UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

SUBJECT:

FROM:

TO:

April 29, 2004

(Supercedes March 2, 2004 memorandum)

Consideration ofPrions as a Pest under FIFRA

Susan B. Hazen ~L-~~. ~1__—~

Principal DeputyAssistant Administ~jor

Office ofPrevention, Pesticides, and Toxic Substances

The Record

The attached document embodies my decision on September 10, 2003, that prions should

be considered to be a pest underthe Federal Insecticide, Fungicide, and Rodenticide Act, as

amended (FIFRA).

Attachment
Record of Decision by Principal Deputy AAIOPPTS Regarding

Status of Prions under FIFRA

April 29, 2004

Supercedes March 2, 2004

Summary ofDecision

On September 10, 2003, Susan Hazen, Principal Deputy Assistant Administrator for the

Office ofPrevention, Pesticides, and Toxic Substances (OPPTS), decided that prions should be

considered to be a “pest” under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA),

as amended. She said a multi-part approach should be followed:

1. The Agency should proceed on the basis that prions are pests under FIFRA.

2. Applications forregistration and for emergency exemptions for products for use

against prions should be examined and appropriate decisions made.

3. EPA should follow an appropriate regulatory process to make explicit the Agency’s

interpretation that prions are pests because they share many ofthe characteristics of

deleterious microorganisms. At the same time, EPA should exercise its authority to

declare prions to be a form ofplant or animal life which is injuriousto health orthe

environment and which is a pest under Section 25(c)(1) ofFIFRA.

4. Coordinate with other EPA offices and other federal agencies as necessary (e.g.,

USDAIAPHIS).

As background forthis decision, OPPTS evaluated a large body of available scientific

information about prions, and consulted with other EPA offices, including the Office ofGeneral

Counsel, the Office ofResearch and Development, and the Office OfEnforcement Compliance

and Assurance. This document summarizes the factual basis and the rationale forthe decision

that prions should be considered to be pests.

Background on Prions

Certain proteins found in cells ofthe central nervous system ofhumans and animals

appear to exist in both a normal(correctly folded), noninfectious form and in an abnormal

(misfolded), infectious form. The normal proteins, which are believed to be involved in

cell-to-cell communication, are designated as PrP. The abnormal, infectious proteins are

called “prions,” and are designated either as PrPSC (for the prion isoform found in

sheep—scrapie) or PrPTeS (for “resistant” prion isoforms) (1, 2). Dr. Stanley Prusiner, who

won a Nobel Prize for identifying prions, initially described prions as “proteinaceous

infectious particles that resist inactivation by procedures which modify nucleic acids” (3).

He later described prions as proteinaceous particles that lack nucleic acids (4).

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• There is a growing consensus that prions can invade and attack the central nervous

systems ofboth animals and man, causing fatal diseases called “transmissible spongiform

encephalopathies” (TSE) (5). In order to demonstrate that prions are the infectious agents

responsible for TSEs, researchers had to establish several principles ofinfectivity. First,

the prions had to be isolated from infected hosts with known cases ofprion disease. Then

the prions had to be re-inoculated into susceptible hosts. Finally, the prions had to be reisolated from the susceptible hosts following the onset ofdisease. Following these

principles, researchers have developed persuasive evidence-that prions are the infectious,

causative agents for TSEs such as Scrapie in sheep, Bovine Spongiform Encephalopathy

(BSE) in cattle, and Creutzfeldt-Jakob Disease (CJD) in humans. BSE is of considerable

public health interest and concern because it has been associated with the variant form of

CJD; both have no known cure and can take many years to manifest symptoms.

Symptoms in humans are severe and can include personality change, dementia and ataxia

(loss ofmotor skills). Once symptoms are exhibited, death usually occurs within six

months to one year.

• Prions appear to be most infectious when they come into direct contact with susceptible

tissue. They may be transmitted from host to host by contaminated surgical instruments,

direct transfer ofinfected tissue, or the ingestion ofcontaminated food orfeed. Cases of

TSE diseases appear to have resulted in humans and animals via all three ofthese routes

ofinfectivity. For example, BSE appears to have been transmitted in herds throughout

England because offal, bones and wastes from infected carcasses were processed and

incorporated into animal feeds. Variant CJD (vCJD) then appears to have been

transmitted from cattle to humans through ingestion ofBSE prion-contaminated beef

products.

• Prions (while not viruses) share characteristics with viruses, which are listed in FIFRA

Section 2(t)(2) among the things that the Administrator may declare to be pests pursuant

to FIFRA section 25(c)(1). Prions, like viruses, lack certain characteristics commonly

associated with life (and are not currently considered to be “living”): theyneither eat nor

excrete and have no apparent metabolic activity on their own. Neitherprions norviruses

reproduce sexually or asexually, however, both replicate through infection ofliving

tissue. Prions and viruses differ in several ways. First, prions appear to contain only

protein and lack genetic material, whereas viruses contain proteins and either DNA or

RNA. Also, prions appear to propagate by inducing certain normal proteins present in

host cells to fold into the same abnormal, infectious form. In contrast, viruses attach

themselves to host cells, utilize the host’s genetic material, and replicate using the host’s

mechanisms forreproducing cells. Despite the difference in the mechanisms of

replication, both prions and viruses utilize a host or host tissue, both disrupt normal cell

functi?n, both increase in number in the host, and, in the process, both produce disease.

• Prions are extremely resistant to inactivation by ultraviolet light, irradiation, boiling, dry

heat, formalin, freezing, drying and changes in pH. Methods for inactivatingprions in

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infected tissues orwastes include incineration at very high temperatures and alkaline

hydrolysis. There is no known method ofinactivating prions within living host tissue.

• There are currently no EPA registered products approved for inactivation ofCWD agents

from contaminated surfaces. Several states in Region 8 have applied for an emergency

exemption under FIFRA for the use of a commercial aqueous acid phenolic product for

inactivation ofthe CWD agent on contaminated surfaces. Ifan emergency exemption is

granted, the product must be used according to the conditions ofthe exemption. The

Centers for Disease Control and Prevention (CDC) and the World Health Organization

recommend sodium hydroxide and sodium hypochiorite (bleach) forinactivating TSE

agents on surfaces (6). However, these chemicals would need to be granted an exemption

(or a registration) prior to sale and distribution in the U.S. with claims for this use.

Rationale

The Principal Deputy AAIOPPTS decided that prions should be considered to be a

“pest” under FIFRA for the following reasons, based on the information presented to her:

• As discussed above, prions are unquestionably injurious to the health ofhumans and

other animals. They cause TSE diseases that attack the nervous system, inflict

irreversible damage, and are always fatal to infected animals and humans. These

infectious particles, once introduced into an animal or human, induce neuronal cells to

replicate otherprions that in turn attack other neuronal cells, primarily in the central

nervoussystem. Finally, prions are considered among the most difficult ofall biological

entities to inactivate and few methods are available for effectively destroying them.

• FIFRA section 2(t) provides that “~tjhe term ‘pest’ means (1) any insect, rodent,

nematode, fungus, weed, or(2) any other form ofterrestrial or aquatic plant or animal life

or virus, bacteria, or other micro-organism (except viruses bacteria, or othermicroorganisms on orin living man or other living animals) which the Administrator declares

to be a pest under section 25(c)(1).” Thus, Congress has determined that all members of

the classes listed in section 2(t)(l) are pests, and has in addition authorized EPA to

declare as pests members ofthe classes listed in section 2(t)(2). Section 25(c)(1)

authorizes the Administrator, after notice and opportunity for hearing, “to declare a pest

any form ofplant or animal life (other than man and other than bacteria, virus, and other

micro-organisms on orin living man or other living animals) which is injurious to health

orthe environment.” Pursuant to section 25(c), EPA promulgated the rule now codified

at 40 C.F.R. §152.5, where it declared any microorganism to be a pest under

circumstances that make it deleterious to man orthe environment (other than those on or

in living man or other living animals). As explained below, since prions share many of

the characteristics ofdeleterious microorganisms, they canbe considered to be pests

inasmuch asthey are clearly deleterious to man and the environment.

• Microorganisms are defined differently in different dictionaries. The American Heritage

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Dictionary (7) defines “microorganism” as “~am animal or plant ofmicroscopic size,

especially a bacterium or a protozoan.” Dorland’s Medical Dictionary (8) defines

“microorganism” as “a minute living organism, usuallymicroscopic. Those of medical

interest are bacteria, rickettsiae, viruses, molds, yeasts, and protozoa.” This definition

explicitly considers viruses to be living organisms, so prions might fall within its scope as

well. Webster’s Collegiate Dictionary (9) defines “microorganism” as “an organism of

microscopic or ultramicroscopic size;” and “organism” as “1: a complex structure of

interdependent and subordinate elements whose relations and properties are largely

determined by their function in the whole.” Whether prions may be considered to be a

“microorganism” is subject to interpretation. Prions might reasonablybe considered to

share many ofthe characteristics ofmicroorganisms because they mayhave “a complex

structure ofinterdependent and subordinate elements whose relations and properties are

largely determinedby their function in the whole,” and because they are “ofmicroscopic

or ultramicroscopic size.”

• Another view is that prions are a “form of... plant or animal life” because they originate

in living organisms, they replicate within those host organisms by converting parts ofthe

host into prions, and they can be transmitted to other host organisms. Like viruses, prions

lack certain characteristics commonly associated with life, however, prions share with

other pests the characteristics ofbeing able to increase in number and spread by attacking

host organisms, with catastrophic harm to the host organism. In addition, prions consist

ofprotein, one ofthe critical components oflife. Thus, one can reasonably argue that

prions can be considered to be a “form ofplant or animal life” along with viruses, bacteria

and other microorganisms. Ifso, the Administrator might declare these forms oflife to be

pests pursuant to section 25(c)(l).

• Under FIFRA, EPA regulates a wide range of pesticide products that are intended to

prevent or destroymicroorganisms. Such products include biocides, sanitizers,

disinfectants, and sterilants. EPA’s charge under FIFRA is to assure that “no

unreasonable adverse effects” will result from the use ofthese products. In particular, for

products intended to kill microorganisms ofpublic health significance, the EPA reviews

product performance (efficacy) data to determine that the product will kill the target

microorganisms. Ifproducts claimed to prevent or destroy prions were not regulated

under FIFRA, it is not clear that an adequate mechanism for regulatory oversight ofthe

safety and efficacy ofsuchproducts could be put into place in a timely manner to address

a public health crisis. Absentregulatory oversight such as that provided under FIFRA,

persons who need to control prions would have no assurance that products claiming to

control prions were either effective or safe.

• In 2002, pursuant to FIFRA section 28(d), EPA issued a list ofpests of “significant public

health importance” in Pesticide Registration Notice 2002-1. This list, which included

prions, was compiled in coordination with the Departments of Health and Human

Services and Agriculture, and issued afterpublic notice and opportunity to comment.

There were no comments objecting to EPA’s inclusion ofprions on this list ofpests of

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significantpublic health importance.

• For the foregoing reasons, the Agency believes that prions share enough characteristics of

either “micro-organism” orof “form of... plant or animal life” to fall within the scope of

FIFRA section 2(t)(2). The Administrator has declared deleterious microorganisms to be

pests in 40 C.F.R. §152.5, and the Administrator might also declare prions to be forms of

life which are injuriousto health or the environment and which arepests, pursuant to

FIFRA section 25(c)(l).

• The reasonableness of EPA’s decision to consider prions pests is supported by the fact

that Congress has also considered prions to be pests — albeit in the context of animal

health legislation. The Animal HealthProtection Act (AHPA) of2002 includes prions

within the definition of a “pest.” That statute states that a pest is: “any ofthe following

that can directly orindirectly injure, cause damage to, or cause disease in livestock:..(E)

A virus or viroid...(F) An infectious agent or other pathogen...(I) A prion... (K) Any

organism similarto or allied with any ofthe organisms described in this paragraph.”

This definition is more expansive than the definition of“pest” in FIFRA, which includes

“(1) any insect, rodent, nematode, fungus, weed, or(2) any other form ofterrestrial or

aquatic plant or animal life or virus, bacteria, or other micro-organism.., which the

Administrator declares to be a pest under section 25(c)(l).”2

• Finally, the definition of“pest” as it appears in FIIFRA Section 2(t)(2) has not been

changed by Congress since 1972. The existence ofprions was widely not postulated or

demonstrated until well after that date. Given Congress’ inclusion ofviruses in that

definition, even though viruses are not living microorganisms, it is reasonable to suggest

that the intent ofCongress was that EPA, under FIFRA, should regulate deleterious forms

ofanimal or plant life that share the characteristics ofviruses and other microorganisms.

Conclusion

7 U.S.C. §8302(13). This statute was passed in order to effectuate the finding of

Congress that “~T]heprevention, detection, control and eradication ofdiseases and pests of

animals are essential to protect... the health and welfare ofthe people ofthe United States.” See

7 U.S.C. §8301(2).

2 ~ U.S.C. §136(t).

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The Principal Deputy AA/OPPTS has decided, based on the best available scientific

information and a reasonable interpretation ofFIFRA, that EPA should regulate on the basis that

prions are a pest under FIFRA. The Agency will follow the four-step approach outlined above.

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References

(1) Prusiner S.B., Baron H., Carison G., Cohen F.E., DeArmond S.J., Gabizon R., Gambetti

P., Hope J., Kitamoto T., Kretzschmar H.A., Laplanche J.-L., Tateishi J., Telling G.,

WeissmannC., Will R., In press. “Prions.” In: Virus Taxonomy. 7Ih Report of the

International Committee on Taxonomy of Viruses. Academic Press.

(2) Raymond, G.J., A. Bossers, L.D. Raymond, K.I. O’Rourke, L.E., McHolland, P.K. Bryant

ifi, M.W. Miller, E.S. Williams, M. Smits and B. Caughey. 2000. “Evidence ofa

molecular barrier limiting susceptibility ofhumans, cattle and sheep to chronic wasting

disease.” The EMBO Journal 19(17): 4425-4430.

(3) Prusiner S.B. 1982. “Novel proteinaceous infectious particles cause scrapie.” Science.

252: 136-144.

(4) Prusiner S.B. 1997. “Prion Diseases and the BSE Crisis.” Science. 278: 245-251.

(5) Collinge J. 2001. “Prion Diseases ofHumans and Animals: TheirCauses and Molecular

Basis.” Annual Reviews, Neuroscience. 24: 519-550.

(6) World Health Organization. 1999. “WHO Infection Control Guidelines for

Transmissible Spongiform Encephalopathies.” Report ofa WHO Consultation, Geneva,

Switzerland, 23 — 26 March, 1999. 38 pp.

(7) American HeritageDictionary. 1976. Houghton Mifflin Company, Boston,

Massachusetts, USA.

(8) Dorland’s Illustrated Medical Dictionary. 1974. W.B. Saunders Company, USA

(9) Webster’s Ninth New Collegiate Dictionary. 1986. Merriam-Webster, Inc. Springfield,

Massachusetts, USA.

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