[Federal Register: September 15, 2003 (Volume 68, Number 178)]
[Notices]
[Page 53984-53989]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15se03-87]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2003D-0399]
Guidance for Industry on Pentetate Calcium Trisodium and
Pentetate Zinc Trisodium for Treatment of Internal Contamination with
Plutonium, Americium, or Curium; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing that we
(FDA) have concluded that pentetate calcium trisodium (Ca-DTPA) and
pentetate zinc trisodium (Zn-DTPA), when produced under conditions
specified in approved new drug applications (NDAs), can be found
[[Page 53985]]
to be safe and effective for the treatment of internal contamination
with plutonium, americium, or curium to increase the rates of
elimination. We encourage the submission of NDAs for Ca-DTPA and Zn-
DTPA drug products. We are also announcing the availability of a
guidance for industry entitled ``Calcium-DTPA and Zinc-DTPA Drug
Products--Submitting a New Drug Application.'' This guidance is
intended to assist manufacturers who plan to submit NDAs for Ca-DTPA
and Zn-DTPA.
ADDRESSES: Submit NDAs to the Food and Drug Administration, Center for
Drug Evaluation and Research, Central Document Room, 12229 Wilkins
Ave., Rockville, MD 20857. Submit requests for copies of draft labeling
to the Division of Medical Imaging and Radiopharmaceutical Drug
Products (HFD-160), Center for Drug Evaluation and Research, Food and
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-
7510. Copies of the reports referred to in this document will be on
display at the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Submit written requests for single copies of the guidance to the
Division of Drug Information (HFD-240), Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857. Send one self-addressed adhesive label to assist that office
in processing your requests. Submit written comments on the guidance to
the Division of Dockets Management (address given previously). Submit
electronic comments to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments. See the
SUPPLEMENTARY INFORMATION section for electronic access to the guidance
document.
FOR FURTHER INFORMATION CONTACT: Kyong Kang, Center for Drug Evaluation
and Research (HFD-160), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-827-7510.
SUPPLEMENTARY INFORMATION:
I. Background
A. Plutonium, Americium, and Curium
Plutonium, americium, and curium are transuranium radioactive
elements of the actinide series. They are products of nuclear
bombardment and are found in the fallout from the detonation of nuclear
weapons and the waste from nuclear power plants. These elements are
used in various types of research. All isotopes of plutonium,
americium, and curium are radioactive.
Contamination with plutonium, americium, or curium can occur
through a variety of routes including ingestion, inhalation, and/or
wounds. Contamination can cause serious illness or death when high
radiation absorbed doses are delivered to critical organs. Lower doses
have been associated with the development of cancer long after
exposure. In addition to concerns about exposure to plutonium,
americium, or curium in industrial and research environments,
contamination by radioactive elements such as these, is of particular
concern because of their potential use in a radiological dispersal
device (RDD), commonly called a ``dirty bomb.'' An RDD is a
conventional explosive or bomb containing radioactive material. The
conventional bomb is used as a means to spread radioactive material. An
RDD is not a nuclear weapon and does not involve a nuclear explosion.
Significant amounts of radioactive material, particularly plutonium,
could also be spread by the detonation of an improvised nuclear device
by terrorists. The extemporized design and construction of such a
terrorist weapon could lead to an incident where only a small portion
of the weapon's plutonium is consumed in the atomic reaction, and the
rest of the plutonium is spread through the air by the explosion of the
device. There are currently no approved treatments for internal
contamination with plutonium, americium, or curium.
B. Ca-DTPA and Zn-DTPA
Diethylenetriaminepentaacetate (DTPA) is a ligand that acts as a
chelator with a very high affinity for plutonium, americium, and
curium. The calcium salt of DTPA is known as pentetate calcium
trisodium and is referred to as Ca-DTPA. The zinc salt of DTPA is known
as pentetate zinc trisodium and is referred to as Zn-DTPA.\1\
---------------------------------------------------------------------------
\1\ For purposes of this document Ca-DTPA refers only to
pentetate calcium trisodium, which has an empirical formula of
Na3CaC14H18N3O10
and the Chemical Abstracts Service (CAS), registry number 12111-24-
9. Zn-DTPA refers only to pentetate zinc trisodium, which has an
empirical formula of
Na3ZnC14H18N3O10
and the CAS registry number 125833-02-5.
---------------------------------------------------------------------------
For several decades, Ca-DTPA and Zn-DTPA have been used
investigationally to enhance the excretion of plutonium, americium, and
curium from the body by means of ion exchange, chelation, and,
ultimately, excretion through the urine. Because DTPA has a very high
affinity for these transuranium elements, when it comes in contact with
such elements, the calcium or zinc ions of Ca-DTPA and Zn-DTPA drugs
are readily exchanged for the transuranium elements. The transuranium-
DTPA complex is then rapidly excreted in the urine. There are currently
no approved NDAs for drug products containing Ca-DTPA or Zn-DTPA.
Ca-DTPA and Zn-DTPA in sterile aqueous solution have been used
under investigational new drug applications (INDs) held by the
Radiation Emergency Assistance Center/Training Site (REAC/TS). REAC/TS
is part of the Oak Ridge Associated Universities (ORAU). ORAU operates
the Oak Ridge Institute for Science and Education under a contract with
the Department of Energy. The INDs are for treatment of contamination
resulting from nuclear power or other industrial accidents.
Traditional clinical trials have not been conducted because it
would be unethical to deliberately expose patients to radiation; it
would also be unethical to withhold potential beneficial medications
from patients who have been accidentally exposed. Instead, under these
INDs, accidentally exposed patients were treated empirically and the
findings were reported in the literature as observational studies.
REAC/TS has retained the medical case reports on 646 patients
treated with Ca-DTPA and Zn-DTPA for radiation contamination during the
last 40 years. To facilitate the development and ultimate approval of
Ca-DTPA and Zn-DTPA drug products, we have reviewed the medical reports
on the patients in the REAC/TS database and reviewed the available
published literature. This notice announces our conclusions about the
safety and effectiveness of Ca-DTPA and Zn-DTPA drug products, and it
is addressed primarily to persons interested in submitting NDAs for Ca-
DTPA or Zn-DTPA drug products.
II. Safety and Effectiveness of Ca-DTPA and Zn-DTPA Drug Products
We have concluded that Ca-DTPA and Zn-DTPA drug products, when
produced under conditions specified in approved NDAs, can be found to
be safe and effective for the treatment of patients with known or
suspected internal contamination with plutonium, americium, or curium
to increase the rates of elimination. As described in section II.A of
this document, our conclusion is based on our review of medical reports
in the REAC/TS database.
We encourage the submission of NDAs for both Ca-DTPA and Zn-DTPA
drug products. If you are interested in submitting NDAs for these
products, please contact the Center for Drug
[[Page 53986]]
Evaluation and Research's (CDER's) Division of Medical Imaging and
Radiopharmaceutical Drug Products for a copy of the draft labeling (see
ADDRESSES). We also recommend that you consult the guidance entitled
``Calcium-DTPA and Zinc-DTPA Drug Products--Submitting a New Drug
Application,'' which is being made available with this notice (see
section V of this document).
A. Basis for Finding of Safety and Effectiveness
We have reviewed medical reports in the REAC/TS database and have
determined that Ca-DTPA and Zn-DTPA drug products, when produced under
conditions specified in an approved NDA, can be found to be safe and
effective for treatment of patients with known or suspected internal
contamination with plutonium, americium, or curium to increase the
rates of elimination. Our conclusion is supported by our review of
reports in the literature, which provided information consistent with
that in the REAC/TS database.
Administration of a loading dose of Ca-DTPA followed by maintenance
treatment with Zn-DTPA increases the rate of elimination of these
radioactive elements from the body and is expected to decrease the risk
of death and major morbidity from radiation complications.
In reaching our determination on the effectiveness of Ca-DTPA and
Zn-DTPA, we evaluated reports from the REAC/TS database on 646 patients
who received one or more doses of these drugs during the last 40 years.
Ca-DTPA was administered either by inhalation or by intravenous
injection. Zn-DTPA was administered by intravenous injection. Data on
the type of transuranium element and amount of urine elimination were
available for detailed analysis from 18 patients. In these patients,
administration of Ca-DTPA by inhalation or intravenous injection of a
1-gram (g) dose of Ca-DTPA in a 5 milliliter (mL)-sterile aqueous
solution increased the rate of radiation elimination in the urine an
average of 39-fold. Maintenance doses of Zn-DTPA administered once
daily resulted in continued elimination of radiation.
Some adverse effects were identified as resulting from Ca-DTPA and
Zn-DTPA administration. The primary adverse effects of Ca-DTPA
administration were the elimination from the body of endogenous
essential trace metals, particularly zinc, but also including magnesium
and manganese. The endogenous trace metal decreases occurred after
treatment for several days and appeared to increase when the drugs were
given in divided doses over 1 day. Although Zn-DTPA is also believed to
decrease serum magnesium and manganese, no serious toxicity has been
observed with the administration of Zn-DTPA in humans or animals. In
patients undergoing administration of Ca-DTPA or Zn-DTPA drug products,
blood levels of these endogenous trace metals should be followed
closely and can be treated with nutritional supplements.
In pregnant animals, multiple doses of Ca-DTPA are associated with
fetal malformations and fetal death. Similar effects on animal fetuses
were not seen with Zn-DTPA. As a result, Zn-DTPA should be used to
begin treatment in pregnant patients. However, if Zn-DTPA is not
available, the risks related to radiation contamination should be
weighed against the risks of Ca-DTPA to the mother and fetus.
Intravenous administration of Ca-DTPA is recommended and should be
used if the route of radioactive contamination is not known or if
multiple routes of contamination are possible. In patients whose
contamination is only by inhalation within the preceding 24 hours, Ca-
DTPA administered as a single loading dose by nebulized inhalation is
an alternative route of administration. However, administration of Ca-
DTPA by inhalation may irritate some patients, especially those with a
history of respiratory disorders. In these patients, the intravenous
route can be used. Other rare adverse events are discussed in the
published literature and in the draft labeling we have prepared.
B. Labeling for Ca-DTPA and Zn-DTPA
We have prepared draft labeling for Ca-DTPA supplied as 1 g in a 5
mL-sterile aqueous solution for administration either by inhalation
(with a 1:1 dilution with saline and delivered by nebulization) or
intravenous injection. We have also prepared draft labeling for Zn-DTPA
supplied as 1 g in a 5-mL sterile aqueous solution for intravenous
injection. You can submit this draft labeling as part of an NDA for Ca-
DTPA or Zn-DTPA drug product that relies on our findings of safety and
effectiveness. The draft labeling reflects our conclusion on the
potential safety and effectiveness of Ca-DTPA and Zn-DTPA for treatment
of patients with known or suspected internal contamination with
plutonium, americium, or curium to increase the rates of elimination.
The draft labeling may need to be modified if you submit an NDA for
either Ca-DTPA or Zn-DTPA and there is not an approved NDA for the
other DTPA drug product, or the other drug product is otherwise
unavailable. If you wish to change the labeling to include a different
or broader indication or different dosage, or if you wish to make any
other significant changes to the draft labeling, you should provide, as
part of your NDA, additional literature or other studies to support
your requested changes. If you submit an NDA for either a Ca-DTPA or
Zn-DTPA drug product that is not based on our findings of the safety
and effectiveness of Ca-DTPA and Zn-DTPA, you cannot use the draft
labeling because it is based on our review of the REAC/TS database and
published literature. If you submit such an NDA, your labeling must be
based on the safety and effectiveness data contained in your NDA.
The draft labeling for NDAs based on our review of the REAC/TS
database and published literature is available on the Internet at
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/drug/infopage/dtpa/default.htm. You may also
contact CDER's Division of Medical Imaging and Radiopharmaceutical Drug
Products for a copy of the draft labeling (see ADDRESSES).
III. Conclusions
We have determined that Ca-DTPA and Zn-DTPA can be safe and
effective for treatment of patients with known or suspected internal
contamination with plutonium, americium, or curium to increase the
rates of elimination. We encourage the submission of NDAs for Ca-DTPA
and Zn-DTPA drug products. The requirement under 21 U.S.C. 355(b)(1)
for full reports of investigations to support these NDAs may be met by
citing this notice and the published literature we relied on in
preparing this notice. For a list of this published literature see
section V of this document. A list of the published literature and
reprints of the reports will be available for public inspection in the
Division of Dockets Management (see ADDRESSES). It is unnecessary to
submit copies and reprints of the reports from the listed published
literature. We invite applicants to submit any other pertinent studies
and literature of which they are aware.
IV. Availability of a Guidance
A. Notice of Availability
In this document, we are also announcing the availability of a
guidance for industry entitled ``Ca-DTPA and Zn-DTPA Drug Products--
Submitting a New Drug Application.'' The guidance is intended to assist
manufacturers who plan to submit NDAs for Ca-DTPA and Zn-DTPA.
[[Page 53987]]
This guidance is being issued as a level 1 guidance consistent with
our good guidance practices regulation (21 CFR 10.115). It is being
implemented immediately without prior public comment because we believe
it is in the interest of the public health to communicate this
information to the public as quickly as possible. However, we welcome
comments on the guidance, and if comments are submitted, we will review
them and revise the guidance if appropriate. The guidance represents
our current thinking on issues associated with the submission of NDAs
for Ca-DTPA and Zn-DTPA drug products. It does not create or confer any
rights for or on any person and does not operate to bind FDA or the
public. An alternative approach may be used if such approach satisfies
the requirements of the applicable statutes and regulations.
B. Comments
Interested persons may, at any time, submit written comments on the
guidance to the Division of Dockets Management (see ADDRESSES). Two
copies of any mailed comments are to be submitted except that
individuals may submit one copy. Comments are to be identified with the
docket number found in the brackets in the heading of this document.
The document and received comments are available for public examination
in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
C. Electronic Access
Persons with access to the Internet may obtain the guidance at
either http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm or http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
V. Published Literature on the Safety and Effectiveness of Ca-DTPA and
Zn-DTPA
The published literature we have relied on in making the
determinations regarding Ca-DTPA and Zn-DTPA contained in this notice
is listed in this section of this document. Copies of the published
literature will be on display in the Division of Dockets Management
(see ADDRESSES) and can be seen by interested persons between 9 a.m.
and 4 p.m., Monday through Friday. (FDA has verified the Web site
address, but we are not responsible for subsequent changes to the Web
site after this document publishes in the Federal Register.)
1. Aronson, A. L., P. B. Hammond, and A. C. Strafuss, ``Studies
with Calcium Ethylenediaminetetraacetate in Calves; Toxicity and Use
in Bovine Lead Poisoning,'' Toxicology and Applied Pharmacology,
12:337-349, 1968.
2. Bair, W. J., J. F. Park, G. E. Dagle, et al., ``Overview of
Biological Consequences of Exposure to Plutonium and Higher
Actinides,'' Radiation Protection Dosimetry, 26:125-135, 1989.
3. Ballou, J. E., G. E. Dagle, K. E. McDonald, et al.,
``Influence of Inhaled Ca-DTPA on the Long-term Effects of Inhaled
Pu Nitrate,'' Health Physics, 32:479-487, 1977.
4. Blakely, W. F., P. G. S. Prasanna, M. B. Grace, et al.,
``Radiation Exposure Assessment Using Cytological and Molecular
Biomarkers,'' Radiation Protection Dosimetry, 97:17-23, 2001.
5. Breitenstein, B. D., ``1976 Hanford Americium Exposure
Incident: Medical Management and Chelation Therapy,'' Health
Physics, 45:855-866, 1983.
6. Breitenstein, B. D., and H. E. Palmer, ``Lifetime Follow-up
of the 1976 Americium Accident Victim,'' Radiation Protection
Dosimetry, 26:317-322, 1989.
7. Breitenstein, B. D., S. A. Fry, and C. C. Lushbaugh, ``DTPA
Therapy: The U.S. Experience 1958-1987,'' in The Medical Basis for
Radiation Accident Preparedness II: Clinical Experience and Follow-
up Since 1979, eds. R. C. Ricks and S. A. Fry (New York: Elsevier,
1990), 397-406.
8. Brodsky, A., N. Wald, K. E. Lee, et al., ``Plutonium-
Americium Contamination Aspects of a Dry Box Involving Hand
Amputation,'' in Health Physics Operational Monitoring, eds. C. A.
Willis and J. S. Handloser (New York: Gordon and Breach, 1972),
1601-1620.
9. Brodsky, A., J. A. Sayeg, N. Wald, et al., ``The Measurement
and Management of Insoluble Plutonium-Americium Inhalation in Man,''
in Proceedings of the First International Congress on Radiation
Protection, eds., W. S. Snyder et al.(New York: Pergammon Press,
1968), 1181-1190.
10. Brodsky, A., N. Wald, I. S. Horm, et al., ``The Removal of
Americium-241 from Humans by DTPA,'' Health Physics, 17:379, 1969.
11. Bruenger, F. W., W. Stevens, D. R. Atherton, et al.,
``Biological Mechanisms and Translocation Kinetics of Particulate
Plutonium,'' in Actinides in Man and Animals--Proceedings of the
Snowbird Actinides Workshop, Snowbird, UT, October 15 through 17,
1979, ed. McDonald E. Wrenn, (Salt Lake City, UT: RD Press, 1981),
413-426.
12. Bruenger, F. W., D. M. Taylor, G. N. Taylor, et al.,
``Effectiveness of DTPA Treatments Following the Injection of
Particulate Plutonium,'' International Journal of Radiation Biology,
60:803-818, 1991.
13. Calder, S. E., C. W. Mays, G. N. Taylor, et al., ``Zn-DTPA
Safety in the Mouse Fetus,'' Health Physics, 36:524-526, 1978.
14. Catsch, A., ``Removal of Transuranic Elements by Chelating
Agents,'' in Diagnosis and Treatment of Incorporated Radionuclides:
Proceedings of an International Seminar, Vienna, December 8 through
12, 1975, (Vienna: International Atomic Energy Agency, 1976), IAEI-
SR-6/103, 295-305, 1976.
15. Catsch, A., and A. E. Harmuth-Hoene, ``New Developments in
Metal Antidotal Properties of Chelating Agents,'' Biochemical
Pharmacology, 24:1557-1562, 1975.
16. Catsch, A., and A. E. Harmuth-Hoene, ``Pharmacology and
Therapeutic Applications of Agents Used in Heavy Metal Poisoning,''
in The Chelation of Heavy Metals, Alexander Catsch (Oxford:
Pergammon Press, 1979), 171-183.
17. Chen, W. Y., Y. C. Wang, and M. S. Kuo, ``Determination of
Total Mercury and Methylmercury in Human Hair by Graphite-Furnace
Atomic Absorption Spectrophotometry Using 2,3-Dimercaptopropane-1-
sulfonate as a Complexing Agent,'' Analytical Sciences, 18:255-260,
2002.
18. Cohen, N., McD. E. Wrenn, R. A. Guilmette, et al.,
``Enhancement of 241Am Excretion by Intravenous Administration of
Na3 (CA-DTPA) in Man and Baboon,'' in Diagnosis and Treatment of
Incorporated Radionuclides: Proceedings of an International Seminar,
Vienna, December 8 through 12, 1975. (Vienna: International Atomic
Energy Agency, 1976), IAEA-SR-6/20, 461-475.
19. Dilley, J. V., ``Effect of DTPA on Inhaled 239PuF4 in
Beagles,'' Radioelement Removal Studies, 5.14-5.17, 1970.
20. Dolphin, G. W., ``Review of Some Problems and Recent
Research Work Associated with the Use of Chelating Agents for the
Removal of Incorporated Radionuclides from Humans,'' in Diagnosis
and Treatment of Incorporated Radionuclides: Proceedings of an
International Seminar, Vienna, December 8 through 12, 1975, (Vienna:
International Atomic Energy Agency, 1976), IAEA-SR-6/104, 403-418.
21. Doolan, P. D., S. L. Schwartz, J. R. Hayes, et al., ``An
Evaluation of the Nephrotoxicity of Ethylenediaminetetraacetate and
Diethylenetriaminepentaacetate in the Rat,'' Toxicology and Applied
Pharmacology, 10:481-500, 1967.
22. Fasiska, B. C., D. E. Bohning, A. Brodsky, et al., ``Urinary
Excretion of 241Am under DTPA Therapy,'' Health Physics, 21:523-529,
1971.
23. Ferguson, C. D., T. Kazi, and J. Perera, Commercial
Radiation Sources: Surveying the Security Risks, (Monterey, CA:
Monterey Institute of International Studies, 2003).
24. Fisher, D. R., S. E. Calder, C. W. Mays, et al.,``Ca-DTPA-
induced Fetal Death and Malformation in Mice,'' Teratology,14:123-
128, 1976.
25. Fisher, D. R., C. W. Mays, and G. N. Taylor, ``Ca-DTPA
Toxicity in the Mouse Fetus,'' Health Physics, 29:780-782, 1975.
26. Gabard, B., ``The Influence of
Diethylenetriaminepentaacetate on the Synthesis of DNA, RNA, and
Proteins in the Regenerating Rat Liver,'' Biochemical Pharmacology,
23:901-909, 1974.
27. Goans, R. E., ``Update on the Treatment of Internal
Contamination,'' in The Medical Basis for Radiation Accident
Preparedness: Proceedings of the 4th International REAC/TS
Conference, eds. Robert C. Ricks, et al. (New York: Elsevier, 2001),
201-216.
28. Hall, R. M., G. A. Poda, R. R. Fleming, et al., ``A
Mathematical Model for Estimation of Plutonium in the Human Body
from Urine Data Influenced by DTPA Therapy,'' Health Physics,
34:419-431, 1978.
[[Page 53988]]
29. Hartvig, P., ``Chemical Principles of Chelate Therapy in
Neurotoxicology,'' Acta Neurologica Scandinavica, 70:199-202, 1984.
30. International Commission for Radiological Protection.
Committee 2, The Metabolism of Compounds of Plutonium and Other
Actinides; a Report Prepared by a Task Group of Committee 2 adopted
by the Commission in May 1972, (Oxford: Pergamon Press, 1972), ICRP
Publication 19.
31. International Commission on Radiological Protection.
Committee 4, The Principles and General Procedures for Handling
Emergency and Accidental Exposures of Workers, (Oxford: Pergamon
Press, 1978), ICRP Publication 28.
32. Jones, C. W., C. W. Mays, G. N. Taylor, et al., ``Reducing
the Cancer Risk of 239Pu by Chelation Therapy,'' Radiation Research,
107:296-306, 1986.
33. Kalkwarf, D. R., V. W. Thomas, K. K. Nielson, et al., ``1976
Hanford Americium Exposure Incident: Urinary Excretion of Trace
Metals During DTPA Treatments,'' Health Physics, 45:937-947, 1983.
34. Katz, J., M. H. Weeks, and W. D. Oakley, ``Relative
Effectiveness of Various Agents for Preventing the Internal
Deposition of Plutonium in the Rat,'' Biology Research Annual Report
1953, HW-30437, 112-113, 1954.
35. Langham, W. H., S. H. Bassett, P. S. Harris, et al.,
``Distribution and Excretion of Plutonium Administered Intravenously
to Man,'' Health Physics, 38:1031-1060, 1980.
36. Lloyd, R. D., S. S. McFarland, G. N. Taylor, et al.,
``Decorporation of 241Am in Beagles by DTPA,'' Radiation Research,
62:97-106, 1975.
37. Lloyd, R. D., C. W. Mays, S. S. McFarland, et al., ``A
Comparison of Ca-DTPA and Zn-DTPA for Chelating 241Am in Beagles,''
Health Physics, 31:281-284, 1976.
38. Lucke-Huhle, C., ``Proliferation-Dependent Cytotoxicity of
Diethylenetriaminepentaacetate (DTPA) In Vitro,'' Health Physics,
31:349-354, 1976.
39. Mays, C. W., G. N Taylor, and D. R. Fisher, ``Estimated
Toxicity of Ca-DTPA to the Human Fetus,'' Health Physics, 30:247-
249, 1976.
40. Morgan, R. M., and H. Smith, ``The Effect of Acute and Sub-
acute Treatment with Diethylenetriaminepentaacetic Acid on the
Hepatic Function of Mice,'' Toxicology, 2: 43-49, 1974.
41. Morgan, R. M., and H. Smith, ``Histological Changes in
Kidney, Liver, and Duodenum of the Mouse Following the Acute and
Subacute Administration of Diethylenetriaminepentaacetic Acid,''
Toxicology, 2:153-163, 1974.
42. Morin, M., J. C. Nenot, and J. Lafuma, ``The Behavior of
237Np in the Rat,'' Health Physics, 24:311-315, 1973.
43. Muggenburg, B. A., J. A. Mewhinney, J. J. Miglio, et al.,
``The Removal of Inhaled 239Pu and 238Pu from Beagle Dogs by Lung
Lavage and Chelation Treatment,'' in Diagnosis and Treatment of
Incorporated Radionuclides: Proceedings of an International Seminar,
Vienna, December 8 through 12, 1975, (Vienna: International Atomic
Energy Agency, 1976), IAEA-SR-6/30, 341-355.
44. Norwood, W. D., ``DTPA Effectiveness in Removing Internally
Deposited Plutonium from Humans,'' Journal of Occupational Medicine,
2:371-376, 1960.
45. Norwood, W. D., ``Long-Term Administration of DTPA for
Plutonium Elimination,'' Journal of Occupational Medicine, 8:130-
132, 1962.
46. Norwood, W. D., ``Therapeutic Removal of Plutonium in
Humans,'' Health Physics, 8:747-750, 1962.
47. Planas-Bohne, F., and H. Ebel, ``Dependance of DTPA-Toxicity
on the Treatment Schedule,'' Health Physics, 29:103-106, 1975.
48. Planas-Bohne, F., and J. Lohbreier, ``Toxicological Studies
on DTPA,'' in Diagnosis and Treatment of Incorporated Radionuclides:
Proceedings of an International Seminar, Vienna, December 8 through
12, 1975, (Vienna: International Atomic Energy Agency, 1976), IAEA-
SR-6/1, 505-515.
49. Rosenthal, M. W., and A. Lindenbaum, ``Influence of DTPA
Therapy on Long-Term Effects of Retained Monomeric Plutonium:
Comparison with Polymeric Plutonium,'' Radiation Research, 31:506-
521, 1967.
50. Rosenthal, M. W., J. F. Markley, A. Lindenbaum, et al.,
``Influence of DTPA Therapy on Long-Term Effects of Retained
Plutonium,'' Health Physics, 8:741-745, 1962.
51. Seidel, A., ``Comparison of the Effectiveness of CaDTPA and
ZnDTPA in Removing 241Am from the Rat,'' Radiation Research, 54:304-
315, 1973.
52. Seidel, A., ``A Multivariate Analysis of Ca-DTPA-
Effectiveness in Removing 241Am from the Rat,'' Zeitschrift Fur
Naturforschung. Teil C: Biochemie, Biophysik, Biologie, Virologie,
28:316-318, 1973.
53. Seidel, A., ``Removal of 252Cf and 241Am from the Rat by
Means of Ca-DTPA and Zn-DTPA,'' in Diagnosis and Treatment of
Incorporated Radionuclides: Proceedings of an International Seminar,
Vienna, December 8 through 12, 1975, (Vienna: International Atomic
Energy Agency, 1976), IAEA-SR-6/2, 323-339.
54. Seidel, A., and V. Volf, ``Removal of Internally Deposited
Transuranium Elements by Zn-DTPA,'' Health Physics, 22:779-783,
1972.
55. Silini, G., and S. Hornsey, ``Studies on Cell-Survival of
Irradiated Ehrlich Ascites Tumour III. A Comparison of the X-ray
Survival Curves Obtained with a Diploid and a Tetraploid Strain,''
International Journal of Radiation Biology, 5:147-153, 1961.
56. Smith, V. H., J. E. Ballou, J. E. Lund, et al., ``Aspects of
Inhaled DTPA Toxicity in the Rat, Hamster and Beagle Dog and
Treatment Effectiveness for Excorporation of Plutonium from the
Rat,'' in Diagnosis and Treatment of Incorporated Radionuclides:
Proceedings of an International Seminar, Vienna, December 8 through
12, 1975, (Vienna: International Atomic Energy Agency, 1976), IAEA-
SR-6/26, 517-530.
57. Smith, V. H., J. E. Ballou, W. J. Clarke, et al.,
``Effectiveness of DTPA in Removing Plutonium from the Pig,''
Proceedings of the Society for Experimental Biology and Medicine,
107:120-123, 1961.
58. Smith, V. H., ``The Effect of DTPA Dose on Plutonium Removal
from Rats,'' (Richland, WA: U.S. Atomic Energy Commission, 1971),
BNWL-1550, 96-97.
59. Stather, J. W., H. Smith, A. C. James, et al., ``The
Experimental Use of Aerosol and Liposomal Forms of Ca-DTPA as a
Treatment for Plutonium Contamination,'' in Diagnosis and Treatment
of Incorporated Radionuclides: Proceedings of an International
Seminar, Vienna, December 8 through 12, 1975, (Vienna: International
Atomic Energy Agency, 1976), IAEA-SR-6/14, 387-400.
60. Stather, J. W., H. Smith, M. R. Bailey, et al., ``The
Retention of 14C-DTPA in Human Volunteers after Inhalation or
Intravenous Injection,'' Health Physics, 44:45-52, 1983.
61. Stevens, W., F. W. Bruenger, D. R. Atherton, et al., ``The
Retention and Distribution of 241Am and 65Zn Given as DTPA Chelates
in Rats and of [14C]DTPA in Rats and Beagles,'' Radiation Research,
75:397-409, 1978.
62. Suslova, K. G., V. F. Khokhryakov, Z. B. Tokarskaya, et al.,
``Extrapulmonary Organ Distribution of Plutonium in Healthy Workers
Exposed by Chronic Inhalation at the Mayak Production Association,''
Health Physics, 82:432-444, 2002.
63. Takada, K., and V. Wolf, ``Comparison of the Effectiveness
of CaDTPA and ZnDTPA in Removing 242Cm from the Rat,'' Radiation
Research, 70:164-172, 1977.
64. Taylor, D. M., and F. D. Sowby, ``The Removal of Americium
and Plutonium from the Rat by Chelating Agents,'' Physics in
Medicine and Biology, 7:83-91, 1962.
65. Taylor, D. M., and J. D. Jones, ``Effects of
Ethylenediaminetetraacetate and Diethylenetriaminepentaacetate of
DNA. Synthesis in Kidney and Intestinal Mucosa of Folate Treated
Rats,'' Biochemical Pharmacology, 21:3313-3315, 1972.
66. Taylor, G. N., and C. W. Mays, `` Fetal Injury Induced by
Ca-DTPA in Dogs,'' Health Physics, 35:858-860, 1978.
67. Taylor, G. N., J. L. Williams, L. Roberts, et al.,
``Increased Toxicity of Na3CaDTP When Given by Protracted
Administration,'' Health Physics, 27:285-288, 1974.
68. Volf, V., ``Plutonium Decorporation in Rats: Experimental
Evidence and Practical Implications,'' in Diagnosis and Treatment of
Incorporated Radionuclides: Proceedings of an International Seminar,
Vienna, December 8 through 12, 1975, (Vienna: International Atomic
Energy Agency, 1976), IAEA-SR-6/3, 307-322.
69. Volf, V., Treatment of Incorporated Transuranium Elements,
(Vienna, Austria: International Atomic Energy Agency, 1978),
Technical Report Series No. 184.
70. Volf, V., A. Seidel, and K. Takada, ``Comparative
Effectiveness of Ca-DTPA, Desferrioxamine B and their Combination in
Removing Transuranium Elements from Rats,'' Health Physics, 32:155-
157, 1977.
71. Washington State Department of Health, ``Report on the
Response to the Accident on May 14, 1997 on the Hanford Site,''
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.doh.wa.gov/ehp/rp/rp-prf.htm (21 June 2002).
72. Weber, K. M., F. Bohne, and U. Rabe, ``Decrease of DNA
Synthesis in Duodenal Crypt Cells of Rats Treated with
Na3 (Ca-DTPA),'' European Journal of Pharmacology,
11:117-118, 1970.
[[Page 53989]]
Dated: September 8, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-23489 Filed 9-12-03; 8:45 am]
BILLING CODE 4160-01-S