[Federal Register: January 3, 1997 (Volume 62, Number 2)]
[Proposed Rules]
[Page 551-583]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[[Page 551]]
Part IV
Department of Health and Human Services
Food and Drug Administration
21 CFR Part 589
Substances Prohibited From Use in Animal Food or Feed; Animal Proteins
Prohibited in Ruminant Feed; Proposed Rule
[[Page 552]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 589
[Docket No. 96N-0135]
RIN 0910-AA91
Substances Prohibited From Use in Animal Food or Feed; Animal
Proteins Prohibited in Ruminant Feed
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the regulations to provide that animal protein derived from ruminant
and mink tissues is not generally recognized as safe (GRAS) for use in
ruminant feed, and is a food additive subject to certain provisions of
the Federal Food, Drug, and Cosmetic Act (the act). The proposed
regulations would establish a flexible system of controls, designed to
ensure that ruminant feed does not contain animal protein derived from
ruminant and mink tissues in a manner that encourages innovation. FDA
is also considering alternatives to this proposed ruminant-to-ruminant
prohibition, and is requesting comment on the relative merits and
disadvantages of the alternatives. FDA is proposing this action because
the feeding to ruminants of protein derived from potentially
transmissible spongiform encephalopathy (TSE)-infective tissues may
cause TSE in animals. TSE's are progressively degenerative central
nervous system (CNS) diseases of man and animal that are fatal.
Epidemiologic evidence gathered in the United Kingdom (U.K.) suggests
an association between an outbreak of a ruminant TSE, specifically
bovine spongiform encephalopathy (BSE) and the feeding to cattle of
protein derived from sheep infected with scrapie, another TSE. Also,
scientists have postulated that there is an epidemiologic association
between BSE and a form of human TSE, new variant Creutzfeldt-Jakob
disease (nv-CJD) reported recently in England. BSE has not been
diagnosed in the United States. However, this proposed rule is intended
to prevent the establishment and amplification of BSE in cattle in the
United States, and thereby minimize any risk which might be faced by
animals and humans.
DATES: Written comments by February 18, 1997. FDA proposes that any
final rule that may issue based on this proposal become effective 60
days after the date of its publication in the Federal Register.
Submit written comments on the collection of information
requirements by February 18, 1997.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857. Submit written comments on the information
collection requirements to the Office of Information and Regulatory
Affairs, Office of Management and Budget (OMB), New Executive Office
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, ATTN: Desk
Officer for FDA.
FOR FURTHER INFORMATION CONTACT:
Regarding Scientific and Industry Issues:
George A. (Bert) Mitchell, Center for Veterinary Medicine (HFV-1),
Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855,
301-594-1761.
Regarding Procedural and Regulatory Issues:
Richard E. Geyer, Center for Veterinary Medicine (HFV-201), Food
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-
594-1761.
SUPPLEMENTARY INFORMATION
Table of Contents
I. Summary
A. Introduction
B. GRAS Status of Ruminant and Mink Tissues
C. The ``No Action'' Alternative
D. The Basis for the Agency's Proposed Action
1. General Discussion
2. Analysis of Risk Factors
a. The risk of BSE occurring in the United States
b. The risk of amplification in the cattle population
c. The risk of transmission to humans
E. Enforcement Provisions
F. Alternatives
II. Background
A. TSE's
1. Scrapie
2. BSE
3. Other Animal TSE's
4. TSE's of Humans
a. CJD
b. nv-CJD
c. Gertsmann-Strausller-Scheinker (GSS) syndrome
d. Kuru
e. Fatal familial insomnia (FFI)
5. Etiology
6. Pathogenesis
7. Transmission
8. Genetics
9. Diagnostics
10. Inactivation
B. The Association Between Scrapie and BSE
C. The Association Between Animal TSE's and Human TSE's
D. Infectivity of Specific Tissues
E. Potential Risk of TSE's to the United States
1. Overview
2. Comparison with the U.K. Conditions
F. Historical Efforts to Control TSE's
1. U.S. Actions
a. FDA
b. USDA
c. Public Health Service
i. CDC
ii. National Institutes of Health (NIH)
iii. Other actions
2. International Actions
a. United Kingdom
b. WHO
c. OIE
d. European Community (EC)
3. Voluntary Measures by the U.S. Animal Industries
a. Voluntary ban on rendering adult sheep
b. Voluntary ban on feeding ruminant proteins to ruminants
G. Processing Animal Tissues for Feed Ingredients
1. Current Rendering Practices
2. Assay Methodologies for Proteins
III. Statutory Provisions Regarding Food Additives
A. GRAS Determination
B. Prior Sanction
C. Food Additive Status of Ruminant Tissues
IV. Comments
V. Analysis of Alternatives
A. Overview
B. Ruminant-to-Ruminant Prohibition
C. Partial Ruminant-to-Ruminant Prohibition
D. Mammal-to-Ruminant Prohibition
E. Prohibition of Materials from U.S. Species diagnosed with
TSE's (sheep, goats, mink, deer, and elk)
F. Sheep-Specified Offal Prohibition
G. No Action
VI. Description of the Proposed Rule
A. Introduction
1. Regulatory Alternatives
2. The Regulated Industry
3. Enforcement Consideration
B. Outline of the Proposed Regulation
VII. Specific Protein Sources
A. Milk Proteins
B. Gelatin Proteins
C. Blood Meal Proteins
D. Canine and Feline Derived Proteins
VIII. Environmental Impact
IX. Analysis of Impacts
A. The Need for Regulation
B. Benefits
1. Methodology
2. Reduced Risk to Public Health
3. Reduced Risk of Direct Livestock Losses
4. Costs of Future Regulation
5. Reduced Risk of Losses in Domestic Sales and Exports
6. Total Losses Averted
7. Comparison of Alternatives
C. Industry Impacts
1. The Proposed Rule
2. Partial Ruminant-to-Ruminant Prohibition
3. Mammalian-to-Ruminant Prohibition
4. Other Regulatory Alternatives
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D. Small Business Impacts
E. Unfunded Mandates Analysis
X. The Paperwork Reduction Act of 1995
XI. Federalism
XII. References
XIII. Request for Comments
I. Summary
A. Introduction
In the Federal Register of May 14, 1996 (61 FR 24253), FDA
published an advance notice of proposed rulemaking (ANPRM) that
solicited information and public comment on the issue of using protein
derived from ruminants (cattle, sheep, goats, deer, and elk) in
ruminant feed. The agency requested information and comment on a number
of issues because it was assessing whether to prohibit the use of
ruminant protein in ruminant feed. BSE has not been identified in the
United States. The agency issued an ANPRM because of its concern about
the possible adverse effect on animal and human health if TSE's were to
be spread through animal feed. After reviewing the ANPRM comments and
other sources of information, the agency is proposing to prohibit the
use of ruminant and mink animal tissue in the feed of ruminants.
Because TSE has been found in U.S. mink, the agency is also including
mink tissue in the proposed prohibition. The agency is also considering
alternatives to the proposed ruminant-to-ruminant prohibition,
including the alternative of taking no action.
B. GRAS Status of Ruminant and Mink Tissues
The agency is proposing to declare that protein derived from tissue
from ruminant animals and mink is not GRAS, by qualified experts, for
use in ruminant feed and is therefore a ``food additive'' under the
law. As a result, because neither a food additive regulation nor an
exemption is in effect for ruminant and mink tissues intended for
feeding to ruminants, such tissues would be deemed adulterated. Milk
and gelatin proteins derived from ruminants, and blood from cattle are
exempt from the proposed prohibition. The proposed rule does not apply
to any nonprotein animal tissues such as tallow or other fats.
Expert opinion that the tissues are GRAS would need to be supported
by scientific literature, and other sources of data and information,
establishing that there is a reasonable certainty that the material is
not harmful under the intended conditions of use. Expert opinion would
need to address topics such as whether it is reasonably certain that
BSE does not, or will not, occur in the United States; whether it is
reasonably certain that the BSE agent will not be transmitted through
animal feed, i.e., that the processed tissues are not infected by the
agent, are deactivated by the rendering process or are not transmitted
orally; and whether it is reasonably certain that the agent will not be
transmitted to humans through consumption of ruminant products.
``General recognition'' cannot be based on an absence of studies that
demonstrate that a substance is unsafe; there must be studies to
establish that the substance is safe. Also, the burden of establishing
that substance is GRAS is on the proponent of the substance. See U.S.
v. An Article of Food * * * Co Co Rico, 752 F.2d 11 (1st Cir. 1985).
Although the ANPRM did not specifically ask for opinion on the GRAS
issue, a number of comments from scientific organizations and
individual scientists strongly suggest that the comments would support
the view that ruminant and mink tissue is not GRAS when fed to
ruminants. Some of these comments submitted data and information that
would support such opinions. Only a few comments included statements by
scientists, or scientific organizations, to the contrary. Similarly,
the opinions stated by scientists who spoke during a 1996 symposium on
TSE's would, in general, support the ``nonGRAS'' position. The
symposium, ``Tissue Distribution, Inactivation and Transmission of
Transmissible Spongiform Encephalopathies,'' was cosponsored by FDA and
USDA, and was held in Riverdale, MD, on May 13 and 14, 1996.
FDA has searched for but has not found sufficient literature or
other sources of data and information that would, on balance, support
expert opinion that ruminant and mink protein is GRAS as a ruminant
feed additive. Previous comments on the agency's proposal to prohibit
the feeding of specified sheep and goat offal (59 FR 44584, August 29,
1994) did not include either written GRAS opinions from qualified
experts, or data and information that would support such opinions. The
relevant data and information, and lack thereof, are discussed more
fully in this section, and in section II. of this document. See Section
III.A., of this document, for a further explanation of ``GRAS'' and
``food additive.''
C. The ``No Action'' Alternative
Even when, as in this case, FDA has taken steps leading to a
tentative determination that a substance added to food is not GRAS, the
agency is not required to issue a proposal declaring that the substance
is not GRAS and is a food additive subject to section 409 of the act.
Section 570.38 provides that the agency may take such an action. The
agency considered the possibility of not issuing a proposal with regard
to the feeding of ruminant and mink tissues to ruminants.
The fact that the data and information do not document an immediate
threat to the U.S. public health supports this ``no action''
alternative. Moreover, certain of the available data and information
can be used to support the view that the threat, if any, is minimal.
The evidence suggesting that there is no immediate threat is
summarized as follows. First, BSE has not been detected in cattle in
the United States despite an extensive surveillance effort that has
been in place for several years. Restrictions on the importation of
cattle, cattle products and feed ingredients from BSE-affected
countries are in place to minimize the possibility of BSE entering into
the United States. Surveillance, training of veterinary practitioners
and diagnosticians, and other efforts are in place to detect any
occurrence of BSE quickly, and to minimize its spread among the cattle
population. No empirical scientific evidence is available to establish
that BSE will occur from any of the possible sources, such as
transmission from another U.S. species in which TSE's have been
diagnosed; spontaneous occurrence in cattle; or importation of live
animals or animal feed products carrying the BSE agent. For example,
transmission between any two species is difficult to predict, based on
available data, because of variability in species barriers (Ref. 1).
Second, even if BSE did develop in the United States there is no
conclusive scientific evidence that the disease would be spread through
animal feed, the product that provides FDA's jurisdictional nexis.
Although there is strong epidemiological evidence that the feeding of
processed tissue from sheep containing scrapie to cattle caused the
widespread BSE infections in the United Kingdom, many experts believe
that the chances that the United States will have a BSE outbreak,
similar to the epidemic that took place in the United Kingdom, are low.
For example, most of the industry practices and other conditions
believed to have been associated with the BSE epidemic in the United
Kingdom do not exist in the United States. Further, the U.K.
epidemiological evidence of transfer from sheep to cattle has not been
confirmed by direct scientific data. This has caused some to question
the assumption that the BSE originated from scrapie (Ref. 1). Further,
some
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experimental information suggests that the TSE's in general are not
readily transferred by the oral route. Experimentally, the oral route
has been suggested to be the least efficient means of transmission for
TSE's (Ref. 1).
Third, the postulated connection between BSE and CJD has not been
definitively established. Scientists have theorized an association
between BSE and the recent appearance of nv-CJD in the United Kingdom.
While the epidemiological association, both in time and geography, of
these two diseases in the United Kingdom provides suggestive evidence
of an association between the two, the available evidence does not
establish causation. Although the BSE agent has been transmitted to
laboratory animals, the species barrier between cattle and humans may
be higher than between cattle and mice (Ref. 1). Epidemiological
evidence linking BSE with classical CJD is even less supportive.
Although CJD occurs in the United States, nv-CJD has not been reported
in this country.
The FDA's conclusion that there is no immediate threat to the
public health in the United States is supported by a statement from the
World Health Organization (WHO) that the ``risk, if any, of exposure to
the BSE agent in countries other than the U.K. is considered lower than
in the U.K.'' (Ref. 2). A number of comments to the ANPRM made a
similar assertion, urging that FDA's regulatory decision be made on the
basis of scientific information and contending that the available
information did not support the contemplated action.
D. The Basis for the Agency's Proposed Action
1. General Discussion
Even though there is no immediate threat to the U.S. public health
and some information that indicates that a threat, if any, is minimal,
after careful consideration the agency has tentatively concluded that
regulatory action is necessary to protect animal and human health. The
agency has reached that tentative conclusion because there is a growing
body of data and information that affirmatively raises public health
concerns.
The data and information raise concern that BSE could occur in
cattle in the United States; and that if BSE does appear in this
country, the causative agent could be transmitted and amplified through
the feeding of processed ruminant protein to cattle, and could result
in an epidemic. The agency believes that the high cost, in animal and
human lives and economics, that could result if this scenario should
occur, justifies the preventive measure reflected by the proposed
regulation. Although the agency expects some continued voluntary
reduction in the feeding of ruminant and mink tissues to ruminants, the
reduction is not expected to be extensive enough to obviate the need
for mandatory preventive measures.
Statements from several prominent public and animal health
organizations support this proposal to regulate the feeding of ruminant
tissues to ruminant animals. For example, the Centers for Disease
Control and Prevention (CDC) has urged the agency to adopt a ruminant-
to-ruminant feed prohibition (Ref. 3), and USDA has recommended the
same action. Although WHO considers the risk in countries such as the
United States to be minimal, that organization has nevertheless called
on all countries to prohibit the use of ruminant tissues in ruminant
feed (Ref. 2).
A number of comments to the ANPRM, including comments by several
consumer groups, supported regulatory action by FDA. The Pharmaceutical
Research and Manufacturers of America urged FDA to take all necessary
steps to prevent an outbreak of BSE, and to prevent the potential
spread of BSE should a case occur in the United States. One
pharmaceutical firm emphasized the importance of acknowledging public
perception, stating that a ruminant-to-ruminant prohibition would
``significantly decrease the concern regarding this perceived risk.''
Another pharmaceutical firm characterized the risk as ``small but
real.'' A group of livestock producers, veterinary associations and
scientific organizations cited the WHO recommendations to support their
call for a voluntary ruminant-to-ruminant prohibition. The group stated
that such a prohibition would ``eliminate any risk, no matter how
remote [and would] totally prevent BSE from ever occurring in the
United States.''
The agency is concerned about the public health issues raised but
not resolved by the available scientific information. The fact that the
causative agent or agents for TSE's have not been clearly identified,
and their transmissibility has not been fully characterized, adds to
the concern. However, certain information that is well documented
supports the agency's decision as well. TSE's are 100-percent fatal
diseases that have been diagnosed in humans and a number of animal
species. The diseases are progressively degenerative CNS diseases that
are characterized by a relatively short clinical course of neurological
signs. TSE's have a prolonged incubation period, i.e., 2 to 8 years in
animals, and scientific evidence supports the view that TSE's can be
transmitted in the preclinical stage. There is no practical method to
detect the presence of TSE's during the preclinical stage.
2. Analysis of Risk Factors
This section describes the evidence that supports the agency's
tentative conclusion. The evidence relates to the risks that BSE could
occur in cattle in the United States; that the BSE agent or other TSE
agents could be amplified in the cattle population by the feeding of
ruminant and mink tissues to cattle; and that the agent could
potentially be transmitted to humans.
a. The risk of BSE occurring in the United States. BSE has not been
diagnosed in the United States. FDA does not have evidence to support
the theory that BSE already exists, undiagnosed, in this country.
However, the agency does find plausible the arguments of the theory
that BSE could develop in the United States from three possible
sources: Transmission of TSE's from other susceptible species,
spontaneous occurrence, and importation in live animals or animal
products.
The evidence concerning transmission from other species is
summarized as follows. TSE's other than BSE have been diagnosed in
animals in the United States. These include scrapie in sheep and goats,
transmissible mink encephalopathy (TME), and chronic wasting disease
(CWD) in deer and elk. Feline spongiform encephalopathy (FSE) has been
diagnosed in cats in other countries. In general, the TSE's have been
shown to be naturally transmissible within species and are believed by
some scientists to be naturally transmissible (as distinguished from
experimentally transmissible), at least to a limited extent, between
species. Consumption of meat and bone meal (the predominant animal
tissue-containing product fed to animals) which was produced under
conditions similar to the meat and bone meal which was implicated in
the U.K. BSE epidemic, as well as the feeding of raw bovine tissue,
also appeared to cause TSE in exotic cats and various zoo animals. This
implies that the species barrier for BSE may be uncharacteristically
low. (See e.g., Refs. 3 and 4). In addition to the epidemiological
evidence relating to TSE transmission from sheep to cattle in the
United Kingdom, there is limited experimental evidence of transmission
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of the BSE agent from cattle to sheep. Many laboratory animal species
have also been experimentally infected following the administration of
tissues from animals with TSE disease.
There is some evidence to support the theory that BSE can occur
spontaneously in cattle. The leading theory as to the causative agent,
e.g., infectious protein or prion, inherently suggests that the BSE
could occur spontaneously. Additional support arises from the fact that
85 percent of CJD cases are sporadic, and have no familial or
identifiable link as to their cause. Recent surveillance information
from Northern Ireland and Switzerland also supports the spontaneous
theory. In these countries, BSE has occurred in cases in which no
exposure to rendered protein can be found, and there is no evidence of
BSE in the parental stock or herd mates of affected animals (Ref. 5).
As described more fully in section II.F.1.b. of this document,
USDA-APHIS has implemented import restrictions on live animals and
animal products from BSE-affected countries. As a result of the
restrictions, the potential risk of BSE occurring in this country as a
result of exposure from imported cattle and imported animal protein
products appears to be small (Ref. 6). However, the risk from foreign
sources of BSE introduction into the United States cannot be dismissed
entirely because the USDA import restrictions are unlikely to be 100
percent effective even though no cases of BSE have been diagnosed to
date in the United States. The USDA regulations are intended to reduce
or control risk, not completely eliminate it. See e.g., 56 FR 63866,
December 6, 1991.
b. The risk of amplification in the cattle population. Research has
shown that various animal tissues can transmit BSE infectivity. There
is also evidence supporting the view that the agent could be
transmitted orally (e.g., through animal feed). Although some
experimental evidence suggests that the TSE's in general are more
readily transmitted by means other that the oral route, research also
suggests that the BSE agent is more susceptible to oral transmission.
In most cases (e.g., the U.K. epidemic) the natural route of exposure
to TSE's including BSE is suspected to be oral. This belief is
supported by the dramatic decline in BSE cases in the United Kingdom
following implementation of the ruminant-to-ruminant feeding
prohibition. In the United Kingdom, where more than 160,000 cases of
BSE have been diagnosed, a 1988 ban on the feeding of ruminant-derived
protein supplements to other ruminants was associated with a steady
decrease in the disease incidence starting in 1993. The 5-year period
between the initiation of the ruminant-to-ruminant ban and the decline
in the incidence of BSE is consistent with the known incubation period
in cattle of 2 to 8 years. Further, preliminary experimental data show
that the BSE agent can be transmitted orally to cattle through feeding
of material from an infected cow (Ref. 3). Thus, there is a chance that
BSE could be spread in animal feed if it developed in the U.S. cattle
population, whether spontaneously, from another species or by some
other means.
The greatest risk factor for cattle may not be the single
occurrence of a BSE case. Instead, the greatest risk may arise from the
potential, given the prolonged incubation period, for unrecognized
amplification of BSE in the cattle population, resulting in a potential
for greater animal exposure. The possibility of risk from recycling
ruminant tissues is enhanced by the fact that current rendering methods
have not been shown, and are not expected, to completely deactivate the
BSE agent, and that practical tests are not available for detecting
either the BSE agent in rendered material or the presence of ruminant
material in feed.
The preliminary experimental cow-to-cow TSE transmission data
previously described occurred with as little as a single dose (one-time
exposure) of 1 gram of brain material from the infected cow, indicating
a low transmitting dose. This means, among other things, that FDA
cannot determine the level of feed ingredients from animals tissues, if
any, that is considered safe in ruminants.
c. The risk of transmission of humans. Finally, there exists the
theoretical possibility of the transmission of a TSE in animals, such
as BSE, to humans. CDC agrees that the link between BSE, and TSE's in
humans, has not been fully demonstrated. Some of the ANPRM comments
agreed. For example, one pharmaceutical firm stated that the evidence
is not entirely conclusive. Nevertheless, a body of epidemiological and
experimental evidence is developing to support the postulated
association between BSE and nv-CJD. This and other scientific evidence
developed more fully in section II leads the agency to propose for
comment the prudent risk reduction regulatory action that is
incorporated in the proposed rule.
E. Enforcement Provisions
The agency is issuing this proposed rule within the context of
comprehensive government-wide efforts to minimize the risks previously
described, and within the statutory authority provided to the agency.
The proposed rule has two major components. First, the agency proposes
to prohibit feeding animal materials derived from ruminant and mink
tissues to ruminants, in the absence of a food additive regulation or
investigational exemption. Thus, the prohibition would ensure that
tissues which could contribute to a TSE epidemic by spreading the
causative agent rapidly would not be allowed in ruminant feed.
The second component of the rule provides for a system of controls
to ensure that the proposed rule would achieve its intended purpose.
These provisions are necessary because limited controls are in place,
or available, to prevent the spread of BSE through animal feed in the
United States, should BSE occur. The proposed regulation places two
general requirements on persons that manufacture, blend, process and
distribute animal protein products, and feeds made from such products.
The first requirement is to place cautionary labeling on the protein
and feed products. The second is to provide FDA with access to sales
and purchase invoices, for compliance purposes.
Firms that handle animal protein products from both ruminant and
nonruminant sources, and that intend to keep the two kinds of products
separate, would have certain additional requirements. These
requirements would relate to the need for separate facilities or
cleanout procedures; the need for standard operating procedures
(SOP's); and in the case of renderers, their source of nonruminant
material. Similar requirements would be placed on firms that handle
animal feed containing animal protein products from both ruminant and
nonruminant sources, and intend to keep the two kinds of feed separate.
Requirements would be greater for the firms that intend to separate the
animal protein products and feeds, because of the greater risk these
operations would present for the possibility that ruminant protein
might be fed, inadvertently, to ruminants.
However, the regulatory system would be flexible, allowing the
regulated firms to innovate and choose the most cost-effective means of
compliance. For example, some or all of the regulatory requirements
previously described would not apply if any of the following
innovations were developed and validated by FDA: Processing methods
that deactivate the agent that causes BSE; test methods to detect the
presence of the agent; or methods of marking or otherwise identifying
the
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material that contains ruminant protein. Further, the agency will
consider modifying or revoking any final rule that is published
prohibiting the use of ruminant and mink tissues in ruminant feed, if
scientific and technical advances permit even greater flexibility than
that offered in the proposed regulation. Conversely, the diagnosis of
one or more cases of BSE in the United States, or new scientific
findings, could lead to stricter regulatory requirements.
F. Alternatives
The agency is soliciting comments on several alternative means of
minimizing the risk of transmitting TSE's in ruminant feed, in addition
to the proposed ruminant-to-ruminant prohibition. These alternatives
include:
(1) A partial ruminant-to-ruminant prohibition which would exclude
all ruminant and mink tissues from ruminant feed except those bovine
tissues that have not been found to present a risk of transmitting
spongiform encephalopathy. Possible exclusions include slaughter
byproducts from cattle that have been inspected and passed in inspected
slaughter facilities, except tissues that have been shown through
experimental trials and bioassays to transmit spongiform
encephalopathy. Examples of the latter might include the brain, eyes,
spinal cord and distal ileum. The agency solicits comments on the scope
of this alternative;
(2) A prohibition on the feeding of all mammalian tissues to
ruminants;
(3) A prohibition on the feeding of rendered material from those
animal species in which TSE's have been diagnosed in the United States
(sheep, goats, mink, elk, and deer);
(4) A prohibition on the feeding of specified offal from adult
sheep and goats as proposed in 1994;
(5) Other alternative approaches that meet the agency's regulatory
objectives and that might be suggested in comments to the proposed
rule. The agency may in any final rule issued adopt such alternative
approaches. Such alternatives may be more or less stringent than this
proposal or may be a combination of provisions from this proposal and
other alternatives. For example, one such option might be a proposal to
exclude from the scope of any regulation certain facilities that apply
specified risk-reduction measures in addition to, or in place of, those
included in the regulation FDA is proposing in this publication.
Therefore, the agency specifically requests comments on other
approaches that would achieve the agency's regulatory objectives. Any
proposed alternative approaches should be explained in detail, and
their justification should be well documented. To the extent possible,
please include information on costs and benefits of the proposals; and
(6) The ``no action'' alternative as it relates to this proposed
rule. Again, detailed explanation and well-documented justification
should be presented.
The agency's views on the advantages and disadvantages of these
options appears in section V of this document. The agency invites
comments on the relative merits and disadvantages of all these
alternative concepts.
FDA has estimated that the annualized costs of the proposal,
comprised of both the direct compliance costs and various indirect
gains and losses, would range from $21.4 to $48.2 million. The agency
also estimated that the annualized costs could range from $45.0 to
$56.5 million for the mammalian-to-ruminant option; from $28.5 to $37.3
million for the partial ruminant-to-ruminant option; and would total
less than $10 million for each of the remaining options. On the other
hand, if the agency chooses the ``no action'' option and a BSE epidemic
occurs, the above costs could be expanded by a great magnitude.
Because the body of scientific research related to TSE's is growing
rapidly, the agency will place in the Docket copies of relevant
scientific literature published after the agency completes work on this
proposal, and before the agency completes work on any final regulation.
The agency will add to the Docket, as appropriate, a brief statement of
its assessment of the significance of the literature, and will invite
comments. However, substantive changes from the proposed rule would be
made in accordance with the discussions in the preceding paragraphs and
the Administrative Procedure Act.
II. Background
A. TSE's
1. Scrapie
Scrapie is a slowly progressive, transmissible disease of the CNS
in sheep and goats. Scrapie is characterized by a prolonged incubation
period averaging 2 years, followed by a clinical course of 2 to 6
months when the animal exhibits sensory and motor malfunction,
hyperexcitability, and death. The agent presumably moves from infected
to susceptible animals by direct or indirect contact and enters through
the gastrointestinal tract. Consequently, its spread appears to be both
vertical (mother to offspring in utero) (Ref. 7) and horizontal (direct
contact) between sheep (Ref. 8). Early signs of scrapie include subtle
changes in behavior or temperament which may be followed by scratching
and rubbing against fixed objects. Other signs include loss of
coordination, weight loss despite a good appetite, biting of feet and
limbs, tremor around head and neck, and unusual walking habits (Ref.
9).
The scrapie agent is found in lymphatic tissue (spleen, thymus,
tonsil, and lymph nodes) in sheep with preclinical infections; however,
in clinically affected sheep, the agent is identified in the
intestines, nervous tissues (brain and spinal cord), and lymphatic
tissues as determined by experimental infectivity studies in a
susceptible animal model (Ref. 8). The brain has been demonstrated to
have the highest level of infectivity of all tissues (Ref. 10).
Scrapie is known to have existed in Britain, Ireland, France, and
Germany for over 200 years. It has been observed in the United States
and Canada for about 50 years. The first case of scrapie in the United
States was diagnosed in Michigan in 1947. From 1947 through January
1993, approximately 653 flocks have been diagnosed with scrapie (Ref.
11). At the present time, there are 67 known scrapie-infected flocks
(flocks with sheep diagnosed with scrapie), and there are 8 known
scrapie-source flocks (flocks to which scrapie-infected sheep were
traced) (Ref. 12). In the absence of an antemortem diagnostic test, it
is not possible to establish with absolute certainty that a flock is
free of scrapie. Moreover, lack of reporting, the long incubation
period, and open range husbandry practices in the western United States
make it difficult to detect classical clinical signs and completely
monitor scrapie in the United States.
2. BSE
BSE is a transmissible, slowly progressive, degenerative disease of
the CNS of adult cattle. This disease has a prolonged incubation period
in cattle following oral exposure (2 to 8 years) and is always fatal.
BSE is characterized by abnormalities of behavior, sensation, posture,
and gait. These signs are similar to those seen in sheep that are
infected with scrapie. BSE is associated with spongiform lesions in the
gray matter neuropil of the brainstem and neuronal vacuolization (Ref.
13). The clinical signs usually begin with changes in animal behavior,
and may include separation from the rest of the herd while at pasture,
disorientation, or excessive licking of the nose or flanks (Ref. 14).
The most common history given by the herdsman was nervousness
[[Page 557]]
or altered behavior or temperament, weakness associated with pelvic
limb ataxia, paresis, and loss of body weight (Ref. 15). In some
animals there are few gross pathological changes at necropsy associated
with BSE other than the loss of body weight. However, postmortem
histopathology of BSE distinguish it from other neurological disorders
(Refs. 16 and 17). Neither vertical nor horizontal transmission has
been documented for BSE.
BSE was first recognized as a new cattle disease by researchers at
the Central Veterinary Laboratory of the British Ministry of
Agriculture, Fisheries, and Foods at Weybridge, England in November
1986. As of November 15, 1996, BSE had been diagnosed in Great Britain
in more than 165,000 head of cattle from more than 31,000 herds. Cases
have been confirmed in 59.2 percent of the dairy herds and 15.3 percent
of the beef herds (Ref. 18). The BSE epidemic curve for Great Britain
peaked in January 1993 and is decreasing steadily, concomitantly with
changes in rendering and feeding practices. BSE has also been reported
in native cattle of Northern Ireland, Guernsey, Jersey, Isle of Man,
the Republic of Ireland, Switzerland, France, and Portugal. BSE has
been confirmed in cattle exported from Great Britain to Oman, the
Falkland Islands, Germany, Denmark, Canada, and Italy.
There have been no cases of BSE in cattle in the United States.
There has been one case of BSE in a cow imported into Canada from Great
Britain. That cow was destroyed, along with its herdmates and other
nearby cattle considered by animal health authorities in Canada to have
possibly been exposed to the cow with BSE (Ref. 19).
3. Other Animal TSE's
Other animals have TSE's with typical characteristics of long
incubation, neurological degeneration, and a 100-percent death rate.
These animals include: Mink, elk and deer, zoo ruminants, and exotic
and domestic cats.
TME is a mink disease with clinical signs and brain lesions similar
to those of sheep infected with scrapie. TME is a rare disease in the
United States. Since the disease was first recognized in 1947, in
Wisconsin, four additional outbreaks have occurred in the United
States. The last outbreak occurred in 1985 and was limited to a single
mink ranch in Wisconsin (Ref. 20).
CWD of deer and elk is characterized by emaciation, changes in
behavior and excessive salivation, polydipsia, and polyuria. The
clinical course is from several weeks to 8 months, and the disease is
invariably fatal (Ref. 20). From 1967 to 1979, CWD was observed in 53
captive mule deer in Colorado and Wyoming. Clinical signs were seen in
adult deer and included behavioral alterations, progressive weight loss
and death in 2 weeks to 8 months. Consistent histopathologic change was
limited to the CNS and characterized by widespread spongiform
transformation of the neuropil. The disease is a specific,
spontaneously occurring form of spongiform encephalopathy (Ref. 21).
Topographic distribution and lesion severity were most similar to those
of scrapie and BSE. The duration of the clinical disease did not
significantly influence lesion distribution or severity in either
species (Ref. 22).
Scrapie-like encephalopathies have been described in certain zoo
ruminants, i.e., a nyala, an Arabian oryx, and a greater kudu. Clinical
signs included ataxia and loss of coordination with a short,
progressive clinical course. Histopathological examination of the
brains revealed spongiform encephalopathy characteristic of that
observed in scrapie and BSE (Refs. 23, 24, and 25). Strain typing of
the agent suggests that all of the cases are directly related to BSE.
Seventy domestic cats in the United Kingdom have developed FSE, a
spongiform encephalopathy that was never previously reported. The cats
all had progressive, neurological disease involving locomotor
disturbances, abnormal behavior and, in most cases, altered sensory
responses. Histopathological examination of the central nervous system
revealed changes pathognomonic of spongiform encephalopathy; this
included widespread vacuolization of the gray matter neuropil and
neuronal perikarya (Refs. 26 and 27). Infective tissue from several of
these cases, when injected into mice, resulted in brain lesions with a
distribution and morphology that is undistinguishable from the lesions
produced by BSE infective tissue injected into mice.
4. TSE's of Humans
The TSE's of humans are divided into specific clinical types, which
may appear similar histopathologically but are either transmitted
differently or demonstrate different patterns of distribution and
prevalence.
a. CJD. CJD was first described in 1920 and 1921 when it was known
as ``spastic pseudosclerosis'' or ``subacute spongiform
encephalopathy'' (Ref. 28). The illness exists throughout the world and
is claimed to have a similar prevalence in each of the countries tested
with an annual incidence of approximately one case per million of the
population. Autopsies are sometimes not performed on persons who may
have died of CJD and many older people dying of a dementing illness do
not have autopsies performed. There is an increased incidence among
Libyan Jews (26 cases per million) and spatial or temporal clusters in
areas of Slovakia, Hungary, England, the United States, and Chile. The
average age of a typical CJD victim is 56 years of age, and only a few
cases involving persons between 4 and 29 years have been reported prior
to 1993. Between 4 and 15 percent of cases have a familial connection
with other cases. There is a slightly higher incidence of CJD in women
compared to men. Clinical prodromal symptoms start with changes in
sleeping and eating patterns, and often include confusion,
inappropriate behavior, vague visual complaints and/or ataxia. Those
symptoms progress over a few weeks to a clearly neurological syndrome.
A rapid onset of neurological symptoms appears in 20 percent of cases,
most commonly myoclonic jerks and dementia with loss of higher brain
function and behavioral abnormalities. The disease progresses with
continued deterioration in cerebral and cerebellar function, and the
onset of seizures. Ninety percent of the cases end in death within 1
year of onset. Diagnosis is by clinical assessment of patients and by
examination of electroencephalogram patterns. Post mortem diagnosis is
currently carried out by histological examination of cerebral tissue
under the light microscope, although this is not always reliable.
Research techniques that have been used to demonstrate CJD (and other
TSE's) include electron microscopic examination of brain tissue
extracts for scrapie-associated fibrils (SAF), immuno-staining of the
tissue for prion-protein (PrP) antigens, western blotting of extracted
PrP antigens and the intracerebral injection of tissue suspensions into
test animals.
In some patients, the source of CJD has been claimed to be an
infection transferred from other patients with the condition. For
example, in one case, cerebral electrodes that had been sterilized with
alcohol and formalin vapor after use in a patient with CJD, were used
in the brains of two young epileptic patients, both of whom contracted
CJD after a short incubation. The transfer of CJD by corneal transplant
in 1 patient, by cadaveric dura mater grafts in several patients and by
pituitary-derived human growth hormone injections in over 80 patients
has also been reported.
[[Page 558]]
Only the medical procedures described previously have been
conclusively linked to transmission. The transmission of the disease
from animal sources has been suggested; see further discussion in
section II.C. of this document.
b. nv-CJD. A previously undetected new variant of CJD (nv-CJD) was
reported by British scientists at a meeting of international experts
convened by WHO on April 2 and 3, 1996 (Ref. 29), and published 3 days
later (Ref. 30).
The major evidence for the existence of nv-CJD is the recognition
of a new neuropathologic profile and the unusually young ages of 10
U.K. patients. Although all the cases had evidence of the pathognomonic
spongiform changes characteristic of classic CJD, and therefore were
appropriately classified as a form of CJD, the clinical course of the
disease was atypical of classic CJD. The most striking and consistent
neuropathologic feature of nv-CJD was the formation of amyloid plaques
surrounded by halos of spongiform change. Plaques were extensively
distributed throughout the cerebrum and cerebellum. Many of these
plaques resembled those in kuru and were visible when examined by
routine staining methods.
The temporal cluster of cases of nv-CJD in young patients (three
were teenagers, five were in their twenties, and two were in their
thirties at onset of disease) is highly unusual. Five of the eight
deceased patients died before 30 years of age. (The expected annual
mortality rate for CJD in persons under 30 years of age is less than
five per billion.) The characteristic clinical features of the nv-CJD
cases were: (1) A psychiatric presentation, (2) onset of a progressive
cerebellum syndrome with ataxia within weeks or months of the initial
presentation, (3) memory impairment with dementia in the late stages,
(4) myoclonus, and (5) the absence of electroencephalographic changes
typical of classic CJD.
Review of the patients' medical histories and consideration of
various risk factors for CJD yielded no adequate clues as to the cause
of this disease. The PrP genotype was determined for eight cases. The
researchers noted that all genotypes were methionine homozygotes at
codon 129 of the PrP gene. The research did not identify any of the
known mutations associated with the inherited forms of CJD (Ref. 30).
Although scientists have stated that exposure to the BSE agent
prior to the U.K. bans described in section II.F. of this document is
the most plausible explanation for these findings, no clear
epidemiologic link to BSE was identified. (See further discussion in
section II.C. of this document.) Another potential explanation is
exposure to TSE agents from animals other than cattle. Because the
United Kingdom reinstituted epidemiological surveillance for CJD in
1990, increased surveillance is still another potential reason for the
identification of this cluster of 10 cases of nv-CJD.
c. Gertsmann-Strausller-Scheinker (GSS) syndrome. GSS syndrome is
an autosomal dominant condition in about 50 percent of siblings of
reference cases (Ref. 28). The disease is similar to CJD except that it
has a more extended onset and duration, a tendency towards cerebellar
ataxia as the initial predominant neurological sign, and a large number
of amyloid plaques present among the spongiform encephalopathic changes
of the brain. The extensive distribution of amyloid plaques in the
patient's brain is an observation shared by GSS syndrome and v-CJD. It
has been transmitted to monkeys and rodents by intracerebral
inoculation.
d. Kuru. Kuru is a condition of the Fore people of the Okapa
district of the Eastern Highland in Papua New Guinea, in which a
practice of ritual cannibalism of fellow tribesmen took place until
approximately 1956 (Ref. 28). This TSE disease, which affected mainly
adult women and children of both sexes, caused an annual disease
specific mortality of approximately 3 percent. Most deaths of women in
the tribe occurred through this disease. Some men who died from this
disease were thought to have contracted it when they were young. Kuru
may be transmitted by eating infected tissue or through open wounds.
The brains of dead tribal members were eaten by women and children and
the muscle tissue by men. The cohort of children born since 1957 have
not suffered from kuru at all.
Clinically the disease causes a progressive cerebellar ataxia,
uncoordinated movements, neurological weakness, palsies, and decay in
brain stem function. Most patients dying of kuru are not demented, a
major clinical difference between kuru and CJD.
e. Fatal familial insomnia (FFI). FFI is another inherited TSE-
linked disease (Ref. 31). FFI is characterized clinically by
untreatable progressive insomnia, dysautonomia, and motor dysfunctions.
The disease often starts between 35 and 60 years of age and leads to
death within 7 to 32 months. FFI is characterized pathologically by
atrophy, neuronal loss, and gliosis in the anterior and dorsomedial
nuclei of the thalamus (Ref. 32). FFI has been successfully transmitted
to mice (Ref. 33), but not to primates.
5. Etiology
The cause of TSE's is controversial. The TSE agent: (1) Is
presumably smaller than most viral particles and is highly resistant to
heat, ultraviolet light, ionizing radiation, and common disinfectants
that normally inactivate viruses or bacteria; (2) causes little
detectable immune or inflammatory response in the host; and (3) has not
been observed microscopically.
Resistance of the TSE agent to physical and chemical methods that
destroy nucleic acid have essentially ruled out conventional
microbiological agents as the cause. Currently, the infectious protein
or prion theory is favored. Other proposed causes are an unconventional
virus, consisting of virus-coded protein and virus-specific nucleic
acid with unconventional properties, and a ``virino'' consisting of a
core of nontranslated nucleic acid associated with host cell proteins
(Ref. 34). Proposed causes of TSE's with less supporting evidence are:
(1) Retroviruses (Ref. 35), (2) a spiroplasma (Refs. 36 and 37), (3)
organophosphates (Ref. 38), and (4) peptide hormones (Ref. 39).
The prion theory suggests that the causative agent is a normal host
protein (PrP or PrP-C) that is posttranslationally transformed into the
causative agent or PrP-Sc. Transformation of the PrP can occur from
rare somatic mutation of the prion gene, spontaneously or from contact
with extraneous PrP-Sc. The spread of BSE in the United Kingdom is
postulated to have occurred through the feeding of ruminant protein
that contained the PrP-Sc protein and thus follows the portion of the
theory that involves contact with extraneous PrP-Sc. This explanation
requires that one accept that abnormal prion protein from sheep crossed
the species barrier and resulted in BSE in cattle. An alternate
explanation is that a spontaneous mutation or transformation or other
nonorally induced event, occurred and resulted in undetected disease in
a bovine. These explanations are not mutually exclusive and it is
possible that both occurred.
Recent surveillance information from Northern Ireland and
Switzerland tend to support the spontaneous mutation as a method by
which BSE can occur. Northern Ireland has had more than 10 cows produce
offspring, after the feeding ban, that developed BSE. Thus, 10+ cases
are theorized to be spontaneous because there is no evidence of feeding
meat and bone meal to the offspring and the dams are alive
[[Page 559]]
and show no signs of BSE (Ref. 5). Switzerland, which has one of the
most aggressive BSE investigational surveillance of any European Union
(EU) country, has reported 205 cases of BSE. Some of these cases are in
animals that were fed only grass and hay (Ref. 5). Regardless of how
the initial cases occurred, however, the resulting unrecognized disease
was amplified by the feeding of ruminant protein to ruminants.
Additional support for the feasibility of the TSE spontaneous
mutation explanation is the fact that 85 percent of all CJD cases are
sporadic and have no familial or identifiable link as to their cause.
It is these cases that give rise to the very stable, 1 in a million per
year, world wide incidence of the disease. DeArmond and Prusiner (Ref.
40), and Lansbury and Caughey (Ref. 41) have postulated that a
noninduced somatic cell mutation or the spontaneous conversion of PrP-C
into PrP-Sc are plausible explanations for the sporadic cases of CJD.
DeArmond and Prusiner theorized that the 1 in a million
* * * may represent the combined probabilities that a mutation
occurs in the PRNP gene, the probability that the mutation leads to
the synthesis of the PrP-cjd (the abnormal protein), and the
probability that the resultant PrP-cjd targets other neurons for the
synthesis of more PrP-cjd at a rate fast enough to cause clinical
disease in the patient's lifetime.
The etiology of human and animal TSE's are similar. Therefore the
spontaneous mutation explanation cannot be dismissed with regard to
BSE.
6. Pathogenesis
Following oral exposure of goats or sheep to the scrapie agent, the
agent first accumulates in gut-associated lymphoid organs (tonsils and
Peyers patches of terminal ileum) and later in other lymphoid organs,
such as spleen and thymus, and finally in the spinal cord and brain
(Ref. 8).
Likewise, in mice inoculated intra-peritoneally with the CJD agent,
the agent localizes first in Peyer's patches and spleen, followed by
the central nervous system (Ref. 42). The agent may enter the body
through macrophages in the tonsils and domes over Peyer's patches in
the intestine (distal ileum). The proposed routes of spread from the
point of entry to other tissues and central nervous system are blood
stream or nerve trunks. In experimentally inoculated animals, spread
from the inoculation site in the eye of monkeys and peritoneum of mice
has been shown to be by optic and splanchnic nerves respectively (Ref.
43).
Other investigators have demonstrated transient infectivity in the
blood of experimentally infected laboratory animals, and naturally
occurring infections of humans and mink, causing speculation that the
agent is carried in the blood (Refs. 45 to 49). With one exception in
serum (Ref. 50), all attempts to isolate TSE agents from the blood or
milk of sheep or cattle have failed (Refs. 51 to 54). When TSE agents
are injected intravenously into mice, the rate of clearance from the
blood is extremely rapid (Ref. 55). In natural cases of BSE,
infectivity has been found only in the brain, spinal cord, and eye; in
experimental cases the agent has also been identified in the ileum
(Ref. 56).
The question of disease mechanism remains open. Candidate
mechanisms are the storage or accumulation of a large amount of
abnormal PrP in the brain (Refs. 57 to 60), or insufficient amounts of
normal PrP.
7. Transmission
There is little information about the natural transmission of TSE's
of animals. In most cases the natural route of exposure to the TSE
agent is suspected to be oral, although genetic disposition is known to
play a role in sheep scrapie (Ref. 61). Investigators have suspected
transmission of scrapie in sheep and goats by ingestion of placenta and
have been successful in experimentally transmitting scrapie by feeding
placenta to sheep (Ref. 62); however, genotyping of the PrP gene was
not conducted.
In 1993, a study by Foster, et al., (Ref. 63) using a line of sheep
in which natural scrapie does not occur demonstrated that sheep can be
experimentally infected with BSE by intracerebral or oral
administration. The intracerebral challenge resulted in five of six
sheep developing the disease. The oral challenge resulted in one of six
sheep developing the disease. Brain and spleen were recovered from the
orally infected sheep and from one of the intracerebrally injected
sheep. Goldmann, et al. (Ref. 64), confirmed that both sheep had the
same PrP genotype. In 1996, Foster, et al. (Ref. 65) reported the
results of injecting homogenized tissue harvested from these infected
animals into a panel of mice. Transmission from the brains and spleen
of both sheep gave incubation periods and pathology in mice similar to
those seen in direct BSE transmissions from cattle to mice. Foster's
work supports the position that BSE can cross species barriers by the
oral route and that, when judged by the mouse bioassay, the disease
manifested in sheep retains the incubation time and pathology
characteristic of BSE rather than scrapie. However, the manifestation
of BSE in the sheep is histopathologically and clinically
indistinguishable from natural scrapie.
Information regarding the interaction of the TSE agents and the
environment is limited. In 1964, Gordon reported the transmission of
scrapie among bands of unrelated sheep on pasture. The mode of
transmission was unknown (Ref. 66). In an effort to eradicate scrapie
from Iceland a large area was depopulated of sheep and restocked with
new sheep following a period of 3 years. Despite this effort, a few
flocks of the new sheep developed scrapie; the origin was believed to
be from scrapie that survived in the environment and not from
reintroduction of the agent with the new sheep or through contaminated
hay remaining on farms. However, a 1996 report suggests that six
species of hay mites may be potential vectors associated with
transmission of TSE's in Iceland (Ref. 67).
8. Genetics
There is a genetic component associated with several of the human
TSE diseases. A specific point mutation at codon 178 is associated with
fatal familial insomnia (Ref. 68). Point mutations at codons 102, 105,
117, 145, 198, and 217 are associated with GSS syndrome (Ref. 69).
Point mutations at codons 178, 180, 200, 210, and 232 are associated
with CJD (Refs. 68 and 70). Various insertions into the octapeptide
repeat region of the PrP gene have also been associated with human
TSE's (Ref. 71). It appears that the methionine/valine polymorphism at
codon 129 may modify the phenotype and the transmission rate from GSS
syndrome patients to mice (Ref. 72). No abnormalities in the sequence
of the PrP gene in kuru patients were found.
There is also a genetic component associated with sheep scrapie.
Point mutations at codon 171 of the sheep PrP gene are linked to the
disease in the Corriedale, Lacaune, Romanov, Suffolk, and Texel breeds
(Refs. 73 to 76).
An analysis of 370 cattle from Scotland revealed no difference
between healthy cattle and cattle with BSE in the number of octapeptide
repeat sequences (either five or six) and in a silent HindII
restriction site polymorphism on the PrP gene (Ref. 77). No data were
found that compared the sequence of the PrP gene of healthy deer, elk,
mink, and goats with those afflicted by TSE's.
9. Diagnostics
Because of the long incubation period, the ability to diagnose the
presence of a BSE infection prior to the onset of the
[[Page 560]]
clinical disease would enhance the efficacy of surveillance and
prevention programs. Because there is no fully characterized immune
response to BSE or scrapie, diagnosis in live animals has been thought
to be possible only when clinical signs are evident and must be
confirmed by histopathology at post mortem (Ref. 10), or brain biopsy
of moribund patients. Recently published research suggests antemortem
tests for the TSE agent may be possible.
The observation of histopathological changes in the brain, such as
vacuolization of the brainstem in BSE are positive indicators of
disease (Ref. 78). Other available diagnostic tests are
immunohistochemical staining and immunoblotting of the abnormal protein
(Ref. 10). Detection and titration of the TSE agent can also be
accomplished by intracerebral inoculation in mice or hamsters with a
brain homogenate from a suspected animal. After an appropriate
incubation period, the brain of the laboratory animal is examined for
histopathological changes characteristic of TSE (Ref. 8).
The potential antemortem tests that have been published are
described as follows: (1) Tests specific for PrP: (a) A capillary
electrophoresis test (Ref. 79), and (b) a western blot test with
increased sensitivity (Ref. 80); and (2) tests which identify
metabolites of infected animals or humans: (a) A cyclic voltametric
method which describes metabolites in urine (Ref. 81), and (b) an
immunoblot test describing metabolites in cerebral spinal fluid (Ref.
82). Antemortem tests have not yet been validated for practical use.
Recent research has shown some promise for antemortem testing.
Research by Shreuder et al. (Ref. 83), detected scrapie-associated
PrPsc protein in tonsils from scrapie susceptible sheep about a year
before the expected onset of the clinical disease. The research holds
promise for preclinical detection in sheep, but needs further
development. With regard to cattle, the researchers concluded that the
technique may not work but is worth investigating. Research by Hsich et
al. (Ref. 84), describes an experimental assay in humans and animals.
The research found that a positive immunoassay in human dementia
patients supports a diagnosis of CJD. The authors concluded that the
assay may be helpful in premortem diagnosis of TSE in humans and
animals showing clinical signs associated with TSE's. The validity of
the test as a preclinical screen has not been established.
10. Inactivation
The agency considered requiring procedures for the manufacture of
animal-derived proteins that would inactivate TSE infectivity. There
have been several studies on the inactivation of TSE agents. The only
broad generalization that can be drawn is that agents that denature
protein can diminish the infectivity of the TSE agents. TSE infectivity
does not appear to be markedly diminished by radiation or UV-light.
Recent research (Ref. 85) showed that 11 of the 15 rendering
procedures tested produced meat and bone meal with no detectable BSE
infectivity in a mouse bioassay. Only limited conclusions can be drawn
about safety from these 11 procedures because the infectivity titer of
the spiked starting material (which consisted of 10 percent brain) was
several logs lower than that typically found in brain that is not
minced and not stored at -20 deg.C. Also, the question of the adequacy
of the mouse bioassay as the regulatory test which acceptably assures
the absence of TSE infectivity to animals or man remains to be answered
through future research investigations.
The four procedures that failed included two protocols using
continuous vacuum rendering of high fat material and two protocols
using continuous atmospheric rendering of natural fat material. The
continuous vacuum rendering processes that failed were 120 deg.C for
20 minutes at a vacuum of 0.38 bar and 121 deg.C for 57 minutes at a
vacuum of 0.4 bar. The continuous atmospheric rendering processes of
natural fat material that failed were end temperatures of 112 and 122
deg.C after 50 minutes; however, end temperatures of 123 and 139 deg.C
after 125 minutes both inactivated the BSE agent. Unexpectedly, the BSE
agent was inactivated by three wet rendering processes that only
reached a maximum temperature of 119 deg.C with a cooking time of 240
minutes, a maximum temperature of 101 deg.C with a cooking time of 120
minutes, and a maximum temperature of 72 deg.C with a cooking time of
240 minutes under a vacuum of 0.85 bar.
Preliminary, unpublished results indicate that the only rendering
process which completely inactivates the scrapie agent (which was
spiked with higher infectivity than that in the BSE experiments
described in this section) is batch rendering under pressure (Ref. 86).
The agency encourages more research in this area.
B. The Association Between Scrapie and BSE
Epidemiological studies of the outbreak of BSE in the United
Kingdom, including a computer simulation of the BSE epidemic, have
characterized it as an extended common-source epidemic. Each case has
been considered a primary case resulting from exposure to a single
common source of infection. It is believed in the United Kingdom that
rendered feed ingredients contaminated with scrapie infected sheep, or
cattle with a previously unidentified TSE, served as the common source
of infection. One study demonstrated that meat and bone meal could be
incorporated into cattle feed in sufficient quantity to transmit BSE to
some of the animals that consumed the feed (Ref. 87). Thus far, other
research including research by USDA has not confirmed that the feeding
of U.S.-origin scrapie-infected feed ingredients to cattle produces
BSE. Therefore, the theory that BSE evolved naturally in cattle has not
been ruled out (Ref. 88). See also the discussion in II.A.5. of this
document.
Furthermore, the U.K. studies suggest that the spread of BSE
appeared to have been exacerbated by the practice of feeding
ingredients from rendered BSE-infected cattle to cattle, including
young calves, a practice that was subsequently banned. Incomplete
immediate compliance with the feeding ban may account for the fact that
some cattle born after the ban continue to be infected with BSE and has
complicated any theory of vertical transmission of the disease. The
research findings of maternal transmission of BSE are inconclusive, but
if it occurs, it does so at a rate insufficient to maintain the
epidemic (Ref. 89).
C. The Association Between Animal TSE's and Human TSE's
All the animal and human TSE's have been shown to be transmissible
experimentally to laboratory animals. The human and animal diseases are
pathologically similar and share some etiological similarities. TSE's
are not officially considered zoonotic diseases, i.e., known to be
naturally transmissible from animals to humans. The distribution of CJD
in the world does not coincide with that of scrapie in sheep or of BSE
in cattle. Human exposure to sheep or cattle has a low correlation with
CJD. However, the recent report from the United Kingdom of nv-CJD, and
its possible relationship to BSE, is causing scientists around the
world including those at CDC to
[[Page 561]]
reevaluate whether BSE may be a zoonotic disease.
This concern is further supported by the recent report of
experimental BSE transmission to macaques, with the development of nv-
CJD-like plaques in these monkeys (see the following discussion in this
section).
The possibility of transmission of TSE's from animals to humans has
been suggested, most recently in connection with the identification of
nv-CJD in the United Kingdom. Scientists in the United Kingdom
concluded that the nv-CJD cases may be unique to the United Kingdom,
raising the possibility that they are causally linked to BSE. The
scientists stated that ``the common neuropathological picture may
indicate infection by a common strain of the causative agent, as in
sheep scrapie in which strains of the disease have been identified * *
* '' (Ref. 30). The United Kingdom Spongiform Encephalopathy Advisory
Committee (SEAC) stated that ``although there is no direct evidence of
a link, on current data and in absence of any credible alternative the
most likely explanation at present is that these cases are linked to
exposure to BSE before introduction of the SBO [specified bovine offal]
ban in 1989'' (Ref. 90). A WHO consultation in April 1996 concluded
that ``a link has not yet been proven between v-CJD in the U.K. and the
effect of exposure to the BSE agent. The most likely hypothesis for v-
CJD is the exposure of the United Kingdom population to BSE'' (Ref. 2).
However, a second WHO consultation, in May 1996 concluded that ``the
clinical and neuropathological features of the newly recognized CJD
variant do not provide information which could be used to prove the
possible link between this disease and BSE in cattle'' (Ref. 91).
The recent finding of florid amyloid plaques in the brains of
macaques inoculated with suspensions of BSE-infected cow brains
increases suspicion that exposure to the BSE agent may be the source of
nv-CJD. Amyloid plaques have never before been seen in monkeys with
TSE's, and the florid plaques resembled those in nv-CJD patients (Ref.
92). In a recent paper by Collinge, et al. (Ref. 93), it is stated that
``strains of transmissible encephalopathies are distinguished by
differing physicochemical properties of PrPsc, the disease-related
isoform of prion protein, which can be maintained on transmission to
transgenic mice. 'New variant' CJD has a strain characteristic distinct
from other types of CJD and which resembles those of BSE transmitted to
mice, domestic cat and macaque, and is consistent with BSE being the
source of this new disease. Strain characteristics revealed here
suggest that the prion protein may itself encode disease phenotypes.''
The possible association between BSE and nv-CJD may be further
clarified by results from studies that are under way (e.g.,
experimental inoculation of brain tissue from the nv-CJD patients into
mice).
D. Infectivity of Specific Tissues
The WHO in a recent publication has summarized the infectivity of
various tissues from sheep, goat, and cattle (Ref. 94). Scientific
studies are currently being conducted in which calves are fed
homogenized brain tissue from United Kingdom cattle confirmed to have
BSE, and then various tissues are collected from the calves at 4-month
intervals (Refs. 56 and 95). The tissues from these calves are being
analyzed for the presence of the BSE agent. The study has been in
progress for 18 months and only brain, spinal cord, and retina have
been shown to be highly infectious. Distal ileum has been shown to be
infectious, but much less than the previously mentioned tissues. No
other tissues, most notably, muscle meat, milk, or blood have been
shown to be infectious. The results of these current experiments
parallel the previous research as summarized by WHO. However, the
agency notes that infectivity of other tissues that might be fed to
ruminants has not been definitively determined. This is, in part,
because of the lack of desired sensitivity in the available assay
methods.
In summary, meat, milk, milk products, and blood have not been
shown to transmit BSE infectivity. These products are considered safe
for human consumption by health authorities including the WHO.
E. Potential Risk of TSE's to the United States
1. Overview
This proposed FDA action is designed to reduce the risk of a BSE
epidemic in the United States and thereby protect the health of animals
and possibly of people if there is, in fact, a zoonotic relationship
between BSE and CJD. Risk is defined as the probability of an adverse
effect to an individual or a population. The four steps that are
typically involved in risk analysis are hazard identification, hazard
exposure, dose response, and risk characterization.
While BSE has not been found in the United States, the agency
believes it presents a potential risk to the health of animals and
people. There are incubational and symptomatic similarities (as well as
several differences) among the TSE's. The scientific characterization
of these diseases is incomplete. However, interspecies cross-infections
have been scientifically demonstrated by parenteral injection and oral
routes of exposure.
The typically long incubation period and the potentially
devastating effect that a BSE outbreak would have on animal health and
U.S. agribusiness also supports a conservative regulatory approach
aimed at prevention. While the current level of exposure to products
derived from animals with a TSE is extremely low or absent, the
potential consequences of such exposure and the apparent small intake
of the agent needed to achieve infection in some animals further
encourage a conservative regulatory policy.
Dose response assessments will be difficult because of the lack of
good exposure data and the possibility of different susceptibilities,
e.g., age or genetic factors, in different subpopulations. Although the
TSE's are generally transmissible to laboratory animals following
intraperitoneal (ip) or intracerebral (ic) routes of administration,
the limited data that are available following the oral route of
administration suggests that this route is much less efficient than ip
or ic. Currently, it is quite difficult to make an accurate dose
response assessment for a TSE agent following oral administration.
A number of actions, in addition to this proposed rule, have been
taken to manage a reduction in risk that BSE will enter the United
States cattle population. Restrictions have been placed on the
importation of live cattle (July 1989) and ruminant products (e.g.,
meat and bone meal, bone meal, blood meal, offal, fat, and glands) from
countries which have BSE. Live animals imported prior to the
restrictions on imports have been regularly monitored by Animal and
Plant Health Inspection Service (APHIS) veterinarians, and APHIS is
currently in the process of purchasing the remaining live cattle for
diagnostic research purposes. Histopathological examination of brain
tissues has been carried out on more than 5,000 specimens from cattle
that were disabled or that demonstrated neurological signs prior to
slaughter or on the farm, e.g., nonambulatory or rabies-negative
cattle. Histopathological and immunohistochemical examination of the
nonambulatory or ``downer'' cows has been carried out since 1993. There
has been no finding of BSE in tissues from these animals. These animals
represent the highest BSE risk in the country, however, they also
represent an extremely small percentage of the cattle
[[Page 562]]
slaughtered in the United States. This active surveillance program is
continuing and may be expanded. The expansion of this program was
indirectly supported by a comment to the ANPRM that all ``downer'' cows
should be examined for BSE.
Voluntary actions by industry have reduced the feeding of rendered
sheep proteins to ruminants and the rendering of adult sheep. A
voluntary Scrapie Flock Certification Program was implemented in 1992.
The program, a cooperative effort among industry, State animal health
officials and APHIS, seeks to reduce the prevalence of scrapie in U.S.
sheep. A considerable educational effort continues to increase the
awareness of veterinarians, veterinary laboratory diagnosticians,
livestock and related industry businesses, and producers to the early
clinical signs of BSE. Videos of United Kingdom BSE affected animals
have been distributed to USDA veterinarians to enhance their ability to
clinically diagnose BSE in suspect live animals. CDC has recently
published an update (Ref. 96) of its previous review of national CJD
mortality and the results of active CJD surveillance in five sites in
the United States. These reviews did not detect evidence of the
occurrence of the newly described variant form of CJD in the United
States. As an important complement to these other public health
efforts, this proposed rule would declare that animal protein derived
from ruminant and mink tissues is an unapproved food additive for use
in ruminant feeds, and would establish enforcement procedures. These
actions, individually and collectively, contribute to a greatly reduced
risk of a BSE epidemic ever occurring in the United States.
2. Comparison With the U.K. Conditions
Investigators have identified several major risk factors that
apparently contributed to the emergence of the disease and the
resultant epidemic in the United Kingdom. These are: (1) A large sheep
population relative to the cattle population, (2) a large,
uncontrolled, scrapie incidence rate, (3) the production of
``greaves,'' an incompletely processed intermediate product in the
rendering process, (4) changes in rendering processes, such as the
reduced use of solvent extraction, and (5) the feeding of significant
amounts, up to 4 percent of the diet, of meat and bone meal to young
dairy calves.
In addition to the risk factors described in section II.E.2. of
this document, the practice of processing dead sheep and cattle in the
United Kingdom likely contributed to the amplification of the TSE
agent. In the United Kingdom, sheep which may have died of scrapie and
cattle with BSE, were picked up by ``knackers'' for rendering into
animal feed. This material was partially rendered into ``greaves,''
which might have contained large amounts of the scrapie/BSE agent, and
was fed to dairy calves in large amounts. The spread of BSE appeared to
be facilitated by the feeding of rendered BSE-infected cattle back to
calves. The BSE agent is postulated to have recycled from cows to
calves through ruminant-to-ruminant feeding until the practice ceased
following the 1989 ban on the practice.
In the United States, the cattle population is much larger than the
sheep population, the incidence of scrapie is much lower and a scrapie
control program is in place; renderers in the United States do not
manufacture greaves; and the rendering processes used in the United
States are thought to reduce the titre (level) of TSE agents if any.
The lack of a practice of feeding large amounts of meat and bone meal
to calves in the United States, and the comparatively younger average
age of U.S. dairy cattle are also differences that are believed to be
important in protecting the United States against a U.K.-type BSE
epidemic. Nevertheless, scrapie does exist in the United States, sheep
are rendered and included in ruminant feed, the rendering process does
not totally inactivate TSE agents, and calves are fed meat and bone
meal. Therefore the risk of a BSE epidemic in the United States, while
much less, cannot be completely discounted.
F. Historical Efforts to Control TSE's
1. U.S. Actions
a. FDA. FDA is the Federal agency responsible for the safety and
effectiveness of a large number of products and commodities. Briefly,
these include, drugs for use in people and animals, human biological
products, medical devices, food, dietary supplements, cosmetics, and
animal feeds. Each of these product groups provides the potential for
the transmission of spongiform encephalopathies in man or animals. FDA
formed a Working Group composed of the Deputy Commissioner for
Operations and representatives from the Centers to consider TSE's in
relation to FDA regulated products. As a result of the Working Group's
deliberations, FDA has taken the following actions:
<bullet> In 1992, letters were sent to manufacturers of dietary
supplements asking those manufacturers to reformulate their products to
be certain they do not contain materials from BSE or scrapie infected
animals;
<bullet> In 1993, letters were sent to manufacturers of drugs,
biologics, and devices asking them not to use bovine-derived materials
from countries with BSE; and
<bullet> In 1996, letters were sent to manufacturers of drugs,
biologics, devices, and animal feeds noting a possible relationship
between BSE and nv-CJD and asking that they not use materials from BSE
countries.
In 1992, FDA conducted a survey of major sheep rendering plants to
determine compliance with a 1989 voluntary industry ban on the use of
adult sheep offal in ruminant feeds. The voluntary ban and results of
the survey are described in section I.F.3. of this document. In the
Federal Register of August 29, 1994 (59 FR 44584), FDA published a
proposed rule proposing to declare that specified offal from adult
sheep and goats is an unapproved feed additive in ruminant feed
(hereinafter referred to as the August 1994 proposed rule). In the
Federal Register of May 14, 1996, FDA published an ANPRM stating that
FDA was considering whether to provide that the use of protein derived
from ruminants in ruminant feed be prohibited.
An international symposium entitled ``Tissue Distribution,
Inactivation, and Transmission of Transmissible Spongiform
Encephalopathies'' and cohosted by APHIS and FDA's Center for
Veterinary Medicine (CVM) was held on May 13 and 14, 1996, in
Riverdale, MD. The symposium participants engaged in discussion of
findings from unpublished, recently completed, and in-progress
scientific investigations on TSE's, and optimal approaches to managing
any risk of TSE's to animal health.
b. USDA. USDA policy has been both proactive and preventive. The
Food Safety and Inspection Service (FSIS) and APHIS have been active in
taking measures in surveillance, prevention, and education about TSE's.
In 1990, APHIS created a BSE Issues Management Team to analyze risks of
BSE to the United States, disseminate accurate information about the
disease, and act as a reference source for responding to questions
about BSE. APHIS has also collaborated in the education of veterinary
practitioners, veterinary laboratory diagnosticians, industry and
producers on the clinical signs and pathology of BSE.
APHIS has increased its surveillance efforts to verify that the
United States is free of BSE and to detect the disease should it be
introduced into the United
[[Page 563]]
States. As part of an ongoing active surveillance program, more than 60
veterinary diagnostic laboratories across the United States, and the
National Veterinary Service Laboratories (NVSL) of APHIS, continue to
examine bovine brains from the following sources: (1) APHIS
investigations in the United States where suspected encephalitic
conditions in cattle are reported under the foreign animal disease
investigation program; (2) CDC and State public health laboratories
(specimens from bovine that were found negative for rabies); and (3)
FSIS (specimens from ``downer'' cows or those exhibiting CNS
abnormalities). More than 5,000 bovine brains have been examined, and
none of these specimens contained lesions with the characteristics and
distribution typical for BSE (Refs. 12 and 97). APHIS is currently in
the process of purchasing the 69 living cattle (from a total of 496
cattle) imported from the United Kingdom between 1981 and 1989. In July
1989, the importation of live ruminants and ruminant products from all
countries known to have BSE in native animals was banned.
USDA continues to analyze and report epidemiologic findings and
potential risks to the United States. In 1991, USDA issued two reports
analyzing risk factors associated with BSE in the United Kingdom based
on the British hypothesis of the disease occurring as a result of
feeding scrapie-contaminated meat and bone meal (Refs. 98 and 84).
Because of some similarities in the animal industries between the two
countries, the possibility of BSE occurring in the United States could
not be eliminated. However, the probability of occurrence was
determined to be very low as the amount of sheep offal was found to be
0.6 percent of all U.S. rendered product compared to the estimate of 14
percent of all U.K. rendered product. Furthermore, the incidence of
scrapie in the United States is much lower than in Great Britain; a
scrapie eradication or control program has been in effect in the United
States and rendered products are not routinely incorporated into calf
diets as was the practice in the United Kingdom.
Since 1991, USDA has closely followed scientific findings and has
updated the BSE risk factor analysis, first in 1993 (Ref. 99) and as
recently as February 1996 (Ref. 4). Changes within each of the risk
factors have been evaluated, and because there has either been no
change or a decrease in the magnitude of risk factors, the overall risk
of BSE in the United States is believed to have decreased. The
February, 1996 report estimated the maximum potential 1-year period
prevalence of BSE to range from 2.3 to 12 cases per 1 million adult
cattle. In other words, under the worst case scenario between
approximately 115 and 600 adult cattle would become infected with BSE
each year, in a U.S. population of nearly 50 million adult cattle.
APHIS has had a scrapie control program in effect since 1952.
Flocks that have been enrolled in the voluntary certification program
for sheep for 5 years, and have not had a diagnosed case of scrapie
within 5 years or a case traced back to the flock during that period,
may apply for APHIS certification and be officially identified as such.
This new control effort provides a mechanism to recognize flocks as
scrapie-free in the absence of a live animal diagnostic test.
There is no official USDA program on TME or CWD. Although the last
TME case detected in the United States was in 1985, monitoring for this
disease continues. APHIS cooperates with State wildlife and diagnostic
officials in Colorado and Wyoming in the limited areas where CWD has
been reported.
In December 1991, APHIS placed a ban on importation of certain
products of ruminant origin from countries known to have BSE (56 FR
63865, December 6, 1991). These products include: Meat and bone meal,
bone meal, blood meal, offal, fat, and glands. In addition to
prohibiting the materials listed previously, the regulation requires
that imported meat for human or animal consumption from bovines be
deboned, with visible lymphatic and nervous tissue removed; that it be
obtained from animals which have undergone a veterinary examination
prior to slaughter; and that it be obtained from ruminants which have
not been in any country in which BSE has been reported during a period
of time when that country permitted the use of ruminant protein in
ruminant feed. APHIS may allow the importation of the banned products
under a special permit for scientific or research purposes, or under
special conditions to be used in cosmetics. No bovine meat from the
United Kingdom has been allowed to be imported into the United States
by FSIS for human consumption since before the BSE epidemic occurred in
the United Kingdom. The network of private veterinary practitioners
that refers unusual cases to veterinary schools or State diagnostic
laboratories around the United States provides an extensive
surveillance system. FSIS performs both antemortem and post mortem
inspections at all federally-inspected slaughter establishments, and
inspectors condemn all animals with central nervous system disorders.
State-inspected slaughter operations follow the same procedures.
USDA also maintains a database on these and other conditions. The
Veterinary Diagnostic Laboratory Reporting System (VDLRS) is a database
of selected disease conditions submitted by 29 State and university
veterinary diagnostic laboratories throughout the United States, and
includes the results of histologic examinations for BSE. The VDLRS is a
cooperative effort of the American Association of Veterinary Laboratory
Diagnosticians (AAVLD), the U.S. Animal Health Association (USAHA),
APHIS' Veterinary Service Centers for Epidemiology and Animal Health,
and the 29 laboratories mentioned previously.
c. Public Health Service (PHS). i. CDC. CDC conducts surveillance
for CJD through examination of death certificate data compiled by the
National Center for Health Statistics, CDC, for U.S. residents for whom
CJD was listed as one of the multiple causes of death (Ref. 100). These
data indicate that the annual CJD mortality rates in the United States
between 1979 and 1993 have been relatively stable, ranging between only
0.8 case per million in both 1979 and 1990 and 1.1 cases per million in
1987. In addition, CJD deaths in persons younger than 30 years of age
in the United States remain extremely rare (<5 cases per billion per
year) (Ref. 101).
CDC is working with the Council of State and Territorial
Epidemiologists to consider expansion of current CJD surveillance. CDC
is also working with its four established Emerging Infections Programs
(Minnesota, Oregon, Connecticut, and the San Francisco Bay area,
California), the Georgia Department of Human Resources, and the Atlanta
Metropolitan Active Surveillance Program to pilot enhanced surveillance
efforts for CJD (Ref. 101). This effort includes an active search for
v-CJD as described in the United Kingdom (Ref. 30). On August 9, 1996,
the results of this enhanced CJD surveillance effort was published; no
evidence of the occurrence of the newly described variant form of CJD
was found in the United States. No evidence of v-CJD has been found in
the United States.
ii. National Institutes of Health (NIH). A project of the
Laboratory of Central Nervous System Studies of the National Institute
of Neurological Diseases and Stroke is conducting investigations on
slow, latent, and temperate viral infections associated with chronic
degenerative neurological diseases. Important areas of study are the
pathogenesis of slow infections and mechanisms of persistence in kuru
and
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CJD. Also intensive molecular, biological, genetic, and immunological
studies are being conducted on amyloid formation in the brain in
Alzheimer's disease, normal aging, Down's syndrome, and slow viral
infections, and the elucidation of the de novo generation of infectious
amyloid proteins from normal host precursor proteins in kuru, CJD, GSS
syndrome, scrapie and BSE. Research on TSE's has also been conducted by
the NIH Laboratory of Persistent Viral Disease. FDA maintains close
contact with scientists in the laboratories and expects to use their
expertise in the evaluation of inactivation methods and transmission
studies.
iii. Other actions. On April 8, 1996, an interagency meeting at CDC
including representatives from CDC, NIH, FDA, USDA, and the U.S.
Department of Defense was held to disseminate conclusions from the WHO
consultation regarding v-CJD and to coordinate preventive activities
among these agencies to address the BSE and CJD issues.
2. International Actions
a. United Kingdom. Regulatory controls taken to manage the BSE
epidemic in the United Kingdom and to address public health concerns
include: (1) An action in June 1988 to make the disease reportable; (2)
a ban in July 1988 on the feeding of ruminant-derived protein
supplements to other ruminants; (3) an order in August 1988 for the
compulsory slaughter and incineration of BSE suspect cattle; (4) a ban
in November 1989 on the inclusion of specified bovine offal (brain,
spinal cord, thymus, spleen, tonsils, and intestines) for human
consumption; and (5) a ban in September 1990 on use of specified bovine
offal in any animal feed.
A CJD Surveillance Unit was established to monitor CJD numbers in
the United Kingdom. SEAC, consisting of experts in neurology,
epidemiology, and microbiology from outside the British government, was
established in 1990 to oversee all aspects of TSE's and human and
animal health. USDA has a representative on this committee.
Major regulatory actions occurring after the SEAC report on nv-CJD
(Ref. 90) include legislation to ban the feeding of mammalian meat and
bone meal to any farmed animal, and legislation to ban the use of
cattle head meat for human consumption.
b. WHO. WHO has held meetings on the spongiform encephalopathies in
1991, 1993, 1995, and 1996, and a meeting in collaboration with the
Office International des Epizooties (OIE) in 1994. The general purposes
of these meetings were to review the existing state of knowledge on
spongiform encephalopathies including BSE, to evaluate possible means
of transmission, and to identify risk factors for infection. A specific
purpose was to review the possible human public health implications of
animal spongiform encephalopathies, with special emphasis on BSE. The
group of international experts convened in April 1996 by WHO
recommended that all countries should ban the use of ruminant tissues
in ruminant feed. The WHO group also declared that milk and milk
products, including such products from the United Kingdom, are safe for
human consumption and that gelatin in the food chain is considered safe
because its preparation effectively destroys BSE. Finally, the group
concluded that tallow could be safe if effective rendering procedures
are in place (i.e., rendered as protein-free) (Ref. 2).
c. OIE. OIE has supported the U.K. ban on the use of specified
offals and has recommended that the same action be taken in other
countries with a high incidence of the disease (Ref. 102). OIE has held
meetings in 1990, 1991, 1992, 1995, and 1996, and has developed
guidelines concerning animals and animal products to prevent movement
to unaffected countries.
d. European Community (EC). The EC has held a series of meetings
related to BSE. Following issuance of the U.K. SEAC statement
suggesting a possible link between nv-CJD and BSE, the EC imposed a ban
on British cattle, beef and bovine derivatives (Ref. 103).
3. Voluntary Measures by the U.S. Animal Industries
a. Voluntary ban on rendering adult sheep. In 1989, the National
Renderers Association (NRA) and the Animal Protein Producers Industry
(APPI) recommended to their members that they stop rendering adult
sheep or providing sheep offal for sale as meat and bone meal for
inclusion in cattle feed (Ref. 104). Following the recommendation of
the voluntary ban, FDA carried out a survey of current practices in the
United States for rendering or otherwise disposing of adult sheep
carcasses and parts, specifically head, brain, and spinal cord. Limited
inspections of rendering plants were conducted in 1992 to: (1) Assess
compliance by U.S. renderers with the voluntary ban; (2) identify
rendering plant practices concerning adult sheep; and (3) determine if
rendered adult sheep protein byproducts were being sold or labeled for
use as feed or feed components for cattle. Of the 19 plants surveyed,
15 rendered carcasses or offal of adult sheep. These 15 plants
processed more than 85 percent of the adult sheep rendered in the
United States. Eleven of the 15 plants rendered carcasses of adult
sheep with heads, 7 of the 15 rendered sheep carcasses separately from
other species, 6 of the 15 maintained meat and bone meal from adult
sheep separate from meat and bone meal from other species, and 4 of the
15 rendered sheep that had died of causes other than slaughter. Six of
the 11 renderers processing adult sheep with heads had sold meat and
bone meal to manufacturers of cattle feed. Thus, the rendering
industry's voluntary ban on the rendering of adult sheep or providing
sheep offal for use in cattle feed was not fully implemented at the
time of the survey (Ref. 105).
b. Voluntary ban on feeding ruminant proteins to ruminants. On
March 29, 1996, the National Cattlemen's Beef Association (NCBA), the
National Milk Producers Federation, the American Sheep Association, the
American Veterinary Medical Association, the American Association of
Veterinary Medical Colleges, and the American Association of Bovine
Practitioners announced the recommendation of a voluntary ban on the
feeding of ruminant-derived proteins to ruminant animals (Ref. 106).
USDA, PHS, the American Society of Animal Science, and other
organizations announced support for the voluntary ban (Refs. 107 and
108). According to the NCBA (Ref. 109), a comprehensive communication
strategy, seeking removal of ruminant-derived proteins from the rations
of ruminants, was implemented in May 1996 by the feed industry,
nutritionists, veterinarians, extension specialists, and dairy and beef
producers. NCBA has not conducted a survey to assess the impact of its
communication strategy; however, NCBA did point out that past requests
for voluntary action by the cattle industry have been quite successful,
approaching 90 percent compliance. In contrast, an anonymous comment to
the ANPRM suggested a compliance level of less than 5 percent (Ref.
110). FDA has not conducted a survey to ascertain the level of
compliance with the voluntary ban.
G. Processing Animal Tissues for Feed Ingredients
1. Current Rendering Practices
The following discussion on current rendering practices comes
directly from comments supplied to FDA in response to the ANPRM from
representatives of
[[Page 565]]
APPI and NRA. Knowledge about the four basic types of rendering systems
that are most commonly used in the United States today may be crucial
in dealing with the TSE issue in this country. Data on the inactivation
of the BSE and scrapie agents following simulation of the most commonly
used basic types of rendering systems in the United States could be
quite useful, especially because some of these systems do not appear to
have been used in the only published rendering study on BSE
inactivation (Ref. 85).
Rendering, the process of cooking raw material to remove the
moisture and fat from the solid protein portion of animal tissues, has
been practiced by humans for more than 2,000 years. The United States
rendering industry has developed over the last 160 years. Modern
rendering systems are high-technology recycling processes that
efficiently convert animal byproducts (shop fat and bone, beef and pork
slaughterhouse materials, poultry offal, fish, etc.) to stable protein
and fat supplements for feed.
Current technology consists of four basic types of rendering
systems--batch cooker, continuous cooker, continuous multi-stage
evaporator, and continuous preheat/press/evaporator. All systems
consist of three basic steps: Grinding the raw material, cooking it to
remove moisture, and separating the melted fat from the protein solids.
Batch cookers are multiple units, each consisting of a horizontal,
steam-jacketed cylindrical vessel with an agitator. Batch cookers are
operated at atmospheric pressure. The cooked material is discharged to
the percolator drain pan, which contains a perforated screen that
allows the free-run fat to drain and be separated from the protein
solids known as ``tankage.''
Because ``tankage'' contains considerable fat, it is processed
through a screw press to complete the separation of fat from solids.
The fat discharged from the screw press usually contains fine solid
particles that are removed by either centrifuging or filtration. The
protein solids discharged from the screw press are known as
``cracklings,'' which normally are screened and ground with a hammer
mill to produce protein meal.
The continuous cooker rendering system normally consists of a
single continuous cooker, operating at atmospheric pressure. The
discharge from the continuous cooker usually passes across either a
vibrating screen or stationary perforated screen to allow the free-run
fat to drain. The subsequent steps in the continuous cooker rendering
process are similar to those described before for the batch cooker.
In the continuous multi-stage evaporator rendering system, crushing
is used as the first stage of size reduction of the raw material. A fat
recycle stream is then used to deliver the material as a pumpable
slurry through the secondary grinding step to reduce further the
particle size. Particle size and fat ratios are important components of
this system. The slurry discharge from the final stage of evaporation
is pumped to a centrifuge which removes most of the fat and part of it
is recycled back to the second stage of size reduction. The solids
discharged from the centrifuge are conveyed to screw presses which
complete the separation of fat from the protein solids.
The continuous preheat/press/evaporator rendering system is known
by a variety of names including the Stord dewatering rendering system
and the Atlas low temperature wet rendering system. In either case, raw
material is ground in two stages and passes through the preheater to
raise the temperature to 180 to 190 deg.EF before entry to the twin
screw press. The press separates this material into two phases: A
presscake of solids containing moisture and a low fat concentration,
and a liquid containing mostly water (stickwater) with fine solids,
soluble protein, insoluble protein and melted fat.
The press liquid is processed either by passing through a
multistage evaporator system to remove the water before centrifuging to
remove the fine solids from the fat, or by passing through a centrifuge
to separate the fat before multistage evaporation of the remaining
water/fine solids fraction. The liquid separation system consisting of
two stages of centrifuges completes the separation of the melted fat
from the solids and water. In this system, the screw press normally
used to process the ``tankage'' is no longer needed. Longer drying
times are needed with this system as compared to previous systems
because of the early fat removal (less fat means less effective heat
transfer).
The agency encourages further research into methods of deactivation
of the BSE agent during the rendering process.
2. Assay Methodologies for Proteins
Enforcement of the proposed regulation would be facilitated if a
test to detect and distinguish ruminant from nonruminant materials in
feeds or feed ingredients was available. However, practical assays that
could be used to enforce the proposed regulation are not available at
this time. The test procedure would need to exhibit a high degree of
sensitivity and selectivity; that is, the test must be able to detect
the analyte of interest to the exclusion of other components. A test
for acceptable rendered products in animal feed must therefore be able
to discriminate and differentiate between permitted and prohibited
animal derived proteins. Other factors of importance are the ruggedness
of the test method, speed, and simplicity of design.
An enzyme-linked immunosorbant assay (ELISA) based analytic method
that is both sensitive (detects low levels of analyte) and specific
(detects primarily the analyte of interest) is one possibility. ELISA
is a relatively straightforward methodology. There are numerous
commercial sources for antisera capable of binding to bovine, ovine,
porcine, and caprine proteins. Antisera have also been generated from
muscle extracts and validated for use in USDA-approved ELISA methods to
determine the identity of raw and cooked meats (Refs. 111 and 112).
However, rendered products present a unique problem because rendering
causes the destruction of most of the antibody binding epitopes needed
for an ELISA test. Therefore, detection of rendered proteins by a given
antibody cannot be automatically assumed.
Other potential methodologies include western blot analysis,
capillary electrophoresis, and high pressure liquid chromatography. The
applicability of these three methods to this issue has not been
addressed. Furthermore, they require expensive, specialized equipment
and a high degree of technical competence.
The agency encourages research to detect and distinguish ruminant
from nonruminant materials in rendered products and animal feeds.
III. Statutory Provisions Regarding Food Additives
The term ``food'' as defined in the act includes animal feed.
Section 201(f) of the act (21 U.S.C. 321(f)) defines food as ``articles
used for food or drink for man or other animals'' and ``articles used
for components of any such article.'' Furthermore, any substance whose
intended use results or may reasonably be expected to result in its
becoming a component of food is a food additive unless, among other
things, it is GRAS or is the subject of a prior sanction. Section
402(a)(2)(C) of the act (21 U.S.C. 342(a)(2)(C)) deems food adulterated
``if it is, or it bears or contains, any food additive which is unsafe
within the meaning of section 409 * * *.'' Under section 409(a) of the
act (21 U.S.C 348(a)), a food additive is unsafe unless
[[Page 566]]
a food additive regulation or an exemption is in effect with respect to
its use or its intended use.
A food additive regulation is established by the submission and
approval of a food additive petition, as provided in 21 CFR 571.1, or
on FDA's initiative as provided in 21 CFR 570.15. FDA on its own
initiative or at the request of an interested party, also may propose
to determine that a substance intended for use in animal feed is not
GRAS and is a food additive subject to section 409 of the act as
provided in Sec. 570.38 (21 CFR 570.38). Subsequent to the publication
of such a proposal and after consideration of public comments, FDA may
issue a final rule declaring the substance to be a food additive and
require discontinuation of its use except when used in compliance with
a food additive regulation.
A. GRAS Determination
A determination that a substance added directly or indirectly to a
food is GRAS, is generally based on specific information regarding the
composition of the substance, its use, method of preparation, methods
for detecting its presence in food, and information about its
functionality in food (21 CFR 570.35) as determined by experts
qualified by scientific training and experience to evaluate the safety
of such a substance. A substance added to food becomes GRAS as the
result of a common understanding about the substance throughout the
scientific community familiar with safety of such substances. The basis
of expert views may be either scientific procedures, or, in the case of
a substance used in food prior to January 1, 1958, experience based on
common use in food (Sec. 570.30(a)) (21 CFR 570.30(a)). General
recognition of safety through experience based on common use in food
prior to January 1, 1958, may be determined without the quantity or
quality of scientific studies required for the approval of a food
additive regulation. However, substances that are GRAS based on such
use must be currently recognized as safe based on their pre-1958 use.
(See United States v. Naremco, 553 F.2d 1138 (8th Cir. 1977); compare
United States v. Western Serum, 666 F.2d 335 (9th Cir. 1982).) A
recognition of safety through common use is ordinarily to be based on
generally available data and information (Sec. 570.30(c)). An
ingredient that was not in common use in food prior to January 1, 1958,
may achieve general recognition of safety only through scientific
procedures.
General recognition of safety based upon scientific procedures
requires the same quantity and quality of scientific evidence as is
required to obtain approval of a food additive regulation for the
ingredient (Sec. 570.30(b)). (See United States v. Naremco, 553 F.2d at
1143.) A substance is not GRAS if there is a genuine dispute among
experts as to its recognition (An Article of Drug * * * Furestrol
Vaginal Suppositories, 251 F. Supp. 1307 (N.D. Ga. 1968), aff'd 415
F.2d 390 (5th Cir. 1969).) Further, general recognition of safety
through scientific procedures must be based upon published studies
(United States v. Articles of Food and Drug Colitrol 80 Medicated, 372
F. Supp. 915 (N.D. Ga. 1974), aff'd, 518 F.2d 743, 747 (5th Cir.
1975)), so that the results are generally available to experts. It is
not enough, in attempting to establish that a substance is GRAS, to
establish that there is an absence of scientific studies that
demonstrate the substance to be unsafe; there must be studies that show
the substance to be safe (United States v. An Article of Food * * * Co
Co Rico, supra.)
Conversely, a substance may be ineligible for GRAS status if
studies show that the substance is, or may be, unsafe. This is true
whether the studies are published or unpublished (50 FR 27294 at 27296,
July 2, 1985). If there are studies that tend to support a finding that
a particular substance is GRAS, but also studies that tend to support a
contrary position, the conflict in the studies, just as a conflict in
expert opinion, may prevent the general recognition of the safe use of
the substance.
B. Prior Sanction
Under section 201(s) of the act, the term ``food additive'' does
not apply to any substance used in accordance with a sanction or
approval granted prior to enactment of section 201(s) of the act and
granted under the act, the Poultry Products Inspection Act (21 U.S.C.
451 et seq.), or the Federal Meat Inspection Act (21 U.S.C. 601 et
seq.). Section 570.38(d) provides that if the Commissioner of Food and
Drugs is aware of any prior sanction for use of a substance, he will,
concurrently with a notice determining that a substance is not GRAS and
is a food additive subject to section 409 of the act, propose a
separate regulation covering such use of the substance.
In the case of the materials subject to this proposed rule, FDA has
determined that it is unaware of any applicable prior sanction. Any
person who intends to assert or rely on such sanction is required to
submit proof of the existence of the applicable prior sanction. The
failure of any person to come forward with proof of such an applicable
prior sanction in response to this notice will constitute a waiver of
the right to assert or rely on such sanction at any later time.
C. Food Additive Status of Ruminant Tissues
The agency recognizes that processed ruminant byproducts have a
long history of use in animal feeds without known adverse effects.
However, the evidence as discussed in sections I and II.A. through
II.D. of this document, for the development of a new pattern of disease
transmission, now indicates that these ingredients can no longer be
categorically regarded as safe. The agency tentatively concludes that,
based on this evidence, use of such products in ruminant feed is not
GRAS. The agency is proposing this regulation in light of the findings
and conclusions described in sections I and II in this notice. Nor is
the agency aware of a prior sanction for any feed products that contain
these tissues. Therefore, FDA is proposing that the addition of protein
derived from ruminant tissues to ruminant feed would constitute the use
of an unapproved food additive because no regulation is in effect
providing for such use. Any ruminant feed that contains protein derived
from ruminant and mink tissues would be adulterated. Accordingly, FDA
is proposing to list protein derived from ruminant tissues in part 589.
IV. Comments
FDA's May 1996 ANPRM requested public comment and information on
all aspects of TSE's, including BSE, and the potential consequences of
a prohibition on the feeding of ruminant protein to ruminants. The
agency received nearly 600 comments, including many that were submitted
long after the comment period ended. The agency has attempted to
address the comments in this proposal. If there are any significant
concerns that the agency has not addressed, these concerns should be
brought to the agency's attention in timely comments on this proposal.
Comments that were specific to the topics covered by the other sections
of this preamble were considered in the preamble as written. Comments
are discussed in the text of some of these sections. The following is a
general discussion of the comments received.
Many comments, especially from renderers, meat packers, feed
companies and farmers, opposed the prohibition of ruminant protein
being fed to ruminants. The main reasons offered were the lack of
evidence of BSE in the United States, lack of scientific data to
support the proposal in the absence of
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BSE, environmental concerns, lack of an assay or other practical means
to support enforcement, and the economic hardship that would fall upon
the animal producers, slaughter facilities, renderers, feed
manufacturers, and packers. Support for such a prohibition from
consumer groups, pharmaceutical firms, scientists and veterinarians,
and some livestock organizations, emphasized a potential effect on
human health, the experience and data from the United Kingdom, and
significant economic detriment if a BSE epidemic were to occur in this
country. Other comments described a need to ensure that exported U.S.
bovine-derived products met international standards and guidelines, and
to maintain consumer confidence in the beef and dairy industries even
though those comments acknowledged that there is a minimal potential
risk of infectivity to animals and humans.
The agency requested scientific information regarding the
occurrence, transmission, etiology, pathogenesis, epidemiology, and
inactivation of TSE agents. Many comments were received that contained
useful scientific information that was considered in the preparation of
this proposed rule, as described in this preamble and supporting
documents.
Three comments suggested that the documented existence of nonBSE
TSE's, and the presence of ``downer'' cows (cows unable to walk) in the
United States is evidence that BSE is present in this country. Three
comments stated that the BSE surveillance in the United States provides
sufficient assurance that BSE does not exist in this country. A number
of persons commented on whether specific tissues, such as milk, blood,
and gelatin, should be excluded from any prohibition, with nearly all
supporting such exclusion.
The agency requested information on the economic impact of the
described action. Numerous comments provided data on volume of product
impacted, potential economic benefits, and cost of compliance to
affected persons. The data were used to develop the preliminary
economic assessment supporting this proposed rule.
The agency requested information on the environmental impact and
potential mitigating factors of the described action. Many comments
stated that alternative disposal of the prohibited carcasses would be
less environmentally safe than rendering. These and other comments were
considered in the development of the environmental assessment.
Numerous comments were received regarding the need to prohibit only
tissues that have been demonstrated to be infective. Generally, the
comments stated that tissues that have been proven to be noninfective
should be exempted. Although the agency is proposing a rule that would
prohibit the use of all ruminant-derived protein in ruminant feeds, the
agency will, as explained elsewhere in this document, consider a
partial ruminant-to-ruminant prohibition as well as a mammalian-to-
ruminant prohibition.
Many comments supported establishment of Hazard Analysis Critical
Control Points (HACCP) for the rendering industry, often with
concurrent support for current good manufacturing practices (CGMP's)
for animal-derived proteins. For example, the American Feed Industry
Association proposed a specific set of Good Manufacturing Practices for
the producers of animal protein products, and the National Renderers
Association proposed a specific HACCP regulation for rendering
operations. The agency agrees that the need for HACCP, perhaps
supported by CGMP's, for animal-derived proteins could be considered in
future rulemaking. Several comments were received regarding labeling
requirements for animal-derived proteins. The majority of the comments
supported a statement of the origin of animal-derived protein. The
agency has included a labeling requirement in the proposed rule.
V. Analysis of Alternatives
A. Overview
In addition to the proposed ruminant-to-ruminant rule, the agency
is considering alternative approaches. The alternatives include: (1)
excluding from ruminant feed all ruminant and mink materials except
those that have not been found to present a risk of transmitting
spongiform encephalopathy (partial ruminant-to-ruminant prohibition);
(2) prohibiting the use in ruminant feed of all mammalian protein
(mammalian-to-ruminant prohibition); (3) prohibiting the feeding of
materials from species in which TSE's have been diagnosed in the United
States (sheep, goats, mink, deer, and elk); (4) prohibiting the feeding
of specified sheep and goat offal, as proposed by the agency in 1994;
(5) other alternatives that might be proposed by the comments; and (6)
no action.
Analysis of the advantages and disadvantages of the options
follows. Analysis of costs and benefits, including detailed economic
analysis, also appears in section IX. of this document. Environmental
consequences are discussed in section VIII. of this document.
In determining the scope of the final rule, the agency will weigh
carefully the comments received, along with material contained in the
administrative record for this proposal and the comments submitted in
response to the ANPRM. Comments regarding the scope of the rule,
including those comments supporting other options other than the
proposed option, should be addressed accordingly.
B. Ruminant-to-Ruminant Prohibition
Advantages of this option, compared with the ``no action'' option,
are discussed in detail in section I. of this document. The advantages
of this option that are discussed in that section would apply if BSE
were to occur in this country. As discussed in separate sections that
follow, there would also be environmental and economic advantages to
the ruminant-to-ruminant option, if BSE were to occur in this country.
Disadvantages of the ruminant-to-ruminant option, compared to the ``no
action'' option, would be relevant primarily if BSE did not occur in
the United States. These disadvantages would include the time and
expense required to comply with the provisions of the regulation, and
the limited, short term environmental effects described in section
VIII. of this document.
Compared with the mammalian-to-ruminant option, the ruminant-to-
ruminant option has the advantages of being tailored more precisely to
the identified scientific concerns, and less burdensome on the affected
industries. Economic and environmental costs would be less. The major
disadvantage is that the ruminant-to-ruminant option results in more
complexity for the regulated industries, and thereby provides less
assurance of compliance. This is explained further in the discussion of
the mammalian-to-ruminant option, in section V.D. of this document.
Compared to the other remaining options, which are less
restrictive, the ruminant-to-ruminant option provides greater assurance
of protection of the public health and, if BSE were to occur in the
United States, lower economic and environmental costs. The
disadvantages relate generally to the greater economic and
environmental costs that would be incurred if BSE did not occur in the
United States.
C. Partial Ruminant-to-Ruminant Prohibition
As an alternative to the proposed ruminant-to-ruminant prohibition,
the agency is considering a partial
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ruminant-to-ruminant prohibition which would exclude from ruminant feed
all ruminant and mink materials except those that have not been found
to present a risk of transmitting spongiform encephalopathy. The
exclusions would be in addition to milk products, gelatin and bovine
blood, which are excluded in the proposed rule. Possible exclusions
include slaughter byproducts from bovine that have been inspected and
passed in inspected slaughter facilities, except the brain, eyes,
spinal cord, and distal ileum. The four named tissues would be
prohibited because they have been shown through experimental trials and
bioassays to transmit spongiform encephalopathy. The remaining tissues
have not been demonstrated to transmit spongiform encephalopathy.
This option has the advantage of having its prohibitions based
primarily on scientific information related to infectivity of specific
tissues. A number of persons who commented on the ANPRM urged the
agency to base its regulation entirely on such scientific information.
In addition, this option would likely involve lower lost sales revenues
to the affected industries, and could have fewer adverse economic
effects, than would the other options.
However, the agency has three concerns with regard to the adequacy
of this option in providing sufficient protection for the public
health. First, FDA recognizes that it may be impractical in the
slaughter and rendering processes to segregate and exclude the bovine
tissues that have not been found to present a risk. For example, USDA
has expressed reservations that separating the distal ileum from the
other intestinal offal could jeopardize a slaughter plant's ability to
meet pathogen reduction goals required under USDA's HACCP regulations.
Furthermore, regulatory enforcement of a prohibition affecting only
specified bovine tissues may be impractical in the absence of specific
diagnostic methods for identifying protein derived from such tissues.
If a partial prohibition were adopted, it would be based on a finding
that practical methods can be implemented for segregating, processing,
storing, and identifying feed materials derived from tissues that have
not been found to present a risk.
Second, this option would be inconsistent with actions taken in a
number of other nations. For example, CDC has commented that any
prohibition of lesser scope than a ruminant-to-ruminant prohibition
would place the United States out of step with the international public
health community.
Third, limiting the prohibition of tissues to those that have been
shown to be infective would not address the risk that may be presented
by other tissues. Definitive assays using methods more sensitive than
currently available methods might identify such additional tissues as
infective. The possibility of undetected low dose exposure cannot be
eliminated, particularly for tissues such as lymph nodes and spleens
which would be expected to be infective (Ref. 1).
These issues raise a substantial question as to whether the tissues
could be GRAS. To achieve the highest level of public health
protection, the agency believes that it may be reasonable to assume
that, in the absence of scientific data definitively establishing that
each tissue does not transmit spongiform encephalopathy, all ruminant
tissues present a risk of infectivity.
The agency nevertheless welcomes comments on this alternative to
the proposed ruminant-to-ruminant prohibition and especially invites
comments on possible practical means of separating the distal ileum in
compliance with USDA and industry standards, as well as the
practicality of the removal of brain, spinal cord, and eye and the
segregation of these tissues from others in the slaughter plant.
D. Mammal-to-Ruminant Prohibition
The agency received comments in support of a rule that would
prohibit the use in ruminant feed of all mammalian-derived protein. For
instance, the American Feed Industry Association, NRA, and APPI
expressed concerns that segregating certain mammalian derived proteins
from others would not be feasible because of regular commingling of
protein products at feed mills and rendering facilities. A mammalian-
to-ruminant prohibition would provide greater assurance of industry
compliance than either a partial or total ruminant-to-ruminant
prohibition because practical analytical methods exist for
distinguishing mammalian from nonmammalian proteins. Implementation of
a mammal-to-ruminant prohibition by the regulated industries would be
less complex, and would reduce the potential for contamination of
cattle feeds with material intended for feeding monogastric animals.
Contamination of cattle feeds with material intended for feeding
nonruminants was the primary reason that the United Kingdom has
prohibited mammalian proteins in the rations of cattle. A mammal-to-
ruminant prohibition would enable the continued use of Association of
American Feed Control Officials definitions for the purpose of
identifying and labeling products covered by the prohibition, and would
not require additional or new labeling. Finally, concerns were
expressed that allowing certain products containing meat and bone meal
to be used in ruminant feeds while prohibiting others would lead to
instability in financially sensitive commodity markets for animal
protein.
On the other hand, the agency is not aware of any scientific data
that establish or suggest TSE infectivity in nonruminant mammals except
in mink. Thus, excluding nonruminant tissues from ruminant feed would
be based primarily on the view that the possibility of infection of
nonruminant tissue through cross-contamination or commingling with
ruminant tissue is sufficient to preclude GRAS status for the
nonruminant tissue. However, FDA is aware that some portions of the
affected industries would prefer to segregate ruminant from nonruminant
tissues, and believe that such separation is practical. Accordingly,
the agency invites comments on the relative merits and disadvantages of
a mammal-to-ruminant prohibition compared with a total or partial
ruminant-to-ruminant prohibition.
E. Prohibition of Materials From U.S. Species Diagnosed With TSE's
(Sheep, Goats, Mink, Deer, and Elk)
This option would involve requiring that ruminants not be fed any
proteins derived from any U.S. animal species in which a TSE has been
diagnosed. This includes sheep, goats, mink, deer, and elk. This
approach would eliminate the scrapie agent, along with TME and CWD,
from ruminant feed, and thereby reduce the risk of BSE in cattle caused
by TSE transmission from other species. However, it would not prevent
the spread of BSE among cattle if BSE occurred for some other reasons,
e.g., by a spontaneous mutation in cattle or importation of animals
with BSE, and the animals were processed and subsequently included in
ruminant feed. As explained in section IX. of this document, this
option involves lower economic costs than the three options previously
described, in the absence of a BSE outbreak.
F. Sheep-Specified Offal Prohibition
The option of prohibiting only protein from specified offal from
sheep and goats for use in ruminant feed would eliminate the scrapie
agent from bovine feed. However, it would not prevent the spread of BSE
among cattle if BSE occurred for some other reason, e.g., by
[[Page 569]]
a spontaneous mutation in cattle or importation of animals with BSE,
and the animals were processed and subsequently included in ruminant
feed. The agency notes that if it were to select this option, it would
reconsider its statement in the 1994 proposed rule that sheep less than
12 months of age presented a minimal risk. Cases of scrapie in sheep as
young as 7 months have been reported (Ref. 113). Although the risk
presented by young animals may be minimal, excluding them may provide
inadequate protection to the public health. As explained in section IX.
of this document, this option involves lower economic costs than the
options described previously, in the absence of a BSE outbreak.
G. No Action
The advantages and disadvantages of this option, in relation to the
other options, are discussed in detail in section I. of this document
and in the preceding subsections of this section, as well as the
environmental and economic sections. In general, this option offers
lower economic and environmental costs if BSE does not occur in the
United States, and higher such costs (in addition to public health
implications) if BSE does occur.
VI. Description of the Proposed Rule
A. Introduction
1. Regulatory Alternatives
Typically, FDA regulates products that are of public health concern
through a combination of regulatory tools including: labeling for
appropriate use; CGMP regulations and, recently, HACCP regulations;
specifications for the product or its manufacture; and testing to
determine the presence or level of the agent of concern. Use of two or
more of these means provides for appropriate reinforcement to ensure
that the public is protected.
The agency's choice of readily available approaches for regulating
animal protein products derived from ruminant and mink tissues is
limited. For example, there are no practical tests for the presence of
the TSE agent or of ruminant protein in animal feed. No commercial
method of deactivating the TSE agent in animal protein products has
been scientifically validated as effective. None of the agency's CGMP
or HACCP regulations apply to this situation. Labeling requirements can
be used but, by themselves, do not meet the agency's regulatory
objectives.
2. The Regulated Industry
Often, the industry that manufactures and distributes an FDA-
regulated product is fairly easily characterized. This facilitates
regulation. That is not the case for animal protein products, as the
following brief overview makes clear.
Renderers collect animal tissues from a variety of sources, and
process these tissues into both protein and nonprotein products. The
renderers may be specialized (packer/renderer) or independent. The
packer/renderer, which involves a renderer associated with a large
slaughter operation, specializes in one species--primarily cattle,
swine, or poultry. Thus, whether the packer/renderer handles ruminant
materials is fairly easily determined. The independent renderer, on the
other hand, obtains a variety of raw materials ranging from restaurant
scraps to byproducts from multi-species slaughtering operations to dead
animals obtained from farmers. Typically, the independent renderer does
n