Page 1 of 5 EPA Response to Written Comments Received from HHS On the Proposed Rule: Declaration of Prion as a Pest under FIFRA and

Amendment of EPA’s Regulatory Defi nition of Pests to Include Prion RIN 2070-AJ26; Docket ID No. EPA–HQ–OPP–2010–0427
Prions_NPRM_HHS-FDAcomments_EPAresponses_2010-10-18.docx

In accordance with section 21(a) of the Fede ral Insecticide, Fungicide, and Rodenticide Act (FIFRA), EPA submitted a draft of the proposed rule to the Secretary of Health and Human Services (HHS). Written comments received from HHS/Food and Drug Administration (FDA) on August 12, 2010, and EPA responses to th ose comments provided on August 30, 2010, are presented in this document. HHS participated in the interagency revi ew process under Executive Order 12866, and changes made to the proposed ru le in response to all comments received during that interagency review are documented in the docket as required by Executive Order

12866.

1. FDA Comment: Pages 1, 4, 5, etc.: Scope of Prions to Be Defined as Pests: The proposed rule would add “prion” to the list of things th at are defined as pests under 40 CFR 152.5(d). The draft proposed rule states that this change would mean that “a product intended to reduce the infectivity of any prion on inanimate surfaces” w ould be considered a pesticide regulated under the Federal Insecticide, Fungicide, and Rodentic ide Act (FIFRA). The EPA states that this change would codify the agency’s current polic y regarding prions and products intended to inactivate prions.

Because the draft proposed rule describes prion- inactivating pesticides as products intended to reduce the infectivity of prions on inanimat e surfaces, the degree to which FDA-regulated products might be affected by the proposal is un clear. Our understand ing is that the EPA’s reference to prions on “inanimate surfaces” is simply a shorthand way of referring to those prions that are not found “on or in living man or othe r living animals and those on or in processed food or processed animal feed, bevera ges, drugs (as defined in FFDCA sec. 201(g)(1)) and cosmetics (as defined in FFDCA sec. 201( i)),” consistent with 40 CFR 152.5(d). To eliminate any potential confusion concerning pri ons that would be regarded as pests under FIFRA and prions that would be subject to FDA regulation, the pr oposed rule should make clear that prions that meet the defi nition of pest under § 152.5(d) woul d not include prions on or in living man or other living animals and prions on or in processed food or processed animal feed, beverages, drugs, and cosmetics. The proposed ru le also should make clear that, even if a product may be considered a “pestic ide” if it is “intended to reduc e the infectivity of any prion on inanimate surfaces,” the product may not necessar ily be considered a “pesticide chemical” or “pesticide chemical residue” for purposes of sections 201(q) and 408 of the FFDCA (see the statutory exclusions to “pestici de chemical” and “pesticide chem ical residue” in section 201(q) of the FFDCA).

We also recommend that the proposed rule identify the exception, in the definition of “pesticide” in 7 U.S.C. 136(u), for liquid chemical sterilant products for use on a critical or semi-critical

medical device as defined in 21 CFR 321. Correspondingly, we recommend inclusion of a statement that the rule would not change the 1994 memorandum of understanding (MOU) between the EPA and FDA concerning regulator y oversight of liquid chemical sterilants and general purpose germicides, along with a stat ement that germicides used to reduce prion infectivity are outside the scope of that MOU. We further re commend that the proposed rule state that the EPA is not exercising primary re gulatory authority over germicide products (thatPage 2 of 5 might also be considered by the EPA to be pesticid es) that are used to reduce prion infectivity on

medical devices.

EPA Response: EPA generally agrees and will add th e following paragraph to the preamble of the proposed rule to make clear the limits of EPA’s regulatory authority over products intended to reduce the infectivity of prions on inanimate surfaces:

“EPA would like to make clear that not all prions and prion- related products are affected by the proposed rule. Firstly, EPA’s regula tions at 40 CFR 152.5(d) exclude pests “...in or on living man or other living animals and those on or in processed food or processed animal feed, beverages, drugs...and cosmetics. ” Therefore, the proposed rule would not apply to those uses of prion -related products. Secondly, the definition of “pesticide” in FIFRA Section 2(u) excludes new animal drugs and liquid chemical sterilants intended

for use on a critical or semi-critical device. Accordingly, products which fall into the latter categories would not be covered by the proposed rule.”

2. FDA Comment: Pages 1, 4, etc.: “Prion Product”: The draft proposed ru le would designate a product that is intended to reduc e the infectivity of any prion on inanimate surfaces as a “prion product.” We recommend that such a product be called a “pri on-inactivating product” or an “anti-prion product.”

EPA Response: The term “prion product” has been created for convenience and has no legal significance since it is not used in the regula tion itself. FDA’s recommendation for “prioninactivating product” conflic ts with the FDA’s and EPA’s current position that “inactivation” of prions (i.e., complete and irrevers ible destruction) has not yet been demonstrated, so that term is not acceptable. FDA’s recommendation of “anti-p rion product” is reasonable, but EPA prefers the term “prion-related product” since EPA has pr eviously used similar designations such as “anthrax-related products” and “mold-related products.” Accordingly, EPA will use “prionrelated product” in the Preamble to the proposed rule.

3. FDA Comment: Page 3: Potentially Affected Entities: We recommend adding the following to the list of entities that might be affected by the proposed rule: morticians,

manufacturers of medica l tissue devices of human and animal origin, manufacturers of other

human cellular and tissu e products, organ procurement and tr ansplantation programs, and blood and plasma establishments.

EPA Response: Although all of these entiti es are currently unaffected by the proposed rule, it is possible that some of them could be interested in commenting on it. Therefore, EPA will add

these entities to th e list of potentially affected parties in proposed rule.

4. FDA Comment: Pages 5 and 7: All-Protein Theory of Prions: The draft proposed rule appears to endorse without qualifica tion the all-protein theory of the nature of prions, i.e., that a prion is composed entirely of a misfolded, hos t-encoded, ubiquitous protein devoid of nucleic acid. Page 5 of the proposal states that prions “may occur in the central nervous system tissues of animals as an abnormal (‘misfolded’), infectious form of prion protein.” Page 7 states: “One entity that shares the characteri stics of pathogenicity, infectivity, transmissibi lity, the ability to increase in number and the ability to evolve (but which, like viruse s, is not alive) is the prion,

which is an infectious conforma tion of misfolded prion protein that causes TSE diseases in humans and animals.” Some scientists, including some members of the EPA’s FIFRA Scientific Advisory Panel, do not agree with this view of prions. In addition, the draft proposed rule appears to suggest that prions are found only in the central nervous system tissues, while prionsPage 3 of 5 actually are widely distributed in tissues outside the nervous syst em in both humans and animals with TSEs. Therefore, we suggest that the draft proposed rule be revi sed to state: “A prion is an infectious agent occurring in th e tissues of animals that is widely, though not universally, believed to be composed of an abnormal (misfo lded) protein without nucleic acid.” As a reference for this statement, the proposed rule could cite the minutes from the March 31-April 1, 2009, FIFRA Scientific Advisory Panel meeti ng (Ref. 3 in the draf t proposed rule).

EPA Response: EPA agrees that not all scientists agr ee with that misfolde d prion proteins are the causative agent of TSEs. Therefore, EPA w ill adopt FDA’s proposed change to make that point clear in the preamble.

5. FDA Comment: Page 5: Different Types of Prions : The draft proposed rule states: “Different types of prions are designated by th e type of diseases they produce, such as PrP Sc
(prions associated w ith scrapie) and PrP BSE (prions associated with bovine spongiform encephalopathy—mad cow disease).” We do not belie ve that this terminology is widely used in the TSE field. Therefore, we recommend that this sentence be deleted (along with the references

to PrP Sc in the subsequent sentence on page 5 of the draft).

EPA Response: EPA has observed in the scientific lit erature concerning TSE research that the designations to which FDA refers are commonly used, but not by everyone in this field. In addition, EPA believes that these de signations are useful in distingu ishing the different isoforms of prions. Accordingly, EPA intends to revise the sentence that FDA has quoted by inserting the word “commonly” in front of “designated” to indicate that these desi gnations are common but not necessarily used by all sc ientists in the TSE field.

6. FDA Comment: Page 5: Discussion of Human and Animal TSEs: We believe that the discussion of animal and human TSEs is selective and somewhat incomplete. Forms of CJD

other than cattle/beef-related vC JD, such as “sporadic CJD (sCJD),” “familial CJD (fCJD),” and “iatrogenic CJD (iCJD)” are not mentioned; the latter is particularly significant from an FDA perspective because of its association w ith corneal transplants and dura mater grafts, contaminated surgical instruments, and cadave r-pituitary sources. Addi tionally, other commonly

known animal TSEs such as transmissible mi nk encephalopathy (TME) and feline spongiform encephalopathy (FSE) are not discussed; nor, ot her than kuru, are human TSEs such as Fatal (Familial) Insomnia (FFI)) and Gerstmann-Strau ssler Syndrome (GSS) (see J. Bjornsson, et al., eds., Slow Infections of the Central Nervous System: The Legacy of Dr. Bjorn Sigurdsson, Annals of the New York Academy of Sciences , New York, Vol. 724; C. Soto (op. cit.)).

EPA Response: The EPA’s “white paper,” which was provided to the FIFRA Scientific Advisory Panel (SAP) for review in 2009, desc ribes most of the additional types of TSEs mentioned here by FDA. This paper will be pos ted in the docket to th e proposed rule and be available for comment. Because the purpose of the preamble to the proposed rule is to summarize key information which is available in detail in EPA’s support documents, EPA not does believe it is necessary to include all known TSEs in the Preamble.

7. FDA Comment: Page 5: Legal/Regulat ory Background: To help place the proposed rule in the proper context, we suggest that the proposed rule briefly mention some of the actions that other Federal agencies, including USDA and FDA, have taken to prevent prions from harming the public. These steps have been well documented in the literature, are integral parts of the domestic inspectional programs and import policie s of both agencies, and are publicly available on the agencies’ Web sites. For example, FDA has issued an interim final rule (69 FR 42256, July 14, 2004) prohibiting the use of certain cat tle materials in human food and cosmetics toPage 4 of 5 address the potential risk of BSE (21 CFR 189.5 and 700.27); USDA regulations concerning

BSE include those set forth at 9 CFR 94.18 and 9 CFR 95.4.

EPA Response: EPA agrees and will add a brief desc ription of some of FDA’s and USDA’s efforts to protect the public from prions.

8. FDA Comment: Page 6: “Reproduction” of Prions: The draft proposed rule states that “microbiologists do not generally classify viruse s as microorganisms because they are not alive (i.e., they cannot reproduce, grow or perform self-maintenance). Therefore, the term ‘other micro-organism’ as used in FIFRA appears broa d enough to include some entities that are not alive.” Both viruses and prions are self-replicating, and we be lieve that most microbiologists would consider self-replication of a pathogen to be reproduction. Therefore, we recommend deleting this paragraph.

EPA Response: EPA disagrees that replication and re production are synonymous. Historically to biologists, “reproduction” refers to sexual or asexual reproduction, which involves the independent copying of genetic material in orde r for a living organism to produce “offspring.” Viruses have genetic material but are incapable of independent replication. The nature of prion replication is not entirely clear, but it is de pendent upon a host. To make clear the historical meaning of “reproduce” EPA will insert the phrase “sexually or asexually” after that term in the preamble of the proposed rule.

EPA’s and FDA’s differences on this issue not withstanding, adopting F DA’s definition of reproduction would not change EPA’s observations on in the Preamble. There EPA states that microbiologists generally do not classify viruses as microorganisms because they are not alive (i.e., they cannot reproduce, grow or perform self-maintenance). The Preamble goes on to point out that the term “other micro-organism” as used in FIFRA appears broad enough to include

some entities that are not alive. Even if one were to adopt FDA’s apparent definition of reproduction as including or being equivalent to replication, EPA’s statement would still stand based on the inability of viruses to grow or perform self-maintenance.

9. FDA Comment: Page 7: Effect of Prions on Neurona l Cells: The draft proposed rule states: “These infectious particles [prions], once in troduced into an animal or human, can induce neuronal cells to change into pri ons that in turn attack other neuronal cells, primarily in the central nervous system.” We do not believe that this description of the pathogenesis of TSEs is

accurate. Because this sentence is not essen tial to the proposal, we recommend deleting it.

EPA Response: EPA will correct the sentence to read, “T hese infectious particles [prions], once introduced into an animal or human host, can indu ce the formation of new prions in the animal or

human host.”

10. FDA Comment: P. 9: Draft Performance Test Guid elines: The draft proposed rule states that the EPA has developed draft guidelines for pe rformance tests that will ensure that the EPA

receives the data needed to make determinati ons on whether a prion-in activating product meets the agency’s efficacy data requirements for regi stration. Does the EPA intend to publish notice of the availability of the draf t guidelines concurren tly with the issuance of the proposed rule?

EPA Response: Yes, EPA intends to publish the draft guidance for public comment concurrently with the proposed rule.

11. FDA Comment: Regarding defining different types of prions: More rigor ous definitions of terms such as PrP (BSE) and PrP (Sc) should be given and used, if available. Alternative andPage 5 of 5 more science-based nomenclature is available in the literature. For ex ample, a more recent definition for PrP (Sc) than that given in the NP R (i.e., "prions associated with scrapie", p. 5, paragraph 1) has been given elsewhere as: "...D isease-associated misfolded prion protein present in individuals affected by TSE. This form is infectious, rich in beta-sheet conformation, insoluble, and mostly protease-re sistant..." (see "The Infectious Agent and the Prion Hypothesis" in C. Soto, Prions. The New Biology of Prot eins, CRC Press/Taylor Francis Group-Informa, Boca Raton, FL (2006), Chapter 2, p.16).

EPA Response: EPA appreciates the FDA’s suggesti on that EPA adopt more scientific definitions of different types of prions. However, in this opening section of the preamble, EPA is intending to provide only a basic introduction to the general public concerning prions, prion proteins, types of prions, and the types of TSE dis eases associated with prions. Toward that end, EPA has provided simplified descriptions of se veral key terms such as the ones mentioned by FDA. EPA believes that these descriptions are accurate and appropriate for the preamble, and that more detailed, scientific de scriptions of the key terms are not needed in the preamble. The terminology of prions is discussed in greater detail in EPA’s scie ntific “white paper,” which will

be made available in the docket for those who wi sh to delve further into available, relevant

scientific information.

Attachment:

Incoming Written Comments from FDA, 08/12/201008/12/2010

FDA Comments on EPA’s Draft Proposed Rule to Declare Prions as Pests

The Food and Drug Administration appreciat es the opportunity to comment on the Environmental Protection Agency’s (EPA’s) draft proposed rule enti tled “Declaration of Prion as a Pest under FIFRA and Amendment of EPA’s Regulat ory Definition of Pests to Include Prion.”

Our comments are set forth below.

1. Pages 1, 4, 5, etc.: Scope of Pr ions to Be Defined as Pests

The proposed rule would add “prion” to the list of things that are define d as pests under 40 CFR 152.5(d). The draft proposed rule states that this change would mean that “a product intended to reduce the infectivity of any prion on inanim ate surfaces” would be considered a pesticide regulated under the Federal Inse cticide, Fungicide, and Roden ticide Act (FIFRA). The EPA states that this change would codify the agen cy’s current policy regard ing prions and products intended to inactivate prions.

Because the draft proposed rule describes prion- inactivating pesticides as products intended to reduce the infectivity of prions on inanimat e surfaces, the degree to which FDA-regulated products might be affected by the proposal is un clear. Our understand ing is that the EPA’s reference to prions on “inanimate surfaces” is simply a shorthand way of referring to those prions that are not found “on or in living man or othe r living animals and those on or in processed food or processed animal feed, bevera ges, drugs (as defined in FFDCA sec. 201(g)(1)) and cosmetics (as defined in FFDCA sec. 201( i)),” consistent with 40 CFR 152.5(d). To eliminate any potential confusion concerning pri ons that would be regarded as pests under FIFRA and prions that would be subject to FDA regulation, the pr oposed rule should make clear that prions that meet the defi nition of pest under § 152.5(d) woul d not include prions on or in living man or other living animals and prions on or in processed food or processed animal feed, beverages, drugs, and cosmetics. The proposed ru le also should make clear that, even if a product may be considered a “pestic ide” if it is “intended to reduc e the infectivity of any prion on inanimate surfaces,” the product may not necessar ily be considered a “pesticide chemical” or “pesticide chemical residue” for purposes of sections 201(q) and 408 of the FFDCA (see the statutory exclusions to “pestici de chemical” and “pesticide chem ical residue” in section 201(q) of the FFDCA).

We also recommend that the proposed rule identify the exception, in the definition of “pesticide” in 7 U.S.C. 136(u), for liquid chemical sterilant products for use on a critical or semi-critical

medical device as defined in 21 CFR 321. Correspondingly, we recommend inclusion of a statement that the rule would not change the 1994 memorandum of understanding (MOU) between the EPA and FDA concerning regulator y oversight of liquid chemical sterilants and general purpose germicides, along with a stat ement that germicides used to reduce prion infectivity are outside the scope of that MOU. We further re commend that the proposed rule state that the EPA is not exercising primary re gulatory authority over germicide products (that might also be considered by the EPA to be pesticid es) that are used to reduce prion infectivity on

medical devices.2 2. Pages 1, 4, etc.: “Prion Product”

The draft proposed rule would designate a product that is intended to reduce the infectivity of any prion on inanimate surfaces as a “prion product.” We recommend that such a product be called a “prion-inactivating produc t” or an “anti-prion product.”

3. Page 3: Potentia lly Affected Entities

We recommend adding the following to the list of entities that might be affected by the proposed rule: morticians, manufacture rs of medical tissue devices of human and animal origin,

manufacturers of other human cellular a nd tissue products, organ procurement and transplantation programs, and bl ood and plasma establishments.

4. Pages 5 and 7: All-Protein Theory of Prions

The draft proposed rule appears to endorse without qualification the all-protein theory of the nature of prions, i.e., that a pr ion is composed entirely of a misfolded, host-encoded, ubiquitous protein devoid of nucleic acid. Pa ge 5 of the proposal states that prions “may occur in the central nervous system tissues of animals as an abnor mal (‘misfolded’), infectious form of prion protein.” Page 7 states: “One entity that shares the characteri stics of pathogenicity, infectivity, transmissibility, the ability to increase in num ber and the ability to evolve (but which, like viruses, is not alive) is the pr ion, which is an infectious confor mation of misfolded prion protein

that causes TSE diseases in humans and animals. ” Some scientists, including some members of the EPA’s FIFRA Scientific Advisory Panel, do not agree with this view of prions. In addition, the draft proposed rule appears to suggest that prions are fo und only in the central nervous system tissues, while prions actua lly are widely distributed in ti ssues outside the nervous system in both humans and animals with TSEs. Therefore, we suggest that the draft proposed rule be revised to state: “A prion is an infectious agent occurring in the tissues of animals that is widely, though not universally, believed to be composed of an abnormal (misfolded) protein without nucleic acid.” As a reference for this statement, the proposed rule could cite the minutes from the March 31-April 1, 2009, FIFRA Scientific A dvisory Panel meeting (Ref. 3 in the draft proposed rule).

5. Page 5: Differe nt Types of Prions

The draft proposed rule states: “D ifferent types of pri ons are designated by the type of diseases they produce, such as PrP Sc (prions associated with scrapie) and PrP BSE (prions associated with bovine spongiform encephalopathy—mad cow di sease).” We do not believe that this terminology is widely used in the TSE field. Therefore, we recommend that this sentence be deleted (along with the references to PrP Sc in the subsequent sentence on page 5 of the draft).

6. Page 5: Discussion of Human and Animal TSEs

We believe that the discussion of animal and hu man TSEs is selective and somewhat incomplete. Forms of CJD other than cattle/beef-related vCJD, such as “sporadic CJD (sCJD),” “familial3 CJD (fCJD),” and “iatrogenic CJD (iCJD)” are not mentioned; the latter is particularly significant from an FDA perspective because of it s association with corneal transplants and dura mater grafts, contaminated surgical instrument s, and cadaver-pituitary sources. Additionally, other commonly known animal TSEs such as transmissible mink encephalopathy (TME) and feline spongiform encephalopathy (F SE) are not discussed; nor, ot her than kuru, are human TSEs such as Fatal (Familial) Insomnia (FFI)) and Gerstmann-Straussler Syndrome (GSS) (see J. Bjornsson, et al., eds., Slow Infections of the Ce ntral Nervous System: The Legacy of Dr. Bjorn Sigurdsson, Annals of the New York Academy of Sciences, New York, Vol. 724; C. Soto (op. cit.)).

7. Page 5: Legal/Regulatory Background

To help place the proposed rule in the proper context, we sugges t that the proposed rule briefly

mention some of the actions that other Federa l agencies, including USDA and FDA, have taken to prevent prions from harming the public. These steps have been well documented in the literature, are integral parts of the domestic inspectional programs and import policies of both agencies, and are publicly available on the agencies ’ Web sites. For example, FDA has issued an interim final rule (69 FR 42256, July 14, 2004) prohibi ting the use of certain cattle materials in human food and cosmetics to address the pot ential risk of BSE (21 CFR 189.5 and 700.27); USDA regulations concerning BS E include those set forth at 9 CFR 94.18 and 9 CFR 95.4.

8. Page 6: “Reproduction” of Prions

The draft proposed rule states that “microbi ologists do not generally classify viruses as microorganisms because they are not alive (i.e., they cannot reproduce, grow or perform selfmaintenance). Therefore, the term ‘other micro-organism’ as used in FIFRA appears broad enough to include some entities that are not alive.” Both viruses and prions are self-replicating, and we believe that most microbiologists would consider self-replicati on of a pathogen to be reproduction. Therefore, we r ecommend deleting this paragraph.

9. Page 7: Affect of Prions on Neuronal Cells

The draft proposed rule states: “These infectious particles [p rions], once introduced into an animal or human, can induce neuronal cells to ch ange into prions that in turn attack other neuronal cells, primarily in the central nervous syst em.” We do not believe that this description of the pathogenesis of TSEs is accurate. Because this sentence is not essential to the proposal, we recommend deleting it.

10. P. 9: Draft Performance Test Guidelines

The draft proposed rule states th at the EPA has developed draft guidelines for performance tests

that will ensure that the EPA receives the data needed to ma ke determinations on whether a prion-inactivating product meets the agency’s efficacy data requi rements for registration. Does the EPA intend to publish notice of the availability of the draft gui delines concurrently with the issuance of the proposed rule?