Substances Prohibited From Use in Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed

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

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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:

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;

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

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

[[Page 564]]

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

[[Page 567]]

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

[[Page 568]]

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

not have a practical method to separate incoming ruminant from

nonruminant materials, and thus commingles both ruminant and

nonruminant materials in the rendering process. The rendered product is

typically designated ``meat and bone meal,'' but rendering operations

produce a variety of other products. Renderers sell their products to

animal protein blenders, animal feed manufacturers or pet food

manufacturers. Virtually all rendered material at present is used

ultimately for pet food or the feed of livestock or poultry.

Animal protein blenders mix animal and plant protein materials to

meet a protein guarantee stated on the label, and to make a balanced

nutritional product. Typically, the blender does not separate ruminant

from nonruminant animal protein in its blending operation, although it

may keep mammalian, poultry, fish and soybean meal protein separate at

least in the initial stages. The blender sells its products to feed or

pet food manufacturers. Some renderers also blend animal protein

products.

Feed manufacturers use the protein material to make a complete feed

(ready to be feed to animals), or a concentrated feed that needs to be

further diluted (blended) before it can be fed to animals. The feed may

be manufactured by an off-farm miller, or on the farm. Feed that is

manufactured off-farm may be sold to one or more persons (for blending

and/or further distribution) before reaching the farm.

Farmers that feed animals typically raise one species, but may have

more than one (including both ruminants and nonruminants). Only about

10 percent of all animal protein products are fed to ruminants (mainly

cattle) but approximately half of all animal protein products comes

from ruminants.

3. Enforcement Considerations

The industry scenario described in the preceding section presents

unique enforcement challenges. The agency is aware, from the comments

to the ANPRM and other sources, of concerns that the regulatory impact

be minimized. The agency is also aware of the need to provide incentive

for innovation, e.g., in testing methodology and manufacturing

technology, that would reduce the need for regulation. Finally, the

agency is aware of the need, in designing a regulatory program, to

acknowledge the different circumstances that exist in the industries

previously described.

Therefore, the agency has designed a proposed regulatory scheme

using the following principles. First, the agency has identified

minimally necessary requirements to meet its regulatory objectives. The

agency's goal is to apply risk management principles that minimize

risk. Second, the proposed regulation applies greater restriction where

the risk is greater--for example, where a firm handles both ruminant

and nonruminant materials and intends to keep them separated. Third,

the agency intends to rely on normal business records for much of the

documentation it needs.

A fourth and most important principle concerns the related

objectives of flexibility and providing incentives to reduce

recordkeeping and labeling requirements. The proposed regulation

provides for the reduction or elimination of recordkeeping and labeling

requirements, upon the development of methods for detection,

deactivation, or verification of product identity. These provisions are

described further in the discussion that follows.

Industry-wide adoption of scientific advances including, or in

addition to, those specified in the regulation, could ultimately lead

to amendment or revocation of any final regulation. An example of an

additional method would be the development of a practical method to

detect the presence of ruminant protein in animal protein products or

feed, which could be used for quality control by firms that separate

ruminant from nonruminant protein, and by firms downstream from

renderers.

Similarly, research leading to identification of the TSE causative

agent and the etiology of BSE, and the characterization of the zoonotic

nature of animal TSE's, could also lead to amendment or revocation of

any final regulation.

[[Page 570]]

The agency has tentatively decided not to place any record keeping,

labeling or other specific requirement on firms that handle only

protein materials from nonruminant sources. An example would be a

rendering operation that is part of a swine slaughter operation.

However, if these firms would use or intend to use animal protein

products containing ruminant tissues in ruminant feed, or caused such

use or intended use, the feed would be adulterated under the act.

The agency has also tentatively decided to require farmers (those

responsible for feeding ruminant animals) only to make available copies

of invoices and labeling for feed purchases. Farmers would not be

required to maintain written procedures for handling animal protein

products. These minimal requirements would apply even if the farmers

were feeding both ruminant and nonruminant animals. Purchase records

would be used primarily for traceback purposes. Because only minimal

requirements would be placed on farmers, the proposed rules require

that labeling for the animal protein and feed products caution against

feeding the products to ruminants. Comments on these two tentative

decisions are encouraged.

B. Outline of the Proposed Regulation

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 a requirement to provide FDA with access to sales and purchase

invoices, for compliance purposes. For example, an invoice obtained

from a feed manufacturer for a protein product not labeled with the

cautionary statement could be used to trace back to the supplying

renderer to ensure that it manufactures and distributes animal protein

product from nonruminant sources.

Firms (renderers, blenders, and feed manufacturers and

distributors) that handle animal protein products from both ruminant

and nonruminant sources, and that intend to keep the products separate,

would have certain additional requirements related to their source of

nonruminant material; the need for separate facilities or cleanout

procedures; and the need for SOP's. The same requirements would apply

to firms that handle feeds containing animal protein products from both

ruminant and nonruminant sources, and that intend to keep the feeds

separate. Requirements would be greater for these operations because of

the greater risk they would present for the possibility of ruminant

protein being fed to ruminants.

The proposed rule provides that some or all of the regulatory

requirements would not apply if innovations such as development of test

methods and deactivation processes for TSE agents were scientifically

validated and put into commercial use. Provisions for use of such

methods do not imply that the agency believes that such agents are or

will be in the animal protein products. The objective is to minimize

the risk that the agent would occur in the products, regardless of the

level of risk. Certain minimal but additional requirements would be

imposed in such circumstances. For example, because the innovations

likely would be applied by renderers, the renderers would need to

certify to downstream customers that the methods were being utilized.

Section 589.2000(a) presents definitions of certain words used in

the regulation. The definition of ``protein derived from ruminant and

mink tissues'' excludes blood from bovines, milk proteins, and

gelatins. Thus, those products are not subject to the regulatory

provisions of the regulation. The proposed rule does not apply to any

nonprotein animal tissues such as tallow or other fats. ``Renderer''

includes firms, not traditionally considered to be included within the

definition of that term, but that collect animal tissues from various

sources and subject them to minimal processing before offering the

materials for use in animal feed. Also, ``feed manufacturers'' is

defined to include both off-farm and on-farm feed manufacturing

operations.

Section 589.2000(b) declares that protein derived from ruminant and

mink tissues is not GRAS when intended for use in the feed of ruminant

animals. The use or intended use of such material in ruminant animal

feed causes the feed to be adulterated.

Section 589.2000(c) establishes regulatory requirements for

renderers that manufacture products that contain or may contain protein

derived from ruminant and mink tissues. (``May contain'' allows for the

fact that the renderer may not be able to determine the species of some

incoming material). These renderers typically process both ruminant and

nonruminant materials, but do not attempt to separate ruminant from

nonruminant materials. Section 589.2000(e) covers renderers that intend

to separate such materials. As mentioned, renderers that process

exclusively nonruminant materials are not covered by the specific

requirements of the regulation. Section 589.2000(c) applies to animal

protein products intended for use in animal feeds, as well as animal

feeds containing such products.

Two requirements would be placed on renderers covered by

Sec. 589.2000(c). First, they would be required to label their products

to indicate that they contain (or may contain) protein derived from

ruminant and mink tissues, and that the materials should not be fed to

ruminant animals or used to manufacture feed for ruminants. Second, the

renderers would be required to maintain copies of sales invoices for

all their animal protein products, and to make those copies readily

available for inspection. As an example, FDA would use the invoices to

follow up with customers to verify that the customers are not using the

products to manufacture ruminant feed. Because sales invoices are

normal business records, the agency believes that the additional burden

imposed by this requirement would be minimal.

Section 589.2000(c) renderers would be exempted from the labeling

and record requirements if they used a manufacturing method that

deactivates the agent that causes TSE's, or a test method that detects

the presence of the agent that causes TSE's. Both methods would have to

be validated by FDA, and made available to the public. The regulation

would require ``routine'' use. That is, renderers would be required to

use the test method on all incoming material or in each batch it

manufactures.

Section 589.2000(c) renderers would be exempted from the record

requirements (but not the labeling requirement) if they used a safe

method to mark the presence of the materials. The marking could be

visible to the naked eye, e.g., through use of a dye, or by a nonvisual

means. One ANPRM comment recommended use of a colored uniform fine iron

product to identify specific feed ingredients. If the marking is not

visible, the marking agent must be detectable by a method that has been

validated by FDA, and made available to the public. The mark must be

permanent, i.e., it must be visible in mixed feed as used on the farm.

Section 589.2000(d) establishes regulatory requirements for persons

other than renderers and persons responsible for feeding ruminants that

handle animal protein products or feeds containing such products. This

includes protein blenders, and feed manufacturers and distributors.

However, as in the case of renderers, those firms that would otherwise

be included in Sec. 589.2000(d) but that handle both ruminant and

nonruminant

[[Page 571]]

materials and intend to separate the materials would be covered by

Sec. 589.2000(e) instead. Protein blenders, and feed manufacturers and

distributors, that handle only nonruminant materials are excluded from

the regulatory requirements of the proposed rule.

Persons covered by Sec. 589.2000(d) would be subject to the same

requirements as renderers, i.e., labeling and records. The records

would include invoices both to cover purchases and sales of animal

protein products and feeds containing those products. For on-farm

mixers, production records could be substituted for sales invoices.

Section 589.2000(d) firms would be exempt from the labeling and

record requirements if they purchased materials from renderers that

certified the use of deactivation or detection methods as described in

Sec. 589.2000(c). They would also be exempt from the labeling and

record requirements if they purchased materials from persons other than

renderers who certified that they purchased materials from renderers

who certified the use of deactivation and detection methods as

described in Sec. 589.2000(c). Paragraph (d) firms would also be exempt

if they used the deactivation or detection methods described in

Sec. 589.2000(c), where use of such method is appropriate for the

particular firm.

Paragraph (d) firms would be exempt from the record requirements if

they purchased visibly-marked materials, or purchased from renderers

that certified the use of marking methods as described in

Sec. 589.2000(c). They would also be exempt from the record

requirements if they used the marking methods as described in

Sec. 589.2000(c).

Section 589.2000(e) establishes regulatory requirements for

renderers, protein blenders, feed manufacturers and distributors, and

independent haulers that handle both ruminant and nonruminant

materials, and intend to keep the products separate. Section

589.2000(e) establishes four kinds of requirements. First, the firms

would have the same labeling and recordkeeping requirements as

specified in paragraphs (c) and (d) of Sec. 589.2000, except that the

labeling requirement would apply only to the ruminant and mink

materials. Second, a renderer's source of nonruminant protein materials

would be limited to single-species facilities, i.e., facilities

slaughtering only swine. A renderer could purchase nonruminant protein

from more than one single-species facility. The agency believes that

this restriction is necessary because of its understanding that it is

not likely to be feasible for mixed species slaughterhouses to

undertake the additional compliance costs, and possibly additional

facility costs, that would be required to assure separation of ruminant

and nonruminant materials. The restriction would therefore help assure

that enforcement of Sec. 589.2000(e) would be practicable. However, the

agency specifically requests comments on this provision.

Third, the firms would be required to establish separate equipment

and facilities for the two kinds of materials, or cleanout procedures

to prevent cross contamination. Fourth, the firms would need to

establish written SOP's specifying the cleanout procedures, if used,

and specifying procedures for separating the materials from the time of

receipt until the time of shipment. Although Sec. 589.2000(e) applies

to several different kinds of firms, the agency's preliminary

expectation is that only feed manufacturers and distributors will find

it feasible to separate ruminant and nonruminant materials. As an

example, a feed manufacturer might obtain ruminant materials from an

independent renderer and swine materials from a packer/renderer, and

use these materials to manufacture feed both for ruminants and

nonruminants. The feed manufacturer would be required to meet the

criteria listed previously, including the use of separate equipment and

facilities or cleanout procedures, and the establishment of SOP's. The

requirements of Sec. 589.2000(e) would be applicable in the

transportation process, whether the material is hauled by the feed

manufacturer or another party such as an independent hauler. The

requirement for separate facilities, procedures or SOP's would not

apply to a firm, e.g., a feed mill or hauler, that handles only

nonruminant materials, or only ruminant materials. Nor would it apply

to a firm that handles both ruminant and nonruminant materials but does

not attempt to separate the two kinds of materials.

The paragraph (e) firms would be exempted from the labeling and/or

record keeping requirements, and the requirements related to sourcing,

facilities and SOP's, if they meet the appropriate criteria for

exemption. That is, renderers covered by Sec. 589.2000(e) would be

exempt from the labeling and recordkeeping requirements if they used

deactivation or detection methods, and from the recordkeeping

requirements if they used marking methods. Blenders and feed

manufacturers and distributors would be exempt in a similar manner.

Section 589.2000(f) establishes requirements for those who are

responsible for feeding ruminant animals. The only requirement

contained in this paragraph is that those persons make available to FDA

copies of purchase invoices and labeling for all incoming feeds.

However, Sec. 589.2000(f) does not apply to the feed manufacturing

portion of farms and feedlots that have on-farm feed manufacturing

operations. Section 589.2000 (d) and (e) would apply in those

instances. Furthermore, persons who feed or intend to feed ruminant

protein to ruminant animals would be subject to regulatory action for

using or intending to use an unapproved feed additive as established in

Sec. 589.2000 (b).

Section 589.2000(g) establishes that violations of Sec. 589.2000

(c) through (f) would cause animal protein products or feed containing

animal protein products to be adulterated under sections 402(a)(4) or

402(a)(2)(d) of the act, or misbranded under section 403(a)(1).

Section 589.2000(h) establishes inspection and records retention

requirements for persons covered by section 589.2000 (c) through (f).

Records that are required under those paragraphs would need to be kept

for a minimum of 2 years. The agency believes that this time period is

adequate for purposes of verifying compliance with the regulation's

procedural requirements. The agency invites comments on the need for a

longer retention period related to the BSE incubation period,

especially the practicality of using such records for epidemiologic

investigation.

Section 589.2000(h) also requires that written procedures required

by the regulation be made available for inspection and copying by FDA.

The written procedures referred to are those specified in

Sec. 589.2000(e)(3). Affected firms would be required to have a copy of

the current procedures available at all times.

VII. Specific Protein Sources

A number of comments discussed the exemption of certain tissues,

including fluids, from any prohibitory rule. Most commentors favored

the exemption of one or more tissues, including milk products; blood

products; skeletal muscle and gelatin; and a variety of other tissues

including both protein and nonprotein materials. Most of the comments

cited published studies as well as positions taken by the European

Union, European Commission, WHO and the government of France. The

agency's comments on the status of milk, gelatin and blood follow. In

addition, we discuss a comment on the use of canine and feline derived

protein.

[[Page 572]]

A. Milk Proteins

Data available to the agency suggests that milk proteins do not

transmit the TSE agent. Research with oral exposure, intracerebral, and

intraperitoneal administration of milk or mammary glands from BSE-

infected bovine to normal and BSE-sensitive mice has not demonstrated

the development of TSE's (Refs. 42 and 52). An expert group under the

auspices of WHO recommended that all countries prohibit the use of

ruminant tissues in ruminant feed. The WHO expert group also declared

that milk and milk products, including such products from the United

Kingdom, are safe for human consumption. In addition, OIE has

recommended, because of lack of infectivity, that restriction of import

or transit of milk products from healthy animals from BSE countries

need not be instituted. Therefore, the proposed rules provide that

protein derived from ruminant tissues does not include milk proteins

derived from bovine, ovine, caprine, and cervine.

B. Gelatin Proteins

Data available to the agency suggest that gelatin does not transmit

the TSE agent. The WHO has concluded that gelatin in the food chain is

considered to be safe, as the conventional manufacturing process for

gelatin has been demonstrated to significantly inactivate any residual

infective activity that may have been present in source tissues (Ref.

2). FDA concurs with this statement and the scientific information on

which it is based. Thus, the proposed rule excludes gelatin from

protein derived from ruminant tissues.

C. Blood Meal Proteins

Data available to the agency suggests that bovine blood components

do not transmit the TSE agent (Refs. 56, 78, and 94). Therefore, the

proposed rule does not include blood meal from bovine as a protein

derived from ruminant tissues.

D. Canine and Feline Derived Proteins

One comment suggesting that canine- and feline-derived proteins

should not be fed to ruminants because of the finding of FSE in

domestic cats in the United Kingdom. The agency is also aware of an

ethically-based objection by some to the rendering of the carcasses of

pet animals. TSE has not been diagnosed in dogs or other canines. FSE

has not been diagnosed in the United States. The agency has considered

the information provided by the comments and the published scientific

literature (Refs. 26 and 27), and has preliminarily determined that

there is no measurable risk of the spread of TSE's from canine- or

feline-derived proteins to ruminants in the United States. However, the

agency is inviting further comment on this issue.

VIII. Environmental Impact

FDA has carefully considered the potential environmental effects of

this proposed rule and of five possible alternative actions. In doing

so, the agency reviewed ANPRM comments submitted by a number of

organizations and individuals. The comments were mostly concerned with

the volume of material (e.g., dead animals and slaughter byproducts)

that would be affected, and the nonrendering or rendering alternative

means by which these materials could be disposed of, or utilized,

safely. Comments suggested a number of uses for the processed

materials, other than ruminant feed, including use in nonruminant

animal feed and fertilizers, and disposal methods such as on-farm

burial, landfilling, and incineration.

In the environmental assessment that accompanies this proposed

rule, FDA evaluated the environmental consequences of six different

options. These included: No action; ruminant and mink-to-ruminant

prohibition (the proposed action); partial ruminant and mink-to-

ruminant prohibition; mammalian-to-ruminant prohibition; prohibition of

feeding tissues from any animal species in which TSE has been detected

in the United States; and sheep and goat specified offal prohibition.

The environmental assessment considered each of the alternatives in

the context of two scenarios. The first assumes that BSE does not occur

in the United States, regardless of the alternative selected. The

second scenario assumes that BSE does occur in the United States, again

regardless of the alternative selected. In the first scenario, the

assessment considered environmental impacts related to on-farm

disposal, landfill, incineration, and industry wastes produced. The

second scenario considered environmental impacts related to production

losses and impacts, wildlife exposure, on-farm disposal, landfill, and

incineration.

In the first scenario (no BSE), the ``no action'' alternative does

not have environmental consequences because it is the ``status quo'' or

baseline alternative. Environmental impacts for the other alternatives

ranged from slight to moderate increases in environmental effects. For

the proposed option (ruminant-to-ruminant) there would be moderate

increases in environmental effects from on-farm disposal and landfill

use, and slight increases in the other effects. Increases in waste

disposal (on-farm, landfill, etc.) are anticipated to be temporary,

however, as the markets are expected to adjust quickly to the more

restricted uses of the ruminant materials.

In the second scenario (occurrence of BSE), the greatest negative

environmental effect would occur in the case of the ``no action''

alternative. This is because the likely spread of the BSE agent through

animal feed before the first BSE case is diagnosed would result in

disposal of large numbers of animals by means other than rendering.

Similar large impacts would occur with the sheep and goat, and TSE

animal, options. Minimum environmental consequences would occur with

the proposed option (ruminant-to-ruminant), because the spread of the

BSE agent would have been controlled. Minimum to small effects would

result from the remaining two options, partial ruminant prohibition and

mammalian-to-ruminant prohibition.

The agency has concluded that the proposed rule will not have a

significant impact on the human environment, and that an environmental

impact statement is not required. FDA's finding of no significant

impact (FONSI) and the evidence supporting that finding, contained in

an environmental assessment (EA) prepared under 21 CFR 25.31, may be

seen in the Dockets Management Branch (address above) between 9 a.m.

and 4 p.m., Monday through Friday. FDA invites comments and submission

of data concerning the EA and FONSI.

IX. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),

and under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive

Order 12866 directs agencies to assess all costs and benefits of

available regulatory alternatives and, when regulation is necessary, to

select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; and distributive impacts and equity). The Regulatory

Flexibility Act requires agencies to analyze regulatory options that

would minimize any significant impact of a rule on small entities. The

Unfunded Mandates Reform Act requires that agencies prepare an

assessment of anticipated costs and benefits before proposing any rule

that may result in an annual expenditure by State, local, and tribal

governments, in the aggregate, or by the private sector, of

$100,000,000 (adjusted annually for inflation). FDA

[[Page 573]]

concludes that this proposed rule is consistent with the principles set

forth in the Executive Order and in these two statutes.

A study of the impacts on industry of the proposed rule (on file

with the Docket Management Branch (Ref. 114)) conducted for FDA by the

Eastern Research Group (ERG), a private consulting firm, and the

discussion in the remainder of this section, demonstrate that the

proposed rule constitutes an economically significant rule as described

in the Executive Order. The agency has further determined that the

proposed rule will have a significant impact on a substantial number of

small entities. The proposal makes no mandates on government entities

and is estimated to result in aggregate net annual costs ranging from

$21.4 to $48.2 million to the private sector.

A. The Need for Regulation

Although BSE has not been diagnosed in the United States, the need

for regulatory action is based on a need to protect U.S. livestock from

the risk of contracting BSE. In its guidelines for the preparation of

Economic Impact Analyses, the Office of Management and Budget (OMB)

directs Federal regulatory agencies to determine whether a market

failure exists, and if so, whether that market failure could be

resolved by measures other than new Federal regulation. In this

instance, private incentive systems for both suppliers and purchasers

may fail in markets for cattle, rendering, and ruminant feed. The

potential for market failure among the suppliers in these sectors

results from the externality that could be created by individual

suppliers imposing economic hardships on other suppliers within the

industry. The potential for market failure among the purchasers results

from the inadequate information that would be available to purchasers

of potentially infective products.

Any renderer, feed manufacturer, or cattle producer that permits

animal protein derived from ruminants and mink to be placed in ruminant

feed increases the risk that other renderers, feed manufacturers, or

cattle producers will suffer the severe economic consequences that

would follow an outbreak of BSE in the United States. The industry is

aware of this risk, as evidenced by the existence of voluntary programs

aimed at reducing the transmission of the infectious agent. These

include an adult sheep rendering ban recommended by the NRA, a

recommended ban on the feeding of rendered ruminant protein to

ruminants by the NCBA and others, and scrapie-free certification

programs by individual sheep producers. Although the benefits of such

programs--the reduction or elimination of the risk of an outbreak of

BSE and the increased consumer confidence in the safety of the

industries' products--accrue to all members of these industries,

compliance with these measures is incomplete, because individual

noncomplying members can avoid the costs of risk reduction measures

while still enjoying the benefits of compliance by others in the

industry.

If purchasers could easily identify the risks of infective agent

contamination associated with products from specific suppliers, they

could more easily take defensive actions to reduce these risks (e.g.,

refusing products from cattle known to have consumed specified ruminant

proteins). Purchasers are unlikely to obtain the information they need,

however, for several reasons. First, the long incubation period for BSE

creates a lag between the actual onset and the recognition of the

disease and could lead to a suboptimal level of risk prevention by the

concerned parties during the incubation period. By the time the first

signs of disease are observed, many animals may have been already

exposed. Moreover, renderers sell their product to feed manufacturers

who frequently combine proteins from many different plant sources and

animal species to produce cattle feed. Ruminant producers, therefore,

have no sure way of knowing whether a particular batch of feed is free

from potentially infective proteins and cannot easily avoid purchasing

risky feed. Finally, if renderers or feed manufacturers do not believe

that BSE is an important threat they may choose not to take preventive

action, regardless of the risk levels perceived by epidemiological

experts or consumers.

B. Benefits

The proposed rule would reduce the risk of an outbreak and

subsequent proliferation of BSE disease in the United States. It may

also forestall the loss of consumer confidence in the U.S. beef market

due to concerns about BSE and its implications. Thus, the benefits of

this proposal would include the value of reduced risks to human and

animal health and to the economic stability of the U.S. livestock and

livestock dependent industries compared to the ``no action'' option. In

technical terms, these benefits measure the expected value of the

future disease-related costs that might be averted by the proposed

rule. Specifically, they are calculated as a product of three factors:

(1) The probability that, in the absence of this rule, BSE would be

introduced and proliferate in the United States, (2) the costs, both

direct and indirect, that would be associated with the spread of BSE in

the United States, and (3) the extent to which the proposed rule would

reduce the likelihood of BSE proliferation.

BSE has not been detected in the United States and the probability

that it currently exists is remote. Nevertheless, it is possible that

BSE could develop in the future. Once developed, BSE could remain

undetected for several years because of its long incubation period and

because, at present, it can be diagnosed reliably only by microscopic

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