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 of

Prions as a Pest under FIFRA Susan B. Hazen 

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# ~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).

AttachmentRecord ofDecision by Principal Deputy AAIOPPTS Regarding Status ofPrions 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 thatprions 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 forproducts for use againstprions should be examined and appropriate decisions made. 3. EPA should follow an appropriate regulatoryprocess 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 injurious to 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 largebody ofavailable scientific information aboutprions, and consultedwith other EPA offices, including the Office ofGeneral Counsel, the Office of

Research and Development, and the Office OfEnforcement Compliance and Assurance. This document summarizes the factual basis and the rationale forthe decision that prions should be consideredto be pests. Background on Prions Certain proteins found in cells ofthe central nervous system ofhumans and animals appearto exist in both a normal (correctly folded), noninfectious form and in an abnormal (misfolded), infectious form. The normalproteins, 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 (forthe prion isoform foundin sheep—scrapie) or PrPTeS (for “resistant” prion isoforms) (1, 2). Dr. Stanley Prusiner, who won a Nobel Prize foridentifying prions, initially describedprions as “proteinaceous infectious particles that resist inactivation byprocedures which modify nucleic acids” (3). He later described prions as proteinaceous particles that lacknucleic acids (4).
1• 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 severalprinciples 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-thatprions are the infectious, causative agents forTSEs such as Scrapie in sheep, Bovine Spongiform Encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob Disease (CJD) in humans. BSE is ofconsiderable 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 whenthey comeinto direct contact with susceptible tissue. They may be transmitted from host to host by contaminated surgical instruments, direct transfer ofinfected tissue, orthe 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 Englandbecause 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, lackcertain characteristics commonly associated with life (and are not currently consideredto be “living”): theyneither eatnor excrete and have no apparent metabolic activity on theirown. Neitherprions norviruses reproduce sexually orasexually, however, both replicate through infection ofliving tissue. Prions and viruses differ in several ways. First, prions appearto contain only protein and lack genetic material, whereas viruses contain proteins and either DNA or RNA. Also, prions appearto propagate by inducing certain normalproteins 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, bothprions and viruses utilize a host or host tissue, both disruptnormal cell functi?n, both increase in numberin the host, and, in the process, both produce disease.

• Prions are extremelyresistant to inactivation by ultraviolet light, irradiation, boiling, dry heat, formalin, freezing, drying and changes in pH. Methods for inactivatingprions in
2infected 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 forthe use ofa commercial aqueous acidphenolic product for inactivation ofthe CWD agent on contaminated surfaces. Ifan emergency exemption is granted, the productmust be used according to the conditions ofthe exemption. The Centers forDisease 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 forthis use. Rationale The Principal Deputy AAIOPPTS decided that prions should be consideredto be a “pest” under FIFRA forthe following reasons, based on the information presentedto her:

• As discussed above, prions are unquestionablyinjurious 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 orhuman, induce neuronal cells to replicate otherprions that in turn attack other neuronal cells, primarily in the central nervous system. 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 “~tjheterm ‘pest’ means (1) anyinsect, rodent, nematode, fungus, weed, or (2) any other form ofterrestrial or aquatic plant or animal life orvirus, bacteria, or other micro-organism (except viruses bacteria, or othermicro

organisms on orin living man orother living animals) which the Administrator declares to be apest 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, afternotice and opportunity forhearing, “to declare a pest any form of

plant or animal life (other than man and other than bacteria, virus, and other micro-organisms on orin living man orother living animals) which is injurious to health orthe environment.” Pursuant to section 25(c), EPA promulgatedthe rule now codified at 40 C.F.R. §152.5, where it declared any microorganism to be apest under circumstances that make it deleterious to man orthe environment (other than those on or in living man orother living animals). As explained below, since prions share many of the characteristics ofdeleterious microorganisms, they canbe consideredto be pests inasmuch as they are clearly deleterious to man and the environment.

• Microorganisms are defined differently in different dictionaries. The American Heritage
3Dictionary (7) defines “microorganism” as “~am animal orplant ofmicroscopic size,

especially abacterium ora protozoan.” Dorland’s Medical Dictionary (8) defines “microorganism” as “a minute living organism, usuallymicroscopic. Those ofmedical 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 orultramicroscopic size;” and “organism” as “1: a complex structure of interdependent and subordinate elements whose relations and properties are largely determined by their functionin the whole.” Whether prions may be consideredto be a “microorganism” is subjectto interpretation. Prions might reasonablybe consideredto share many ofthe characteristics ofmicroorganisms becausethey mayhave “a complex structure ofinterdependent and subordinate elements whose relations and properties are largely determinedby their functionin the whole,” and becausethey are “ofmicroscopic orultramicroscopic size.”

• Another view is that prions are a “form of... plant or animal life” becausethey 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 lackcertain characteristics commonly associated with life, however, prions share with otherpests 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 consideredto be a “form ofplant oranimal life” along with viruses, bacteria and other microorganisms. Ifso, the Administrator might declare these forms oflife to be pests pursuant to section25(c)(l).

• UnderFIFRA, EPA regulates a wide range ofpesticide products that are intended to prevent ordestroymicroorganisms. Suchproducts 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 productperformance (efficacy) datato determine that the product will kill the target microorganisms. If

products claimedto prevent ordestroyprions were not regulated under FIFRA, it is not clear that an adequate mechanism forregulatory oversight of the safety and efficacy ofsuchproducts could be put into place in a timely manner to address a public health crisis. Absentregulatory oversight such as thatprovided under FIFRA, persons who need to controlprions would have no assurance that products claiming to controlprions were either effective or safe.

• In 2002, pursuant to FIFRA section 28(d), EPA issued a list ofpests of“significantpublic health importance” in Pesticide Registration Notice 2002-1. This list, which included prions, was compiled in coordination withthe Departments ofHealth and Human Services and Agriculture, and issued afterpublic notice and opportunity to comment. There were no comments objecting to EPA’s inclusion of prions on this list ofpests of
4significantpublic health importance.

• For the foregoing reasons, the Agencybelieves that prions share enough characteristics of either “micro-organism” orof“form of... plant oranimal 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 injurious to health orthe environment and which arepests, pursuant to FIFRA section 25(c)(l).

• The reasonableness ofEPA’s decision to consider prions pests is supported by the fact that Congress has also consideredprions to be pests

— albeit in the context ofanimal health legislation. The Animal HealthProtection Act (AHPA) of2002 includes prions within the definition ofa “pest.” That statute states that a pest is: “any ofthe following that can directly orindirectly injure, cause damage to, orcause disease in livestock:. .(E) A virus or viroid.. .(F) An infectious agent orotherpathogen.. .(I) A prion... (K) Any organism similarto orallied with any of the organisms describedin this paragraph.” This definition is more expansivethan 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 orvirus, bacteria, or other micro-organism.., which the Administrator declares to be apest under section25(c)(l).”2

• Finally, the definition of“pest” as it appears in FIIFRA Section 2(t)(2) has not been changedby Congress since 1972. The existence ofprions was widely not postulated or demonstrated until well afterthat 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 orplant lifethat share the characteristics ofviruses and other microorganisms. Conclusion

7 U.S.C. §8302(13). This statute was passedin 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).

5The Principal Deputy AA/OPPTS has decided, based onthe 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.

6References

(1) Prusiner S.B., Baron H., Carison G., CohenF.E., DeArmond S.J., Gabizon R., Gambetti P., HopeJ., Kitamoto T., Kretzschmar H.A., Laplanche J.-L., Tateishi J., Telling G., WeissmannC., Will R., In press. “Prions.” In: Virus Taxonomy. 7Ih Report ofthe International Committee on Taxonomy ofViruses. 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 molecularbarrierlimiting 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 of Humans and Animals: TheirCauses and Molecular Basis.” AnnualReviews, 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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