892-7010, (301) 496-9838.

SUPPLEMENTARY INFORMATION: Today's action is being promulgated under 
the NIH Guidelines for Research Involving Recombinant DNA Molecules. 
This proposed action was published for comment in the Federal Register 
of August 18, 1994 (58 FR 44098), November 8, 1994 (59 FR 55796), 
February 8, 1995 (60 FR 7630), and May 22, 1995 (60 FR 27207), and 
reviewed and recommended for approval by the NIH Recombinant DNA 
Advisory Committee (RAC) at its meeting on June 8-9, 1995.

I. Background Information and Decisions on Actions Under the NIH 
Guidelines

A. Amendments to Sections II, III, IV, V, Appendices B, C, H, and Q of 
the NIH Guidelines Regarding Updating the Classification of 
Microorganisms

    In a letter dated June 24, 1993, Dr. Diane Fleming, President of 
the Mid-Atlantic Biological Safety Association requested the revision 
and updating of Appendix B, Classification of Microorganisms on the 
Basis of Hazard. The Mid-Atlantic Biological Safety Association 
submitted an updated list of the classification of microorganisms for 
the Recombinant DNA Advisory Committee to review which included the 
latest taxonomy and agent risk group classifications as defined by the 
Centers for Disease Control and Prevention.
    During the September 9-10, 1993, meeting, the Recombinant DNA 
Advisory Committee recommended by consensus that the current 
classification of etiological agents described in the Biosafety in 
Microbiological and Biomedical Laboratories, 3rd edition, May 1993, 
U.S. Department of Health and Human Services, should be endorsed by the 
Committee. The Committee retained the option to adopt any modifications 
to the Centers for Disease Control and Prevention listing. The 
Committee recommended that the revised Appendix B, Classification of 
Microorganisms on the Basis of Hazard, submitted by Dr. Fleming should 
not be adopted until the Committee received letters of concurrence from 
both the Centers for Disease Control and Prevention and the NIH 
Division of Safety.
    In a telephone call on October 20, 1994, Dr. Fleming stated that 
Appendix B, Classification of Microorganisms on the Basis of Hazard, 
would be reviewed by experts from the Centers for Disease Control and 
Prevention and the American Society for Microbiology. The revised 
Appendix B was submitted to the Recombinant DNA Advisory Committee 
December 1-2, 1994, meeting for review and discussion. During the 
December 1994 meeting, the Committee recommended publishing the revised 
Appendix B in the Federal Register for public comment, with further 
review of this proposal and possible approval during the March 6-7, 
1995, meeting.
    During the March 6-7, 1995 meeting, the Recombinant DNA Advisory 
Committee deferred approval of the proposed amendments to Appendix B 
pending additional revisions to the remaining sections and appendices 
of the NIH Guidelines that are required to adequately accommodate the 
revised Appendix B (Sections II, III, IV, V, Appendices C, H, and Q). 
The motion for deferral included a recommendation that a subcommittee 
consisting of Dr. Stephen Straus (Chair of the Subcommittee), ad hoc 
experts, and Office of Recombinant DNA Activities staff would meet to 
develop the required modifications. The motion passed by a vote of 17 
in favor, 0 opposed, and no abstentions.
    On May 5, 1995, the Appendix B Subcommittee met to finalize the 
document in terms of its listing of pathogens and the text of the NIH 
Guidelines related to Appendix B in other sections and appendices 
(Sections II, III, IV, V, Appendices C, H, and Q). During the June 8-9, 
1995 meeting, the Recombinant DNA Advisory Committee reviewed the 
document. There was a concurrence that the Risk Group classification 
serves as an initial guidance to assign an appropriate containment 
level for a particular experiment by the Institutional Biosafety 
Committees and the investigators. Since the new Appendix B is primarily 
concerned with human pathogenicity, it addresses only the human 
etiologic agents and omits all animal agents. The Committee observed 
that this omission created a problem because some of the animal agents, 
particularly the group of viruses known as oncogenic viruses are 
frequently used as vectors for gene transfer in the laboratories or in 
human studies. The Recombinant DNA Advisory Committee approved a motion 
to: (1) establish a working group to recommend exemption of additional 
vector systems in Appendix C (exempt host-vector systems), and (2) 
accept the proposed amendments to Appendix B with the provision to 
develop a new Appendix B-V relating to animal viruses relevant to human 
studies, and to list specific examples of agents under Appendix B-I, 
Risk Group 1 (RG1) Agents. The motion was approved by a vote of 17 in 
favor, 0 opposed, and no abstentions.
    On June 13, 1995, the Office of Recombinant DNA Activities 
forwarded two versions of the Appendix B-V, Animal Viral Etiologic 
Agents in Common Use to the Appendix B Subcommittee. Most of these 
agents were previously listed as Class 2 oncogenic viruses in two 
separate categories of low and moderate risk agents in the original 
Appendix B. Since none of these animal etiologic agents are associated 
with disease in healthy human adults, one version of Appendix B-V 
listed these agents as a single group recommended for Biosafety Level 1 
containment and another version listed them in a two-tier system for 
either Biosafety Level 1 or Biosafety Level 2 containment. Subsequent 
discussion with the members of the Appendix B Subcommittee concluded 
that while there was no reason to have a separate group of ``moderate'' 
risk agents in this list, it was prudent to recommend conducting 
experiments under a Biosafety Level 2 containment with several agents 
that are capable of infecting human cells, e.g., amphotropic and 
xenotropic murine leukemia virus.
    During the September 11-12, 1995, meeting, the Recombinant DNA 
Advisory Committee reviewed the updated Appendix B along with other 
sections and appendices of the NIH Guidelines (Sections II, III, IV, V, 
Appendices C, H, and Q) relating to classification of microorganisms. 
It was observed that some viruses in the moderate risk group could 
infect human cells but their replication was largely restricted to 
their animal hosts. Some Committee members pointed out that 

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some viruses with oncogenes such as SV40 have been treated more 
cautiously than viruses without oncogenes; therefore, a two-tier list 
should be used. Dr. Wivel explained that listing a group of animal 
viruses as ``moderate risk'' agents introduces an inconsistency into 
Appendix B. Some strains of these viruses, although capable of 
infecting human cells, have not been shown to be associated with any 
disease in healthy human adults. They fall within the definition of 
Risk Group 1 agents, i.e., agents that are not associated with disease 
in healthy adult humans. Two committee members inquired why several 
viruses in the original Appendix B are not listed in the new version. 
Dr. Thomas Shih (Executive Secretary, Appendix B Subcommittee) 
explained that several rarely used viruses such as chick embryo lethal 
orphan virus are deleted from the new list. The list includes commonly 
used organisms, and it is not intended to be inclusive since many other 
animal agents are not listed. Dr. Walters (Chair, Recombinant DNA 
Advisory Committee) stated that the consensus of the committee is to 
accept the list of animal viruses in Appendix B-V as a reasonable 
modification of Appendix B.
    The actions are detailed in Section II--Summary of Actions. I 
accept these recommendations, and the NIH Guidelines will be amended 
accordingly.

II. Summary of Actions

A. Amendments to Section II, Safety Considerations (Previously the 
Entire Section II was Entitled Containment)

    Section II is amended to read:
Section II. Safety Considerations
Section II-A. Risk Assessment
Section II-A-1. Risk Groups

    Risk assessment requires the exercise of sound judgment by the 
investigator. The investigator must make an initial risk assessment 
based on the Risk Group (RG) of an agent (see Appendix B, 
Classification of Human Etiologic Agents on the Basis of Hazard). 
Agents are classified into four Risk Groups (RGs) according to their 
relative pathogenicity for healthy adult humans by the following 
criteria: (1) Risk Group 1 (RG1) agents are not associated with disease 
in healthy adult humans. (2) Risk Group 2 (RG2) agents are associated 
with human disease which is rarely serious and for which preventive or 
therapeutic interventions are often available. (3) Risk Group 3 (RG3) 
agents are associated with serious or lethal human disease for which 
preventive or therapeutic interventions may be available. (4) Risk 
Group 4 (RG4) agents are likely to cause serious or lethal human 
disease for which preventive or therapeutic interventions are not 
usually available.
Section II-A-2. Criteria for Risk Groups
    Classification of agents is based on the potential effect of a 
biological agent on a healthy human adult and does not account for 
instances in which an individual may have increased susceptibility to 
such agents, e.g., preexisting diseases, medications, compromised 
immunity, pregnancy or breast feeding (which may increase exposure of 
infants to some agents) (see Appendix B, Classification of Human 
Etiologic Agents on the Basis of Hazard).
    Personnel may need periodic medical surveillance to ascertain 
fitness to perform certain activities; they may also need to be offered 
prophylactic vaccines and boosters (see Section IV-B-1-f, 
Responsibilities of the Institution, General Information).
Section II-A-3. Comprehensive Risk Assessment
    In deciding on the appropriate containment for an experiment, the 
initial risk assessment from Appendix B, Classification of Human 
Etiologic Agents on the Basis of Hazard, should be followed by a 
thorough consideration of the agent itself and how it is to be 
manipulated. Factors to be considered in determining the level of 
containment include agent factors such as: virulence, pathogenicity, 
infectious dose, environmental stability, route of spread, 
communicability, operations, quantity, availability of vaccine or 
treatment, and gene product effects such as toxicity, physiological 
activity, and allergenicity. Any strain that is known to be more 
hazardous than the parent (wild-type) strain should be considered for 
handling at a higher containment level. Certain attenuated strains or 
strains that have been demonstrated to have irreversibly lost known 
virulence factors may qualify for a reduction of the containment level 
compared to the Risk Group assigned to the parent strain (see Section 
V-B, Footnotes and References of Sections I through IV).
    A final assessment of risk based on these considerations is then 
used to set the appropriate containment conditions for the experiment 
(see Section II-B, Containment). The containment level required may be 
equivalent to the Risk Group classification of the agent or it may be 
raised or lowered as a result of the above considerations. The 
Institutional Biosafety Committee must approve the risk assessment and 
the biosafety containment level for recombinant DNA experiments 
described in Sections III-A, Experiments that Require Institutional 
Biosafety Committee Approval, RAC Review, and NIH Director Approval 
Before Initiation, III-B, Experiments that Require NIH/ORDA and 
Institutional Biosafety Committee Approval Before Initiation, and III-
C, Experiments that Require Institutional Biosafety Committee Approval 
Before Initiation.
    Careful consideration should be given to the types of manipulation 
planned for some higher Risk Group agents. For example, the RG2 dengue 
viruses may be cultured under the Biosafety Level (BL) 2 containment 
(see Section II-B); however, when such agents are used for animal 
inoculation or transmission studies, a higher containment level is 
recommended. Similarly, RG3 agents such as Venezuelan equine 
encephalomyelitis and yellow fever viruses should be handled at a 
higher containment level for animal inoculation and transmission 
experiments.
    Individuals working with human immunodeficiency virus (HIV), 
hepatitis B virus (HBV) or other bloodborne pathogens should consult 
Occupational Exposure to Bloodborne Pathogens; Final Rule (56 FR 64175-
64182). BL2 containment is recommended for activities involving all 
blood-contaminated clinical specimens, body fluids, and tissues from 
all humans, or from HIV- or HBV-infected or inoculated laboratory 
animals. Activities such as the production of research-laboratory scale 
quantities of HIV or other bloodborne pathogens, manipulating 
concentrated virus preparations, or conducting procedures that may 
produce droplets or aerosols, are performed in a BL2 facility using the 
additional practices and containment equipment recommended for BL3. 
Activities involving industrial scale volumes or preparations of 
concentrated HIV are conducted in a BL3 facility, or BL3 Large Scale if 
appropriate, using BL3 practices and containment equipment.
    Exotic plant pathogens and animal pathogens of domestic livestock 
and poultry are restricted and may require special laboratory design, 
operation and containment features not addressed in Biosafety in 
Microbiological and Biomedical Laboratories (see Section V-C, Footnotes 
and References of Sections I through IV). For information regarding the 
importation, possession, or use of these agents see Sections V-G and V-
H, Footnotes and References of Sections I through IV.

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Section II-B. Containment
    Effective biological safety programs * * *

[Rest of Section II remains unchanged.]

B. Amendments to Section III, Experiments Covered by the NIH Guidelines

    Section III-C is amended to read:
Section III-C. Experiments That Require Institutional Biosafety 
Committee Approval Before Initiation
    Prior to the initiation of an experiment that falls into this 
category, the Principal Investigator must submit a registration 
document to the Institutional Biosafety Committee which contains the 
following information: (i) the source(s) of DNA; (ii) the nature of the 
inserted DNA sequences; (iii) the host(s) and vector(s) to be used; 
(iv) an indication of what protein will be produced if an attempt is to 
be made to obtain expression of a foreign gene; and (v) the containment 
conditions that will be implemented as specified in the NIH Guidelines. 
For experiments in this category, the registration document shall be 
dated, signed by the Principal Investigator, and filed with the 
Institutional Biosafety Committee. The Institutional Biosafety 
Committee shall review and approve all experiments in this category 
prior to their initiation. Requests to decrease the level of 
containment specified for experiments in this category will be 
considered by NIH (see Section IV-C-1-b-(2)-(c), Minor Actions).
    Section III-C-1. Experiments Using Risk Group 2, Risk Group 3, Risk 
Group 4, or Restricted Agents as Host-Vector Systems (see Section II-A, 
Risk Assessment).
    Section III-C-1-a. Experiments involving the introduction of 
recombinant DNA into Risk Group 2 agents will usually be conducted at 
Biosafety Level (BL) 2 containment. Experiments with such agents will 
usually be conducted with whole animals at BL2 or BL2-N (Animals) 
containment.
    Section III-C-1-b. Experiments involving the introduction of 
recombinant DNA into Risk Group 3 agents will usually be conducted at 
BL3 containment. Experiments with such agents will usually be conducted 
with whole animals at BL3 or BL3-N containment.
    Section III-C-1-c. Experiments involving the introduction of 
recombinant DNA into Risk Group 4 agents shall be conducted at BL4 
containment. Experiments with such agents will usually be conducted 
with whole animals at BL4 or BL4-N containment.
    Section III-C-1-d. Containment conditions for experiments involving 
the introduction of recombinant DNA into restricted agents shall be set 
on a case-by-case basis following NIH/ORDA review. A U.S. Department of 
Agriculture permit is required for work with plant or animal pathogens 
(see Section V-G and V-L, Footnotes and References of Sections I 
through IV). Experiments with such agents shall be conducted with whole 
animals at BL4 or BL4-N containment.
    Section III-C-2. Experiments in which DNA From Risk Group 2, Risk 
Group 3, Risk Group 4, or Restricted Agents (see Section V-A, Footnotes 
and References of Sections I through IV) is Cloned into Nonpathogenic 
Prokaryotic or Lower Eukaryotic Host-Vector Systems.
    Section III-C-2-a. Experiments in which DNA from Risk Group 2 or 
Risk Group 3 agents (see Section II-A, Risk Assessment) is transferred 
into nonpathogenic prokaryotes or lower eukaryotes may be performed 
under BL2 containment. Experiments in which DNA from Risk Group 4 
agents is transferred into nonpathogenic prokaryotes or lower 
eukaryotes may be performed under BL2 containment after demonstration 
that only a totally and irreversibly defective fraction of the agent's 
genome is present in a given recombinant. In the absence of such a 
demonstration, BL4 containment shall be used. The Institutional 
Biosafety Committee may approve the specific lowering of containment 
for particular experiments to BL1. Many experiments in this category 
are exempt from the NIH Guidelines (see Section III-E, Exempt 
Experiments). Experiments involving the formation of recombinant DNA 
for certain genes coding for molecules toxic for vertebrates require 
NIH/ORDA approval (see Section III-B-1, Experiments Involving the 
Cloning of Toxin Molecules With LD50 of Less than 100 Nanograms 
Per Kilogram Body Weight) or shall be conducted under NIH specified 
conditions as described in Appendix F, Containment Conditions for 
Cloning of Genes Coding for the Biosynthesis of Molecules Toxic for 
Vertebrates.
    Section III-C-2-b. Containment conditions for experiments in which 
DNA from restricted agents is transferred into nonpathogenic 
prokaryotes or lower eukaryotes shall be determined by NIH/ORDA 
following a case-by-case review (see Section V-L, Footnotes and 
References of Sections I through IV). A U.S. Department of Agriculture 
permit is required for work with plant or animal pathogens (see Section 
V-G, Footnotes and References of Sections I through IV).
    Section III-C-3. Experiments Involving the Use of Infectious DNA or 
RNA Viruses or Defective DNA or RNA Viruses in the Presence of Helper 
Virus in Tissue Culture Systems.
    Caution: Special care should be used in the evaluation of 
containment levels for experiments which are likely to either enhance 
the pathogenicity (e.g., insertion of a host oncogene) or to extend the 
host range (e.g., introduction of novel control elements) of viral 
vectors under conditions that permit a productive infection. In such 
cases, serious consideration should be given to increasing physical 
containment by at least one level.
    Note: Recombinant DNA or RNA molecules derived therefrom, which 
contain less than two-thirds of the genome of any eukaryotic virus (all 
viruses from a single Family) (See Section V-J, Footnotes and 
References of Sections I through IV) being considered identical (see 
Section V-K, Footnotes and References of Sections I through IV), are 
considered defective and may be used in the absence of helper virus 
under the conditions specified in Section III-D-1, Experiments 
Involving the Formation of Recombinant DNA Molecules Containing No More 
than Two-Thirds of the Genome of any Eukaryotic Virus.
    Section III-C-3-a. Experiments involving the use of infectious or 
defective Risk Group 2 viruses (see Section V-A, Footnotes and 
References of Sections I through IV, and Appendix B-II, Risk Group 2 
Agents) in the presence of helper virus may be conducted at BL2.
    Section III-C-3-b. Experiments involving the use of infectious or 
defective Risk Group 3 viruses (see Section V-A, Footnotes and 
References of Sections I through IV, and Appendix B-III-D, Risk Group 3 
(RG3)--Viruses and Prions) in the presence of helper virus may be 
conducted at BL3.
    Section III-C-3-c. Experiments involving the use of infectious or 
defective Risk Group 4 viruses (see Section V-A, Footnotes and 
References of Sections I through IV, and Appendix B-IV-D, Risk Group 4 
(RG4)--Viral Agents) in the presence of helper virus may be conducted 
at BL4.
    Section III-C-3-d. Experiments involving the use of infectious or 
defective restricted poxviruses (see Section V-A and V-L, Footnotes and 
References of Sections I through IV) in the presence of helper virus 
shall be determined on a case-by-case basis following NIH/ORDA review. 
A U.S. 

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Department of Agriculture permit is required for work with plant or 
animal pathogens (see Section V-G, Footnotes and References of Sections 
I through IV).
    Section III-C-3-e. Experiments involving the use of infectious or 
defective viruses in the presence of helper virus which are not covered 
in Sections III-E-3-a through III-C-3-d may be conducted at BL1.
    Section III-C-4. Experiments Involving Whole Animals.
    This section covers experiments involving whole animals in which 
the animal's genome has been altered by stable introduction of 
recombinant DNA, or DNA derived therefrom, into the germ-like 
(transgenic animals) and experiments involving viable recombinant DNA-
modified microorganisms tested on whole animals. For the latter, other 
than viruses which are only vertically transmitted, the experiments may 
not be conducted at BL1-N containment. A minimum containment of BL2 or 
BL2-N is required.
    Caution--Special care should be used in the evaluation of 
containment conditions for some experiments with transgenic animals. 
For example, such experiments might lead to the creation of novel 
mechanisms or increased transmission of a recombinant pathogen or 
production of undesirable traits in the host animal. In such cases, 
serious consideration should be given to increasing the containment 
conditions.
    Section III-C-4-a. Recombinant DNA, or DNA or RNA molecules derived 
therefrom, from any source except for greater than two-thirds of 
eukaryotic viral genome may be transferred to any nonhuman vertebrate 
or any invertebrate organism and propagated under conditions of 
physical containment comparable to BL1 or BL1-N and appropriate to the 
organism under study (see Section V-B, Footnotes and References of 
Sections I through IV). Animals that contain sequences from viral 
vectors, which do not lead to transmissible infection either directly 
or indirectly as a result of complementation or recombination in 
animals, may be propagated under conditions of physical containment 
comparable to BL1 or BL1-N and appropriate to the organism under study. 
Experiments involving the introduction of other sequences from 
eukaryotic viral genomes into animals are covered under Section III-C-
4-b, Experiments Involving Whole Animals. For experiments involving 
recombinant DNA-modified Risk Groups, 2, 3, 4, or restricted organisms, 
see Sections V-A, V-G, and V-L, Footnotes and References of Sections I 
through IV. It is important that the investigator demonstrate that the 
fraction of the viral genome being utilized does not lead to productive 
infections. A U.S. Department of Agriculture permit is required for 
work with plant or animal pathogens (see Section V-G, Footnotes and 
References of Sections I through IV).
    Section III-C-4-b. For experiments involving recombinant DNA, or 
DNA or RNA derived therefrom, involving whole animals, including 
transgenic animals, and not covered by Sections III-C-1, Experiments 
Using Risk Group 2, Risk Group 3, Risk Group 4, or Restricted Agents as 
Host-Vector Systems, or III-C-4-a, Experiments Involving Whole Animals, 
the appropriate containment shall be determined by the Institutional 
Biosafety Committee.

[The rest of the Section III-C remains unchanged.]

C. Amendments to Section IV, Roles and Responsibilities

    Section IV-C-1-b-(2)-(e) is amended to read:
    Section IV-C-1-b-(2)-(e). Setting containment under Sections III-C-
1-d, Experiments Using Risk Group 2, Risk Group 3, Risk Group 4, or 
Restricted Agents as Host-Vector Systems, and III-C-2-b, Experiments in 
which DNA from Risk Group 2, Risk Group 3, Risk Group 4, or Restricted 
Agents is Cloned into Nonpathogenic Prokaryotic or Lower Eukaryotic 
Host-Vector Systems;

[The rest of the Section IV-C-1-b-(2) remains unchanged.]

D. Amendments to Section V, Footnotes and References of Sections I 
Through IV

    Section V is amended to read:
Section V. Footnotes and References of Sections I through IV
    Section V-A. The NIH Director, with advice of the RAC, may revise 
the classification for the purposes of the NIH Guidelines (see Section 
IV-C-1-b-(2)-(e), Minor Actions). The revised list of organisms in each 
risk group is reprinted in Appendix B, Classification of Human 
Etiologic Agents on the Basis of Hazard.
    Section V-B. Section III, Experiments Covered by the NIH 
Guidelines, describes a number of places where judgments are to be 
made. In all these cases, the Principal Investigator shall make the 
judgment on these matters as part of his/her responsibility to ``make 
the initial determination of the required levels of physical and 
biological containment in accordance with the NIH Guidelines'' (see 
Section IV-B-4-c-(1), Principal Investigator). For cases falling under 
Sections III-A through III-D, Experiments Covered by the NIH 
Guidelines, this judgment is to be reviewed and approved by the 
Institutional Biosafety Committee as part of its responsibility to make 
an ``independent assessment of the containment levels required by the 
NIH Guidelines for the proposed research'' (see Section IV-B-2-b-(1), 
Institutional Biosafety Committee). The Institutional Biosafety 
Committee may refer specific cases to NIH/ORDA as part of NIH/ORDA's 
functions to ``provide advice to all within and outside NIH'' (see 
Section IV-C-3, Office of Recombinant DNA Activities). NIH/ORDA may 
request advice from the RAC as part of the RAC's responsibility for 
``interpreting the NIH Guidelines for experiments to which the NIH 
Guidelines do not specifically assign containment levels'' (see Section 
IV-C-1-b-(2)-(f), Minor Actions).
    Section V-C. U.S. Department of Health and Human Services, Public 
Health Service, Centers for Disease Control and Prevention and the 
National Institutes of Health. Biosafety in Microbiological and 
Biomedical Laboratories, 3rd edition, 1993. Copies are available from: 
Superintendent of Documents, U.S. Government Printing Office, 
Washington, DC 20402 (stock # 017-040-00523-7), Phone (202)-512-2356.
    Section V-D. Classification of Etiologic Agents on the Basis of 
Hazard, 4th Edition, July 1974, U.S. Department of Health, Education, 
and Welfare, Public Health Service, Centers for Disease Control, Office 
of Biosafety, Atlanta, Georgia 30333.
    Section V-E. Benenson, Abram S. ed., Control of Communicable 
Diseases in Man, 15th edition. 1990. American Public Health 
Association, Washington, DC.
    Section V-F. World Health Organization Laboratory Biosafety Manual, 
2nd edition. 1993. WHO Albany, NY. Copies are available from: WHO 
Publication Centre, USA, (Q Corp) 49 Sheridan Avenue, Albany, New York 
12210; Phone: (518)-436-9686 (Order # 1152213).
    Section V-G. A U.S. Department of Agriculture permit, required for 
import and interstate transport of plant and animal pathogens, may be 
obtained from the U.S. Department of Agriculture, ATTN: Animal and 
Plant Health Inspection Service (APHIS), Veterinary Services, National 
Center for Import-Export, Products Program, 4700 River Road, Unit 40, 
Riverdale, MD 20737. Phone: (301)-734-8499; Fax: (301)-734-8226.

[[Page 1486]]

    Section V-H. American Type Culture Collection Catalogues of plant 
viruses, animal viruses, cells, bacteria, fungi, etc. are available 
from American Type Culture Collection, 12301 Parklawn Drive, Rockville, 
Maryland 20852-1776. Phone: (800)-638-6597; Fax: (301)-231-5826.
    Section V-I. U.S. Department of Labor, Occupational Safety and 
Health Administration. 1991. Occupational Exposure to Bloodborne 
Pathogens, Final Rule (56 FR 64175-64182).
    Section V-J. As classified in the 6th Report on the International 
Committee on Taxonomy of Viruses: Classification and Nomenclature of 
Viruses, F.A. Murphy et al., Archives of Virology/Supplement 10, 1995, 
Springer-Verlag, New York, New York.
    Section V-K. i.e., the total of all genomes within a family shall 
not exceed two-thirds of the genome.
    Section V-L. Organisms including alastrim, smallpox (variola) and 
whitepox may not be studied in the United States except at specified 
facilities. All activities, including storage of variola and whitepox, 
are restricted to the single national facility (World Health 
Organization Collaborating Center for Smallpox Research, Centers for 
Disease Control and Prevention, Atlanta, Georgia).
    Section V-M. In accordance with accepted scientific and regulatory 
practices of the discipline of plant pathology, an exotic plant 
pathogen (e.g., virus, bacteria, or fungus) is one that is unknown to 
occur within the U.S. (see Section V-G, Footnotes and References of 
Sections I through IV). Determination of whether a pathogen has a 
potential for serious detrimental impact on managed (agricultural, 
forest, grassland) or natural ecosystems should be made by the 
Principal Investigator and the Institutional Biosafety Committee, in 
consultation with scientists knowledgeable of plant diseases, crops, 
and ecosystems in the geographic area of the research.

E. Amendments to Appendix B, Classification of Human Etiologic Agents 
on the Basis of Hazard

    Appendix B is amended to read:
Appendix B. Classification of Human Etiologic Agents on the Basis of 
Hazard
    Appendix B includes those biological agents known to infect humans, 
as well as selected animal agents, that may pose theoretical risks if 
inoculated into humans. Included in the lists are species known to be 
pathogenic, mutated, or recombined; non-pathogenic species and strains 
are not considered. Non-infectious life cycle stages of parasites are 
excluded.
    This appendix reflects the current state of knowledge and should be 
considered a resource document. The more commonly encountered agents 
are included; however, this appendix is not meant to be all inclusive. 
Information on agent risk assessment may be found in the Agent Summary 
Statements of the Centers for Disease Control and Prevention/National 
Institutes of Health publications, Biosafety in Microbiological and 
Biomedical Laboratories (see Sections V-C, V-D, V-E, and V-F, Footnotes 
and References of Sections I through IV). Further guidance on agents 
not listed in Appendix B may be obtained through: Centers for Disease 
Control and Prevention, Biosafety Branch, Atlanta, Georgia 30333, 
Phone: (404)-639-3883, Fax: (404)-639-2294; National Institutes of 
Health, Division of Safety, Bethesda, Maryland 20892, Phone: (301)-496-
1357; National Animal Disease Center, U.S. Department of Agriculture, 
Ames, Iowa 50010, Phone: (515)-862-8258.
    A special committee of the American Society for Microbiology will 
conduct an annual review of this appendix and its recommendation for 
changes will be presented to the Recombinant DNA Advisory Committee as 
proposed amendments to the NIH Guidelines.
Appendix B--Table 1.--Basis for the Classification of Biohazardous 
Agents by Risk Group (RG)

Risk Group 1 (RG1).....................  Agents that are not associated 
                                          with disease in healthy adult 
                                          humans.                       
Risk Group 2 (RG2).....................  Agents that are associated with
                                          human disease which is rarely 
                                          serious and for which         
                                          preventive or therapeutic     
                                          interventions are often       
                                          available.                    
Risk Group 3 (RG3).....................  Agents that are associated with
                                          serious or lethal disease for 
                                          which preventive or           
                                          therapeutic interventions may 
                                          be available (high individual 
                                          risk but low community risk). 
Risk Group 4 (RG4).....................  Agents that are likely to cause
                                          serious or lethal human       
                                          disease for which preventive  
                                          or therapeutic interventions  
                                          are not usually available     
                                          (high individual risk and high
                                          community risk).              
                                                                        

Appendix B-I. Risk Group 1 (RG1) Agents
    RG1 agents are not associated with disease in healthy adult humans. 
Examples of RG1 agents include asporogenic Bacillus subtilis or 
Bacillus licheniformis (see Appendix C-IV-A, Bacillus subtilis or 
Bacillus licheniformis Host-Vector Systems, Exceptions), Eschenrichia 
coli-K12 (see Appendix C-II-A, Escherichia coli K-12 Host-Vector 
Systems, Exceptions), and adeno-associated virus types 1-4.
    Those agents not listed in Risk Groups (RGs) 2, 3 and 4 are not 
automatically or implicitly classified in RG1; a risk assessment must 
be conducted based on the known and potential properties of the agents 
and their relationship to agents that are listed.
Appendix B-II. Risk Group 2 (RG2) Agents
    RG2 agents are associated with human disease which is rarely 
serious and for which preventive or therapeutic interventions are often 
available.
Appendix B-II-A. Risk Group 2 (RG2)--Bacterial Agents Including 
Chlamydia
--Acinetobacter baumannii (formerly Acinetobacter calcoaceticus)
--Actinobacillus 
--Actinomyces pyogenes (formerly Corynebacterium pyogenes)
--Aeromonas hydrophila 
--Amycolata autotrophica 
--Archanobacterium haemolyticum (formerly Corynebacterium haemolyticum)
--Arizona hinshawii--all serotypes
--Bacillus anthracis 
--Bartonella henselae, B. quintana, B. vinsonii 
--Bordetella including B. pertussis 
--Borrelia recurrentis, B. burgdorferi 
--Burkholderia (formerly Pseudomonas species) except those listed in 
Appendix B-III-A (RG3))
--Campylobacter coli, C. fetus, C. jejuni 
--Chlamydia psittaci, C. trachomatis, C. pneumoniae 
--Clostridium botulinum, Cl. chauvoei, Cl. haemolyticum, Cl. 
histolyticum, Cl. novyi, Cl. septicum, Cl. tetani 
--Corynebacterium diphtheriae, C. pseudotuberculosis, C. renale 
--Dermatophilus congolensis 
--Edwardsiella tarda 
--Erysipelothrix rhusiopathiae 
--Escherichia coli--all enteropathogenic, enterotoxigenic, 
enteroinvasive and strains bearing K1 antigen, including E. coli 
O157:H7
--Haemophilus ducreyi, H. influenzae 
--Helicobacter pylori 
--Klebsiella--all species except K. oxytoca (RG1)
--Legionella including L. pneumophila
--Leptospira interrogans--all serotypes
--Listeria 
--Moraxella 
--Mycobacterium (except those listed in Appendix B-III-A (RG3)) 
including M. avium complex, M. asiaticum, M. bovis BCG vaccine strain, 
M. chelonei, 

[[Page 1487]]
M. fortuitum, M. kansasii, M. leprae, M. malmoense, M. marinum, M. 
paratuberculosis, M. scrofulaceum, M. simiae, M. szulgai, M. ulcerans, 
M. xenopi
--Mycoplasma, except M. mycoides and M. agalactiae which are restricted 
animal pathogens
--Neisseria gonorrhoea, N. meningitidis 
--Nocardia asteroides, N. brasiliensis, N. otitidiscaviarum, N. 
transvalensis 
--Rhodococcus equi 
--Salmonella including S. arizonae, S. cholerasuis, S. enteritidis, S. 
gallinarum-pullorum, S. meleagridis, S. paratyphi, A, B, C, S. typhi, 
S. typhimurium
--Shigella including S. boydii, S. dysenteriae, type 1, S. flexneri, S. 
sonnei
--Sphaerophorus necrophorus 
--Staphylococcus aureus 
--Streptobacillus moniliformis 
--Streptococcus including S. pneumoniae, S. pyogenes
--Treponema pallidum, T. carateum 
--Vibrio cholerae, V. parahemolyticus, V. vulnificus
--Yersinia enterocolitica 
Appendix B-II-B. Risk Group 2 (RG2)--Fungal Agents
--Blastomyces dematitidis 
--Cladosporium bantianum, C. (xylohypha) trichoides
--Cryptococcus neofomans 
--Dactylaria galopava (Ochroconis gallopavum) 
--Epidermophyton 
--Exophiala (Wangiella) dermatitidis 
--Fonsecaea pedrosoi
--Microsporum 
--Paracoccidioides braziliensis 
--Penicillium marneffei 
--Sporothrix schenckii 
--Trichophyton 
Appendix B-II-C. Risk Group 2 (RG2)--Parasitic Agents
--Ancylostoma human hookworms including A. duodenale, A. ceylanicum
--Ascaris including Ascaris lumbricoides suum
--Babesia including B. divergens, B. microti
--Brugia filaria worms including B. malayi, B. timori
--Coccidia 
--Cryptosporidium including C. parvum
--Cysticercus cellulosae (hydatid cyst, larva of T. solium)
--Echinococcus including E. granulosis, E. multilocularis, E. vogeli
--Entamoeba histolytica 
--Enterobius 
--Fasciola including F. gigantica, F. hepatica
--Giardia including G. lamblia
--Heterophyes 
--Hymenolepis including H. diminuta, H. nana
--Isospora 
--Leishmania including L. braziliensis, L. donovani, L. ethiopia, L. 
major, L. mexicana, L. peruvania, L. tropica
--Loa loa filaria worms
--Microsporidium 
--Naegleria fowleri 
--Necator human hookworms including N. americanus
--Onchoerca filaria worms including, O. volvulus
--Plasmodium including simian species, P. cynomologi, P. falciparum, P. 
malariae, P. ovale, P. vivax
--Sarcocystis including S. sui hominis
--Schistosoma including S. haematobium, S. intercalatum, S. japonicum, 
S. mansoni, S. mekongi
--Strongyloides including S. stercoralis
--Taenia solium
--Toxocara including T. canis
--Toxoplasma including T. gondii
--Trichinella spiralis
--Trypanosoma including T. brucei brucei, T. brucie gambiense, T. 
brucei rhodesiense, T. cruzi
--Wuchereria bancrofti filaria worms
Appendix B-II-D. Risk Group 2 (RG2)--Viruses
Adenoviruses, Human--All Types
Alphaviruses (Togaviruses)--Group A Arboviruses
--Eastern equine encephalomyelitis virus
--Venezuelan equine encephalomyelitis vaccine strain TC-83
--Western equine encephalomyelitis virus
Arenaviruses
--Lymphocytic choriomeningitis virus (non-neurotropic strains)
--Tacaribe virus complex
--Other viruses as listed in the reference source (see Section V-C, 
Footnotes and References of Sections I through IV)
Bunyaviruses
--Bunyamwera virus
--Rift Valley fever virus vaccine strain MP-12
--Other viruses as listed in the reference source (see Section V-C, 
Footnotes and References of Sections I through IV)
Calciviruses
Coronaviruses
Flaviviruses (Togaviruses)--Group B Arboviruses
--Dengue virus serotypes 1, 2, 3, and 4
--Yellow fever virus vaccine strain 17D
--Other viruses as listed in the reference source (see Section V-C, 
Footnotes and References of Sections I through IV)
Hepatitis A, B, C, D, and E Viruses
--Herpesviruses--except Herpesvirus simiae (Monkey B virus) (see 
Appendix B-IV-D, Risk Group 4 (RG4)--Viral Agents)
--Cytomegalovirus
--Epstein Barr virus
--Herpes simplex types 1 and 2
--Herpes zoster
--Human herpesvirus types 6 and 7
Orthomyxoviruses
--Influenza viruses types A, B, and C
--Other tick-borne orthomyxoviruses as listed in the reference source 
(see Section V-C, Footnotes and References of Sections I through IV)
Papovaviruses
--All human papilloma viruses
Paramyxoviruses
--Newcastle disease virus
--Measles virus
--Mumps virus
--Parainfluenza viruses types 1, 2, 3, and 4
--Respiratory syncytial virus
Parvoviruses
--Human parvovirus (B19)
Picornaviruses
--Coxsackie viruses types A and B
--Echoviruses--all types
--Polioviruses--all types, wild and attenuated
--Rhinoviruses--all types
--Poxviruses--all types except Monkeypox virus (see Appendix B-III-D, 
Risk Group 3 (RG3)--Viruses and Prions) and restricted poxviruses 
including Alastrim, Smallpox, and White-pox (see Section V-L, Footnotes 
and References of Sections I through IV)
--Reoviruses--all types including Coltivirus, human Rotavirus, and 
Orbivirus (Colorado tick fever virus)
Rhabdoviruses
--Rabies virus--all strains
--Vesicular stomatitis virus--laboratory adapted strains including VSV-
Indiana, San Juan, and Glasgow
Togaviruses (see Alphaviruses and Flaviviruses)
--Rubivirus (rubella)
Appendix B-III. Risk Group 3 (RG3) Agents
    RG3 agents are associated with serious or lethal human disease for 
which preventive or therapeutic interventions may be available.

[[Page 1488]]

Appendix B-III-A. Risk Group 3 (RG3)--Bacterial Agents Including 
Rickettsia
--Bartonella
--Brucella including B. abortus, B. canis, B. suis
--Burkholderia (Pseudomonas) mallei, B. pseudomallei
--Coxiella burnetii
--Francisella tularensis
--Mycobacterium bovis (except BCG strain, see Appendix B-II-A, Risk 
Group 2 (RG2)--Bacterial Agents Including Chlamydia); M. tuberculosis
--Pasteurella multocida type B--``buffalo'' and other virulent strains
--Rickettsia akari, R. australis, R. canada, R. conorii, R. prowazekii, 
R. rickettsii, R. siberica, R. tsutsugamushi, R. typhi (R. mooseri)
--Yersinia pestis
Appendix B-III-B. Risk Group 3 (RG3)--Fungal Agents
--Coccidioides immitis (sporulating cultures; contaminated soil)
--Histoplasma capsulatum, H. capsulatum var. duboisii
Appendix B-III-C. Risk Group 3 (RG3)--Parasitic Agents
None
Appendix B-III-D. Risk Group 3 (RG3)--Viruses and Prions
Alphaviruses (Togaviruses)--Group A Arboviruses
--Semliki Forest virus
--St. Louis encephalitis virus
--Venezuelan equine encephalomyelitis virus (except the vaccine strain 
TC-83, see Appendix B-II-D, Risk Group 2 (RG2)--Viruses)
--Other viruses as listed in the reference source (see Section V-C, 
Footnotes and References of Sections I through IV)
Arenaviruses
--Lymphocytic choriomeningitis virus (LCM) (neurotropic strains)
Bunyaviruses
--Hantaviruses including Hantaan virus
--Rift Valley fever virus
Flaviviruses (Togaviruses)--Group B Arboviruses
--Japanese encephalitis virus
--Yellow fever virus
--Other viruses as listed in the reference source (see Section V-C, 
Footnotes and References of Sections I through IV)
Poxviruses
--Monkeypox virus
Prions
--Transmissible spongioform encephalopathies (TME) agents (Creutzfeldt-
Jakob disease and kuru agents) (for containment instruction, see 
Section V-C, Footnotes and References of Sections I through IV)
Retroviruses
--Human immunodeficiency virus (HIV) types 1 and 2
--Human T cell lymphotropic virus (HTLV) types 1 and 2
--Simian immunodeficiency virus (SIV)
Rhabdoviruses
--Vesicular stomatitis virus
Appendix B-IV. Risk Group 4 (RG4) Agents
    RG4 agents are likely to cause serious or lethal human disease for 
which preventive or therapeutic interventions are not usually 
available.
Appendix B-IV-A. Risk Group 4 (RG4)--Bacterial Agents
None
Appendix B-IV-B. Risk Group 4 (RG4)--Fungal Agents
None
Appendix B-IV-C. Risk Group 4 (RG4)--Parasitic Agents
None
Appendix B-IV-D. Risk Group 4 (RG4)--Viral Agents
Arenaviruses (Togaviruses)--Group A Arboviruses
--Guanarito virus
--Lassa virus
--Junin virus
--Machupo virus
Bunyaviruses (Nairovirus)
--Crimean-Congo hemorrhagic fever virus
Filoviruses
--Ebola virus
--Marburg virus
Flaviruses (Togaviruses)--Group B Arboviruses
--Tick-borne encephalitis virus complex including Absetterov, Central 
European encephalitis, Hanzalova, Hypr, Kumlinge, Kyasanur Forest 
disease, Omsk hemorrhagic fever, and Russian spring-summer encephalitis 
viruses
Herpesviruses (alpha)
--Herpesvirus simiae (Herpes B or Monkey B virus)

    Hemorrhagic fever agents and viruses as yet undefined.
Appendix B-V. Animal Viral Etiologic Agents in Common Use
    The following list of animal etiologic agents is appended to the 
list of human etiologic agents. None of these agents is associated with 
disease in healthy adult humans; They are commonly used in laboratory 
experimental work.
    A containment level appropriate for RG1 human agents is recommended 
for their use. For agents that are infectious to human cells, e.g., 
amphotropic and xenotropic strains of murine leukemia virus, a 
containment level appropriate for RG2 human agents is recommended.
Baculoviruses
Herpesviruses
--Herpesvirus ateles
--Herpesvirus saimiri
--Marek's disease virus
--Murine cytomegalovirus
Papovaviruses
--Bovine papilloma virus
--Polyoma virus
--Shope papilloma virus
--Simian virus 40 (SV40)
Retroviruses
--Avian leukosis virus
--Avian sarcoma virus
--Bovine leukemia virus
--Feline leukemia virus
--Feline sarcoma virus
--Gibbon leukemia virus
--Mason-Pfizer monkey virus
--Mouse mammary tumor virus
--Murine leukemia virus
--Murine sarcoma virus
--Rat leukemia virus

F. Amendments to Appendix C, Exemptions Under Section III-E-6

    Appendix C-I-A is amended to read:
Appendix C-I-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation, (ii) experiments described in Section III-B which 
require NIH/ORDA and Institutional Biosafety Committee approval before 
initiation, (iii) experiments involving DNA from Risk Groups 3, 4, or 
restricted organisms (see Appendix B, Classification of Human Etiologic 
Agents on the Basis of Hazard, and Sections V-G and V-L, Footnotes and 
References of Sections I through IV) or cells known to be infected with 
these agents, (iv) experiments involving the deliberate introduction of 
genes coding for the biosynthesis of molecules that are toxic for 
vertebrates (see Appendix 

[[Page 1489]]
F, Containment Conditions for Cloning of Genes Coding for the 
Biosynthesis of Molecules Toxic for Vertebrates), and (v) whole plants 
regenerated from plant cells and tissue cultures are covered by the 
exemption provided they remain axenic cultures even though they 
differentiate into embryonic tissue and regenerate into plantlets.
    Appendix C-II-A is amended to read:
Appendix C-II-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation, (ii) experiments described in Section III-B which 
require NIH/ORDA and Institutional Biosafety Committee approval before 
initiation, (iii) experiments involving DNA from Risk Groups 3, 4, or 
restricted organisms (see Appendix B, Classification of Human Etiologic 
Agents on the Basis of Hazard, and Sections V-G and V-L, Footnotes and 
References of Sections I through IV) or cells known to be infected with 
these agents, may be conducted under containment conditions specified 
in Section III-C-2, Experiments in which DNA from Risk Group 2, Risk 
Group 3, Risk Group 4, or Restricted Agents is Cloned into 
Nonpathogenic Prokaryotic or Lower Eukaryotic Host-Vector Systems, with 
prior Institutional Biosafety Committee review and approval, (iv) large 
scale experiments (e.g., more than 10 liters of culture), and (v) 
experiments involving the cloning of toxin molecule genes coding for 
the biosynthesis of molecules toxic for vertebrates (see Appendix F, 
Containment Conditions for Cloning of Genes Coding for the Biosynthesis 
of Molecules Toxic for Vertebrates).
    Appendix C-III-A is amended to read:
Appendix C-III-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation, (ii) experiments described in Section III-B which 
require NIH/ORDA and Institutional Biosafety Committee approval before 
initiation, (iii) experiments involving DNA from Risk Groups 3, 4, or 
restricted organisms (see Appendix B, Classification of Human Etiologic 
Agents on the Basis of Hazard, and Sections V-G and V-L, Footnotes and 
References of Sections I through IV) or cells known to be infected with 
these agents, may be conducted under containment conditions specified 
in Section III-C-2, Experiments in which DNA from Risk Group 2, Risk 
Group 3, Risk Group 4, or Restricted Agents is Cloned into 
Nonpathogenic Prokaryotic or Lower Eukaryotic Host-Vector Systems, with 
prior Institutional Biosafety Committee review and approval, (iv) large 
scale experiments (e.g., more than 10 liters of culture), and (v) 
experiments involving the deliberate cloning of genes coding for the 
biosynthesis of molecules toxic for vertebrates (see Appendix F, 
Containment Conditions for Cloning of Genes Coding for the Biosynthesis 
of Molecules Toxic for Vertebrates).
    Appendix C-IV-A is amended to read:
Appendix C-IV-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation, (ii) experiments described in Section III-B which 
require NIH/ORDA and Institutional Biosafety Committee approval before 
initiation, (iii) experiments involving DNA from Risk Groups 3, 4, or 
restricted organisms (see Appendix B, Classification of Human Etiologic 
Agents on the Basis of Hazard, and Sections V-G and V-L, Footnotes and 
References of Sections I through IV) or cells known to be infected with 
these agents, may be conducted under containment conditions specified 
in Section III-C-2, Experiments in which DNA from Risk Group 2, Risk 
Group 3, Risk Group 4, or Restricted Agents is Cloned into 
Nonpathogenic Prokaryotic or Lower Eukaryotic Host-Vector Systems, with 
prior Institutional Biosafety Committee review and approval, (iv) large 
scale experiments (e.g., more than 10 liters of culture), and (v) 
experiments involving the deliberate cloning of genes coding for the 
biosynthesis of molecules toxic for vertebrates (see Appendix F, 
Containment Conditions for Cloning of Genes Coding for the Biosynthesis 
of Molecules Toxic for Vertebrates).
    Appendix C-V-A is amended to read:
Appendix C-V-A. Exceptions
    The following categories are not exempt from the NIH Guidelines: 
(i) experiments described in Section III-A which require Institutional 
Biosafety Committee approval, RAC review, and NIH Director approval 
before initiation, (ii) experiments described in Section III-B which 
require NIH/ORDA and Institutional Biosafety Committee approval before 
initiation, (iii) experiments involving DNA from Risk Groups 3, 4, or 
restricted organisms (see Appendix B, Classification of Human Etiologic 
Agents on the Basis of Hazard, and Sections V-G and V-L, Footnotes and 
References of Sections I through IV) or cells known to be infected with 
these agents, may be conducted under containment conditions specified 
in Section III-C-2, Experiments in which DNA from Risk Group 2, Risk 
Group 3, Risk Group 4, or Restricted Agents is Cloned into 
Nonpathogenic Prokaryotic or Lower Eukaryotic Host-Vector Systems, with 
prior Institutional Biosafety Committee review and approval, (iv) large 
scale experiments (e.g., more than 10 liters of culture), and (v) 
experiments involving the deliberate cloning of genes coding for the 
biosynthesis of molecules toxic for vertebrates (see Appendix F, 
Containment Conditions for Cloning of Genes Coding for the Biosynthesis 
of Molecules Toxic for Vertebrates).
    Appendix C-VI is amended to read:
Appendix C-VI. Footnotes and References of Appendix C
    Appencix C-VI-A. The NIH Director, with advice of the RAC, may 
revise the Appendix B classification for the purposes of these NIH 
Guidelines (see Section IV-C-1-b-(2)-(b), NIH Director-Specific 
Responsibilities). The revised list of organisms in each Risk Group is 
reprinted in Appendix B.

G. Amendments to Appendix H, Shipment

    Appendix H-III is amended to read:
Appendix H-III. Footnotes and References of Appendix H
    For further information on shipping etiologic agents contact: (i) 
The Centers for Disease Control and Prevention, ATTN: Biohazards 
Control Office, 1600 Clifton Road, Atlanta, Georgia 30333, (404) 639-
3883, FTS 236-3883; (ii) The U.S. Department of Transportation, ATTN: 
Office of Hazardous Materials Transportation, 400 7th Street SW., 
Washington, DC 20590, (202) 366-4545; or (iii) U.S. Department of 
Agriculture, ATTN: Animal and Plant Health Inspection Service (APHIS), 
Veterinary Services, National Center for Import-Export, Products 
Program, 4700 River Road, Unit 40, Riverdale, MD 20737. Phone: (301) 
734-8499; Fax: (301) 734-8226.

H. Amendments to Appendix Q, Physical and Biological Containment for 
Recombinant DNA Research Involving Animals

    Appendix Q-III-C is amended to read: 
    
[[Page 1490]]

    Appendix Q-III-C. Risk Group 4 and restricted microorganisms (see 
Appendix B, Classification of Human Etiologic Agents on the Basis of 
Hazard, and Sections V-G and V-L, Footnotes and References of Sections 
I through IV) pose a high level of individual risk for acquiring life-
threatening diseases to personnel and/or animals. To import animal or 
plant pathogens, special approval must be obtained from U.S. Department 
of Agriculture, Animal and Plant Health Inspection Service (APHIS), 
Veterinary Services, National Center for Import-Export, Products 
Program, 4700 River Road, Unit 40, Riverdale, MD 20737. Phone: (301) 
734-8499; Fax: (301) 734-8226.
    Laboratory staff shall be required to have specific and thorough 
training in handling extremely hazardous infectious agents, primary and 
secondary containment, standard and special practices, and laboratory 
design characteristics. The laboratory staff shall be supervised by 
knowledgeable scientists who are trained and experienced in working 
with these agents and in the special containment facilities.
    Within work areas of the animal facility, all activities shall be 
confined to the specially equipped animal rooms or support areas. The 
maximum animal containment area and support areas shall have special 
engineering and design features to prevent the dissemination of 
microorganisms into the environment via exhaust air or waste disposal.
    OMB's ``Mandatory Information Requirements for Federal Assistance 
Program Announcements'' (45 FR 39592, June 11, 1980) requires a 
statement concerning the official government programs contained in the 
Catalog of Federal Domestic Assistance. Normally, NIH lists in its 
announcements the number and title of affected individual programs for 
the guidance of the public. Because the guidance in this notice covers 
not only virtually every NIH program but also essentially every Federal 
research program in which DNA recombinant molecule techniques could be 
used, it has been determined not to be cost effective or in the public 
interest to attempt to list these programs. Such a list would likely 
require several additional pages. In addition, NIH could not be certain 
that every Federal program would be included as many Federal agencies, 
as well as private organizations, both national and international, have 
elected to follow the NIH Guidelines. In lieu of the individual program 
listing, NIH invites readers to direct questions to the information 
address above about whether individual programs listed in the Catalog 
of Federal Domestic Assistance are affected.

    Effective Date: December 14, 1995.
Harold Varmus,
Director, National Institutes of Health.
[FR Doc. 96-689 Filed 1-18-96; 8:45 am]
BILLING CODE 4140-01-M