ML20198H887

Informs That Ltr Being Sent at Request of Hoffman Who Expressed Concern During Telcon Re Tri-Med Petition Not Tracking Draft Schedule That NRC Provided to Congressman Burton in Fall of 1996

ML20198H887
Person / Time
Issue date:	04/04/1997
From:	Morris B NRC OFFICE OF NUCLEAR REGULATORY RESEARCH (RES)
To:	Fry W AFFILIATION NOT ASSIGNED
Shared Package
ML20013E023	List: ML20198H571 ML20198H672 ML20198H718 ML20198H780 ML20198H830 ML20198H875 ML20198H887 ML20198H907 ML20198J119 ML20198J157 ML20198J188 ML20198J224 ML20198J252 ML20198J270 ML20198J298 ML20198J324 ML20198J404 ML20198J418 ML20198J664 ML20198J741 ML20198J766 ML20198J793 ML20198J830 ML20198J869 ML20198J932 ML20198J978 ML20198J988 ML20198J995 ML20198K019 ML20198K055 ML20198K065 ML20198K118 ML20198K151 ML20198K202 ML20198K217
References
FRN-62FR32552, RULE-PR-30, RULE-PR-32 AF70-1-021, AF70-1-21, NUDOCS 9801130419
Download: ML20198H887 (1)

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t Mr. William A. Fry, President .

Tri Med Specialties, Inc.-

1500 Avon Street Ext'd '

Charlottesville, VA 22902 -

Dear Mr. Fry; .

I am' sending you this letter at the request of Susie Hoffman of your company. Ms. Hoffman expressed concem during a telephone conversation with one of my staff that work on the Tri-Med petition was not tracking the draft schedule that the NRC provided te Congressman Burton in the dall of 1996.

In accordance with Commission procedures, a draft rulemaking plan was sent to the Agre.:1ent States for review and comment in October 1996. Comments were received from Agreement -

States in November.1 Some Agreemant States indicated that the staff's initial position could be burdensome to both Agreement States and theirlicensees.. Although we are still recommending granting the petition, the approach has been be changed so that we can grant the petition >

-without imposing undue burden on Agreement States or their licensees. '

- I'n February 1997, a finel rulemaking plan reflecting the revised approach to gra.it the petition was sent to the Commission, along with a revised schedule for completing this rulemaking. The Commission advised the staff in March 1997 that it should proceed with rulemaking to grant the petition. I have enclosed a copy of the final rulemaking plan for your information.

. Let me aseure you that work on this petition is a priority, and we are working diligently to o conclude this action.

I ' Sincerely, ,

bhm Bill M. Morris, Director Division of Regulatory Applications

Office of Nuclear Regulatory Research

Enclosurei Final rulemaking plan 1

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.....f RULEMAKING ISSUE (NEGATIVE CONSENT)

February 7, 1997 SEcY-97-031 IQ: The Commissioners FROM: Hugh L. Thompson, Jr, Acting Executive Director for Operations

SUBJECT:

FINAL RULEMAKING PLAN: EXEMPT DISTRIBUTION AND USE OF A RADIOACTIVE DRUG CONTAINING ONE MICROCURIE OF CARBON 14 UREA (PARTS 30 AND 32)

PURPOSE:

To inform the Commission of the staff's rulemaking plan for amending Parts 30 and 32 to allow the distribution of a radioactive drug containing one microcurie of "C urea as an exempt material for "in vivo" diagnostic testing.

BACKGROUND:

On October 6,1994, the Commission docketed a petition for rulemaking (Docket No.

PRM 35-12) from Tri Med Specialties, Inc. (Tri Med). In a letter dated August 23,1994 Tri Med petitioned the NRC to hmend its regulations "to allow for the generallicensing and/or exemption for the commercial distribution by licensed pharmaceutical manuf acturers of a capsule containing one micro-Curie ( Ci) of "C-urea for in vivo diagnostic testing." The purpose of this diagnostic test is to detect the presence of the bacterium Helicobacter pylori (H. pylori), a cause of peptic ulcers.

The petition for rulemaking was noticed for comment in the Federal Reoister on Decemeber 2,1994. A total of 315 comment letters were received. There were 313 letters supporting the petition (mostly form letters) ar'd 2 letters opposing the petition.

NOTE: TO BE MADE PUBLICLY AVAILABLE WHEN THE FINAL SRM IS MADE AVAILABLE CONTACT:

Sam Jones, RES 415 6198 Wa/ 30/93Ns're Q. a ue on

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• 4 OlSCUSSION:

In accordance with the SRM COMSECY 96 035 dated June 11.1996, a copy of the draft rulemaking plan, recommending a general hcense approach, was provided to the Agreement States for review and comment, The comment period closed on October 31, 1996. Ten comment letters were received from Agreement States. Six States agreed with the staff's initial position to grant the petition by making the ."C urea capsules available to any physician under a generallicense. However, three States Georgia, Illinois. and New York while agreeing that the petition should be granted, opposed the staff's recommendation and argued that the capsules should be made available as exempt material. One State, Oregon, stated that it would continue to require that any person who administers a radioactive drug be specifically licensed, in' addition, th6re were some comments related to the process of Agreement State involvement in NRC rulemaking that the staff believes were addressed in SECY 96 035.

and, therefore, are not addressed in the memorandum to the Commission or in the final rulemaking plan, After considering Agreement States' comments, the staff has changed its

- recommendation. We now recommend that manufacturers and distnbutors be permitted to distribute this radioactiv6 drug as exempt matenal to "any person" who .s permitted to receive and use the drug under the appropriatc Federal or State law goveming the distribution and use of the drug.

AGREEMENT STATE COMMENTS ON DRAFT RULEMAKING PLAN:

In accordance with Management Directive 6.3, "The Rulemaking Process," the staff

• draf ted a rulemaking plan in response to a petition for rulemaking submitted by Tri Med Specialties, Inc. Under the draft plan, the staff would have developed a direct final rule amending 10 CFR Part 35 to permit, under a generallicense, any physician to administer to patients capsules containing one microcurie of C 14 as a diagnostic tool for detecting peptic ulcers caused by the Helicobacter pylori bacterium, in accordance with COMSECY-96-035 dated June 11,1996.-a copy of the draft rulemaking plan was provided to the Agreement States on October 1,1996, for a 30 day period of review and comment. Comments were received from ten Agreement States.

Six States (Kentucky, Nebraska, Colorado, Washington, Utah, and Louisiana) supported the staff's initial position to grant the petition via a generallicense to permit physicians who are not authorir d users to receive and use capsules containing 1 pCi of "C-urea.

Kentucky indicated they alreatly have provisions for a generallicense for *!n vivo" use in their regulat ions.

~ One' State, Oregon indicated that'it would not permit administration of the capsules under a generallicense, but would continue to require that.all physicians who administer

. radioactive drugs, including the C 14 capsules, be specifically licensed.

Three States, New York, Georgia and Illinois, opposed the generallicense approach

. recommended by the staffi . Georgia and filinois recommended that physicians wh

" authorized users" be permitted to receive and use capsules containing 1 pCi of "C - ure

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The Commissioners 3 9

as exempt matenal. Georgia argued that their burden would be increased by distribution and use under a general hcense because of repcrts required from distnbutors, invoicing of physicians for generallicense fees, and possible amendment of all of their distribution hcenses. Ilhnois stated that distribution of the capsules as exempt materialis consistent with the NRC's technical evaluation and would ensure that physicians could have access to the capsules without a specific or general hcense Illinois further stated that if the NRC were to require distribution and administration under a general hcense, Agreement States would need to incur the expense of modifying their regulations. lilinois seems to imply that they could avoid rulemaking if the NRC were to adopt the exemption approach.

However, as Georgia correctly observed, the exemption approach would require States to make conforming changes in their regulations as well, New York stated that they agreed that the widespread medical use of the capsules would involve no risk to the public health and saf e'ty or the environment, and would provide significant medical benefits to the population. New York also stated that using a risk-based regulatory approach, there is no need to regulate the capsules for their radioactive content. Further New York argued that a generallicense is an ineffective means of regulatc.v controlin any case. New York also noted that the Food and Drug Administration will regulate the capsules as a drug.

There were further comments from the States aodressing the process of Agreement State involvement in NRC rulemaking that the staff beheves were addressed in SECY 96-035, and therefore are not addressed here. Copies of the comment letters are enclosed.

STAFF RESPONSf:

The staff initially recommended distribution of the capsules under a generallicense because if the capsules were to be distributed as an exempt material, manufacturers and distnbutors located in Agreement States would be required to obtain and maintain both an NRC and Agreement State license. Since the staff had concluded that there was no significant radiolog; cal safety or environmental risk,it did not intend that the general license would be used as a means of exercising regulatory control beyond limiting distribution to physicians. However,in light of the comments received from New York, Illinois, and Georgia, the staff changed its position from permitting distribution to any After physician under a generallicense to permitting exempt distribution to any physician further consideration, the staff decided that manufacturers and distributors should be permitted to distribute this radioactivo drug as exempt materit' :o any person who is permitted to receive and use the drug under the appropriate Federal or State law governing the distribution and use of the drug, Permitting exempt distribution to "any person,"

rather than "any physician," would avoid the need for NRC to amend its regulations if

..e radioactive drug to other Federal or State authorities permit the distribution and use of persons who are not physicians Moreover, the drug will be manuf actured under a specific Part 32 license to ensure that capsules contain only one microcurie of carbon 14 and do not contain any other radioactive contaminants.

POLICY ISSUES:

NRC regulations specify that persons administering radioactive drugs containing byproduct material to patients or human research subjects must have specific authorization. Also, i

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• use of byproduct material as ar' there are no' provisions in NRC ' regulations f or toe >

exempt material. However,in light o' the above, the staff is recommending the distribution of the capsules as exempt material to any person.-

in addition, the Commission should note that current regulatims (t 35.6) addressing the use of byproduct materialin research require licensees to meet specific provisions for the protection of human subjects. Under the staff's recommendation,- the exempt distribution of. the capsules for use in research invetving humans subjects would not be auhorized.

The Commission also should note that all of the options in the draft rulemakir.g plan given to the Agreement States for review in June,1996, explicitly limited the use of the drug to physicians, Hence, the position of the Agreement States on the staff's recommendation this final rule plan to not limit the use to physicians only, but rely on FDA and State Boards

--of Pha~nacy regulations for determining use,is not known.

AGREEMENT STATE COMPATIBILIT(:

Under the Atomic Energy Act, certain regulatory functions are reserved to the NRC.

Among these are the distributton of exempt materials and quantities, as discussed in 10 CFR Part 150. Hence, the stuff's recommended approach is a Division 4 matter of compatibility, with regard to the manufacture and distribution of the capsules All (Part 32).

and a Division 1 matter of compatibility with regard to possession and use (Part 30).

Agreeme:it States will need to adopt regulations to allow arty person to receive capsu containing 1 Ci of "C urea as an e,,empt material.

The Commission should not1 that under the staff's initial recommendation, Oregon (and

-possibly other States, since not all States commented) could have continued its current

_ practice of requiring physicians administering radioactive drugs to humans to be specifically licensed, because the generallicense amendments would have been a Division 3 matter of compatibility.

COORDINATION:

j i The

-The Office of the General Counsel has reviewed this paper and has no legal ob ect on.

Office of the Chief Financial Officer concurs that there will be'no resource impacts be those currently budgeted. The Office of the Chief information Officer concurs that there will be no information technology or management impacts 'oeyond those needed for rulemaking, i

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The Commissioners 5

- FECOMMENDATION:

Unless the Commission directs otherwise within 10 days from the date of this paper. I will implement the rulemaking plan and direct the staff to begin development of a proposed rule to permit the distribution of the radioactive drug as an exempt material for distribution l to any person, CWk 4 Hugh. Thompson. J .

Acting Executive Director for Operations

Enclosures:

1. Final Rulemaking Plan

2. Agreement State Comment Letters SECY NOTE: In the absence of instructions to the contrary, SECY vill notify the staff on February 20, 1997 that the Com:nission, by negative consent, assents to the action proposed in this paper.

DISTRIBUTION:

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RULEMAKING PLAN 1

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RULEMAKING PLAN-FOR-EXEMPT. DISTRIBUTION AND USE OF A RADI0 ACTIVE DRUG CONTAINING ONE MICR0 CURIE OF CARBON 14 UREAL (PARTS 30 AND 32)

- Lead Office: Office of Nuclear Regulatory Research Staff

Contact:

S. Jones, RES/RPHEB SIGNED 8/13/96

- Concurrences: Date-D. Morrison, RES SIGNED 9/19/96 C. Paperiello, NMSS - Date SIGNED 9/20/96 R. Bangart, OSP Date (memo from Stuart Treby) 9/20/96 W. Olmstead, OCG Date (memo from David Meyer) 8/20/96

0. Meyer, ADM Date i b Approval:

- #f@;L.j" l-Date-ND H. L. Thompson, E w

.j FINAL RULEMAKING PLAN 10 CFR PARTS 30 AND 32 EXEMPT DISTRIBUTION OF A RADIOACTIVE DRUG CONTAINING ONE MICROCURIE OF CARBON 14 UREA (PRM 3512)

BACKGROUND On October 6,1994, the Commission docketed a petition for rulemaking (Docket No.

PRM 3512) from Tn.Med Specialties, Inc (Tri Med). In a letter dated August 23,1994, Tri Med petitioned the NRC to amend its regulations "to allow for the generallicensing and/or exemption f or the commercial distribution by licensed pharmaceutical -

manuf acturers of a capsule containing one micro Curie ( Cil of "C urea for in vivo diagnostic testing." The purpose of this diagnostic test is to detect the presence of the bacterium Helicobacter pylori (H. pylori), a cause of peptic ulcers.

• Peptic ulcer disease is a chronic inflammatory condition of the stomach and duodenum'

that affects as many es 10% of people in the United States at some time in their lives.

The disesse has relatively low mortality, but it results in substantial human suffering and high economic costs.* (Source: Article included as an appendix to the petition,' from

- JAMA, July 6,1994 Vol 272, No.1. "H. pylori in Peptic Ulcer Disease NIH Consensus Conference"),

In the petition dated August 23,1994, the petitioner stated the following

Recent medical research has found that peptic uicers are commonly caused by a bacterium called H. pylori. This bacterium lives in the stomach of most ulcer sufferers. By treating ulcer patients vith antibiotics, doctors can now cure most ulcer problems, it is therefore necessary to detect the presence of H. pylori bacteria in ulcer patients so that the new treatment can be given appropriately. In the past, .

this was done by a gastroenterologist who took biopsy samples of,the stomach lining at endoscopy, a procedure which was uncomfortable and expensive

($1000).

With tne new test H. pylori can be detected non invasively using a "C-urea tracer. "C-urea is broken down by H. pylori to form labeled CO, which is expired in the breath. To do the test, a doctor asks the patient to swallow the capsule with 30 mis of water. After 15 minutes the patient blows 2 liters of

breath into a collection bag (a Mylar balloon) which is mailed to a testing

' laboratory, if "C CO more 2

than twice background is present in the breath sample, then the patient must be ;nfected with H. pylori.

CURRENT REGUL ATIONS 10 CPR Part 32, " Specific Domestic Licenses To Manufacture or Transfer Certain items i f r for

.Containing Byproduct Materials," 5 32.72, "Manuf acture, preparat on, or trans e

4. ,

comm:rcial distnbutionfof radioactive drugs containing byproduct material _for medical'use under Part 35,'fprovides for_ commercial distnbution of radioactive drugs containing

~

= byproduct matenal for usa by persons authonzed pursuant to Part 35, Thus, the

regulations currently would_ permit Part 321ecensees to commercially distribute capsules --

containing 1_ Ci of "Ciurea to persons authonzed pursuant to Part 35.

10 CFR Part 35, " Medical _Use of Byproduct Material,' sets forth radiation safety r:;quirements, including requirements for the training and experience of authorized user-physicians to assure the safe possession and use'of radioactive drugs containing

byproduct material.

Exi_ sting e_xemptions for use of byproduct materialin 5 30,14, " Exempt concentrations; cnd i 32.18, Manufacture, diatribution and transfer of exempt quantities of byproduct:

- m:terial: Requirements for license," do not permit the exempt transfer of byproduct material contained in any food, beverage, cosmetic, drug, or any product designed for ingestion or inhalation by, or application to, a human being.

_ REGULATORY ISSUE -

The regulatory issue is whether the "C urea capsules present a sufficiently small radia risk that they can be safely distnbuted to and used by physicians who are not " authorized users" under 10 CFR Part 35, SAFETY ANALYSIS d that

. Based on a safety analysis conducted by an NRC contractor, the staff has conclude the human use of these capsules results in insignificant exposure _s as depicted below:

Maximum Exposed Routine Exposuro Scenario individual Full time worker,- 8,000 Less than 0.7 mrem /yr

_ Worker administering "C-urea breath tests patients /yr Patient tests negative 0.38 mrem / capsule-Routine _ exposure of

. patients from "C urea

- breath tests

' Patient tests positive 0.18 mrem / capsule -

Member of puulic in the Less than 0.0002 mrem

' Release of 150 pCi of "CO, into ' administration area ' administration area Skin (100 cm 2) exposed for 5.8' mrad skin dose

- Rupture of a capsule . 0,075 pCi skin absorption .

causing skin contamination one hour prior to washing 0.029 mrem CEDE-

- of worker or patient -

2

Pathways in the Environment Based on an environmental report prepared by an NRC contractor, the staff concluded that the impacts associated with any releases of "C to the surrounding environment are expected to be very small and the expected risks are minimal.

The earth's atmosphere contains an inventory of naturally occurring "C of about 3.8 million curies (equivalent to the activity in 3.8 trillion breath tests), which is in addition to the hugt inventory of about 240 million curies in the world's oceans. The "C released into the atmosphere from the use of this test would mix with the globalinventory and expose the public and other biotic components of the environment to "C intakes from inhalation drinking water, and all possible food pathways in the same manner as naturally occurring "C, The current world inventory of naturally occurring "C results in an average dose to the public of about 1.25 mrem / year, and the release of 0.6 curies of "C from the total of 600,000 tests assumed to be administered annually (see the REGULATORY. 4 ANALYSIS section below) would result in an additional average annual dose of 2 X 10 mrem. This is far below the EPA reporting level of 1 mrem / year required under the Clean Air Act for routine exposures to a member of the public, or the 4 mrem / year EPA limit for public drinking water, in a total population of about 260 million people in the U.S., the collective annual dose from the breath tests would, be about 0.051 person-rem. In addition, the doses from normal use of breath tests, or from any accidental release of "C to the environment also are expected to be very small because the concentration of CO, released is very low and it would mix immediately with the atmosphere.

Collective Exoosures to Members of the Public The small doses from naturally occurring "C are of little significance to human heaith and the environment. Potentiallong-term impacts from widespread releases of the long-lived "C (5,730 year radiological half life) from breath tests were concluded to be insignificant.

Assuming that the testing in the U.S. would increase over a period of time to an average of a million tests per year for 50 years, the collective annual dose to tbs U.S. population would be about S person rom over the next 50 years. This dose is very small when compared to the annual collective dose to the U.S. population from naturally occurrin of over 300,000 person-rem. and about 78,000,000 person-rem from all naturally occurring radiation. Clearly, an increase of a few person-rem will not significantly change these exposures, and thus there is no expected impact from the widespread use of the breath test on the entire U.S. population.

- COMMENTS FROM THE ADVISORY COMMITTEE ON THE MEDICAL (ACMUI)

- This petition was discussed with the ACMUI at the October 1995 meeting. The ACMUI indicated that it endorsed the wide availability of this diagnostic test and that the radioactive drug could be used under a generallicense or an exemption, whichever the NRC thought to be procedurally easiar.

3

4 -

COMMENTS FROM'THE PUBLIC . -

The " Notice of receipt of petition for.rulemaking* was published for public comment in the -

Federal Reaistg on December 2,1994159 FR 61831).- A total of 315 pubhc comment letters,313 supporting (mostly form letters) and 2 opposing letters, were received.

The two letters opposing the petition made the following two comments:

(1)- The product should not receive an exempt status because the uncontrolled distribution and application of this produc,t could lead to significant risk to the pubhe, and

-(2) ' Medical uses should o' e restricted to short lived isotopes because of disposal problems presented by long lived isotopes.

The staff disagrees with both comments.

(1) As shown in the ' SAFETY ANALYSIS" section of this plan, the radiation dose to workers, patients, and the public is very low.

(2) - As discussed in the " Pathways to the Environment" section of this plan. the impacts associated with any releases of "C to the surrounding environment are expected to be very small and the expected risks are minimal. Also, as discussed in the

" Collective Exposures to Members of the Public* section of this plan, the small doses from naturally occurring "C are of little significance to human health and the environment. Potentiallong term impacts from widespread releases of the long lived "C (5,730-year radiological half life) from breath tests were concluded to be insignificant.

DRAFT RULEMAKING PLAN in accordance with Management Directive 6.3, "The Rulemaking Process," the staff

- draf ted a rulemaking plan in response to a petition for rulemaking submitted by Tri Med Specialties,Inc. Three alternatives were considered in the draft rulemaking plan:

Alternative 1 - Deny the petition.

Alternative 2 - Grant the petition via an exemption to permit physicians who

( e not " authorized users' to receive and use capsules containing 1 Ci of "C-urea.

Alternative 3 - Grant the petition via a generallicense to permit physicians

who are not ' authorized users" to receive and use capsules containing 1 pCi of "C-urea 4

Under the draf t plan, the staff would have develt ped a direct final rule amending 10 CFR Part 35 to permit, under a geretal heense, any physician to administer to patients d capsules

.containing one microcurie of C-14 as a diagnowe tool for detecting peptic ulcers cause by the Hekcobacter pylori bacterium (Alternative 3).

Distribution of byproduct material as exempt material requires an NRC heense; even in an

- Agreement State. Hence, manuf acturers and distributors hcensed by Agreement States would need to obtain and maintain both NRC and Agreement State hcenses to distribute the "C capsules as exempt material. This is not the case for byproduct material to be possessed and used under a yenerallicense. The staff viewed this potential duallicensing as an unnecessary burden with no safety benefit. Therefore, the staff did not recommend distribution to and use as exempt materialin the draf t rulemaking plan. In terms of pubhc health and safety, either Alternative 2 or 3 could be adopted because the radiological risk is negligible.

11,1996, a copy of the draf t In accordance with COMSECY 96-035 dated June rulemaking plan was provided to the Agreement States on October 1,1996, for a 30 day period of review and comment. Comments were received from ten Agreement States.

AGREEMENT STATE COMMENTS ON DRAFT RULEMAKING PLAN Six States (Kentucky, Nebraska, Colorado, Washingten, Utah, and Louisiana) supported the staff's recommended approach (i.e., grant the petition, Ci of "Cand ureapermit physicians who are via a general not authorized users to receive and use capsules containing 1 i Iicense). Kentucky indicated they already have provisions for a generallicense for 'in vivo

• use in their regulations.

One State, Oregon indicated that it would not permit administration of the capsules under a generallicense. but would continue to require that all physicians who administer radioactive drugs, including the "C urea capsules, be specifically licensed.

Three States. New York, Georgia and lilinois, opposed the general license approach recommended by the staff. Georgia and Illinois recommended that physicians urea who are not

• authorized users' be permitted to receive and use capsules containing 1 yCi of "C as exempt material. Georgia argued that their burden would be increased by distribution and use under a generallicense because of reports required from distributors, invoicing o physicians for generallicense fees, and possible amendment of all of their distribution licenses. Illinois stered that distribution of the capsules as exempt materialis consistent with the NRC's technical evaluation and would ensure that physicians could have accessd that if to the capsules without a specific or generallicense. Illincis further state were to require distribution and administration under a generallicense, Agreement States would need to incur the expense of modifying their regulations. Illinois seems to imply that they could avoid rulemaking if the NRC were to adopt the exemption approach.

However. as Georgia correctly observed, the exemption lh app that the widespread medical use of the capsules would involve no risk to the public hea t a'd safety of the environment, and would provide significant medicol benefits to the 5

population. Nsw York also stated that using a risk based regulatory d thatapproach, there need to regulate the capsules for their radioactive content. Further, New York arguein a generallicense is an ineffective means of regulatory controlno e RECOMMENDED APPROACH The staff has determined that the radiolopcal risk of this drug presents such a smal radiation hazard th t the capsules can be Treated without regard to their radioactivity.

Hence, no control of the capsules is neces tary for radiation safety af ter they are manuf actured and distributed, in light of tha, and in light of the comments from Illi and Georgia, the staff has decided not to recunmend distribution and use of th capsules under a generallicense. Rather, the sta'i is now recommending that Pa amended to permit the "C-urea capsules to be distributed to and used by any person, without need of an NRC (or Agreement State) license, who is permitted to receive a

-thethedrug.

drug under an appropriate Federal or State law go State agencies with the responsibility and Theauthority tothat staff believes regulate drugs (as is the c permitting other drugs that do not contain byproduct materials).

exempt receipt of the capsules by "any person who is permitted to receive and us drug under an appropriate Federal or State law,* rather than limiting receipt and u y,hysicians only will provide any controls needed for regulation of the capsule and avoid the need for NRC to amend its regulations if other Federal h or State agen permit under their authority the distribution and use the radioactive drug to perso are not physicians.

The staff believes that NRC should require the drug to be manuf actured under oart 32 license to ensure that capsules contain only one microcurie of carbon-14 not contain any other radioactive contaminants. Hence, conforming amendme be made to Part 32 to provide requirements for a specific license to manuf acture, produce, package, repackage, or transfer capsules c diagnostic testing. Licensees distributing the radioactive drug as an exempt would not be reliev -d from other applicable Federal (e.g., FDA) or State drug manufacturing and distribution requirements.

PREllMINARV REGULATORY ANALYSIS in the letter dated August 23,1994, the petitioner stated, if exempted, the C 14 breath test could be done by most doctors for less t cost to the patient. This 's :. consideraole savings over endoscopy and biopsy

- ($ 1000).

In a letter on November 30,1994, the petitioner stated:

6

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. The test is 95% accurate and quite inexpensive because of its simplicity. The test would permit doctors to determine easily whether or not ulcer patients have been cured of their infection. By providing the pubhc with an inexpensive, easily accessible diagnostic test, more individuals would be accurately diagnosed and treated for their H. pylori infection. This would save the United States an estimated

$500 million per annum over conventional therapy.

Tri Med estirotes annual benefits to be on the order of $500 milhon/ year. This assumes approximately 600,000 "C vrea breath tests / year, at an average cost of $100, in lieu of performing endoscopy at an average cost of $1000/ test, it assumes that the lower cost and gro'ter availability of an unregulated breath test would result in a complete substitution for endoscopy. Tri.Med's benefit analysis provides a measure of the total benefits associated with the test and does not focus on the incremental benefits of administering the test pursuant to 10 CFR 35.100 regulation (status quo) versus releasing the test to all physicians (NRC licensed and non licensed alikel. Implicit in Tri-Med's estimated annual benefits is the presumption that ncne of these "C tests and corresponding savings would accrue if the petition were denied, in reality, under the

-status quo, the '.est would be available and administered by physicians or clinics holding a license under NRC's Part 35. Further, Tri-Meo's estimate did not allow for the substitution of other non-invasive tests (e.g., serological test for igg antibodies to H. pylori antigen's) for both endoscopy and "C-urea tests. In addition, wire service articles dated September 19,1996, stated that the FDA has approved a non-radiological diagnostic breath test using "C for detecting the presence of H. pylori infections.

The staff's benefit analysis focuses on the incremental benefits of granting relief based on the petition. The analysis looks solely at changes relative to the base case or status quo. '

In this analysis, the comparison is between regulated and unregulated "C-ureatests. bmath tests, not unregulated "C-urea breath tests and endoscopies or other non-invas For the purposes of this regulatory analysis, the staff assumes that the same number of breath tests (i.e.. 600,000 tests) will be administered regardless of the level of NRC regulatory control. This view is predicated on the belief that each physician's primary motivation is to provide the best possible care to his or her patients. If the breath test is judged preferable to endoscopy, or other procedure, any physician not authorized to use the test will refer his or her patient to authorized users who could perform the test under existing NRC regulations. This appears fully consistent with standard medical practice, whcieby patients are referred routinely to laboratories and specialists for a wide array of

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tests and procedures.

in the NRC's analysis, the benefits of adopting the petition accrue as a result of reduced patient cost and reduced health care cost resulting om the elimination of the need for referrals from a physician who is not an authorized user (e.g., gastrointestinal specialist).

There would also be some regulatory savings because the NRC would not have to expend resources reviewinn new applications for specific medical use licenses. However, the NRC savings would ',,, small because the staff expects that few physicians who are not authorized ut.ers would apply for a specific NRC license for use of this one product.

The staff's benefit calculation is based on the assumption that a significant portion of the 600,000 patients would receive the "C breath test from physicians who are not 7

.a

~.e authorized users (e.g.i gastrointestinal sp3ctalists) instead of authorized users (s.g.,- _

ber of h

inuclear medicine specialists). Th3 actual savings would be depsndent on t e num y, tests ultimately administered by physicians who are.not authorized users therebyc eliminating the need for a referral. .

. The annual savings could be as high as'approximately $20 million'af there was a complete

. shift of the administration of the tests'from physicians who a're authorized users (i.e., base case) to physicians who are not authorized users. I

. The basis for this' estimate is'as follows; Assuming adoption of the petition eliminates the need for 600,000 referrals, patient savings in averted travel expenses (transportation andfpersonal time incurred with medical -

referral) would be:

~

Assuming round trip of 20 miles @ $0.25/ mile, and personal time of 0.5/ hours / trip valued at 825.00/ hour -

- 600,000 trips / year x (20 miles / trip x $0.25/ mile + 0.5 hours5.787037e-5 days <br />0.00139 hours <br />8.267196e-6 weeks <br />1.9025e-6 months <br /> / trip x $25.00/ hour);=- t

$10.5 million/ year Health Care Savings in averted administrative expenses (administrative costs incurred with i medical referral) would be:

600,000 patients / year x $19.00/ patient = $11.4 million/ year .

-l Assuming $19.00 (administrative cost / patient) as the differential between the cost ,

of an office visit to a general family practice physician by an established patient l

($45.90), and the cost to a new patient ($64.90 per visit) for completion of new e

patient paperwork, reviewing health history, maintaining medical records, etc. The -

patient who is referred to an authorized user (e.g., nuclear medicine specialist) for the ."C-urea breath test would most likely be a new patient for the authorized user.

Total S :vings:

$10.5 million/ year + $11.4 million/ year -- $ 21.9 million/ year

' Alternatively,if only 200,000 or 400,000 of the 600,000 tests were performed by a

- physician who is not an authorized user, the annual cost savings would be approximately .

$7 million/. year and $15 million/ year, respectively.

COMPARISON OF ALTERNATIVES

- , Altemative 1 - . Deny the Petition

- ~

This alternative woul'd maintain the status quo. 'Only physicians who are authorized users

Lunder Part 35'would be allowed to possess and administer thel"C-ures test. Any

- physician could apply to become an authorized user. However, the NRC expects few 3.

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-- physicians would apply for a Part 35 license for the sole _ purpose of using such capsu es tiecause of the requirement for training' and experience and the associated costs of obtaining and maintaining a Part 35 license. Alternatively, physicians who are_ not authorized users could refer theirl patients to physicians who are authorized users to

~

undergo the diagnot, tic test,-but tnis would add expense, inconvenience, and delay to an 1otherwise straight forward procedure.

Alternative 2 - - Grant the petition to permit the "C-urea capsules to be distributed to and used by eny person, without need of an NRC (or Agreement State) license, who i . permitted to receive and use the drug under an appropriate Federal or State law governing the distribution and use of-the drug.

Parts 30 and 32 would be amended to permit the manufacture and distribution of capsules containing one microcurie of "C-urea as an exempt material to any person. The staff has determined that the radioactive component of this drug presents a minimal radiation risk and; therefore, regulatory control of the human use of capsules for radiation safety is not

-necessary.

Alternative 3 - Grant the petition via a generallicense to permit physicians who are not

• authorized users" to receive and use capsules containing 1 yCi of "C urea for in vivo diagnostic testing.

Ci )

This alternative would permit any physician to receive and use capsules containing 1 "C urea ior human use under a generallicense. The health and safety concerns for this alternative are the same as Alternative 2. However,if this attemative were adopted, there could be a burden to those Agreement States and Agreement State licensees in States s

that assess licensing or registration fees for generallicense holders.

RECOMMENDED COURSE OF ACTION The staff recommends proceeding with a rulemaking amending Parts 30 and 32 in conformance with Alternative 2 for the following reasons:

• Health and Safety Based upon the analysis of the radiological impacts discussed above, there do not echnical reasons why the capsules, breath test materials, appear to be any safety or counting fluids and vials, and urine from patients cannot be treated without regard to their radioactivity,

e. Avoided Costs Under Alternative h physicians who are not authorized users would have to refer patients to authorized users to' undergo the diagnostic test. These referrals and 9

_3

att:ndant expense could be avoided under either Alternatives 2 or Alternative 3. ,,

l However compared with Alternative 3. Alternative 2 appears to be less burden for

• Agreement States and their licensees. ,

AGREEMENT STATE IMPLEMENTATION l

Rules pertaining to the distribution of products to persons exempt from NRC requirements f allinto the class of regulatory functions reserved to the NRC pursuant to the AEA and delineated in 10 CFR Part 150. Therefore, the staff's recommended amendment to Part 32 pertaining to the manafacture and distribution of capsules containing 1 Ci of "C - urea for *in vivo" diagnostic testing by persons exempt from licensing would be a Division 4 matter of compatibility. The amendment to Part 30 would be a Division 1 matter of compatibility since Agreement States would need to conform their regulations to recognize that possession and use of "C urea capsules is exempt from licensing. States (e.g.,

Oregon, and possibly others) would not be able to require that physicians administenng radioactive drugs to humans be specifically or generally licensed.

OGC LEGAL SUFFICIENCY ANALYSIS DEMONSTRATING THAT NO KNOWN BASIS EXISTS FOR t.EG AL OBJECTION OGC has reviewed the rulemaking plan and has not identified any environmental issues that would present significant difficulties in pursuing the proposed rule.

Since this rulemaking would address the resolution of PRM 3512 the staff will need to ensure that appropriate procedural actions are taken to close the actions associated with that petition. These actions incitde specifically granting or denying the petition for rulemaking, either in the Federal Register notice associated with the rulemaking or in a separate Federal Register notice, and informing the petitioner of the Commission's decision. The detailed procedures for responding h the rulemaking petition are contained in Part 11 of the Regulations Handbook (NUREG/BH 0053, Rev. 3).

ASSESSMENT OF LIKELY IMPACTS ON NRC AND AGREEMENT STATE LICENSEES This rulemaking would not result in any additional regulatory burden to NRC medical use licensees. Authorized users would continue to be authorized to receive and use this product for medical use.

SUPPORTING DOCUMENTS A regulatory analysis, an environmental assessment, and an OMB information collection approval package will be provided for this rulemaking.

RESOURCES 10

Resources to complete and implement this rule are included in the current budget.

LEAD OFFICE STAFF AND STAFF FROM SUPPORTING OFFICES Concurrino Official Staff level Workino Groun Bill M. Morris RES Sam Jones Donald A. Cool NMSS Donna Beth Howe Stuart A. Treby-OGC Marjorie Rothschild.

Richard L. Bangart OSP Lloyd Bolling David L. Meyer

.ADM - Mike Lesar STEERING GROUPS / WORKING GROUP There is no need for a steering group for this rulemaking. The Working Group is above.

i ENHANCED PUBLIC PARTICIPATION l

This rulemaking will be placed on the electronic bulletin board at FedWorld and ,

published in the Federal Reoister. i r

EDO OR COMMISSION ISSUANCE Because the arnendment involves a pohcy issue (i.e., the capsules would be any person who would be exempt from NRC re0ulationsh it is recommended Commission issue the rule.

SCHEDULE'

' Weeks from the date EDO/Comm approves

Proposed Rule: the Rulemaking plan 2 weeks Send proposed rule to office for concurrence 11

i l Send proposed rule to EDO 6 weeks L

Send proposed rule to Commission 8 weeks .

Receive Commission approval 10 weeks Publish an the Federal Reaister for a 75 day 13 weeks public comment period; and submit information collection approval package to OMB 4

12

...,,....q 9 e 2

AGREEMENT STATE COMMENT LETTERS e

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• COMMONwT.ALW OF KDITVCKY mANKrotT arm:iat: fSc.b) hAS h Turxt rom FUBUC Hl. ALM Cctober 4, 199o LLOYD BOLLING U S NUCLEAR REGULATORY COMMISSION OFFICE OF STATE PROGRAMS WASHINGTON D C 20555

Dear Mr. Dolling:

Kentucky has no opposition te allowing use of carbon-14 in one Cicrocurie amounts under a general license as proposed in the rulemaking plan for 10 CFR rart 35 (SP-96-107).

We already have provisions for a general This license for jn vivo regulation usebe would in our regulat ions under 902 KAR 100:050.

cequired to be amended to include carbon-14 as an authorized material. In the interim of revising the regulation, we wouldA licensing policy.

al. low the use under a general license as a form is required to be submitted for this license; however, only a signature is required. No additional inf rmation is required to be A fee is charged, on an submitted, thus a review is not required.

annual basis, for a general license.

Sincerely, A A10/-

icki D. Jeffs, Supervisor Radioactive Materials '.' nit 8

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-o October 14,1996 -s

$ l Mr. Lloyd Bolling

-Office of State Programs USNRC Mail Stop 3 D 23 Washington, D.C. 20555 RE:

Agteement States Letter SP 96107 Drah Rulemaking Plan 10 CFR i

Dear Mr. Bolling:

We agree with NRC's contractor's conclusion li h lth that and the widespri capsules containing one microcurie of carbon.14 h would opulation.involve no risk

- safety or the environment, and would p ovide significant medical benefits Using a risk based regulatory approach, thereh is, therefore, n  ;

Product for its radioactive content. This is espe (GL). '

The only reasons given by NRC for no: exempting f rers) the recipie all further regulation, is that manufacturers (and d thisinitial distributors would impose a other t would have to obtain NRC licenses authorizing exempt distribution, an regulatory burden on NRC. >

d the present time,-

. Since it appears that there is only one manufacturer l l iuipliesof thisthat- pro uct at this would seem to be at; inconsequential burden.dThe states draA that users rulemsking p an -<

there would be no regulatory burden resulting from a OLh designation, d so be in an

• under a OL would not have to register with NRC, as they did under thtGL Part 35 'and Agreement State regulations. i fr general license ccnditions (such as those in th ,

. possibility.of a regulatory burden on users of the pro uc ,GL invalid. . $4-4

40. n g-x-3 a -

- FAX: $10-457-5545 )

"CQhoneL $10-4571202 .

- _ _ _ . . - . . . . . _ . . - _ _ . ~ ,_ . _ . _ . . _ . _ .

. 2, ,

General Licenses always contam terms and conditions, since they are a means of_ -

exerting regulatory control over the ucers of a GL product. However, they are an ineffective regulatory tool that anempts to establish a gray area between exemption and specific  ;

licensing, and *.8 often leads to inadequate control ever hanrdous radiation sources and -

over regulation of trivial radiation sources.

Having concluded that this product needs no regulatory control after its distntution, it makes no sense to license end users in any way. If decisions on whether a product should be distributed as exempt are io be based on the regulatory burden on NRC, rather than on an appropriate risk benem analysis, we will distort our entire regulatory system. ,

The product should clearly be exempt, and NRC's process re engirrering group should ensure a sneamlined exempt distribution licensing process for it.

Sincerely, it a}gY6 Rita Aldnch Principal Radiophysicist .

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Draft Pu;emaxing F;an ..

Hs Lloyd:

• e favor Brsan Hearty asked that I sent !JRC you an E Mat; saying ena should proceed direct;y to final rule.

Alternative 3 and concur that tact Should you have any questsons regarding this2168.

(402) 471 E mail message please con Brian or me at my E mail address or call H0ve a nice day! ! !

t Joyce I

From: jar.E JA;;8: <wo:ccet;&srtpgate dpne stste :: .s-

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Subjects craft P..;e fer 0 14 :sps.;es Greetings L1 yd The proposed rule re " Medical Use of Capusies Centain2ng cr.e Microcurse of Carbon 14", PRM 35 12, appears appropriate, and should 90 forward If you have any questions, please call.

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From: Fratee. Terry et:f:313 e. t To:

MC1.'.W 9.;ac Date:

10 :: 96 8: )pm Subjects SP.96 1 5 To: Lloyd Bolling, OSP, NRC Rulemaking This is our response to your request for ecmments 1996. on the

• Specifically, Draft the Plan for 10 CFR 35" received by FAX on October 1, " Medic ' U** of Capsules form, con: erns draf. glan, in " Pre decisional" based en PRM 35 12 Containing One Microcurie of Carbon 14' and is We have two summary comments: 1) we support alternative 3 which would and c tablish a " general license" for use of this low risk diagnostic test; been 2) we beliese " parallel rulemaking' with the CRCPD should have considered rather than jumr#cy immediately to a ' direct final rule". is

)

A general license similar to that f or 'in vitro This* includes testing a r. vide range of (10registration CFR 31.11 considered process.

appropriate for this rulemaking.This will provide fee 1 a method required)  : of " authorization

• for (where a registrationlicensed by an Agreement physician users; will be low costallows the manufacturers of the capsule to be fullyregulatory States-if located therein; and provides the plus a database for later use in knowledge of usage withan its jurisdictiondegree of control over this new ovaluating a further relaxation in the eliminating the registration requirement).

product (for instance, W3-agree with the choice of 'D1 visionshould

- 3" for Agreement Statetocompatibility relate it to also be providedprocedures for the c1though a corresponding assessmentthe new classification expected State under the impleme Final Policy Statement on the Adequacy and Programs.

speedy resolution of PRMs and agency initiated hat NRC has Finally, while we supportrulemaking ef forts, we have never supported In the initialthe level of secrecy t devising, and cmployed in the various phases of its rulemaking effort.NRC staff to fixate on a e71u phase, to establish it allrm" themselves in afinal narrowly defined positionin the Commissa.n At the phase, it results scope of an issue and must be defended.

receiving a " decision

• paper that tries to reficct the interested parties as the varying and of ten complex positions We belie'Je of otherrulemaking should be an open the interpreted by NRC staf f alone. what your rationalization, process throughoist its course and, no matterviewed as "secrery" and simply feeds the use of " Pre decisional" documents alas, is some Agreement States' distrust of the public's. the licensees' and, that the Commission seek independent views on NRC's actions. We recommend issues brought before it and that the NRC staff publish (and/or each inactivelyissues and audience) distribute to a wideproposed final rule language for public ccsument,One step toward this tule language, andthere is adequate public involv6 ment. l king' process.

turn, to be sure goal is working with CRCPD in the proposed aparall el ru ema If you have any questions about this e mails...................................................

'This message from: Terry Frasee Quick ways to reach me:

Voice = 360 753-3461 FAX = 360-753-1496 Also," visit our Home Page at

- > http: //www.doh.wa. gov /ehp/rp a

-~_.

Proms Croag Jcnes < ::nes& del siste .: .s>

• To: WN;; WSF9 ". s c i D:ter ;0 ;4 96 ;; ;'p.m .

,i Subjectt 20mrents 3P 96 .:'

Ha L)?yd.

A number of staff within the Division Of P.adiatien 00ntro; nave reviewed the We draft rulemaking plan f or medical use of capsules containing carbon 14.(docket '*:.

eupport option 3 as cut 11ned in the pre Jeelsacnal rule.mak: 7 plan PRM 35 12) Thanks for ths early cppor*. unity to comment.

ud1. i nt e rne t ) ( " B S I NC LAI ade g . s t a t e . ut . u s ' )

CCs

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Fros:

Tor tra:ee Terry .-::f:; s.nw: ::n Dats:  ;; ;) 3( ;; ;;pr

Subject:

I- 37 34 ;;"

i T: :ne final paragrapn. ,

.j your positten en :nsa matter : rp;e:e'yregu;ated :r. uni:y early :n j We support

dould add, '

: .cu;dn :The nur:resu;; :: .ny::ve s;;l te .; easter 7 fcr : hose regulated andto: l regulattens, the decept.'

rulemaking process.We tried this in deveicpang :near :ne wa;;

cgg;ng were adequately.

views worked well. The regulated community fe;t ,

addressed, t 1

CULater;....  !

Bill ,

Fromt Frasee, Terry d. paris; i To; lab l Cc: phl; wpo{dhec4005. columbia 34.autryvr); rratliff; rquillin; 103075.1375; egrad. s ray. nb i clai;  ;

paul. merges; mmobley; 3volpe; dm0020; dilater;davidsen; ecma11.kwangler; l kxr01% albnydh2.bitnet ; rrknyebrh; teff100w; d 23a; robert,schell; hallisey; bill,s; k_ allen; tom _ hill; hwl .ebailey; g wa rkelley Sub3ect; SP 96 107 Date Tuesday, October-22, 1996 5:23PM l f

To: . tloyd Bolling, OSP, t;RC >

for comments on the " Draft This te our response to your requestreceived by FAX on October form, 1. 1996.

concerns Rulemaking Plan for 10 CFR 35" n " Pre + decisional" and is based t

~

Specifically, the draft plan," Medical Use of Capsules Containang One Microcurie i on PRM 35 12.

y

1) we support alternative 3 which would k diagnostic test; and 2) l We have two summary comments: establish a " general license" for use of this low risld ha i we believe

• parallel rulemaking" with the CRCPD shoufinal rule",

rather than Jumping immediately to a " direct (10 CFR 31.11) is l A general license similar to that for "in vitro" testingThis includes a registration of considered appropriate for this rulemaking.

process. This wall provide a method of " authorization" for a wide range (wh d by an Agreement physician. users; will be low cost i h some allows the manufacturers of the. capsule tothisbe newfully productlicenseSt

knowledge of usage within its jurisdiction plus a evaluating a further relaxation in the degree of control over eliminating the registration requirement).

(fer instance, State compatibility ,

d to relate it to We agree with the choice of " Division 3" for Agreementalthough i l

the new classification expected under the implementat on Final- Policy Statement <m the Adequacy and . .

i Compatibility offAgreement State Proc--9s. .

initiated h t NRC has Finally, tulemaking of;a while we support speedy resolution of PRMs and agenc  ;

6 . employed in tha,various p hase s of'its rulemaking effort.l tion of itheir h they own devising, and then feel

pbase c it allows

NRC

'to establish themselves staff in toa fixate on defined narrowly a so u position wh cresults in the Commissio At the final phase,.it e of-an issue and the varying j mustLbe defended. interpreted.by'NRC ,

- a " decision": paper that tries to reflect the-scopauus of ten compl I l

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- 62704 SP Thomas W. Ortager Jim Edgar Director 2' )

Governor aet- .

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f October 28,1996 u>

Paul Lohans y Deputy Director -::

OfRee of State Programs J, s Mail Stop 3D23 ,$

Ofnce of Governmental and Public Affairs

• U.S. Nuclear Regulatory Comrdssion Washington, D.C. 20555

~

Re:

Draft RulemaMng Plan entitled " Medica! Use of Capsules Containing One i

Microcune of Carbon 14."

i

Dear Mr. Lohaus:

The Illinois Department of Nuclear Safety (the Department) hereby su comments on the referenced rulemaking plan. The proposed rulemaking repres changes to 10 CFR Part 35 to authorize the commercial distribution an microcurie C 14 capsule for in vivo diagnostic testing for peptic ulcers under General License.

he Department believes the best option is Alternative 2, in which th would only need to issue a license for the r-M=e and distribution of capsules in ace /.ra with 10 CPR Part 31 Distrib have access to this material without a specine or general license, ne d manufacturer / distributor exempt CA#on licenses will be far fewer t 4s'aa) that would be issued nationwide to physicians who of licenses (or .

potentially une this material. >

' ;' - ~ W of Alternadve 3 would require the NRC and each of t '

Agr e States to have costly rulemaking ped === to add a general license l l to '

the segulations of each agency. General licenses should be used on of control is desired for the product. De NRC's technical analysis ind controls are warranted, so Ahernadve 2 is appropriate and the le S f'-R "y

-m 1 = - - - - - __ - - -

g 7

Paul Lohaus Page 2 a October 28,1996  ;

The Department appr:ciates the opportunity to provide its perspective onl draA rulemaking plan. If you have questions regarding these items, please contact me  ;

or Steven C. Collins at (217) 785-9948.

Thomas W. Ort i \

Director TWO:meb cc: Jim Lyn:h State Agreements Officer l

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Yr. Licyd Bothng Office of State Programs USNRC Mail Stop 3 0 27 Washingtoa DC 70555 Deaf Mr. Bolling:

This is in ruponse to All Agreement States Letter SP 96107 Draft Rule Making support A.temative 2. Although inis places an mitial regulatory burden on the  ;

distrbutors and the Agreement States. This should not place any undue regulatory burd licensees wishing to distribute the one microcurie carbon 14 capsules. The caps manuf acturer to physicians. As there does not appear to be any radiologicalimpa ,

- the analyzing laborotory would not need to be licensed. Agreement States are alw of corgatibility. Therefore, we consider the regulatory burden to be minimal to include th rulemaking.

We do not agree with Alternative 3. granting a generat license. Our regulatory bu' Alternative 3. Although Alt:rnative 3 may not cause a regulatory burden on NRC,it to Georgia licensees, the distributors of the capsules, and will result in generallic physicians.

The specific regulatory burden on Georgia licensees would be as follows:

1, We would continue to require the distributor to send us a report quarterly as f or distnbution under a generallicense.

2.

We will be required to invoice the physicians for the generallicenses fee, w to a person receiving under an exempt distribution license.

3.

We may have to amend all of our distribution licenses to allow Ior dinri generallicense. This will add an additional cost to our licensees f not he c.- used by energt distribution.

We recommend procoadmg with a direct final rule amending Part 35 in ronfor Sincerely Thomas E. Hill, Manager Findioactive Materials Program

' TEHlkic i

= '

Martha O Dabblee < Martha G Ol'eBl.EE40hdma;1 nr state Or. usa ,

Frost ~~

~ Tot 'a'!C 1. WN P 9 ' l eb s 12 6 96 4: 05pm -

Dete OSP F!1.E COOE: SP A 4 Fet;t;:n f:r rule: .ar. n; f :: 0-;4

Subject:

capsules for helterbacter ,

Hello. 1,loyd.

diagnestic procedures under ger.eral Oregon doesn't intend to authorize an /tv:

license. Persons vno use this diagnostic precedure must ce spe ci f i cally regulat20ns suptake, dilution, &

authorized under -i' 6 or equivalent

rizes only in vitro procedures b/ general 12 cense.

- excret ton) . Ore Thank you for the tranoct 4pt of the flRC Briefing that we all attended on Wednesday 13 Novembec. I was glad to see the trJREG finally published.

Martha CC: udl . inte rnet 3 ("Chri st) *_L_h TKLE&ohdmail .hr state . .

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PDk SA1C IH7,97 0SS Tc: Joseph Mate Ofrice of Nuclear Regulatory Research U.S. Nuclear Regulatory Commission 11545 Rockville Pike Rockville, Maryland 20852 ,

From: Abe Zeitoun MCkW Date: April 4,1997 S:hject: Safety Report for the Use of C-14Urca Capsules for Detection of11elicobacter Pylori Bacteria in the liuman Alimentury Tract

'lho Safety Reportfor the Use ofC-HUrea Cajmdesfor Detection ofHelicobacter Pylori Bacteria I 1 the Human Allmentary Tract prepared by Regh.ald L. Gotchy, Ph.D., CHP, i.ewis Battist, Ph.D. ar.d Roy Kcrimi, Sc.D. 'Stience Applications Inteniational Corporation, prepared for U.S. Nuclear Regulatory Commission, Washington, D.C., May 1996 is not a proprietary document and can be used for r blic i information.

Please note that the second paragraph of Section 3.0, Summary and Conclusions, should read as f;llows: "The doses would also be fan below the regulatory limits for members of the general public." Table 1 (Smuma.,/ of Results of Censervative Doses to Workers and Members of the Public) (2 second colunm, last row) should read " Skin (100 cm 2) exposed for one hour prior to washing: 0.075 pCi skin absorption". Table 1 (3 third column, last row) should read "5.8 mrad skin dose, 0.029 mrem (CEDE)."

5 % =

SAIC ID: APP. 07'97 15:17 No.006 P.02

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a 9

Table 1 (cont.)

Release of contents of 600 Pregnant, lactating mother, and Len than 0.00068 rnrem to patient sample balloons from a year old child visiting embryo, and fire measurements laboratory less than 0.00065 mrem to a child Driver trapped in van for one <

Release of"CO: from Less than 0.54 mrem >

oxidation of 150 capsules in hour with no air tumover delivery van Exposure of patients in waiting Patients exposed for 5 minutes less than 0.000007 micm room from fire releasing 150 to 1/10th max. concentration in uCiinto administration area adrninistration aren Administration of "C urea HP~ patiut receiving a 1.1 mrem capsules maximum of three capsules Administration of"C uien llP* pregnant worr . 0.48 mrem capsule to re wrong patient 180 day old fetus 1.3 mrad Administration of three "C. IIP pregnant woman 1.4 mrem urea capsules to patient 180 day old fetus 3.9 mrem Rupture of a capsule causing Skin (100 cm 8) exposed for one 5.8 mrad skin dose, skin contamination of woiker hour prior to washing; 0.029 mrem (CEDE) or nailent n10s uri skin absorntinn _

23 M%Wtf k/' '. _ - _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ - - _ _ _ _ - .

, SAIC' ID: APR 07'97- 15t18 No.006 P.03  !

y O

o 2.4.3 Dhpesel ofSekerHierten Fisid Usedfor Meeswoment of Perlent Sennples The average patient sample counted in liquid scintillation Duid is on the order of 0.0006g pCi; for a given fluid volume of about 15 ml(Marshall, et al,1991, p. 439), the concentration would be about 3.sx104 uCi/g(6.8sl0d uCi/ vial x vial /15 ml x ml/l.2 g). His is about thrw orders of magnitude below the NRC standard of 0.05 uCi of "C per gram of waste, below which Ikenwes may dispose of the material as ifit were not radioactive (NRC,1991; $20.2005).

However, since the fluid contains toluene and xylene which are classified by the Environmental Protection Agency (EPA) as spent solvent huardous wastes, theit disposal in landfills could cause the

.l Resource Conservation and Recov:ry Act (RCRA) to be an Applicable and Relevant or Appropriate Requirement (EPA,1991). Because of these concerns, the current disposal methodology involves incineration. N annual amount of scintillation fluid that would be expected from a hypothetical 1 j

- measurement laboratory 1: about 750 L, and the collected fluide could easily be sent to commerotal waste incir,es= tors for disposal. De total annual fluids volume for 600,000 samples per year (half from HP' )

patients and analyzed in 12 hypothetical laboratories) would be about 9 m'. ben if all the liquid were j

. burned in the same commercial facility, atmospheric dispersion f,om an incinerator stack would not '

result in significant public exposures to "CO,. For example, assuming average meteorology l (Pasquill C stability, and a 3 m/s wind speed), t he ru/Q dispersion factor (m 8) would be on the order of -

10d m8 at 100 meters from a 20 meter stack (Nner,1969). The annual release rate would be 410 pCl/ year, or 1.3x104uCi/s, with an average concentra' ion (x) of about 4.3x10 " uCl/L.

Conservatively assuming that an adah is downwind at 100 m and bruthing at a rate of 20 L/ min for en 4

entire year, the dose to this individust would be on the order of 1.2x10 mrem. Clearly, disposal of the I

entire annual production at an incinerator would result in an inconsequential worst. case exposure of a member of the public. Disposal of the fluids at multiple incinerators, with eac5 incinerator burning smaller quantities, would result in smaller public exposures to individuals. Scintillation vials would be at

background, and could be recycled to reduce wastes.

4 2.4.4 Dinporet of Urinefrom Patienn Ghen Breath Tests Urine from patients given "C-urea capsules contain : mall amounts of "C. urea; the amont will he largest for HP patietits with almost all of the "C.urca excreted in urine (Tri Med,1996a). NRC

, . regulations in 10 CFR ll20.2003(b), already states that urine containing small amounts of radioactivity from patients undergoing diagnosis or therapy using nuclear medicine applications is not subject to the limitation in 10 CFR ll20,2003 (a), and may be disposed in the sanitary sewer.

3.6

SUMMARY

AND CONCLU$10NS .

Table I summarises the resuhs of the analyses in this report. As can be seen, there are no expected impacts of consequence fkom the proposed use of "C urca tests under a general license or exemption.

Both r.ormal and accidental releases would result in small increases in the worker's annual dose (300 '

mrem) from naturally occurring rdiation in the environment (NCRP,1987b, p. 53). Such doses would also be far below the regulatory limits for radiation workers (5,000 mremlycar; NRC,1991, $$ 20.1201).

For individual exposures, the test doses woula generally be less than received annually from naturelly occurring "C (about 1 1.5 mrem /ycar, NCRP,1985, p. 2; NCRP,1987, p.47).

De doses would also be far below the regulatory limits for members of the general public .

20 .

b

.,J.,., , ~ , .~.[

)

~

Safety Report for the Use of C-14 Urea Capsules for Detection of Helicobacter Pylori Bacteria .

In the Human Alimentary Tract Prepaied by:

Reginald L. Gotchy, Ph. D., CilP, Lewis Battist, Ph. D.

Roy Karimi, Sc. D.

Science Applications International Corporation Under Contract with ICF Subcontract No. 7-01 NRC 960065 Task Order No. 4 May 1996 Prepared for:

U.S. Nuclear Regulatory Commission Washington, D.C.

s

- Y '* Y l

Executis'e Summary Tri Med Specialties,Inc.,in accordance with Title 10 Code of Federal Regulation, Pait 2 Subpart Il-Rulemaking has petitioned the United States Nuclear Regulatory Commission (NRC) to allow for the general licensing and/or exemption for commercial distribution by licensed phannaceutical ruauufacturers of a capsule containing one micro Curie ( Ci) of "C. urea for in vivo diagnostic testing.

1hese capsules are to be used to detect the presence of the bacterium liclicobacter pylori, a cause of peptic ulect.

The NRC prosided a task order contract to ICF/SAIC for providing technical as.,istance and imlemaking suppcrt in evaluating the Tri Med Specialtics' petition. Task I of the contract required preparation of a safety report evaluating worker, public, and pat;ent radiation safety hazards associated with handling and administering the I pCi capsules of "C-urea from the points of distribution through waste disposal.

This report documents the potential impaces of routine storage, administration, and disposal of capsules containing "C-urca. Patient samples containing small fractions of the total "C administered for the breath test to detect the presence ofilelicobacter pylori bacteria in the human digestise system. The report also documents the potential dose to patients receiving the capsules, and potential impacts on members of their families and the general public who may come into contact with patients fallowing their breath tests. In addition, this report documents potential exposmes of workers and members of the public resulting from human errors (including errors in administration and skin contamination of health care workers), transportation accidents, and facility accidents such as fire.

This report, based on conservative analyses ofimpacts, concludes that:

(1) the potential impacts associated with the use of the proposed "C urea breath test are so small they are well within normal variations in natural background radiation; (2) the impacts are below all regulatory limits and below the level which would require reporting to the epa under the Clean Air Act (NESilApS);

(3) any potential risks are small relative to the risks avoided (e.g., ulcers and cancer of the stomach and duodenum), and individuals would not be expected to experience any radiation related risks; and (4) there do not appear to be any technical reasons that "C-urea capsules, breath test materials, counting fluids and vials, and urine from patients cannot be treated as if they were not radioactive.

e8 TAHLE OF CONTENTS Exce6tive Summary -

1.0 INTRODUCTION

2.0 SAFETY EVALUATIONS 2.1 Worker Exposures 2.1.1 Routine Exposures of Workers Administering the Tests 21.2 Routine Exposures of Workers Analyzing Patient Samples 2.1.3 ' Accidental Exposures of Workers Administering the Tests

> 2.1.4 Accidental Exposures of Wothers Analyzing Patient Samples 2.2 Exposure of Members of the General Publie 2.2.1 Routine Exposure of a Member of the Public from Storage and Administration of"C-Urca capsules 2.2.2 Routine Exposure of a Member of the Public from Storage and Measurement of Patient Samples 2.2.3 Accidental Exposure of a Member of the Public from the Storage and Administration of"C-Urca capsules 2.2.4 Accidental Exposure of a Member of the Public from the Storage and Measurement of Patient Samples 2.2.5 Accidental Exposure of a Member of the Public from Transportation of"C Urea capsules or Patient Samples 2.3 Patient Exposures 2.3.1 Routine Patient Exposures from "C. Urea Tests 2.3.2 Errors in Administration of Tests to Patients 2.3.3 Accidental Exposures of Patients 2.4 Disposal of"C-Urca capsules or Materials Used for Collection or Measurement of Patient Samples 2.4.1 Disposal of Outdated Capsules 2.4.2 Disposal of Mcterials Used for Collution of Patient Samples 2.4.3 Disposal of Scintillation Fluid Used for Measurement of Patient Samples

-2.4.4 Disposal of Urine from Patients Given Breath Tests 3.0 -

SUMMARY

AND CONCLUSIONS

- 4.0 - REFERENCES

. . . _ _ _ ~

TAllt.ES Table i Summary of Results of Conservative Doses to Workers and Members of the Public FIGURES Figure I liposure Pathways for the Regulatory Analysis Figure 2 liiokineties Model for i uCi "C Urea fireath Test

1.0 INTRODUCTION

Radiation do<.es associated with the distribution, use, and disposal of "C-urea capsules used for the detection of llelicobacter pylori bacteria (ll pylori, or simply llP) in the human digestive tract are evaluated in this report. The conservative estimates of potential impacts provided in this report are intended to support the NRC decision-making procers related to a petition for a general license and/or exemption for this product. The petitioner is Tri Med Specialties, Inc. of Charlottesville, VA. Doses associated with the rnanulacture of "C urca capsules are not addressed for this petition because Tri Med currently has a 10 CPR Part 30 specific license for the manufacture and distribution of these materials.

Potential impacts associated with manufacturing the breath test materials have already been addressed as part of that license application review. The exposure pathways considered in this regulatory analysis are shown in Figure 1.

The breath tests are pcalble because the "C urea in the capsules is metabolized by ll. pylori bacteria in llP' patients :o form "CO (and 2 ammonia), while patients without II.pylor/ present (IIP-) cannot effectively metabolize urea and produce essentially no "CO 2 in their breath. The "CO2 is collected in a myle sample balloon (very tough and essentially leak proof), sent to a measurement facility where a fraction of the total breath sample is collected and counted by liquid scintillation counting (about 90 percent counting efficiency). Since even Gny amounts of "CO 2can be detected by this simple test, it is extremely sensitive for the ,sence of any ll. pylori, and has a very high reliability. A quantitatis e relatio ship between the degree ofII.pyloriinfection is not necessary, since any infection will be treated if detected.

The alternatives to the orenth test include gastric endoscopy accompanied by biopsy of digestive tract tissues to examine for 11. pylori. The tests are expensive, uncomfortable, of lowest sensitivity (i.e., if the infection is missed ir$ the small tissue biopsy, the test would be negative), and have associated risks of mortality and infection. Other tests include scrological tests for antibodies produced in response to the presence ofil. pylori antigens in the GI tract. These tests are also relatively inexpensive, but cannot be adminis,ered again following an initial treatment for many months.

2.G SAFETY EVALUATIONS The subsequeni liscussions provide the results of the conservative analyses performed for this safety report. These analyses are based on the foli +ing assmnptions and input parameters:

- About 50 percent of the patients are llP'(Tri-Med,1996a). The results of clinical trials indicate that the percentage orilP' patients changes with demographics and ethnicity (Peura, et al,1996).

Studies have shown that about 20 percent of adults in the general population are llP' (Chey, et al,1996), while Tri-Med (1996a) estimates that about 50 percent of all patients treated for gastric problems are llP*. This assumption leads to a conservative estimate of public exposures from "CO2 exhaled by llP' patients.

• Exposures of the general public to "CO, exhaled by patients doing breath tests were from llP' patients, since those patients would exhale most of the "CO2 (produced in the G1 tract from H.

pylori bacteria metabolizing the urea capsule).

S C.

• Patient dose calculations are based on the assumption that all patients were llP ThellP-patients excrete most of their 1 pCi intake through their urine at a much lower rate (longer duration), therefore these patients receive the higher internal radiation doses, and in the case of a woman patient the dose could scach an embryo / fetus and/or a breast-fed 1 year old child.

• For exposure of adults to "CO 2, the dose conversion factor of 0.025 mrem /uCi inhaled was used.

This factor was derived from the NRC's Annual Limit on intake ( All) for inhaled "CO, for an adult radiation worker (2x10' uCi) and the 5,000 mrem annual worker dose limit (NRC's tegulation 10 CFh Part 20, Appendix II Table I, Column 2).

+ For exposure of an embr>o/ fetus carried by a woman patient receiving a breath test, the current recommendations in NUREG/CR 5631 were followed: specifically it was assumed that the exposure would occur at 180 days gestation, since the dose conversion factor is the highest at that time (1.29 mrad /uCi as bicarbonate reaching the mother's blood).

• For clinical or laboratory workers, the potential inhalation dose is based on the amount of "CO 2 that would be exhaled by llP' patients into fixed volumes of air (llP patients exhale essentially no "CO 2).

• The potential concentration of "C in exhaled breath ofIIP' patients was based on the measured values of exhaled samples from 200 people in a clinical study (Peura, et al,1996); the average measured activity reported during the first half hour after capsule administration was on the order of 1,500 dpm in i mmol of CO 2from a 2 liter balloon sample (this is an average value calculated using Figure 1 of the Peura report). Using the data provided in Figure 1 of Peura report, it was estimated that an llP' patient would exhale about 40 percent of total "C intake in one hour.

+ In order to conservatively estimate dose, it was assumed that the "C released into the encloseJ air space of all facilities considered (including small automobiles) would begin immediately af ter taking the capsule, and the room concentration would not be diluted by air turnoser during each inhalation exposure period.

• For most accidental releases of"C, it was assumed that the release form was "CO2 resulting either from oxidation of capsules by accidents (e.g., fire) or from f ailed patient sampb balloons (one exception was for skin contamination resulting from a capsule rupture at an administration facility).

• Each samnle of a patient's exhaled air would have a volume of 2 L and contain about 80 ml of CO2,(about 4 percent of exhaled air is CO 2, Cember,1987). For diagnosis and measurement parposes, only I mmol of CO2 (or 22.4 ml) in the balloon sampic is required to saturate a i mmol solution of hyamine hydroxide (the collecting fluid). Therefore, more than 70 percent of the total sample volume (for women, this volume would generally be lower) would be exhausted into a ventilation hooo to the outside air following extraction of the approximately 22 mi of CO2 ,

or 0.55 L of air ( 22/80 x 2 L). The total activity of a typical 2 L sample balloon of an lip

• patient is approximately 5400 dpm.

6

. The aserage "C concentration in llP' patients exhaled breath would be about 0.0012 uCi/L

[1,500 dpm x uCi/(2.22x10' dpm x 22 ml/80 ml x 2 L)).

. To reasonably estimate the potential exposure of health care workers, it was assumed that half of the patients being tested were llP* and would exhale "CO,into the adminictration room for one hour.

. All patients would be scated in a waiting room (assumed to be 20 ft x 15 fl x 8 ft = 2,400 ft' or 68,000 L), with no significant air turnover during a one hour exposure period (i.e., a tight facility with almost total recirculation of air in each room), but a complete turnover of room air occurring during the time the four test patients leas e the facility and four new patients are received for the next round of tests.

. For an embryo / fetus carried by a member of the general public that is exposed to "CO2 (exhaled or released in an accident), it was assumed that all the inhaled "C would reach the matemal blood, and that the dose conversion factor would be the same as for exposure of the embryo / fetus to "C urea ingested by the mother (i.e.,1.29 mrad /uci; Sikov, et al,1992).

. For exposure of children to "CO 2, it was assumed a 1. year old child, who was still being bread fed, who was also exposed to the same "CO, as the mother; the inhalation dose cons ersion factor for the child (5.6 mrem /uCi inhaled) was taken from ICRP Publication 56 (ICRP,1989); the ingestion dose conversion factor for the child (5.9 mrem /uCi of"C ingested in mother's milk) was taken from ICRP Publication 67 (ICRP,1994).

. The average data from the 5-day Tri-Med study (Stubbs,1996) show that in llP subjects, 84.3 perces.: of the "C was excreted in the urine, whereas in llP' subjects,39.8 percent of the "C was excreted in the urine in the llP' patients, only 2.4 percent of the "C was excreted as CO 2 and approximately 13 percent appeared to remain as a long component fraction with a forty day half life. The llP' patient excreted 54.3 percent of the C-14 in the breath and only 5.9 percent remained as a long component fraction. Based on the above data, the EfTective Dose Equivalent (EDE) was 0.38 mrem / Ci for an llP- individual and 0.18 mrem /uCi for an llP' individual.

. Minute volumes and respirate ; ates for exposed persons were taken from ICRP Publication 23 (ICRP,1975; Table 120), and are summarized below:

Subiect Rnting 1.ight Activity licavy Work Adult Male 7.5 L/ min; 15/ min 20 L/ min; 16/ min 43 Umin; 21/ min Adult Female 6.0 Umin; 15/ min 19 Umin; 20/ min 25 Umin; 30/ min (Pregnant) 10 Umin; 16/ min NA NA Child (1 yr) 1.5 Umin; 30/ min NA NA

. In order to reasonably model ana!pu for the proposed action, it was necessary to estimate the number of capsules or patient samples a worker might be required to handle each year. For purposes of analysis, it was assumed that a total of 600,000 tests would be conducted each year 7

in the U.S.. These tests would be performed at 12 laboratories comparable to the Trrhied facility, each analyzing 50,000 samples per year. The bases for these estimates include:

Tri Nied provided NRC with an estimate of saving of $500-million per year in the U.S. if all endoscopies and biopsies were replaced by the "C urca test; at an estirnated savings of about $900 per adtrinistration ($1,000/ endoscopy -

$100/ urea test), this amounts to about 560,000 endoscopies / year w hich could potentially be replaced by "C urea breath tests (Tri-Med,1994, p. 3);

Discussions with Dr. David Peura of the Unis ersity of Virginia hospital indicates that he currently gets about 100 referrals per year for the "C urea test (Tri-Med, 1996b); assuming a similar interest nationwide if the test were made widely available, a physician base of 6.300 gastro-enterologists in the U.S. (as of 1993),

would yield 630,000 tests per year; and Drs. Matthew Combs and Marshall 11arry of Tri-Med indicated that the company expects to provide only about 50,000 test kits per year (Tri Med,1996c).

2.1 Worker Exnourn In this safety report all individuals invoh+d in the administration of the "C urea capsules and collection of breath samples, and individuals involved in storing and analyzing patient samples are considered potential workers.

2.1.1 R<>utine lhparsures esfIl'errker *1 ministering the Test Conservative analyses, as described in this section, show that routine doses (committed elTective dose equivalent, CEDE) for these workers are unlikely to exceed 0.7 mrem /> car.

The assumptions used in this analysis included:

• The worker who administers the test is assumed to work full-time (8 hours9.259259e-5 days <br />0.00222 hours <br />1.322751e-5 weeks <br />3.044e-6 months <br /> / day,2,000 hours0 days <br />0 hours <br />0 weeks <br />0 months <br /> /> car), administering capsules containing "C-urea for 11. p) lori tests and collecting the breath samples in mylar balloons for analysis.

. These workers would admir.ister on average about 4 tests per hour with all patients in a waiting room having a volume of 68 m'. The number of tests were based on an expert estimate that as many as 3 tests per half-hour period might be completed (Marshall, et al,1991, p. 444).

. A resting respiratory rate of 7.5 Umin was used for each patient,(it was assumed all patients were adult males to maximize the amount of "C exhaled).

• Each IIP

• patient would exhale about 0.0090 pCi/ min (0.0012 uCi/L x 7.5 Umin), or about 9.27 uCi (or 27 percent of the total intake) during the first half-hour post-administration. During the first hour, about 0.4 uCi(or 40 percent ofintake) of"CO would 2 be exhaled into the room air.

Since only half of the pati nts (on average) would be expected to be llP', a total of about 0.80 pCi could be released to the room from 4 patients treated each hour.

8

[

. The exhaled "CO 2would instantaneously mix in the room air, and the worker would breath the air at a rate of 20 IJmin (it was assumed 'o be a male doing light work to maximize potential inhalation intake). Each worker would inhale about 0.014 pCi(0.80 pCi/68,0t)01. x 20 Umin x 60 min /hr) each hour. This was assumed to be repeated for 2,000 hours0 days <br />0 hours <br />0 weeks <br />0 months <br /> per working y ear, for an annual dose of about 0.70 mrem /yr (0.014 uCi/hr x 0.025 mrem /uci x 2,000 hr/ year).

j There would be no expected worker doses from routine handling of undamaged capsules by workers p administering the test.

2.1.2 Routine Exposures of WarAers Analy:Ing Patient Samples

\

During normal operations, there would be no expected worker doses from routine handling of undamaged samples. Any residual activity in the sample balloon, after the test would be released through a ventilation hood to the atmosphere. These workers could be exposed to "C if a damaged 1

sample balloon is received. Conservative analyses described in this section show that radiation doses to workers from damaged balloon samples are unlikely to exceed 0.0011 mrem / year. While there is no data regarding leakage of breath samples from mylar balloons,it was noted that excessive leakage rates would not only be economically unacceptable for inexpensive test procedures, but would also result in too many delays from retesting of patients to be a reliable test procedur,:. For this analysis,it was conservatively assumed that:

. Each laboratory would receive 50,000 samples a year, or 200 samples each working day (5 days a week).- It was cssumed that a maximum of 1.0 percent of the 200 balloons received each day i

would leak all of their contents into a storage room (with a volume of 68 m') where a clerk would log in each sample box as part of the quality assurance program. Logging was considered to be a light activity, with an average volume breathing rate of 20 Umin.

. Logging was assumed to involve removal of a bar code from each sample and placing it into the log with the date of receipt, sample number, patient's name, etc. It was assumed that each sample would require on the order of 50 seconds, or 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> for 200 samples. Therefore, the clerk would be in the storage area 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> a day, or 1,000 hours0 days <br />0 hours <br />0 weeks <br />0 months <br /> per year,

. The worker's dose was estimated based on the assumption of a "C concentration of about 0.0012 pCi/L in an llP' patient sample balloon, a uniform mixing of the leaking sample balloons in the storage room air, and an air turnover every 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> (after the worker leaves). The resulting annual dose would be 0.0011 mrem (200 samples x 0.01 failed x 0.0012 uCi/L x 2 L x 0.5 llP'/

sample x 1/68,000 L volume x 20 Umin x 260 min / day x 250 days / year x 0.025 mrem /uCi).

2.1.3 Accidental Exposures of Workers Administering the Test Two potential accident scenarios have been hypothesired. First, it was assumed that a Gre accident would oxidize the total inventory of an administration facility, or 150 capsules (150 pCi), after which a worker would extinguish the Dre. Second, it was assumed that during administration of a capsule, the capsule would break and the content of the capsule would spill on to the worker's skin. Conservative analyses of these scenarios show that it would be unlikely that any worker would receive a dose (CEDE) in excess of 0.035 mrem from the Dre accident, or a skin dose in excess of 5.8 mrad and a CEDE ir, excess of 0.029 mrem from accidental breakage of a capsule.

9

Accidental Fire. Inhalation Dose One of the greatest sources of potential exposure of health care workers is from accidental releases of "CO 2resul ing, t from Gres which might oxidire an entire stored inventory of capsules. According to the petition, the largest shipment of capsules expected to be received by any one unlicensed facility would t -

on the order of 150 (Tri Med,1995, p.1). While it is believed that most users of the proposed breath test would not ins est in such large inventories when regular overnight delivery of capsules is possible, the -

150 dose shipment was assumed to havejust been received in order to conservatively analyze the potential radiological consequences.

For purposes of analysis, the following assumptions were made:

• A small Orc limited to the immediate storage area of the capsules (e.g., a storage cabinet containing combustible liquids, such as alcohol) occurs which cannot be extinguished by a sprinkler system.

• The Ore oxidizes the entire contents of the urea capsules, releasing 150 Ci as "CO2 irito the administration area (assumed to be 68,000 L as for routine exposures).

• The Ore is extinguished quickly by a worker using a Gre extinguisher.

• The resulting smoke sets off the smoke detectors, resulting in the evacuation of all other personnel and patients from the facility while the worker extinguishes the Gre.

• The relcased "CO2 is completely contained within the administration room during the time the worker is extinguishing the Hre (i.e., with no the room air circulation), and the Gre takes 15 minutes to put out.

• During this time, the worker (assumed to be a male to maximite intake) is involved in heavy activity, breathing 43 Umin for 15 minutes. The inhaled volume would contain about 1.4 pCi of "CO 2, resultbg in a dose of about 0.035 mrem.

l'ollowing the Gre the remaining room air was assumed to b. ventilated from the building to remove

, residual smake before anyone was allowed to reenter.

As shown below, the uoses to the general public outside the administration area from the released activ:ty would be much lower than the dose to the hypothetical worker. The released activity would be mixed with the outside air, and concentrations a short distance from the point of release would be orders of magnitude lower than experienced inside the administration area.

Lecidental Skin Exoosure it is possible, although very unt!Lely, that a "C-urea capsule could accidentally break open, spilling some of the contents onto the skin of a worker. After such an accident, it was assumed that the worker would attempt to brush oft some of this material, spreading it over the skin of the hands. The resultant skin dose and w hole body dose (CEDE) from the spill are estimated to be about 5.8 mrads and 0.029 mrem, respectively.

10

8

%c following assumptions were used to estimate the skin dose :

• The contents of a I pCi capsule is 3.7x10' liq: assuming that 25 percent of the capsule contents remains on the skin for one hour after the initial decontamination effort (brushing off from the skin), and is distributed over an area of 100 cm 2

, resulting in contamination of 9.25x10' ilq/cmt

+ Assuming that the "C source on the skin can be approximated by an in0 nite, uniform plane

• source of 9.25 x 10 ll1)/cm 2, the resultant skin dose at 0.005 cm from the dermis (equivalent to the depth of epidermal layer)is estimated to be 5.8 mrads based on a calculated dose rate of 626 nGy/ hour per i liq /cm2of a similar source (Cross, et al,1992).

• One hour following initial skin contamination, the worker was assumed to wash the material from the skin with soap and water. It was assumed that 30 percent of the radioactivity, or 0.075 pCi, would remain on the skin after washing (Kramer, et al,1996), and would be absorbed into the body.

• For the dose equivalent calculation it was assumed that the worker was llP', and absorption of 0.075 uCi of"C urea into the body would result in a dose of about 0.029 mrem (0.075 uCi x 0.38 mrem /uCi intake).

2. l. 4 Accidental Etposures of II'orLers Analyzing Patient Samples in the event of an accident in a measurements laboratory "CO 2in the sample balloons could be released into the room air and expose a worker. The conservative analysis described below indicates that the exposure of a worker would be unlikely to exceed about 0.00032 mrem.

The following assumptions were made for this anal) sis:

. A maximum insentory of 600 patiert sample balloons, equivalent to a daily delivery of 200 plus a tu o-day backlog, were assumed to have failed during a storage room accident (i.e., fire) and release their contents into the room air (assumed to be 68.000 L). This assumption would lead to a release of 0.72 pCi(0.0012 pCi/L x 2 L x 0.5 llP'/ sample x 600 samples) of"CO ,2 and result 4

in an air concentration of 1.06 x 10 pCi/L

. The sprinkler system in the storage area puts out the Ore, but only after the balloons had failed.

. A worker immediately enters the facility aller the Src is out and stays for one hour to clean up with no change of room air (assumed to be light work activity).

Elased on these assumptions, the worker would inhale about 0.013 uCi of "C during the one-hour stay in the room, leading to a dose of 0.00032 mrem (1.06 x 104 uCi/L x 20 L/ min x 60 min x 0.025 mrem /uCi).

The actual risk associated with such accidents would be even lower, since:

1. Ventilition would be necessary to remove smoke before a worker could remain in the room for such a long period of time, and 11

L t

2. Risk is the product of the consequences (above) and the probability of occurrence of the accident.

_ (discussed below). -The likelihood of a Orc in the storage area was estimated to be on the order of 0.001/ year. [This is a conservative assumption reDecting an assumed Gre initiation frequency in laboratory areas as opposed to a frequency of 2x10 5 for office and storage areas (LANL,1992).)

2.2 Exposure of Members of the General Publis

His section conservatively estimates the potential exposures of members of the public worker from -

frequenting or working in an area where "C-urca capsules are stored and administered, or where "CO2 .

samples are stored or analyzed. Also, the potential radiation dose to a worker or member of the public

~ during transportation of capsules or patient sample balloons that may be damaged in transit has been

- analyzed. Part of this analysis also addresses the potential radiation dose to a maximally exposed individual resulting from administration of "C. urea capsules to a patient (e.g., members of the patient's

- family, fellow ofGee workers, or public transportation workers).

-2.2.1 Routine Exposure of a Member of Pubilefrom Storage and Administration of"C-Urea Capsules Members of Public Inside Medical / Clinical Facility in adftinn to clinical workers, there is a potential for the clinical support staff or other persons not

, directly involved in the administration of"C-urca to become exposed to "CO exhaled 2 into the shared room air (c;g., receptionists or patients in waiting areas for unrelated medical assistance). As shown below, the dose (CEDE) from worker exposure of anyone associated with the use of capsules is not expected to exceed about 0.12 mrem per year.

Clearly, based on the conservative analyses provided in section 2.1, the doses to workers exposed continuously to exhaled "CO in 2 administration areas from patients receiving the capsules are already small. Further, the doses to personnel not directly involved in routine storage and administration of"C.

. urea tests would be even smaller because of the opportunities for further dilution in room air and/or shorter exposure periods. For example, a physician or nurse entering the administration area for one ihour a day would receive a dose that would be about 1/8th that of the full-time worker administering the capsules, or about 0.088 mrem / year (1/8 x 0.7 mrem / year),

Under the conditions discussed in section 2.1.1, exhaled "CO2 released into a waiting area could also 3" expose a receptionist and patients waiting for a medical appointment. If a third of the exhaled air were to -

leak into the waiting area and be diluted in half by the air in that area, the dose to a receptionist would be

. about 1/6th the dose received by the worker administering the doses, or about 0.12 mrem / year. Patients

- in the waiting area might wait a half-hour or more, but would be exposed in the waiting area very infrequently during any annual period, so their exposures would be orders of magnitude lower than thc.,e

. received by workers at a medical facility, y

12

- -. ...>-/. . . . _: . _

a .

+

i

Aimbers of Public Outside Medical / Clinical Facility The conservative scenario considered for this analysis involves a i war old child and it's mother in an automobile on en extended trip home from a medical facility where an HP' father exh&s "CO, into a small vehicle.

This analysis used the following assomptions:

• Riding home, with his spouse driving, the f ather would continue to exhale "CO2 into the ah of their compact automobile; the trip was assumed to take 2 hours2.314815e-5 days <br />5.555556e-4 hours <br />3.306878e-6 weeks <br />7.61e-7 months <br />.

An llP' patient would exhale 0.54 Ci of "CO in 2 5 days per I uCi capsule intake (Stubbs,1996). The patient stays in the medical facility for one hour, releasing about 0.40 Ci betore the trip (Ibid.). To maximize the re'. case to the car, it was assumed that all 0.14 uCi of the "CO 2remaining in the patient to be exhaleu would be exhaled during the 2-hour trip.

. It was conservatively assumed the "CO2 would be exhaled into a small car with a volume of about 1,400 L (50 ft'), with no turnover of air in the passenger compartment.

^

. A 1-year old child durirg the 8,.p home breathing air from the passenger compartment at a rMe f 1.5 L/ min would inhale a total of 180 L of air from the passenger compartment.

. Dose conversion factor for a 1 year old child is 1.5x10* SvlBq (5.6 mrem / Ci) innaled (ICRP,1989).

L Based oc these assumptions, the maximum "CO2 concentration in the ca - id be about and the child would inhale about 0.018 pCi leading to a dose of about 0.0 i *em (becaun u be some turnover of compartment air, more realistic doses would be lower).

The potential dose to the child's mother would Le much lower. For example, the mother would inhale "CO 2from the same passenger compartment at a rate of 4.5 L/ minute, and would have an intake (befcre dilution is cons.dered) about 3 times greater than the child. However, the addt dose conversior, factor (0.025 mrem per uCi inhaled) for "CO 2is 224 times smaller than that of the child. Therefore, the inhalation dose to th mother would be about 1/73rd that of the child, or about 0.0014 mrem.

Potential doses to other members of the pub;ic (e.g., office workers, bus or taxi drivers) as the result of continued exha!ation of "CO2 for a few hours following the release ofilP' patients from the g administration fac:lity would be expected to be substantially less than the dose to the child or its mother, since, as shown above, the dose conversion factors for adults are over an order of magnitude lower than for the hypothetical 1-year old child, and diluuon -f the exhr. led "C would be much geater than essumed for the child's exposure scenario.

2.2.2 Routine Exposure of a Member of the Pu dicfrom Storage and Measurement of Patient Samples in order to bound the poten;ici impacts of c.tmospheric releases of "CO2 frorr. laboratory analyses, it was i assumed that the remai . der of each sample (more than 70 percent of the total curies in each sample) in the mylar balloon would be released into a single laSoratorf ventilation hood to maximize the exhaust air 13 ,

g me -- _____ ____.-__-_.__-_:

concentration of"COJ Thtm on thic ordei of 0.0017 pCi/ sample would be released up the stack from each of the 50,000 samples analyzed each year by the laboratory. , As shown below, the dose to a '.

hypotheticd f urson L reathing air ldirectly from the stack (i.e., with.no further dilution) over the entire yea.- would be on the order of 0.006 mrem / year. This dose is orders of magnitude less than the dose of I mrcm/ year which triggers reporting to EPA under the Clean Air Act (EPA,1989).' Therefore, no further

- analyses of exposures to individuals' downwind from the facility are necessary, iThe following assumptions were made for this conservative calculation; e- . It was assumed that the ventilation hood would have a minimum air velocity of 125 linear it/ min L (0.60 m/s) over the hood face (ACGlH,- 1995), and a volumetric How of 250 ft'/ min (0.11 m'/s);

thus,(n annual release from a laboratory measuring 50,000 samples per year would be about 85 -

EuCi, in a total air volume of about 7.9x10' L (for r 2,000 hr/ year operation), with an average -

concentration of about 1.07x10 4 Ci/L [(0.0017 Ci/ sample x 50,000 samples)/(0.11 m'/s x

. 3,600 er x 2,000 hr/yr x 1,0001/m')J.

The hypothetical individual was assumea to brnth this air at the rate of 20 L/ min for the entire year, resulting in a total intake c^about 0.24 uCi of "CO ,2 or a maximum dose of 0.0064 mrem / year [1.07x104 Ci/L x 20 IJmia x 60 min /hr x 2,000 hr/yr x 0.025 mrem /pCi inhaled].

, - 2.2.3 [ I Accidental Esposure of a Member of the Publicfrom the Storage and Administration of"C-Urea Capsules .

As evaluated in 3ection 2.1.3, the doses from accidental inhalation of"CO 2 following a fire are relatively  ;

small compared to routine exposures of the same workers at administration facilities. Dos- dier patients or members of the public who might be exposed to accidental releases are orders of magnitude smaller than this accident analysis, and are not speci0cally analyzed for the worst case f're, f 2.2.4 l Accidental Esposure of a Member of the Pul.llefrom the Storage and Measurenent of Patient l . Samles The exposure for a member of the public from accidents was conservatively assum-d to result from the

' accidental failure of the :omplete inventory o.* patient samples (600 samples in storage) at the measurements laboratory as considered for accidental worker exposure. As a, unlicensed operation, the

~ laboratory would also be open to a variety of people, including maintenance technicians, clerical people, and members of worker's families, including spouses and children of workers during lunch hour. As

. shown below, tbc doses to an assumed breast-fed child (age it highest dose conversion factor of all age groups), and an' embryo / fetus (highest dose conversion factor at 180 days geetation) are not expected to exceed about 0.00068 mrem.

L To conservatively estimate the potentia' radiological impacts from accidents on members of the public (other than employees), calculations were performed to estimate the potential exposuie of a fetus

(180 days gestation) carried by a visiting spouse at the time of the accident, and a 1-year old child accompanying his mother and still being breast fed at the time of the accident. These calculaticas used '

Lt he following asaumptions:

14 ty

l

. A maxiroum dose conversion factor of 1.29 mrad per uCi of "CO, inhaled by the mother was assumed for an embryo / fetus at 180 days gestation. This factor was taken from Table D.3 of NUREG/CR 5631 (Sikov, et al,1992).

. As recommended by ICRP-23, it was assumed that the maternal respiratory rate was 10 LJmin, and that the mother breathed the air for 5 minutes (50 L) before leaving the scene of the accident.

• As stated in section 2.1.4, the air concentration after the fire would be about 1.06x104 uCi/L Duiing the Grst 5 minutes, the mother would !nhale about 5.3x104 uCi of"CO ,2 and the fetus would get a dose of about 0.00068 mrem (5.3x104 uCi x 1.29 mrem /uCi).

In order to ca.lculate the dose to the 1-year old child from breast feeding, it was necessary to estimate the fraction of the "C inhaled ("CO )2 by the lactating mother which is transferred to milk. Ilowever, such information is not currently available for "C as either CO 2or urea. As a result, the analysis utilizes some of the most recent information provided by the petitioner, which permits estimates of the fractions of the total intake excreted in breath or urine (Tri-Med,1996a). The Tri-Md modeling, w hich was independently verified by the 0-k Ridge Institute for Scierse and Education (ORISE), found that sampling of 20 individuals (11 lip and 9 flP') over a period of the days following administralian accounted for between 86.7 percent (llP patients) and 94.1 percent (llP' patients) of the total 1 pCi

> intake in the combined excretion in breath and urine (Attachment to Tri-Med,1996a). The child's dose calculation required the following additional assumptions:

. It was assumed that the total intake by the child from mother's milk cannot exceed some fraction oT the remaining "C that is not excreted by other pathways.

. To cons watively estimate the child's dose, the mother was assumed to be llP-

. It was assumed that half of the total "C intake unaccounted for (i.e.,0.133 uCi) was ingested by the steast-feeding child over a period of weeks, resulting in the child's ingestion of about 3.5x104 Ci(5.3 x 10" x 0.5 x 0.133).

. Using a dose conversion factor of 1.6x10* Sv/Bq (5.9 mrem /uCi) for a 1-year old child from the ingestion of "C as given in !CRP-67, the dose to the child from mother's milk would be about 0.00021 n' rem (3.5x104 uCi x 5.9 mrem /uCi).

9 The effective dose equivalent to a 1-year old child from direct inhalation of"CO, was calculated based on a dose conversion factor of 1.5x10# Sv/Bq (5.6 mrem /uCi) inhaled. The respiratory volume for the t-year old child (resting rate) was 1.5 IJmi e, as recommended in ICRP-23. Assuming the same air volume and room concentration as derived above, and that the child also br:athed the laboratory air for 5 minutes before being remcved, the total activity inhaled by the child would '>e about 7.9x104 uCi (106 x10 4x 1.5 LJmin x 5 min). The inhalation dose would be aoout 0.00044 mrem, bringing the child's total dose to about 0.00065 mrem. '

l5

}

2.2,5 Accidental Exposure of a member of Pubilefrom the Transportation of"C-Urea capsules or Patient Samples To conser atively estimate the potential public radiological impacts, tl:e following assumptions were made:

a It was assumed that all such packages would be shipped by air to the city nearest the facility (the loss of several balloons or a shipment of 150 capsules on a largejetliner would not result in exposure ofindividuals to significant concentrations), and then transferred either to the administration facility or to a measurements laboratory by a local delivery van.

it was funher assumed tha: the release of radioactivity into a "an following a non-fatal accident would provide the most conservative estimate ofimpacts; by assuming that the maximum projected inventory (150 capsules) for any administering facility would be sent in one shipment.

the impacts would also be bounding for shipments of capsules or patient samples.

• It was assumed that a van driver was involved in an accident and was trapped inside the van for one hour before rescuers could free the driver.

% . All 150 capsules were assumed to be dissolved and oxidized (by other materials carried in the delivery van) to "CO ,2 and mixed uniformly in the total van solume of 17,800 L (assumed to be 15 ft x 6 ft x 7 ft = 630 ft') with no loss to the outside air until the driser was freed; the resulting air concentration would be about 0.0084 pCi/L.

• Assuming that the driver was struggling to get out of the van, the respiratory rate would be about that for heavy work; therefore, the driver's would inhale about 21.7 pCi, leading to dose of 0.54 mrem (0.0084 pCill x 43 IJmin x 60 min x 0.025 mrem / Ci).

The likelihood of such an accident is estimated to be on the order of 4x104 per shipment, based on an 3

average U.S. accident rate of about 4x10 shipment kilometer for trucks traveling over imerstate highways in urbanized areas ( ANL,1994, Table A.4), and conservatively assuming an average of 100 km tras el per shipment (in most cases, these shipments would be from the nearest airport freight tenninal).

If the driver had been carrying a one-day delivery of 200 ilP' patient samples, the total amount of activity vehich could be released would be about 0.5 pCi. Therefore, the dose would be about 1/300th the s dose for the capsules accident, or about 0.002 mrem. For an average 50 percent mix of patient IIP' samples that would be expected, the dose would be about 0.001 mrem.

( Doses to any other member of the public (e.g., a rescue worker or onlooker) would of necessity be much less, since the released activity would be diluted rapidly by the surrounding air due to atmospheric

=

dispersion and turbulence.

2.3 bient Exposures This review focuses on typical exposures expected from use of the "C-urea breath tests, and on atypical n (Iow probability) multiple exposures from enors in administratbn to patients, and from accidental skin contamination from rupture of a capsule.

16

2.3.1 Routine Patient E.tposuresfrom "C-Urea Tests in the majority of nuclear medical procedures, radionuclides emitting Eamma radiatica are usea. This diagnosti,: procedure using "C-urea does not emit any gamma radiation (photons). This isotope emits a low -energy beta radiation (maximum be,a ray energy oi0.156 MeV). The production of bremsstrahlung photons .sulting from this beta radiation would be ve y small and of very low energy, particularly in view of the low beta energy and low atomic number of the surrounding materiais. Therefore, there is no measurable source of external exposure from storage or casual handling of a number of the "C-urea capsules; the major concerns are related to skin contamination or internal depositions following

.ce;

• ants.

The most recent information on the excretion of "C-urea received is a draft Tri-Med analysis dated January 15,1996 w hich also provides the most complete information to date (Stubbs,1996). The data carr.: from 20 subjects who participated in a clinical research study at the University of Virginia Health Sciences Center. These patients were administered piototype capsules containing i pCi of"C-urea. In this group, there were 1111P' and 9 IIP

• i.iembers. The biokinetics model employed is shown in Figure 2 (Ibid.).

As shown in this figure, removal o r"C-urea from the stomach was assumed to follow three independent pathways corresponding to ure .c ',icarbonate/CO 2, and a long-term retention compartment of "C labeled organic molecules. In the 6gure, these are referred to as " Stomach-Urea', " Stomach CO2 ", and

" Stomach-Other", respectively.- All remaining activity unaccoumed for in the urine or breath was assumed to be uniformly distributed in the total body, and removed with a long biological hair -life.

Compartments 1 and 2 represent the bicarbonate /COs biokinetics model, and the total body retention of "C was modeled as the sum of the activities of the three biokinetics models within the dashed line in Figure 2, and accounts for the total activity administered.

The dose estimates were made using MIRDOSE 3.1 software (ORAU,1994). The data obtained from a clinical research protocol and discussed above, were used 'o obtain excretion data from the twenty

- patients administered the "C-urea capsule. Urinary exen - . lata were taken for five days and breath sampics were taken for seventy-two hours (20 samples per suoject). These data were supplied to a dosimetry Grm m Oak Ridge, Tennessee and the results and calculational methods were confirmed by ORISE (Oak Ridge Institute for Science and Education (Tri Med, '996a).

The average data from the 5-day Tri-Med study discussed above showed that in llP' subjects, 84.3 percent of the "C was excreted in the urine, whereas in llP' subjects,39 ', p ecent of the "C was excreted in the urine. In the HP patients, only 2.4 percent was excreted as CO2 and approximately 13 percent appeared to remain as a long compor,ent fraction with a forty day half-life. The HP' patient excreted 54.i percent of the C-14 in the breath and only 5.9 percent remamed as a long comoonent fraction. Based on the above data and using MIRDOSE 3.1, the Effective Dose Equivalent (EDE) was

- 0.38 mrem /uC for an llP- individual and 0.18 mrem / Ci for an HP' individual. Independent calculations verified *he Tri-Mad results (Pippen,1996) and showed1 hat the dose to an HP women could be somewhat higher than that provided by Tri-Med for an average group of patients (0.48 mrem /gCi).

The effective half-life of HP' patients "C exhaled as CO2 following ingestion of "C-urea capsule was estimated from the ( Peura, et al,1996) and NUREG/CR-5631 (Sikov, et al,1992) reports to be about 32 17

to 40 minutes, respectively. Using a background instrument count-rate of approximately r

55 counts / minute

• 7 cpm, as reported by Peura, et al,1996 for calculational purposes, it was estimated that it would take no longer than 5 - 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> for the exhaled radioactivity to be indistinguishable from background (assuming samples would be detectable for one str.ndard deviation above background).

More stringent requirements for determining w hen the breath samples are at background, such as two or three standard deviations above background, would result in concluding that background would be reached within 3 - 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br />.

2.3.2 Errors in Adrninistration of Tests to Patients b

For any nuclear medical procedure there are several considerations necessary to ensure the safety of the patient. The possibility of radiation exposure from administering one or more capsules containing this radiopharmaceutical to the wrong patient or administration of an excessive quantity of this radiopharmaceutical is very low.

For the purposes of analysis, two potential error scenarios were considered: a single dose administration to the wrong individual (assumed to be a pregnant woman who is llP') and a multiple dose k administration. In the first scenario, the radiation dose to the woman would be the same as that received y by a llP- female,0.48 nrem. The cumulative dose to the fetus from a 1 pCi intake by the mother under the assumptions dermed below would be 1.29 mrad (Sikov, et al,1992):

The entire 1 microcurie is introduced into the maternal transfer compartment (97 percent is available for transfer to a fetus of an HP' woman whereas only 46 percent is available for transfer across the placenta from an llP' woman).

. To be conservative the "C material is assumed to be equivalent to a hexose or amino acid intake rather as urea, which is rapidly excreted from the body.

. The g,estation period of the fetus was taken to be 180 days, and the dose conversion factor was obtained from Table D-3 of NUREG/CR-5631 (Ibid.).

In the second scenaria, it was assumed that three separate doses are administered to a single patient (two by error). The dose to an llP-individual ingesting three capsules would be about 1.4 mrem.

In the event that a pregnant woman mistakenly rect.ived three separate administrations, the dose to the fetus would be slant 3.9 mrem (3 cap >ules x 1 pCi/ capsule x 1.29 mrem! Ci). The msximum potential

- dose to the fetus (at 180 days gestation) is significantly below the maximum dose allowed to an embryo / fetus carried by a declared, pregnant radiation worker (NRC, 1991; 500 mrem. 20.1208). A

, pregnant woman at 180 days gestation would have to consume over three hundred "C-urea capsules in order for the fetc to receive that dose. Uptake at other stages ergestation would require even more capsules to exceed the NRC embryo / fetus limit.

The likelihood of a pregnant woman experiencing ulcer disease and requiring such a test is small in comparison to the overall incidence of ulcer disease in the general population. In 1992, there were 4,569,000 ulcers in the United States population reported as requiring treatment; the rate for women under 45 was 4.8/1000. This rate increased to 27.8/1000 for women in the 45-64 age group. For women 18 L

c

. , . . ._ . _ . ~ . . ._ _. __ _ _. _ . _ _

y* -

oyer 75, the rate was 75.50000. (DOC,1995, p.114).' As a result, the probability of such exposures are less than estimated for the general population.

2.3.3 [ AccidentalExposures ofPatients The question of accidental' exposures of patients in' health care facilities is bounded by the already s nall 7 dose to'a werker (section 2.1.3) extinguishing a fire that is assumed to release the entire maximum inventory of 150 capsules to the administration area Since it was assumed that patients'in a nearby.

~ waiting room would be evacudied when the' fire alarm went off, it is unlikely that patients would be -

exposed to such releases; For example, if the patients in waitmg (outside the administration area) were exposed during the evacuation to a concentration that was 10 percent of that to which the worker was -

- exposed to, anti for a limited 5 minute period, their doses would be about a 30th that of the worker (i.e.,less than 7x104 mrem).

-The dose to a patient from accidental rupture of a capsule during administration (leading to skin

.. contamination) would be less 'han from the direct intake, and would be the same as the accidental dose

~

to a clinical worker addressed in section 2.1.3 (about 0.029 mrem).

2.4 Disnosal of"C-Urea cansules or Meterials Used for Collection or Measurement of Patient

$amples This section addresses outdated capsules, materials used, and urine from patients, etc. Finally, the issue of disposal of outdated capsules or materials used in the sampling and measurement of patient breath samples must be addressed. These are briefly addressed below:

1 2.4.1 - Disposal of Outdated Capsules Medical users of the "C-urea capsules would be unlikely to acquire significant quantities of outdated capsules, because the shelflife of the capsules based on efficacy tests appears to be at least 2 years based on measurements using up to three-year old capsules (Tri-Med,1996b). If the petition is granted, capsules which exceed the approved shelf-life would be disposed of by incineration, sanitary cewers, or landfiil burial and would not be inconsistent with exsisting NRC regulations based on the following:

. 10 CFR 30.18 exempts 100 pCi quantities of "C from NRC regulation, so smal Iguantities of "C are' disposed by any convenient means-2.4.2 DisposalofMaterials Usedfor CoIIection ofPatientSamples

- The materials used for collection of patient samples (bailoons, etc) are not expected to contain detectable radioactivity following their evacuation based on actual measurements of cut-up balloons from HP' patients by Tri-Med (Tri-Med,1996c), so these and related materials (e.g., collection tubes, etc) could be

. disposed in the same manner as other non-hazardour materials (i.e., sanitary wastes).

19 2 _ _. , _ _

2.4.3 Disposal of Scintillation Fluid Usedfor Measurement of Patient Samples The average patient sample counted in liquid scintillation Guid is on the order of 0.00068 uCi; for a given Guid volume of about 15 ml (Marshall, et al,1991, p. 439). the concentration would be about 3.8x 10 ' uCi/g (6.8x10d pCi/ vial x vial /15 ml x mt!!.2 g). This is about three orders of magnitude below the NRC standard of 0.05 4.Ci of "C per gram of waste, below which licensees may dispose of the matedal as ifit wcre not radioactive (NRC,1991; Q20.2005).

Ilowever, since the Guid contains toluene and xylene which are classi0ed by the Environmental Prctection Agency (EPA) as spent solvent hazardous wastes, their disposal in landfills could caue the Resource Conservation and Recovery Act (RCRA) to be an Applicable and Relevant or Appropriate Requirement (EPA,1991). Because of these concerns, the current disposal methodo!ogy involves incineration. The annual amount of scintillation Guid that would 'oe expected from a hypothetical measurement laboratory is about 750 L, and the collected fluids could easily be sent to commercial waste incinerators for disposal. The total annual Guids volume for 600,000 samples per year (half from HP' patients and analyzed in 12 hypothetical laboratories) would be about 9 mt Even if all the liquid were burned in the same commercial facility, atn ospheric dispersion from an incinerator stack would not result in signincant public exposures to "CO 2. For example, assuming average meteorology (Pasquill C stability, and a 3 m/s wind speed), the xu!Q dispersion factor (m.2) would be on the order of 10" m-2 at 100 meters from a 20 meter stack (Turner,1969). The annual release rate would be 410 uCi/ year, or 1.3x104 pCi/s, with an average concentration (X) of about 4.3x10'" Ci/L.

Conservatively assuming that an adult is downwind at 100 m ane i.reathing at a rate of 20 Umin for an entire year, the dose to this individual would be on the order of 1.2x10' mrem. Clearly, disposal of the g entire annual production at an incinerator would result in an inconsequential worst-case exposure of a member of the public. Disposal of the Guids at multiple incinerators, with each incinerator burning smaller quantities, would result in smaller public exposures to individuals. Scintillation vials would be at background, and could be recycled to reduce wastes.

2.4.4 Disposal of Urinefror*< Pat.ents Given Breath Te is Urine from patients given "C-urea capsules contain small amounts of "C-urea; the amount will be largest for lip patients with almost all of the "C-urea excreted in urine (TrhMed,1996a). NRC regulations in 10 CFR ll20.2003(b), already states that urine containing small amounts of radioactivity from patients undergoing diagnosis or therapy using nuclear medicine applications is not subject te the limitation in 10 CFR 20.2003 (a), and may be disposed in the sanitary rewer.

3.0

SUMMARY

AND CONCLUSIONS Table I summarizes the resuks of the analyses in this report. As can be seen, there are no expected impacts of consequence from the proposed use of "C-urea tests under a general license or exemption.

Both normal and accidental releases would result in small increases in the worker's annual dose (300 mrem) from naturally occurring radiaiion in the environment (NCRP,1987b, p. 53). Such doses would also be far below the regulatory limits for radiation workers (5,000 mrem / year; NRC,1991, 20.1201).

For individual exposures, the test doses would generally be less than received annually from naturally occurring "C (about 1 -1.5 mrem / year; NCRP,1985, p. 2; NCRP,1987, p. 47). The doses would also be 20 x .. . - _ _ _ _ _ _ _ 1

4 (100 mrem! year; NRC, 1991,66 20.1301). Even for a fetus, the conservatis e dose estimates are a small fraction of the natural background radiation dose (including "C) received by an child in its first year of life, and are far below NRC or EPA limits for members of the public (including the 500 mrem limit to the embryo / fetus received by a declared pregnant radiation worker).

In addition, all of these conservative dose estimates would be much less than the additional effective dose equivalent that would be received from increased cosmic radiation during a coast-to-coast flight on ajetliner flying at 39,000 feet MSL (NCRP.1987b, p.19 indicates bout 0.5 mrem /hr of flight). The doses from normal use of the breath tests are also below any Federal (NRC, EPA) regulatory limits, and are generally below the EPA reporting level of I mrem /yr required under the Clean AirAct for routine exposures et .nembers of the public (EPA,1989, Subpart 1), or the 4 mrem / year EPA limit for public drinking water (EPA,1991).

There is no expected increase in risk as a result of the potential applications of the "C-urea breath test.-

Total releases from all potential applications a e expected to be less than the NRC 10 CFR QQ 20.2003(a) limit of one curie of "C per year to sanitary sewers (an insignifican increase compared to the naturally-occurring inventory of nearly 4 million curies of "C found in the atmosphere).

21 V

Table 1. Summary of Results of Conservative Doses to Workers and Members of the Public Scenario Maximum Exposed Routine Exposures - -

Individual Worker administering "C-urea Full-time (2,000 hr/yr) worker, - Less than 0.7 mremlyr breath tests 8.000 patients /yr Worker at laboratory,1% worker, logging daily patient Less than 0.00!! mrem /yr leakage rate of sample balloons samples,50,000 samples per into storage area - year Family of an llP' male exposed 1 yr old child in family car Less than 0.10 mrem per to "CO, exhaled into car while exposure returning home following -

normal administration of a mother of child Less than 0.0014 mrem per capsule exposure Release of all unused patient flypothetical member of public Less than 0.0064 mrem /> ear samples (50,000/yr) up hood breathing air from from measurements laboratory measurements lab. hood Routine exposure of patients llP' patient 0.38 mrem /c>psule from "C-urea breath tests llP' patient 0.15 mrem / capsule Flow of some "CO2 from Receptionist exposed year Less than 0.12 mren/ year administration area to waiting - around to reduced area concentrations _,

Physician or nurse occasionally Physician or nurse exposed one Less than t s88 mrem' year entering administration area hour / day, year around Scenario Maximum Exposed Individual Routine Exposures Worker exposed to. contents of Laboratory worker cleaning up Less than 0.00032 mrem 600 patient sample balloons storage area aller fire from fire Release of 150 pCi of "CO2 - Member of public evacuating Less than 0.0002 mrem into administration facility administration area from fire

! Worker exposed to oxidized . Administration worker putting - Less than 0.035 mrem contents of maximum capsule - out fire after failure of 150 inventory in storace area fire caosules 22

o .

l; ' '

, Table 1 (cont.) =

Release of contents of 600 Pregnant, lactating mother, and Less than 0.00068 mrem to patient sample balloons from a year old child .isiting embryo, and fire - measurements laboratory- less than 0.00065 mrem to a child Release of"COffrom Driver trapped in van for one Less than 0.54 mrem oxidation of 150 capsules in hour with no air turnover delivery van -

Exposure of patients in waiting Patients exposed for 5 minutes Less than 0.000007 mrem room from fire releasing 150 to 1/!9th max. concentration in uCi into administration area administration area Administration of"C-urea llP pu.ient receiving a 1,1 mrem capsules maximum of three capsules Administration of "C-urea llP' pregnant woman 0.48 mrem capsule to a wrong patient 180 day old fetus 1.3 mrad Administration of three "C- IIP' pregnant woman 1.4 mrem urea capsules to patient 180 day old fetus 3.9 mrem Rupture of a capsule causing Skin (100 cm 2) exposed for one 5.8 mrad skin dose, skin containination of worker or nutient 6.,

g 23 o=

l l

l'

4.0 REFERENCES

ACGill, industrial Ventilation Aftmual, American Conference of Governmental Industrial 11ygienists, Cincinnati,011,1995.

Argonne National Laboratory (ANL)," Longitudinal Review of State Level Accidert Statistics for Carriers orinterstate Ficight", ANL/EDS/TM-68, March 1994.

Cember,11., Introduction to #calth Physics, Second Edition, Pergamon Press, Elmsfard, NY,198*,.

Chey, W.D., M. Spybrook, S. Carpenter, T. T. Nostrant, G.ll. E, 2, and J.M. Scheiman, " Prolonged Eftect of Omeprazole on the C-Urea Breath Test", Am. J. of Gastroenterology, Vol. 91, No.1, pp. 89-92, January 1996.

Cross, W.G., N.O. Freeman, and P.Y. Wong, " Beta-Ray Dose Distribution from Point Sources in an Ir4 nite Water Medium",licalth Physics. Vol. 63. No. 2, pp.160 !71, August,1992.

Department of Commerce (DOC), Statistical Abstract of the United States. Item No. 215,115th ed.,

Department of Commerce, Economics and Statistics, Bureau of the Census,1995.

Environm ntal Protection Agency (EPA), National Emission Standardsfor Ha:ardom Air Pollutants:

Radmnuclides,40 CFR Part 61,54 FR 51654, December 15,1989.

Cnvironmental Protection Agency (EPA), National Primary Drinking Water Regulations: Radionuclides, Proposed Rule. 40 CFR Part 141 and 142, July 18,19c!

Environmental Protection Agency (EPA), letter from Sylvia K. Lowrance, Director of the EPA Office of Solid Waste regarding " RCRA ARAR Determination at Maxey Fla's Superfund Site", U.S.

Environmental Protection Agency, Washington, DC, September 4,1991.

International Commission on Radiological Protection (ICRP), Report ofthe Task Group on Reference Afan, ICRP heport No 23 Pergamon Press, Elmsford, NY,1975 International Commission on Radiological Protection (ICRP), Age Dependent Doses to Alembers ofthe Publiefrom Intake of Radionne.' ides: Port 1, ICRP Report No. 56, Pergamon Press, Elmsford, NY,1989.

International Commission on Radiologicat Protection (ICRP), age-dependent Doses to Alembers ofthe Publicfrom Intake ofRadionuclides: Part 2, Ingestion Dose Coefficients,1CRP Repcrt No. 67, Pergamon Press, Elmsford, NY,1994.

Kramer, G.fl., A. Badreddine, T. Tran, and D. Meyerhoff, "Dosimevy of an incident involving "C",

lisal h t Phvsics, Vol. 70 No. 3, pp. 4 I 8-224, March,1996)

- Los Alamos National Laboratory (LANL), "The Chemistry and Metallurgical Research (CMR)

Building, Interim Safety Analysis Report," Los Alamos, NM, March 1992.

24 4

l .

Marshall, B.J., M.W. Plankey, S.R. Iloffman, C.L. Boyd, it.F. Frierson, R.I.. Guerrant, and R.W.

McCallum, "A 20 Minute Breath Test for llelicobackrer p) lor!", The Am. J. of Gastroenterology, Vol.

86, No. 4,438-445, April 1991.

National Council on Radiation Protection and Measurements (NCRP), Carbon-1./ in the Environment, NCRP Report No. 81, Bethesda, MD,1985.

National Council on Radiation Protection and Measurements (NCRP), lonizing Radiation Exposure of the Population ofthe UnitedStates, NCRP Report No. 93, Bethesda, MD,1987a -

National Council on Radiation Protection and Measurements (NCRP), Exposure of the Population ofthe UnitedStates and Canadafrom Natural Bacicground Radiation, NCRP Report No. 94, Bethesda, MD, 19875.

National Institutes of Ilealth, "lielicobacter pylori in Peptic Ulc 3r Disease", Nill Consensus Development Panel on liclicobacter pylori in Peptic Ulcer Disease, JAM A, Vol. 272, No.1,65-69, July 6,1194 Nuclear Regulatory Commission (NRC), Standardsfor ProtectioriAgainst Radiation; Final Rule,56 FR 23360, May 21,1991.

Oak Ridg Associated Universities (ORAU), MIRDOSE 3.1 Documentation Package, Oak Ridge, TN, 1994.

Peura, D.A., D.J. Pamianco, K.R. Dye, C, Lir.d, ll.F. Frierson, S.R. Iloffman, M.J. Combs, E. Gua foyle, and B J. Marshall. " Microdose "C-Urea Breath Test Offers Diagnosis ofit Pylori in 10 Minutei, Am.

J. of Gastroenteroingy, Vol. 91, No. 2, February 1996.

Pipper,1996, letter report to Dr. R. L. Gotchy, SAIC, from Mr. lioward Pippen, SAIC, February 26, 1996.

Sikov, M.R., R.J. Traub T.E. Ilui, ILK. Meinarich, and K.D. Thrall, Contribution ofMuernal Radionuclide Burdens to Prenatal Radiation Doses. Interim Recommendations, NUREGlCR-5631, PNL-7445, Rev.1, U.S. Nuclear Regulatory Commission, Wash., DC, March 1992.

Stubbs, J., Letter report from Dr. James Stubbs, " Report on the Dosimetric Assessment for the Tri-Med C-14 Urea Breath Test," January 15,1996.

Tri Med Specialties, Inc., " Notice to the Nic Director, Freedom ofinformation and Publication Services", August 23,1994.

Tri-Med Specialties,ine., letter to NRC Director, Freedom ofinformation and Publication Services, August 23,1995.

Tri-Med Specialties, Inc.. " Report of the Dosimetric Assessment of the Tri-Med C-14 Breath Test",

submitted to Dr. Lewis Battist, SAIC, in support of the Petition for Exemption to NRC, with attachments, February 9,1996a (Proprietary and Confidential).

25

,0 -

t Tri-Med Specialties, Inc., personal communication from Dr. David Peura to Dr. Leais Battist, SAIC, February 9,1996b.

Tri Med Specialties,Inc, personal communication from Drs. Matthew Combs and Marshall Barry to Dr.

- Lewis Battist, SAIC, February 9,1996c.

Turner, D.ll., IVorkbook ofAtmosphe.~ic Dispersion Estimates, U.S. Dept. of Ilealth, Education, and Welfare, Public 11calt!. Service, Cincinnati,011,1969.

26

l

=o Figure 1. Exposure Pr.thwwys for the Regulatory Analysis AM Acciden:al Incinerate of truck Exposure of

• xfms.mscue e, or. scintillation nuids Idieratory and - general puble and workers, et

,,,c.e wo,kers recycle erepty vials b > hHCO2 HCO2 HCO2 ^

g% Release from hoods l-e Tri-Med Physician's OfEce Scintillation Manufacture -

" Of M(2surements laboratory - D'"

and Viels; mg (under License)

H#tal Admimstration "CO2 y v v Esposure of HCO2 M*Il technicians and h Rtxan Air Balloon > Room Air pneral public Federal Express U

HCO2 1%

Patieds ir 3r AltSpace < 3% Home, Car, Accidental 9

en use of truck [* e,",

- I " 5 "8C"8

• worke'rs, etc. general public

_y HC-urea

-- Exposure of family i' nwnibe s or office Sanitary Sewer workers. etc.

I.

i 27

$\ , - I u 1

i - -

..a

e

- Figure 2. Biokinetics Malel for 1 ;4Ci "C-uren Breath Test i

.i p----------______________,

I Il l' Stomach-Urea 8

Stomach-CO2 Stomach-Other

'l I-I 1

I 1

I I y- 3, l' l

l. ^

l Total Body .

U" 2 1 Id Bdy I

---> Other

.; l I--- ----- _. . _ _ _ _ ,_ _ _ _I '

1r 1r ir Cummentive Urine Cinnalatlee Breath : Cumulative Other Escreta HF = M.3% NF = 2 4% - Hr a 13.3%

HP**39.8% HP* = $4.3% . HP* = 3.9%

Ref: Stubbs,1996 5.' L .

h 1

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IHZ-97-054 Te: Joseph Ma:e Office of Nuclear Regulatory Research U.S. Nuclear Regulatory Commission 11545 Rockville Pike Rockville, Maryland 20852 From: Abe Zeitoun v4/ < l D:te: April 3,1997

Subject:

linvironmental Assessment for the Use of C-14 Urea Brenth Test The Environmental Assessmentfor the Use ofC-14 Urca Breath Test prepared by Ibtnhim 11. Zeitcun, Ph.D., Science Applications International Corporation, prepared for U.S. Nuclear Regulatory Commission, Washington, D.C., May 1996 is not a proprietary document and can be used for public information.

Please note that thewnce in the paragraph of Section 6.0, Finding ofNo Significant impact, should read as follows: It is expected that this action would result in no significant impact to the environment.

N l

Environmental Assessment for the Use of C-14 Urea Breath Test Prepared by:

Ibrahim H. Zeitouri, Ph. D.

Science Applications International Corporation Under Contract with ICF Subcontract No. 7-01 NRC 960065 May 1996 Prepared for:

U.S. Nuclear Regulatary Commission

' Washington, D.C.

4 SV 9Y lY ff N l\\ 7\ p y,

! +

g ENVIRONMENTAL ASSESSMENT For THE USE OF C-14 UREA BREATH TEST

!0 BACKGROUND .

The recent discovery of and the pathogenic implication o'Helicobactorpylort (N. pylori) to antral gastrite and duodenal ulceration has caused a dramatic change in the understanding and treatment of

,-~ peptic t%er disease during the past decade. R.pylorlis a spiral or helical-shaped gram negative bacterium, with 4 to 6 unipolar sheathed flagella. His bacterium normally inhabits the gastric inucous layer epithelium of human stomach and the gastric metaplastic epithelium in the duodenum and esophagus. H. pyloriis probably the most common cause of non autoimmune gastritis.

De proposed action is for the U.S. Nuclear Regulatory Commission (NRC) to grant Tri-Med Specialties, Inc. in Charlottesville. Virginia, its petition filed on August 23,1994 (Tri-Med,1994). This proposed action would be taken to allow, through rulemaking, any physician to receive and use capsules containing I pCi of C-urea for enedical use wi%it obtaining an NRC license.

His medical use is based upon the fact that H. pylori produurs the enzyme urease that is rarely present in human cells and a capable of breaking down urea to ammonia and bicarbonate (Corley, et al,1995,.

CO(NH3 ), + 2 H,0 +H*  ;

2NH.* + HCO 3~

Ammoniusa Bicartioness The HCO2enters the blood stream and can rapidiy be exhaled through the lungs as CO . Since the

administered urea is manufactured with radioactive carbon (t? ), detected CO 2 in thgat;ent breath is indicative of urease presence. Corley, et al,(1995), pointd out that 8'CO 2is usually detectable in the breath 5 minutes aAer administration with a peak excretion in 10 to 15 minutes (Peurs, et al,1996). The urea breath test (US7) using C is only positive if N. pyloriinfection is present. it is ideally suited to

- follow treatment to confirm radication of this specific bacterium.

Specifically, Tri Med Speciahies, Inc. petition is to permit the distribut. ion of the capsu'e containing

CO,either separately or as part of a diagnostic kit which supplies to perform the test. De manufacturing process calls for one yCi of the C-ures to be placed in a gelatin capsule. AAer insertion of the C into the capeele which is inspected extemally for any contamination. The capsule is then placed into a commercial blister pack and then sealed. De sealed package is then placed into another container which is also sealed. Tl'at package is then placed into a shipping container that is approx:mately 15.2 cm ,by 15.21 cm by 5.1 s.m (6"x6"x2").

This proposed procedure is a noniimsive method and positive only if active H. pyloriinfection is present . His test. is ideally suited to follow treatment to confirm eradication of H. pylori and is to be used in lieu c'the gastrointestinal endoscopy procedure which is an invasive test, more costly, and involves some risk to patients (Tri-Med,1994).

I

Test Protu gJ:

Tri-Med Specialties, Inc. (Tri Med,1994) and Marshall, et al, (199i) described the C-UBT for the diagnosis of E pylori The preparation of the patient for this test includes fasting for 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> and assurance that no antibiotics or bismuth salts have been taken at least 4 weeks prior to the test. The capsule is then swallowed with 30 ml of warm water to help the capsule to dissolve and release of -

C-urea into the stomach . After 15 minutes, up to 2 liters of breath sample will be exhaled into a collection bag and promptly mailed by priority mail to a specialized laboratory to cou -t C radioactivity.

Breath samphs containing less than 30 disintegration's per rainute (dpm) above background would be considered HP'. .\ctivities above one hundred dpm are considered HP'. It has been reported that the "C urea breath test has a high diagnostic accuracy, with a sensitivity and specificity of up to 98%

(Marshall,1994 and Peura, et al,1906).

2.0 NEED FOR THE PROF OSED ACTION Currently, physicians who are licensed by the NRC or an Agreement State can receive and use this product. The proposed rulemaking would allow physicians, who do not have an NRC license for the medical use of byproduct material to also receive and use this product. This would provide greater flexibility to test for and monitor the presence of H. pylori in ulcer patients.

It is clear that ensuring eradication of H.pylorlinfection and curing ulcers can have a direct benefit to the approximately 500,000 new ulcer patients seeking health care each year, and more than a niillion hospitalizations each year (Fennerty, et al,1994). The new noninvasve tmt using "C-urea capsules, as proposed by Tri Med Specialties, Inc., has a potential to eliminate the need for many gastroendoscopies performed to view the stomach and duodenal ulcers and to obtain samples for the detection of H Pylori in ulcer patients. Gastroendoscopies are expensive and uncomfortable to patients. Eradication of E pyloriinfection is associated with a marked decrease in the recurrence rate of ulcers. A quantitative relationship U.<een the de, ~ of E pylori infection seems to be unnecessary, since any detectable infection will be treated.

3.0 ENVIRONMENTAL IMPACTS OF THE GRANTING THE PE7ITION The potential impacts associated with granting the Tri Med Specialties, Inc. petition are limited to human health and environment as they pertain to distribution, storage, use, and disposal of materials

- containing small amounts of "C. Impacts associated with the manufacture of the "C urea capsule are not included in this assessment, since the petitioner already has an NRC license to manufacture "C-urea products. The general pathways to th se two major receptors are presented in Figure 3.1 3.1 Pathwave to Hammas Radiation d6ses associated with the distribution and use of the "C-urea capsuks are presented in this section.

2 a

.t. ), j . W'eher Eqosures in this Enviro. nental Assessment, all workers involved in the administration of the "C-urea capsules or '

analyses of patient samples are considered potential workers . Also, a dose conversion factor of 0.025 mrem per uCi inhaled was used in calculating the dose values for exhaled "CO2 by patents. Tliis factor was derived som the NRC's Annual Limit for intake (ALI) for inhaled "CO: for adult radiation workers (2x10' Ci) and the 5,000 mrem regulatory annual dose limit (NRC,1991).

~

Assiement Aechgement g of"M espas ,g Empeemsof Incherste scieseman Runda

**S**- hheresory and generalPehne and a vessee two ser,ct marnviele

" aH CO:

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. Phyeladen's OfRee Manstee64 . Saintinerien -

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Figure 3.1. Diagram depicting the potential "C releases and pathways to the Environment and Humans 3

y. 3; e 3.1.1.1; Rourine Exposures of Workers Who Administer the Test Conservative analyses show that routine doses (commined effective dose e_quivalent, CEDE) for workers

who ader.inister the tew are unlikely to exceed 0.7 mrem / year, and that the potential risks are small a relative to established standards and variations in natural background. Conservative assumptions used in

. this analysis included that the clinical worker works full time (8 hours9.259259e-5 days <br />0.00222 hours <br />1.322751e-5 weeks <br />3.044e-6 months <br /> / day,2,000 hours0 days <br />0 hours <br />0 weeks <br />0 months <br /> / year), the worker -

would administer 4 tests per hour (maximum of 8000 administrations per year) with all pat _ients in a - _

common room with a room air volume of 68 m' (2,400 ft'),50% of patients are infected with H. pylori.,-

and the?'C in the exhaled breath ofinfected patient was instantly and completely mixed with the room air at the start of the hour with no air turnover during the hour for the durat.on of the tests were assumed.

In addition, the analysis assumed that the room air was completely flushed only after each hour of.

^- testir.g despite the fact that buildings require some minimum air tumover. ,

' Bacd on several calculations (Gotchy, et al,1996), the potential concentration of "C in exhaled breath .

- from a H pylori positive patient was calculated to average about 0.0012 Ci/L (Peurs, et al,1996, and i Cember,1957). Also, it was calculated that a total of about 0.8 pCi would be immediately released to .

Ethe room for 4 patients treated each hour. Accordingly, the amount of "C inhaled hourly by the health ,

L care worker at 20 L/ min. would be about 0.014 pCi and the total annual dose would be about 0.7 mrem;  ;

in order to bound the potential impacts, it was assumed that there could be as many as 12 large laboratories national!y, comparable to the Tri Med facility, each analyzing a maximum of 50,0.%

samples per year, for a total of 600,000 samples per year in the U.S. De collective dose for the 75 workers who administer the test (600,000 administrations annually / 8000 tests per an administrator) would be about 0.05 person rem /yeu or less. . - -

The conservatively calculated individual dose represents about a 50% increase of the small dose (about

- 1 1.5 mrem / year) from naturally occurring "C in the environment (NCRP,1985 and NCRP,1987b) and only about a 0.23% increase in the annual radiation dose (300 mrem) from naturally occurring radiation in the environment (NCRP,1987b). It is also comparable to the additional effective dose equivalent that would be received from increased cosmic radiation during about 1.5 hours5.787037e-5 days <br />0.00139 hours <br />8.267196e-6 weeks <br />1.9025e-6 months <br /> on ajetliner flying at 39,000 -

feet MSL (NCRP,1987a). Such doses are far below the NRC and Environmental Protection Agency

-(EPA) regulatory limits for members of the publS. Accordingly, the health impacts to workers who administer the test are expected to be negligible.

' 3.1.1.2 - Poutine Enposures cf Workers Analyzing Patient Samples

[

$ . This analysis addresses the potential impacts on workers measuring exhaled "CO2 in balloon samples

. received from physicians, hospitals or clinics.- Conservative analyses of routine radiation doses to these workers are unlikely to exceed 0.0011 mrem / year. This determination was based on several conservative assumptions including: (1) 50,000 samples are handled at each of 12 large hypothetical laboratories <

annually,50% of patients are infected with H. pylori, and (2) a maximum of 1.0% cf the 200 balloons received each day at each laboratory would routinely leak all of their contents into the storage room

" i v:hore a worker was responsible for logging in all samples,1000 hours0.0116 days <br />0.278 hours <br />0.00165 weeks <br />3.805e-4 months <br /> / year (Gotchy, et al,1996).

. 1 Routine collective dose for the entire group of 12 iaboratory workers would be about 0.0000132 -

person-rem / year (0.0000011 rem / year x 12 persons). 'Ihese conservative release scenarios result in small -

increases in the collective dose to the 12 workers analyzing the samples from naturally occurring "C that

-would result in a collective dose of about 0.02 person-rem / year (1.5x108 rem / year x 12 persons).

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Combined natural background radiation would result in an annual collective dose to these same workers of about 3.6 person rem per year (NCRP,1985 and NCRP,1987b).

- This section focuses on exposures oflaboratory workers involved in measuring exhaled CO, in balloon samples received from physicians, hospitals or clinicsf For medical technicians handling patient samples in a measurements laboratory, there would be no expected doses from routine handling of undamaged samples (any unused breath from the balloon would be released into a hood and removed from the laboratory). For those instances where patient samples arrive damaged or leaking, the laboratory worker could receive a small exposure. These bounding doses are small fractions of the annual radioactive exposure from natural background, and would not expected to result in any significant occupational risks.

3.1.1.3 hiaximum Collective Doses The maximum annual collective dose for workers was calculated to be about 0.05 person-rem which is twice as the I to 1.5 mrem / year annual collective doses for 75 workers from naturally occurring C in the environment (NCRP,1985 and NCRP,1987b), and only bout a 0.5% increase above the annual radiation dose (300 mrem) from naturally occurring radiation in the environment. The routine collective dose for the entire group of 12 laboratory workers analyzing the breath samples in the U.S. would be on the order of 0.0000132 person-rem / year.

As discussed in the NRC Safety Report (Gotchy, et al,1996), corurvative accidental fire scenarios result in small individual doses to workers on the order of 0.035 mrem or less. The probable doses associated with accidents would be even lower, since 1) ventilation would be necessary to remove smoke before a worker could remain in the room for such a long period of time (i.e., diluting the room air concentration), and 2) the risk is the product of the consequences and the probability of the accident occurring. Because the probabilities of the accidents occurring are much less than the expected operating life of such facilities, when the dose consequences of the assumed accidents are multiplied be the probabilities of occurrence, the collective doses would be extremely small, and would not sq,nificantly add to the conservatively calculated collective doses calculated for normal operations (see section 3.1.1.4 below).

3.1.1.4 AccidentalExposures of Workers Two scenarios have been evaluated in this Environmental Assessment. The postulated accidents and potential impacts are described below.

Skin F1nosure It is possible, although highly unlikely, that an accidental C-urea capsule could break and result in spilling some ofits contents onto the skin of a worker who administers the test. The rupture ofC-urea capsule during administration would lead to an exposure of the skin to C-urea powder and a radiation dose. Accidental spilling of the entire contents of a C-urea capsule onto the hands of such a worker is also'not expected to result in a skin dose in excess of 5.8 mrad, or a radiation dose (CEDE) of 0.029 mrem through skin absorption (Gotchy, et al,1996). These exposures are small and far below the EPA and NRC regulatory limits.

5

.o evaluate the potential impact of such an accident, additional assumptions were adopted. These assumptions include that the worker would attempt to brush off some of this material, spreading it over the skin of hands and arms. After an hour, the worker was assumed to wash the material f <om the skin with soap and water. To bound the possible exposure, it is assumed that washing would occur aner one hour and it is further assumed that 30% of the activity, or 0.075 yCi, would remain on the skin after washing (Kramer, et al,1996). The remaining 30% is conservatively assumed to be absorbed into the body. The resultant skin dose and whole body dose from the spill are estimated to be about 5.8 mrad and 0.029 mrem, respectively.

Inhalation Frnosure Following a Fire In the case where a "C-urea capsule is accidentally ruptured, there be an opportunity for accidental ,

- inhalation exposure of a worker from "C-urea powder. Conservative bounding analyses show that it is unlikely any worker would receive a dose in excess of 0.035 mrem from accidents resulting in inhalation exposure associated with the storage or administration of"C urea capsule.

One of the greatest sources of potential expcsure of workers would be from accidental releases of "CO2 resulting from a fire which might oxidize the entire stored inventory of the capsules. According to the stition for exemption, the largest inventory of "C-urea capsules expected to be received by any one unlicensed facility would be 150 (Tri Med,1994). The fire was conservatively assumed to oxidize the entire contents of tb "C-urea capsules, releasing "CO2into the administration area (68,000 L). The dose from inhaling "CO from2 the room air was conservatively estimated to be about 0.035 mrem.

The likelihood of a fire in the storage area was estimated to be on the order of 0.00llycar. This is a conservative assumption reflecting an assumed frequency of' fires thai ranged from 2x104 for offices and storage areas, to lx104 for laborato y areas. Collective doses to workers from such accidents will also be very small. For example, the expected collective dose to workers from this accident would be on the order of 3x104 person rem / year (3.5x104 rem / accident x 104 accidents / year x 75 facilities x 1 person / facility). Such accidents would not add significantly to collective doses from routine exposures.

Details on the dose calculations and assumptions are provided in the NRC Safety Repoit (Gotchy, et al,1996).

3.1.2 Patient Exposures 3.1.2.1 Routine Patient Etposures This diagnostic procedure using "C-urea emits low energy beta radiation, as compared to the low Leta energy and low atomic number of the surrounding tissues. Herefore, there is no measurable source of extemal exposta from storage or casual handling of a number of the "C-urea capsules and the major concerns are mostly related to skin contamination or intemal depositions following accidents.

- Removal of "C-urea from the stomach was assumed to follow three mdependent pathways corresponding to urea, bicarbonate /CO2 , and a long-term retention compartment of "C labeled

. molecules. The detailed description of this process is given in '.he NRC's Safety Report for this proposed actbn (Gotchy, et al,1996). He calculated Effective Dose Equivalent (EDE) is 0.38 mrem / Ci for an HP- individual and 0.1fi mrem /gCi for an HP* individual. These calculated doses are similar to those reported by Pippen (1996) who showed also that women may have a higher EDE value (0.48 mrem /gCi).

6

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in addition, it was estimated that it would take approximately 5 - 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> after taking the capsule for the [

exhaled radioactivit'. to be indistinguishable from background. J I

3.1.2.2 Collective Dous l

It is assumed that there will be a maximuen of 600,000 annual admmistrations of capsules conta..ung dp I uCi of "C-urea in the U A Using an average EDE of 0.3 mrem, the collectise population dose would be about 180 person-rera per year. The collectise annual dose from natural background radiation for that [

same pop: _ ion would Se about 1.8x105 person-rem. Accordingly, these tests would only mcrease the annual collective dose from natural background by about 0.1% for one test.

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3.1.2.3 Errors in Administrations to Patients For the purposes of analysis, assuming two potential consecutive administration were consiaered A #

single dose administration to the wrong individual (assumed to be a pregnant woman who is HP~) and a multiple dose administration. In the first scenario, the radiation dose to the woman lgl would be the same as that received by a HP- female,0.48 mrem. The cumulative dose to the fetus from a g i uCi intake by the mother would be 1.29 trrem (Gotchy, et al,1996). S fl in the second scenario, it was assumed that three doses are administered by minake to a single patient ]

\nother way in which a patient might get a multiple dose would be for the capsules to become separated j from the blister pack and assumed to be analgesic medicat.on, which would then be administered to a i patient. The dose to an HP- individual ingesting three capsules would be about 1.4 mrem. ]

I Given the low probabi"ty of such errors in administration, the probable dose would be much lower than the dose that would be received under normal diagnosis. The maximum potential dose to the fetus is f

d -

significantly below the maximum dose allowed to an embryo carried by a decived, pregont raciiation worker (NRC, 1991; 500 mrem, Q 20.1208), and a pregnant woman would have to consume os er 300 "C-urea capsules in order for the fetus to receive that dose. l l

The likelihocxl of a pregrant woman experiencing ulcer disease and requiring such a test is small in comparison to the overall incidence of ulcer disease in the general population. In 1992, there were i]

4.569,000 ulcers in the United States population reported as requiring treatment; the rate for women  ;

under 45 was 4.8/1000. This rate increased to 278/1000 for women in the 45-64 age group. For women j over 75, the rate we 75.5/1000,(DOC,1995). As a result, the probability of such exposures are less  ;

than estimated for the general population.

3.1.2.4 Accidental Exposures of Patients Assuming the maximum inventory is 150 capsules, doses for workers responding to a fire which is assumed to release the entire maximum inventory of capsules to the administration area. Siue it was 7 assumed that natients in a nearby waiting room would be evacuated when the fire alarm wen off, it is unlikely that patients would be exposed to such releases, and their doses would likely be zero.

Nevertheless, if the patients m a waiting room were exposed during the evacuation to a concentration Aat w .s 10% of that to which the worke was exposed to, and for a limited 5 minute period, their doses would be less than 7x10 mrem or about a 30th that of the worker. The dose to a patient from accidental rupture of a capsule during administration would be substantially less than frorm the direct intake, and

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-would be the same as the accidental dose to a worker administering the test or analyzing patient samples which is about 0.1 mrem. This potential impact and associated risks is considered to be small.

_ l 3.1.3 EnposureafGeneralPuNk  ;

Doses to anyone in the general public outside the administration area from the released activity would be  :

much lower than the dose to the worker, since the released activity would be quickly mixed in outsidnir -  :

'and concentrations a short distance from the point (s) of release would be crders of magnitude lower than "

experienced inside the administration area. The release of 150 uCi of"CO 2to the atmosphere would not represent a significant increase to the large inventory of naturally occurring "C already present there

(= 3.8 x 10' Ci).t All och doses are small fractions of the normal variations in background radiation, and -

would not be~ expected to cause any impact to workers or members of the public.

3.2' Pathwavn as the Enviremament +

The earth's atmesphere contains an inventory of naturally-occurring "C of about 3.8-million curies

[(equivalent to the activity in 3.8-trillion breath tests), which in addition to the huge inventory of about

240 million curies in the world's oceans and oceari's floor (NCRP,1985). De "C released into the

. ' atmosphere would mix with the global inventory and expose the public and other biotic components of  ;

the environment to "C intakes from inhalation, drinking water, and all possible food pathways in the

- same manner as naturally occurring "C. Since the current world inventory of naturally-occurring "C

- results in an average dose to the public of about 1.25 mrem / year, release of 0.6 curies of"C from breath tests would result in an average annual dose of about 2x104 mrem. In a total population of about 260-million people in the U.S., the collective annual dose would be about 0.051 person-rem. He doses from normal use of the breath tests are also below any Federal (NRC and EPA) regulatory limits, and are

- generally below the EPA reporting level of 1 mrem / year required under the Clean Air Act for routine exposures of members of the public (EPA,1989), or the 4 mrem / year EPA limit for public drinking

-- water (EPA,1991). Impacts associated with any releases of."C to surrounding environraental media are expected to be very small due to the fact that the concentration of CO2 released is very low and wouM be mixed in the atmosphere immediately. Therefore, impacts associated with any releases of "C to surrounding environment are expected to be very small and the expected risks are minimal.

3.2.1 Collecht Exposures to Menebers of the Punk :

1 The small increases in doses from naturallp-occurring "C are oflittle significance to human health and the environment. Potential long term impact from wide spread releases of the long-lived "C

-(5,730 year radiological half-life) from breath tests was consided to be insignificant. Assuming that

the testing in the U.S. would increase over a period _of time to an average of a million tests per year for -

50 years, the colbotive annual dose to the U.S. would be about 5 person-rem over the next 50 years.

e This dose !s very small when' compared to the annual collective dose to the U.S. population from 7 naturally occurrms "C of over 300,000 person-rem, and about 78,000,000 person-rem from all L naturally-occurring radiation. ' Clearly, an increase of a few person-rem will not significantly change s those exposures, and there would be no expected impact from the widespread use of breath tests on the L entire U.S. population over periods of decades, 4-

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TAnother potential source of public exposurs could result from exhalation of CO 2 by patients to a 4mily h l member, coworkers, or member of the public. The; collective annual dose would be on the order of L ,

J 2.5 person rem which is expected to introduce very small impactsi

3. 0 l . Dishosal of YC-Ures Cysules or Materials .

There are several disposa(options associated with the proposed action and attemativescThe impacts of.

l these disposal options ~are detailed below. ,  !

- 3.2.2.1 Disposal of Gandated Capsules i q

Medical users of the C-urea breath test would be unlikely 16 acquire significant quantities of outdated (capsule, because the shelflife appears to be at least 2 years, and new capsules can be ordered within a 1 ,

few days. Nevertheless,10 CFR 630.18 exempts 100 uCi quantities of C from NRC regulation, so

- . small numbers of capsules which neced the approved shelf-life could be safely disposed of by either -

~ incineration, sanitary sewers, or sanitary landfills.- Outdated capsules could also be returned to the-n l licensed _ manufacturer for disposal through incineration along with other nuclear medicine wastes if that ;

! were deemed considered necessary. Impacts associated with this action are expected to be small.

3.2.2.2 DisposalofSanple Collection Residues andMaterials

- I'he materials used for collection of patient samples (balloons, etc.) are not expected to contain

~

detectable radioactivity following their evacuation based on actual measurements of cut up balloons n from HP* patients by Tri-Med (Tri-Med,1996b), so these and relate & sampling materials (e.g., collection tubes, etc.) could be disposed of as if ordinary waste material. If disposed of regularly, such materials at individual administration or measurement facilities would always be well below the

exeinpt quantities under 10 CFR {30.18. ,

E

= 1.2.2.3 DisposalofScindilation Fluid The average patient sample counted in liquid scintillation fluid is approximately 0.00068 Ci for a given fluid volume of about 15 ml (Marshall, et al - 1991). The concentration would be about 3.8x10 5 pCi/g of

. liquid scintillation counting medium. This is about three orders of magnitude below the NRC standards

. of 0.05 Ci of C per gram at which licensees may dispose of the medium as ifit were not radioactive

- (NRC,1991; { 20.2005).

However, since the fluid contains toluee and xylene which are classified by the EPA as' spent solvent

, hazardous wunas, ti, sir disposal in landfills could cause Resource Conservation and Recovery Act -

_-(RCRA) to be an Applicable and Relevant or Appropriate Requirement (Lowrance,1991). Also, disposal s_ of scintillation fluids in landfills is associated with the potential of contaminating the drinking water

> sources,Because of these concerns, the disposal methodology for the scintillation fluids should involve 1

incineration.L Due to the small amount that would be expected to be generated (approximately 75 liters

. for s maxim _um of 50,000 samples) at each laboratory monthly, the generator reporting requirement is '

( not mandated by RCRA. These materials could easily be sent to's commercial waste incinerator for disposalf The total annual volume ofliquid scintillation fluid for 600,000 samples per year would be

'about 9,000 liters, and contain'only about 410 uCi of C. His release is far below the NRC { 20.2003

. annual limit of ICi/ year for sewers at licensed facilities.

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Atmospheric dispersion following release from an incinerator stack would present no signincant public exposures to "CO 2. The average concentration released from the incinerator stack is expected to be about 4.3x10-" pCi/L annually. Conservatively assuming an adult is downwind at 100 m for an entire year,

' breathing at a rate of 20 !) min., the dose would be on the order of 1.2x104 mrem. Clearly, disposal of the entire annual production at a small incinerator would result in an inconsequential exposure of a member of the public. Expesures at more incineraters with each facility burning smaller quantities, and -

with the public typically further distant from a release point would be eve... lower.

3.2.2.4 DisposalofContaminated Urine Urine from patients given breath tests contain small amounts of "C. urea; the amount will be largest for HP patients with almost all of the "C-urea excreted in urine (Tri Med,1996a). Voiding volume each Jay would be on the order of 1,400 inl/ day for men and 1,000 ml/ day for women (ICRP,1975). Most of the "C-urea would be excreted in the first 5 days, with smaller amounts excreted over several additional weeks. Ifit were conservatively assumed that the entire intake 1.0 uCi were excreted during the first week, the bounding average concentration in the urine would be on the order of 1.2x10" uCi/ml which is already far below the monthly average concentration (after dilution by the entire liquid volume of all sewer effluents of"C,3x10d Ci/ml) allowed to be released to sanitary sewer (NRC,1991; 5 20.2002(b)). Accordingly, the release to sanitary sewers for HP patients would result in concentrations that would be orders of magnitude below that calculated for HP patients at licensed facilities such as hospitals. Such releases would be benign since they would not result in any impact to the public or the environment.

4.0 ALTERNATIVES TO THE PROPOSED ACTION -

In this Environmental Assessment, two alternatives were considered in addition to the proposed action which is allow!ag any physician to receive and use capsules containing 1 pCi of "C-urea for medi:al use without obtaining an NRC license.

General Licensine Alternative.

This alternative would allow the medical use of the capsules containing i uCi of"C-urea by any physicians under general license, rather than a specific license or exemption.

No Action Alternative.

This alternative would restrict Tri-Med from distributing the capsules containing i uCi of "C-urea for medical use by physicians or clinics holding a specific license under NRC Part 35 regulation.

5.0 ENVIRONMENTAL JUSTICE The analysis in this Environmental Assessment shows that there will be no significant impact to the public and the environment from this proposed action. De analysis showed that both normal and accidental releases would result in small increases in the worker's annual dose from naturally occurring radiation (300 nr - ) in the environment. Such doses would also be far below the regulatory limits for radiation worke - i ac doses would also be far below the regulatory limits set by NRC and EPA for members of the grueral public. The NRC has committed itself to complying in all its actions with the 10

\

I, presidential Executive Order number 12898 " Federal Actions to Address Environmental Justice in Minority Populations and Low income Populations", dated February 11,1994. The NRC has determined that there are no disproportionate, high and adverse impacts on minority and low income populations.

- He NRC, on the other hand, found that granting the proposed action could be associated with health benefits to all populations including minority and low income populations.

The NRC uses the following working def'mition of environmentaljustice: environmentaljustice mesa.:;

the fair treatment and meaningful involvement of all people, regardless of race, ethnicity, culture mcome or educational level with respect to the' development, implementation and enforcement of envirc imental laws, regulations, policies.

6.0 FINDING OF NO SIGNIFICANT IMPACT ne Commission has determined under the National Environmental Policy Act of 1959, as amended, and j the Commission's regulations in Subpart A of 10 CFR Part $1, that the amen <Nents are not a mjor y '

Federal action significantly affecting the quality of the human environment, and therefore an Environmental Impact Statement is not required. Currently, physicians who are licensed by the NRC or ,

an Agreement State can receive and use this product, ne proposed rulemaking would allow physicians, who do not have an NRC license for the medical use of byproduct material to also receive and use this product. It is expected that this action would result in significant impact to the environment.

7.0 REFERENCES

Cember, H., Introduction to Health Physics, Second Editiorr, Pergamon Press, Elmsford, NY,198'/.

Chey, W.D., M. Spybrook, S. Carpenter, T.T. Nostrant, G.H. Etta, and J.M. Scheiman, " Prolonged Effect of Omeprazole on the "C-Urea Breath Test", Am. J. of Gastroentorology, Vol. 91, Nc.1, pp. 89 92, January 1996.

Corley, J., J Yoder, S. Raibon, and G. Burke," Nuclear Medicine's New Role in Peptic Ulcer Disease ,

Management", Joumal of Nuclear Medicine Technology 23 (4), December 1995.

DOC (Department of Commerce), Statistical Abstract of the United States. Item No. 215,115th ed.,

Department of Commerce, Economics and Statistics, Bureau of the Census,1995.

Environmental Protection Agency (EPA), National Primary Drinking Water Regulations: Radionuclides, Proposed Rule,40 CFR Part 141 ad 142,56 FR 33050, July 18,1991.

Er.vironmental Protection Agency (EPA), National Emission Standardsfor Harardous Air Pollutants:

Radionuclides,40 CFR Part 61,54 FR 51654, December 15,1909.

Fennetty, M. B., T. P. Gage, L. A. Laine, D. A. Peura, and D. T. Smoot,"Helicobacterpylori : De New Factor in Management of Ulcer Disease," American Gastroenterological Association,Inc and American Gastroenterological Foundation, Inc., Bsthesda, MD,1994.

Gotchy, R. L., L. Battist, and R. Karimi, Safety Report for the Use of C-14 Urea for the Detection of H.

pylori Bacteria in the Human Alimentary Tract, Prepared for the Us Nuclear Regulatory Commission, May 1996.

11

__ _ _ _ - _ _2_-_. _ _- _ _ _ _ _ _ _ _-_______-_-__ - _-___-____-__ _______-____ __- - __-_ - _ _ _

International Commission on Radiological Protection (ICRP), Report of the Task Group on Reference Afan, ICRP Report No. 23, Pergamon Press, Elmsford, NY,1975.

Kramer, G.H., A. Badreddine, T. Tran, and D. Meyerhoff, Dosimetry of an incident involving "C",

Health Physics, Vol. 70 (3), March,1996.

Lowrance, S. K., RCPA ARAR Determination at Maxey Flats Superfund Site, Memorandum from Director of EPA Office of Solid Waste, to D. J. Guinyard, Director of Waste Management Division, EPA Region IV and John R. Barker, Regional Counsel for EPA Region IV, September,04,1991.

Marshall, B. J., "Helicobacterpylori", The American Journal of Gastroenterology 89 (8),1994.

Marshall. BJ., M.W. Plankey, S.R. Hoffmaa, C.L. Boyd, H.F. Frierson, R.L. Guerrant, and R.W.

McCallum, "A 20-Minute Breath Test for Helicobackrer pylori", The Am. J. of Gastroenterology, Vol.

86, No. 4. 438-445, April 1991.

NCRP (National Council on Radiation Protection and Measurements), Ionizing Radiation Exposure of the Population ofthe UnitedStates, NCRP Report No. 93, Bethesda, MD,1937a.

NCRP (National Council on Radiation Protection and Measurements), Exposure of the Population ofthe United States and Canadafrom Natural Background Radiation, NCRP Report No. 94, Bethesda, MD, 1987b.

NCRP (National Council on Radiation Protection and Measurements), Carbon-H in the Environment, NCRP Report No. 81, Bethesda, MD,1985.

NRC (Nuclear Regulatory Commission), "Standardsfor Protection Against Radiation; Final Rule,56 FR 23360", Mav 21,1991.

Peura, D.A., D.J. Pamianco, K.R. Dye, C. Lind, H.F. Frierson, S.R. Hoffmar., M.J. Combs, E. builfoyle, and B.J. Marshall, " Microdose "C-Urea Breath Test Offers Diagnosis of H. Pylori in 10 Minutes".

American Joumal of Gastroenterology Vol. 91(2), February 1996.

Pippen,1996, letter report to Dr. R. L, Gotchy, SAIC, from Mr. Howa-d Pippen, SAIC, February 26, 1996.

Tri-Med Specialties, Inc.," Report of the Dorimetric Assessment of the Tri-Med C-14 Breath Tes, submitted to Dr. Lewis Battist, SAIC, in support of the Petition for Exemption to NRC, with attachments, February 9,1996a (Proprietary and Con)identtal).

Tri Med Speciakies, Inc., personal communication from Dr. David Peura to Dr. Lewis Battist, SAIC, February 9,1996b.

Tri-Med Specialties, Inc, personal communication from Drs. Matthew Combs and Marshall B,arry to Dr.

Lewis Battist, SAIC, February 9,1996c.

12

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Tri.Med Specialties, Inc., " Letter to the Director, Freedom ofInformation and Publication Servich, U.Si i e ;Nuc. ear Regulatory Commission", August 23.,.1994, =. l 33

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