[Federal Register Volume 68, Number 178 (Monday, September 15, 2003)]
[Notices]
[Pages 53984-53989]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-23489]


-----------------------------------------------------------------------

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://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://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://www.fda.gov/cder/guidance/index.htm or 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://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