Physical, chemical, and biological properties of radiocerium relevant to radiation protection guidelines: Recommendations of the National Council on Radiation ... and Measurements (NCRP report ; no. 60)

NCRP REPORT NO. 60

PHYSICAL, CHEMICAL, A N D BIOLOGICAL PROPERTIES OF RADIOCERIUM RELEVANT T O RADIATION PROTECTION GUIDELINES Recommendations of the NATIONAL COUNCIL O N RADIATION PROTECTION AND MEASUREMENTS

Issued 15 December 1978 National Council on Radiation Protection and Measurements 7910 WOODMONT AVENUE

/ WASHINGTON, D.C. 20014

Copyright O National Council on Radiation Protection and Measurements 1978

AU rights reserved. This publication is protected by copyright. No part of this publication may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotation in critical articles or reviews. Library of Congress Catalog Card Number 79-84486 International Standard Book Number 0-913392-44-8

Preface Cerium, an element in the lanthanide series, has a number of radioactive isotopes. Several of these are produced in abundance in nuclear fission reactions associated with nuclear industry operations or detonation of nuclear devices. This report summarizes our present knowledge of the relevant physical, chemical, and biological properties of radiocerium as a basis for establishing radiation protection guidelines. The first section of the report reviews the chemical and physical properties of radiocerium relative to the biological behavior of internally-deposited cerium and other lanthanides. The second section of the report gives the sources of radiocerium in the environment and the pathways to man. The third section of the report describes the metabolic fate of cerium in several mammalian species as a basis for predicting its metabolic fate in man. The fourth section of the report considers the biomedical effects of radiocerium in light of extensive animal experimentation. The last two sections of the report describe the history of radiatioh protection guidelines for radiocerium and summarize data required for evaluating the adequacy of current radiation protection guidelines. Each section begins with a summary of the most important findings that follow. No literature citations have been included in these s d e s since extensive documentation is contained in the main body of each section. This report also includes numerous citations of the most recent literature on radiocerium. In addition to these publications, there are a number of other publications on cerium that may be of interest to some readers. These are included within the comprehensive bibliography on cerium. The Council has noted the adoption by the 15th General Conference of Weights and Measures of special names for some units of the Systkme International d' Unitks (SI) used in the field of ionizing radiation. The gray (symbol Gy) has been adopted as the special name for the SI unit of absorbed dose, absorbed dose index, kenna, and specific energy imparted. The becquerel (symbol Bq) has been adopted as the special name for the SI unit of activity (of a radionuclide). One gray equals one joule per kilogram and one becquerel is equal to one second to the power of niinus one. Since the transition from the special units currently employed-rad and curie-to the new special names is expected to take some time, the Council has determined to continue, iii

iv

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PREFACE

for the time being, the use of rad and curie. To convert from one set of units to the other, the following relationships pertain: 1 rad = 0.01 J kg-' = 0.01 Gy 1 curie = 3.7 x 10" s-' = 3.7 x 101° Bq (exactly). The report was prepared by the Council's Scientific Committee 30 on Physical, Chemical, and Biological Properties of Radionuclides. Serving on the Committee were: ROGER0.MCCLELLAN, Chairman Director, Inhalation Toxicology Research Institute Lovelace Biomedical and Environmental Research Institute Albuquerque, New Mexico JOHNE. BALLOU Biology Department Battelle Northwest Laboratory Richland, Washington RICHARD G. CUDDIHY Inhalation Toxicology Research Institute Lovelace Biomedical and Environmental Research Institute Albuquerque, New Meiico PATRICIAW.DURBIN Lawrence Radiation Laboratory University of California Berkeley. California Director, Radiobiology Laboratory School of Veterinary Medicine University of California Davis, California MARYJANE(COOK)HILYER 204 Norfolk Drive Concord, Tennessee BERNDKAHN Environmental Resources Center Georgia Institute of Technology Atlanta, Georgia ~ . E D E R K C KW.

LENGEMANN Department of Physical Biology New York State Veterinary College Cornell University Ithaca, New York

ARTHURLINDENBAUM Division of Biological and Medical Research Argonne National Laboratory Argonne, Illinois YOOKNG Bio-Medical Division Lawrence Radiation Laboratory University of California Livermore, California CHESTERR. RICHMOND Associate Director, Biomedical and Environmental Sciences Division Oak Ridge National Laboratory Oak Ridge, Tennessee JAMESS. ROBERTSON Diagnostic Nuclear Medicine Mayo Clinic Rochester; Minnesota BRUCE0.STUART Stouffer Chemical Company Farmington, Connecticut ROBERTG. THOMAS Group Leader, H-4 Biomedical Research Los Alamos Scientific Laboratory Los Alamos, New Mexico

NCRP Secretariat: JAMESA. SPAHN,JR.

The Council wishes to express its appreciation to the members of the Committee for the time and effort devoted to the preparation of this report. WARREN K. SINCLAIR Bethesda, Maryland September 15, 1978

President, NCRP

Contents ...

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . lu 1. Chemical and Physical Properties of Radiocerium . . . . . 1 1.1 Chemistry of Cerium and Other Lanthanides . . . . . . . . . . . 1 1.2 Decay Schemes for Radioisotopes of Cerium . . . . . . . . . . . 5 2 . Sources of Radiocerium in the Environment . . . . . . . . . . . 9 2.1 Sources . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 9 2.2 Pathways to Man . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3 . Metabolism of Cerium in Mammalian Species . . . . . . . . . . 20 3.1 Gastrointestinal Absorption of Ingested cerium . . . . . . . . 21 3.2 Deposition and Retention of Inhaled Cerium . . . . . . . . . . . 24 3.3 Internal Organ Distribution of Absorbed or Injected Cerium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 3.4 Circulatory Transport of Radiocerium . . . . . . . . . . . . . . . . . 46 3.5 Variations in Deposition and Retention Patterns Among Individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 4 . Biomedical Effects of Radiocerium . . . . . . . . . . . . . . . . . . . . 55 4.1 Respiratory Tract, Tracheobronchial Lymph Nodes, and Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 4.2 Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 4.3 Skeleton and Bone Marrow . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 4.4 Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 4.5 Dose-Response Relationships . . . . . . . . . . . . . . . . . . . . . . . . . 67 5 . History of Radiation Protection Guidelines for Cerium Radionuclides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 6. Considerations for Establishing New Radiation Protection Guidelines for Radionuclides of Cerium . . . . . . . . . . . 73 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 The NCRP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 NCRP Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

1. Chemical and Physical Properties of Radiocerium Cerium is a member of the lanthanide group of chemical elements. The elements of this group have similar chemical properties. In neneral, all lanthanides exhibit a principal oxidation state of (111) although some may also exist in the (11)and (IV) valence states.' Most lanthanide compounds are only sparingly soluble in aqueous solutions of nearly neutral pH. Their complexes with many organic and inorganic substances are often much more soluble. The radioactive isotopes of cerium of most concern to humans are 141Ce, '43Ce,and lMCe.These three isotopes, all of which are beta emitters, are abundant products of nuclear fission reactions and have moderately long radioactive halflives.

1.1 Chemistry of Cerium and Other Lanthanides Cerium has 20 isotopes that range in mass from 129 through 148. Only four are naturally occurring (136, 138, 140, and 1421 and their abundances are 0.0019, 0.0025, 0.8847, and 0.1107, respectively, to give an average atomic weight of 140.12. Cerium occupies the position immediately following lanthanum in the periodic system and is the first member of the lanthanide group which encompasses atomic numbers 58 through 71. A thorough review of the inorganic, analytical, and radiochemistry of these elements was published by Stevenson and Nervik (1961). The chemistry of the lanthanides and yttrium has also been summarized by Yost et al. (1947), Vickery (19531, Eyring (1964, Moeller (19561, Kremers (1956), Quill (1956), Schweitzer (1956), Spedding and Powell (1956),Weaver (1956), and Leddicotte (1956). Unless

' Roman numerals in parentheses indicate the oxidation or valence states. These are the effective ionic charges of cerium atoms and ions or as they exist in chemical compounds. 1

2

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1. CHEMICAL AND PHYSICAL PROPERTIES OF RADIOCERIUM

otherwise specified, the material given in the following discussion has been drawn from Stevenson and Nervik (1961). A predominant feature of the atomic structure of the lanthanide group is the sequential addition of 14 electrons to the 4f subshell (Table 1).The f electrons do not participate in bond formation and in ordinary aqueous solutions all of the lanthanides exhibit a principal (111) state. The common (111) state confers a similarity in chemical properties to all lanthanide elements. Some of the lanthanides can also exist in the (11)state (Nd, Sm, Eu, Tm, Yb) or in the (IV) state (Ce, Pr, Nd, Tb, Dy). Except for Ce(IV), Eu(II), and Yb(IT), these unusual lanthanide oxidation states can only be prepared under drastic redox pressure and temperature conditions, and they are not stable in aqueous solutions. Cerium (IV) is a strong oxidizing agent Ce(II1) = Ce(1V) - e-, E, = -1.61 V and this property has been used to separate Ce from lanthanide mixtures. However, Ce(IV) in solution reacts slowly with water and is partially reduced to Ce(II1). Although there is a uniformity of their chemical properties, the lanthanides do not behave identically. There is a gradual contraction of the ionic radii of the lanthanides as the nuclear charge increases (Goldschmidt and Lunde, 1925; Templeton TABLE1-Oxidation slates, electronic configurations, and radii of the (III) ion of the lanthanide elements and yttrium Abmic num-

ber

39 57 58 59 60 61 62 63 64 65 66 67

68 69 70 71

Element

Yttrium Lanthanum Cerium Praeseodymium Neodymium Promethium Samarium Europium Gadolinium Terbium Dysprosium Holmium Erbium Thulium Y tterbiurn Lutecium

Ra~,"(A".~!ll'

0.88 1.06 1.03 1.01 1.00 (0.98)d 0.96 0.95 0.94 0.92 0.91 0.89 0.88 0.87 0.86 0.85

Electronic configuration"

Oxidation atatea'

3 4f

4P 4P

5d1 6s" 6s" 6s2 6s2

4P

6s'

4p

6s' 6s2

4f7 4f7

4P

5d1 6s" 5d' 6s2

4f1" 4f" 4f" 4fI3 4fI4 4f1' 5d1

SS2

6s' 6s'

6s2 6s' 6s'

3 3, 4 3, 4 2,3,4 3 2,3 2, 3 3 3, 4 3, 4 3 3 2.3 2.3 3

" Ion radius of the cubic sesquioxide in Angstroms (lo-" m)calculated by Templeton and Dauben (1954). Ground state of neutral atom (Yost et aL, 1947). ' Italics indicate states that are stable in aqueous solution. Calculated from adjacent elements.

1.1

CHEMISTRY OF CERIUM AND OTHER LAMTHANIDES

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3

TABLE2--Solubility of lmlhanide chlorides, sulfates, and hydroxides and the pH at which the hydroxidesprecipdate from M(N0d3 solutionrP Solubility

MCL?

Y La Ce Pr Nd Prn Sm Eu Gd Tb DY Ho Er Trn Yb Lu

M~(SOI)%

M(OH)asolubility product'

g/lW ml"."

g / l M ml

217 vs 100 334 246

9.8 3.9 26 20 8

-

-

-

s

2.7 2.6 3.3 3.6 5.1 8.2 16

2.0 1.4 1.4 -

s s s -

s vs

-

vs

34

-

66

h%?$;

1.6 8.5 4.4 5.4 2.7

-

0.8 0.6 0.5 0.5

8.0 X 1.0 x 1.5 x 2.7 x 1.9 X 1.0 x 6.8 x 3.4 X 2.1 x 2.0 x 1.4 X 5.0 x 1.3 x 3.3 x 2.9 X 2.5 x

lo-% lo-'g lo-"

70-" lo-" lo-"

at precipita. Lion incidence

7.4 8.4 8.1 7.4 7.0

-

6.9 6.8 6.8

lo-" lo-=

lo-24 lo-"

6.8 6.4 6.3 6.3

"Reproduced from Stevenson and Nervik (1961). In water at O°C to N°C. ' In water at 25°C. " Calculated by Latimer (1952). 'Soluble, s; very soluble, vs.

and Dauben, 1954). This so-called lanthanide contraction leads to decreasing basicity, increasing hydrolysis, and greater stability of complexes (see Tables 1-3). Most lanthanide compounds are sparingly soluble. Among those that are analytically important are the hydroxides, oxides, fluorides, oxalates, phosphates, complex cyanides, 8-hydroxyquinolates, and cupferrates. The solubility of the lanthanide hydroxides, their solubility products, and the pH at which they precipitate, are given in Table 2. As the atomic number increases (and ionic radius decreases), the lanthanide hydroxides become progressively less soluble and precipitate from more acidic solutions. The most common water-soluble salts are the lanthanide chlorides, nitrates, acetates, and sulfates. The solubilities of some of the chlorides and sulfates are also given in Table 2. Lanthanides form soluble complexes with many inorganic and organic substances; however, the nature of the bonding in these complexes has not been completely determined. There is evidence for either ionic or covalent bond formation or a combination of both. Lanthanides are complexed by inorganic ions, but not as readily as are the transition elements. The inorganic complexes are not as important

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1. CHEMICAL AND PHYSICAL PROPERTIES OF RADIOCERIUM TABLE3-Stability constants of lanthanide chelatesa

Chem~calelement

Chelating agent

EDTAD

DCTA'

DTPA"

NTA"

Cilrnte'

AU determinations were made at 25'C. Ethylenediaminetetraacetic acid, EDTA; data of Mackey et al. (1962). 1,2-diaminocyclohexanetetraaceticacid, DCTA; data of Moeller and Hseu (1962). Diethylenetriaminepentaaceticacid, DTPA; data of Moeller and Thompson (1962). ' Nitrilotriacetic acid, NTA and citrate; data of Sillen and Martell (1964).

in either analysis or purification of mixtures as are the lanthanide complexes with polycarboxylic or aminopolycarboxylic acids. Citric acid and nitriloacetic acid (NTA) lanthanide complexes were used in the earliest ion exchange separations of lanthanides from fission product mixtures (Kf = 3.2 for Ce(H3CitJ3 and Kf = 10.8 for CeNTA2) (Sillen and Martell, 1964). More recently such polyarninopolycarboxylic acids as ethylenediaminetetraacetic acid (EDTA), 1,2diarninocyclohexaneacetic acid (DCTA), and diethylenetriaminepentaacetic acid (DTPA) have been prepared. Their lanthanide complexes are very stable (Table 3) and have been widely used in analysis and separation of lanthanide mixtures. They have also been used experimentally to remove internally-deposited l4"Ce and other radioactive lanthanide nuclides from animals and man (Foreman and Finnegan, 1957; Catsch, 1962; Balabukha et al., 1966; Palmer et al., 1968; among others). The trend toward greater complex stability with increasing lanthanide atomic number (see Table 3 for EDTA, DCTA, and DTPA complexes) has also been demonstrated for lanthanide complexes with Kr is the stability constant which is the negative logarithm of the dissociation constant, Ki. T h e dissociation constant is the product of the concentrations of the dissociated ions divided by the concentration of the parent molecule.

CHEMISTRY OF CERIUM AND OTHER LANTHANIDES

1.1

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5

simpler ions. The lanthanide carbonates, oxalates, and potassium sulfates (K2M2 (SO4)a) are insoluble in water (Yost et al., 1947).

1.2

Decay Schemes for Radioisotopes of Cerium

Most of the radioactive isotopes of cerium have very short physical half-lives and do not normally represent a radiological hazard to humans. Only the three longer-lived isotopes, 14'Ce, '43Ce,and 14"Ce, TABLE4-Radioactive decay chains for the longer-lived radioisotopes of cerium

including those which have been identified in environmental studies Half-Life

kUpe

Ce-144 Ce-139 Ce-141 Ce-134 Ce-137m Ce-143 Ce-135

Mode of

Decsy

day

284 140 32.5 3 34 33 17

d d d d h h h

PECh

PEC

IT'

PEC

Pr-144 La-139 Pr- 141 La-134 Ce-137 Pr-143 La-135

Decay rod uct hd?-lifi

Mode of d e ~ y

Decay product'

17.3m

P-

Nd-144

6.7 m 9h 13.6 d 19.5 h

P+

Ba-134 La-137 Nd-143 Ba-135

EC

PEC

" All are stable except for La-137 which has a half-life of 6 x 10" years, but may be considered to be stable for purposes of radiation dosimetry. Electron capture. 'Isomeric transition. TABLE5-Radioactive decay scheme data for radionuclides of cerium observed in

previous environmental surveillance studies "'Ce

B Decay

Radiation

Energy

TVpe

(keV)

ce-L ce-MNO P-1 max avg P-'2 max avg total 8 avg x-ray L x-ray Kaz x-ray Ka, x-ray KJ3

138.605 143.929 434.6 129.6 580.0 180.7 144.7 5 35.55020 36.02630 40.7

145.440 " Auger-L = L-shell Auger electron ce-K = K-shell conversion electron yray ' A = Equilibrium absorbed - dose constant Y

lnremity (%)

2.57 0.73

A'(

red/ &h)

0.0076 0.0022

70.5

0.195

29.5 100 2.6 4.89 8.9

0.114 0.308 0.0003 0.0037 0.0069

3.34

48.4

0.0029

0.150

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1. CHEMICAL AND PHYSICAL PROPERTlES OF RADIOCERIUM TABLE5-Continued '"Ce )¶- Decay Radiation Type

Inbnaity

A

(%)

?::?

Auger-L ce-K Auger-K ce-L ce-M ce-NOP ce-K ce-L p-1 max avg B 2 max avg fl-3 rnax avg p-4 max avg P-5 max avg 8-6 max avg total p- avg Eight weak fls omitted: E,g (avg)* = 151.4; ZIBD= 0.24% X-ray L X-ray Ka2 X-ray La, X-ray Kp Y Y Y

Y Y Y Y Y Y Y

Y Thirty-seven weak y's omitted;

E, (avg) = 629.4; XI, = 0.68%

Eg(avg) = average energy of the omitted radiations ' & = summed intensity of omitted radiations

(g-red/

&i-h)

1.2

DECAY SCHEMES FOR RADIOISOTOPES OF CERIUM

/

Ene

Radiation

Type

(key

Id3Pr8- Decay 932.0 avg 314.3 '"Ce p- Decay % Feeding to '"PI = 98.80 % Feeding to '44mFk = 1.20 Auger-L 4 ce-K 11.42 ce-L 26.74 Auger-K 29.4 ce-M 32.06 ce-L 31.10 ce-K 38.13 ce-M 39.42 ce-K 44.5094 ce-L 46.58 ce-K 49.0 W-L 73.29 ce-M 78.61 ce-L 79.6652 ce-L 84.2 ce-K 91.54 ce-L 126.70 ce-M 132.02 Fl m a x 181.9 avg 49.3 F 2 max 235.3 avg 65.3 P-3 max 315.4 avg 90.2 Total /T avg 81.0 x ray L 5 Y 1 33.57 x ray Ka, 35.55020 x ray Kal 36.02630 x -Y KB 40.7 Y 2 40.93 Y 4 53.41 Y 7 80.12 Y 8 86.5 Y 9 91.0 Y 11 133.53

p- 1 max

Five weak

7's

See also '"Pr IT Decay 11.3 0.0010 0.82 0.0002 0.93 0.0005 0.9 0.0006 0.196 0.0001 1.0 0.0007 3.5 0.0028 0.21 0.0002 0.61 0.0006 0.114 0.0001 0.53 0.0006 0.48 0.0008 0.101 0.0002 0.28 0.0005 022 0.0004 5.3 0.0104 0.73 0.0020 0.153 0.0004

omitted; E, (avg) = 80.4;XI1 = 0.09%

7

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1. CHEMICAL AND PHYSICAL PROPERTIES OF RADIOCERIUM TABLE5-Continued Ene

Redialion

(key

Type

Intawity 1%)

Ar ( rad/

$I--h)

"'Pr IT Decay % IT Decay = 99.94 Feeds '"Pr % p- Decay = 0.06 Auger-L ce-K Auger-K ce-L ce-M ce-NOP x ray L x ray KaZ x ray Ka, x ray KB One weak y omitted: Ey (avg) = 59.0; 21"= 0.123%

IUPrp- Decay 11-1 max

avg P-2 max avg P-3

max

avg Total P- avg Y3 Y7 Y9

811 267.0 2301 894.8 2997 1221.8 1207.6 696.490 1489.15 2185.70 Seven weak y's omitted; E, (avg) = 10.286; XI, = 0.02%

have been identified among the nuclear wastes present in the environment. Several of the other radioactive isotopes of cerium are shown in Table 4 along with their decay products. The radioactive decay products generally have such short physical half-lives that, in radiation dosimetry calculations for biological tissues, they may be considered to be retained and decay in the organs in which they are formed. Further information on photon and particle emissions from the decay of '"Ce, 143Ce, and lUCeis summarized in Table 5 (Lederer et al., 1967; Nuclear Data Tables, 1970;Fasching et al., 1970;Kocher, 1977;NCRP, 1978).

2. Sources of Radiocerium in the Environment To develop a better understanding of the potential health consequences of radiocerium in our environment, it is important to know the possible sources and physical and chemical forms of its release. The metabolism and dosimetry of internally-deposited radiocerium are highly dependent upon the forms of the material presented to the body and the mode of exposure as discussed in Section 3-Metabolism of Cerium in Mammalian Species. The primary sources of environmental radiocerium in the past have been from nuclear explosive devices and nuclear power facilities. The associated high temperature reactions in nuclear explosive devices are generally thought to result in the release of refractory, insoluble chemical forms. The important isotopes of cerium released have been I4'Ce, L43Ce,and 144Ce.Most of these have been in insoluble forms. However, in some studies of environmental samples as much as onehalf of the radiocerium was in readily soluble forms. Radiocerium in the environment can be taken up by plants through roots or other plant surfaces. Plants have achieved concentrations up to 0.5 times the surrounding soil concentrations. Although there are many reports of radiocerium contamination of food crops, there are few measurements of its presence in animal products. This is due to poor absorption and transfer of cerium through biological food chains. Studies in human populations indicate that inhalation is the major route of entry into the body for radiocerium released into the atmosphere from the testing of nuclear explosive devices.

2.1

Sources

Large quantities of radiocerium have been produced and released to the atmosphere in nuclear weapons tests. For the fissioning of 235U, 238U,or 239pUby thermal neutrons, fission-spectrum neutrons, and high-energy (= 14.7 MeV) neutrons, the cumulative fractional yields of 141Ce,143Ce,and 14Ce range from 0.034 to 0.062 (Meek and Rider, 9

10

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2. SOURCES OF RADIOCERIUM IN THE ENVIRONMENT

1974). All of these radionuclides can readily be detected in fresh nuclear debris, but I4'Ce and IMCeare measured more often than 143Ce in fallout because of their longer half-lives (Noyce et al., 1973; UNSCEAR, 1964). From the above fission isotope yield information and nuclear weapons test data, it is estimated that about 600 MCi of I4Ce and 8500 MCi of '"Ce have been produced in weapons tests and injected into the atmosphere through 1976. Both of these radionuclides were monitored in seawater, plankton, and marine foodstuffs in the Central Pacific after weapons tests (Held, 1963; Welander and Palumbo, 1963; Palumbo et al., 1963; Welander, 1969).Average monthly concentrations of 144Ce in surface air are reported at quarterly intervals in the Surface Air Sampling Program conducted by the Environmental Measurements L'aboratory of the Department of Energy (Volchok et al., 1976). The proposed peaceful uses of nuclear explosives include their use in large-scale excavation projects and in the stimulation of oil and gas reservoirs (UNSCEAR, 1972). The U.S. Nuclear Cratering Program has been described by Toman (1970). The Danny Boy experiment employed a 0.43-kt device to produce a crater in basalt (Bonner and Miskel, 1965). The total reported airborne activity contained about 200 Ci of 141Ceand about 5 Ci of 144Ceincluding both the activity deposited in fallout and that retained and transported to greater distances in the cloud. The Schooner experiment employed a 31-kt device to produce a crater in welded tuff (Tewes, 1970). About 300 Ci of 141Cewas transported from the crater site in the main cloud and about 24 Ci in the base surge cloud (Crawford, 1970). In contrast to nuclear cratering explosions that inevitably involve some venting of radioactivity to the atmosphere (Clemente et al., 1973), underground nuclear explosions for gas stimulation, as exemplified by the Gasbuggy and Rulison tests, did not release radiocerium into the atmosphere (UNSCEAR, 1972). In the high temperatures associated with nuclear detonations, the radiocerium formed is thought to exist as particles of oxides or other refractory forms (Palumbo, 1963). Most of the radiocerium in fallout was found to be insoluble; however, in some samples a substantial fraction was soluble. From weapons fallout collected in the USSR, more than 0.8 of the 144Cewas in the insoluble fraction (Zhilkina et al., 1973; Pavlotskaya et al., 1974). About 0.55 to 0.60 was extracted from the insoluble fraction by treatment with ammonium acetate, hydrochloric acid, and dilute nitric acid (Pavlotskaya et al., 1974). The authors suggested that much of the '44Cein fallout is not in the very insoluble dioxide form and that a portion is in the form of complexed compounds with different organic and inorganic ligands present in the

2.1 SOURCES

/

11

atmosphere (Pavlotskaya et al., 1974).Their results, however, do not preclude the possibility that the 14%e may have been in very fine oxide particles that could have been relatively soluble due to having very high particle surface to mass ratios. The distribution of soluble 144Ce among cationic, anionic, and neutral forms was 0.55, 0.18, and 0.27, respectively (Pavlotskaya et al., 1974). In New York City fallout in 1958, 0.42 of the 144Cewas water soluble (Welford and Collins, 1960). These observations lead to the conclusion that radiocerium in fallout exists in soluble and exchangeable forms as well as in relatively insoluble, refractory particles. Current attention is focused mainly on the formation and accumulation of radionuclides in nuclear power production. In a typical lowenrichment light-water reactor, '44Ceis produced at the annual rate of 5.3 kg/1000 MW of electric power (Holden and Walker, 1972) which is equivalent to about 17 MCi/1000 MW years of electric power. Other radioactive isotopes of cerium (14'Ce, 14%e, 145Ce,and 14%e) are produced from uranium fission but they have shorter radioactive halflives and do not accumulate to as great an extent as '44Ce.Cerium-141 (T1/2= 32.5 d) is about one-tenth as abundant as '44Cein irradiated uranium fuel after one year (Blomeke and Todd, 1958). The bulk of this activity is retained within the fuel elements until they are reprocessed. However, ' W e has been measured in the emissions and effluents from various nuclear facilities (Davis et al., 1958; Foster and Soldat, 1966; Heft et al., 1971; Mauchline and Templeton, 1963; Parker et al., 1966; Kahn et al., 1970). The U.S. Environmental Protection Agency is conducting comprehensive radiological surveillance studies at selected nuclear power stations and fuel-reprocessing facilities to characterize the releases of radionuclides to the environment and to evaluate related population exposures. Cerium-141, 14%e, and were identified and measured in the primary coolant from the Dresden Nuclear Power Station, a 210-MWe boihng water reactor, but only '44Ce was measurable in liquid wastes (Kahn et al., 1970). In most samples of liquid waste, a major fraction of the 144Ce was in particulate form. The average release rate of '44Cein high-conductivity liquid effluent was 2 x pCi/sec, and the ratio of the 14%e release rate in liquid effluent to the generation rate in the reactor core was estimated to be 4 x lo-'', among the lowest values for any fission product measured. This is due to the low volatility of cerium compounds and their low solubility in aqueous solvents near neutral pH. Stack releases of airborne particulate pCi/sec. were below the limit of detection, which was less than 3 x In similar studies conducted at the Yankee Nuclear Power Station (a 185-MWe pressurized water reactor), 14'Ce, 143Ce,and 144Cewere not

12

/

2. SOURCES OF RADIOCERIUM IN THE ENVIRONMENT

detected in main coolant water (Kahn et al., 1970). The minimum detectable concentration was 10-"Ci/ml. Cerium-144 was also undetected in stack or liquid effluents. The I4'Ce and '44Ce observed in vegetation, precipitation, and soil of this area were attributed to fallout from weapons tests. In a comprehensive field study of liquid waste from the Nuclear Fuel Services (NFS) facility, the first commercial reprocessing plant in the United States, 9 Ci of '44Cewere discharged from the plant interceptor tanks to the holding ponds between April-August 1969 (Magno et al., 1970). During this period, 0.17 Ci or about 0.02 of the total '"Ce activity discharged from the plant was released from the terminal holding pond to the aquatic environment beyond the plant boundary. The '44Cein the holding ponds and that discharged to the aqueous environment was predominantly in suspended particles. The concentration of '44Cein air particulate samples from the NFS stack ranged from 1.2 x 10-l2 to 4.6 x 10-l2 pCi/cm3. However, this is below the federal regulation for an "allowable concentration for unrestricted area" (CFR, 1976; Cochran et al., 1970). I t is estimated that was discharged to the atmosphere from the NFS reprocessing plant at an Ci/MW of electric power (UNSCEAR, average annual rate of 1 x 1972). In aquatic environments, radiocerium readily forms chemical complexes in seawater and associates with particles by adsorption (Mauchline and Templeton, 1963). When radiocerium was added to natural seawater, it became associated with suspended matter, especially that with apparent particle diameters of 0.02 to 0.1 pm (Carpenter and Grant, 1967). When ionic radiocerium was added to filtered seawater a t pH > 6.0, it hydrolyzed and formed complexes with hydroxide, chloride, or other anions in seawater and went on to form particles (Hirano et al., 1973). Adsorption of radiocerium onto suspended particles has also been noted after its release to freshwater ecosystems (Beninson et al., 1966).

2.2

Pathways to Man

Contamination of food crops by radiocerium in fallout from nuclear weapons tests has been extensively documented in the worldwide literature (Chhabra and Hukkoo, 1962; Merk, 1967; Michelson et aL, 1962; Nezu et al., 1962; Sutton and Dwyer, 1964). The '44Ceconcentrations in spinach leaves and radish roots in Japan in 1960 were within a factor of two of the respective 90Srconcentrations (Nezu et al., 1962).

2.2 PATHWAYS TO MAN

/

13

The average 144Cecontent in the total diets of people in a number of U.S. cities in 1961 was 0.4 of the average '"Sr content and 0.08 of the average 137Cscontent (Michelson et al., 1962).The 14'Ce concentrations in wheat and various milling fractions in the U.S. in 1963were between 0.3 and 1.6 times that of 137Cs(Sutton and Dwyer, 1964). Deposition of airborne radiocerium on exposed plant parts can lead to contamination of food crops by retention on the plant surfaces or through absorption. Deposition of radiocerium on the ground can lead to contamination by absorption through the plant roots. In studies conducted in India, it was concluded that the elevated levels of 144Ce measured in tea during 1959 resulted from absorption of surface contamination and the levels measured in carrots were attributed to uptake through roots. The elevated concentrations of 141Cemeasured in vegetables during March 1960 were clearly due to surface contamination of aerial parts (Chhabra and Hukkoo, 1962). Another study in Switzerland showed that root uptake accounted for 0.1 to 0.3 of the 144 Ce measured in grass and cress during 1964 (Merk, 1967). Studies of the transfer of radiocerium into various plant parts via the soil-root pathway are summarized in Table 6. Other laboratory and field studies employing tracer radiocerium or nuclear weapons fallout simulants are summarized in Tables 7 and 8. In general, the cereal grains and vegetable pulp showed plant-to-soil concentration factors (radioactivity per gram of dry plant material/radioactivity per gram of TABLE6-Plant-to-soil concentration factors" for '"Ce a n d other rare earth isotopesh Plant type

Alfalfa Barley leaves Barley head Bean leaves Bean pods Brome grass Tomato leaves

Cmwth medium'

Sedan ejecta Bravo soil Bravo soil Bravo soil Bravo soil Blanca soil Jangle soil

Concentration factof'

0.06 0.002-0.007 0.001-0.002 0.007-0.03 0.002-0.003 0.02 0.009

Reference

Romney et al. (1966) Selders et aL (1956) Selders et al. (1956) Selders et al. (1956) Selders et al. (1956) Mills & Shields (1961) Selders et ak (1953)

" Activity per gram dry plant material/activity per gram dry soil. Plants grown in soil contaminated with nuclear debris. "Project Sedan was a Plowshare nuclear cratering experiment carried out at the Nevada Test Site (NTS) in 1962 (Nordyke and Williamson, 1965). T h e other soils originated b m nuclear weapons test sites (see U.S. Weather Bureau, 1964). The Bravo Test of Operation Castle was carried out at the Pacific Proving Ground in 1954. The Blanca Test of Operation Hardtack and Buster-Jangle series took place at NTS, the former in 1958 and the latter in 1951. In the case of alfalfa the concentration factor was actually determined for IMCe.For the other plants the concentration factors were determined for the rare-earth group of elements.

14

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2. SOURCES OF RADIOCERIUM

IN T H E ENVIRONMENT

TABLE7-Plant-to-soil concentration factorsa of IJ4Cein crops determined from laboratory studies Plant type

Barley Barley Barley Barley

leaves leaves leaves shoots

Bean leaves Bean leaves Bean leaves Bean leaves Bean fruit Maize shoots Maize shoots Rice (flowering stage) Rice (flowering stage) Rice (6 weeks) Rice (6 weeks) Pea shoots

Growth medium

Concentration factors

Reference

Rediske et a 1 (1955) Rediske et al. (1955) Rediske et al. (1955) Molshanova (1968)

Ephrata sandy loam Wheeler silt loam Winchester fine sand "Meadow turf' sand and soil (1:2) Sassafras sandy loam Hanford sandy loam Sorrento loam S o ~ e n t oloam Sorrento loam Black clay loam Laterite Black clay loam

Nishita & Larson (1957) Nishita & larson (1957) Nishita & Larson (1957) Essington el al. (1963) Essington el al. (1963) Mistry el al. (1974) Mistry el al. (1974) Mistry el al. (1974)

Laterite

Mistry et al. (1974)

Black clay loam Laterite "Meadow turf' sand and soil (1:2)

D'Souza & Mistry (1973) D'Souza & Mistry (1973) Molshanova (1968)

"Activity per gram dry plant material/activity per gram dry soil. From measurements of "Y.

dry soil) between 5 x and 1 x Leafy vegetables had higher and 4 x lo-'. plant-to-soil concentration factors between 2 x These values are substantially higher than those for grains and vegetable meats and may indicate a greater amount of surface contamination through more contact with the soil or resuspended soil dusts per unit mass of plant material. Plant-to-soil concentration factors for "Sr and in most cases those for '37Cs can be expected to exceed those for '44Ce.The fractional uptake of 14%e by oat plants from nine agricultural soils ranged from 3 x to 3 x (Cummings and Bankert, 1971) and were generally two or more orders of magnitude lower than those of '37Cs and 85Sr (Cummings et al., 1969). The concentration factor for radiocerium in crop plants grown in nutrient solution (the activity per gram dry plant divided by the activity per milliliter of solution) varied between and 4 x lop3 (Rediske et al., 1955; D'Souza and Mistry, 1973). Radiocerium can also gain entry into food crops through irrigation or flooding of fields with waters containing these nuclides. However, only small amounts of radiocerium enter food crops by this route compared to the more soluble radioelements that have been studied. Cerium-144 originating from both the Hanford reactors and worldwide

TABLE 8-Pht-to-soil Plant type

Bean leaves Bean fruit Carrot meat Carrot tops

Corn leaves Corn kernel Lettuce head Lettuce leaves Potato leaves Potato meat Radish tops Tomato leaves Tomato leaves Tomato meat Tomato meat

concentration factors. of '"Ce in crops contaminated with fallout simulcrnts Growth medium

Sand Loam Clay Sand ham Clay Sand Loam Clay Sand ham Clay Clay loam Oakley sandy loam Pleasanton loam Clear lake clay Oakley sandy loam Pleasanton loam Clear lake clay Sand Loam Clay Sand Loam Clay Oakley sandy loam Pleasanton loam Clear lake clay Oakley sandy loam Pleasanton loam Clear lake clay Loam Sand ham Clay Oakley sandy loam Pleasanton loam Clear lake clay Sand Loam Clay Oakley sandy loam Pleasanton loam Clear lake clav

Concentration factor

Reference

Sartor et al. (1966) Sartor et al. (1966) Sartor et al. (1966) Sartor et al. (1966)

Sartor et al. (1968) Sartor et al. (1968) Sartor et al. (1966) Sartor et al. (1966) Sartor et al. (1968) Sartor et al. (1968) Sartor e t al. (1966) Sartor et al. (1966) Sartor et aL (1968) Sartor et al. (1966) Sartor et al. (1968)

16

/

2. SOURCES OF RADIOCERIUM IN THE ENVIRONMENT

Plant type

Wheat leaves

Wheat leaves Wheat grain Wheat grain

Gmwih medium

Sand Loam Clay Clay loam Oakley sandy loam Pleasanton loam Clear lake clay Clay Clay loam Oakley sandy loam Pleasanton loam Clear lake clay

Concentration fnrtnr

0.064 0.021 0.030 0.014 0.0091 0 . ~ ~ 7 0.0064 0.00014 0.00043 0.0015 0.0013 0.00077

Reference

Sartor el a1. (1966)

Sartor el al. (1968) Sartor el al. (1966) Sartor et al. (1968)

fallout has been measured in produce and forage irrigated with Columbia River water (Perkins and Nielsen, 1967).In a field study of fallout radionuclides in flooded rice fields during 1963-1964, not more than 0.28 of the 14'Ce in rice shoots was due to indirect contamination through water (Bourdeau et al., 1965).In experiments with potted soil, nutrient solutions, or model irrigation syste~ns(Myttenaere et al., 1967), the fractional uptake from water to rice grain was lowest for ld4Ce(Table 9) and increased in the order 60Co (Myttenaere et al., 1969a; 1969b);"Mn (Myttenaere et al., 1969~); and 137Cs(Myttenaere et al., 1969a; 1969b). The uptake of radiocerium by rice plants from water was comparable to that from soil, but uptake of nuclides of Mn, Co, Sr, and Cs from water exceeded that from soil (Verfaillie et aL, 1967). Relatively large quantities of radioceriurn have been deposited and retained on plants after nuclear weapons tests, but there are few reports of its presence in animal products. Cerium-141 and 14%e originating from Plumbbob Test Series3 fallout accounted for 0.01 or less of the total radioactivity in bone and muscle of jackrabbits (Larson et al., 1966). Cerium-144 was measured in cattle and horse bones in Japan in 1960 a t a concentration about one-tenth that of "Sr (Nezu et al., 1962). In wild mule deer collected in Colorado during 1963 and 1964, the concentration of '44Cein liver was three times that of 137Cs (Whicker et al., 1967). For caribou collected a t Anaktuvak Pass, Alaska in 1967, the muscle-to-lichen concentration ratio was less than onetenth that of '37Cs (Jenkins and Hanson, 1969). In contrast to 134Cs and 137Cs,14%e was not detected in wolves that prey on caiibou. The low tissue content of radiocerium s.ubsequent to its release to these The Plurnbbob Test Series was conducted at the Nevada Test Site in 1957 (see U.S. Weather Bureau, 1964).

2.2 PATHWAYS TO M A N

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17

TABLE 9-Fractional uptake of radionuclides from water into rice grain Fractional uptake x lo4 leotope

Observation

Whole

Hulled

nce

rice

"Mn

Flooded soil in pots

0.05

WCo

Model irrigation

0.003

1:17cs

Model irrigation

0.18

144Ce

IMCe

Lowland rice, nutrient 0.003 solution Upland rice, nutrient 0.003 solution Lowland rice, soil 0.002

'44Ce

Upland rice, soil

I4"Ce

0.002

HUll

Reference

Myttenaere et al. (1969~) Myttenaere et al. (1969a; 1969b) Myttenaere et al. (1969a; 196913) Myttenaere et al. (1967) Myttenaere et al. (1967) Myttenaere et al. (1967) Myttenaere et al. (1967)

environments is doubtlessly explained by low gastrointestinal absorption as has been observed in laboratory studies that are discussed in Section 3. Chertok and Lake (1971a, 1971b) fed atmospheric debris from Plowshare cratering events to peccary pigs; 14'Cewas not detected in urine and less than 0.005 of the ingested quantity remained in the animals at the end of 8 days. The potential uptake of 14%e from forage into muscle of commonly used food animals can be estimated. Assuming gastrointestinal absorption of 5 x of the ingested cerium in adult animals (see Table lo), deposition of 0.1 of the absorbed cerium in animal muscle (see Figure 5, page 30) and an average retention time of 400 days; then the total animal muscle mass would accumulate 144Ceup to an equilibrium level equal to 0.02 of the daily ingested amount. Radiocerium is poorly transferred from feed to milk. Although I4'Ce and 144Cefrom worldwide fallout were easily measured in forage, they were not detected in milk from cows feeding on the forage (Potter et al., 1967; 1969; Voilleque and Pelletier, 1974).After receiving oral doses or less into milk (Ekman and of tracer l4*CeCL,goats secreted 3 x Aberg, 1961; Stanchev et al., 1971) and cows secreted 1 x to 1.6 x lo-' (Garner et al., 1960). The transfer of radiocerium from forage to cow's milk is equivalent to about 2 x 10-%f the daily intake of radiocerium secreted in milk per liter at equilibrium. This transfer coefficient is low, but it is interesting that cerium seems to be concentrated during its transfer from plasma to milk. The average milk-toplasma ratio of 14Ce at 20 hours and beyond following intravenous administration of CeC13 to ewes was 3.4 (McClellan et al., 1962). The

18

/

2. SOURCES OF RADIOCERIUM IN T H E ENVIRONMENT

TABLE10--Gastrointestinal absorption of cerium in laboratory animals" Animab

Age at admin-

Chemical form

ktratiorr

chloride chloride in rats milkh nitrate

FracLional a& sorption

Mice Mice Rats Rats

0d 21 d 0-11 d 0d

Rats

7d

nitrate

0.015

Rats

14 d

nitrate

0.009

Rats

26 d

nitrate

<0.0004

Rats

5d

chloride

0.2

Rats

13 d

chloride

0.04

Rats

100 d

chloride

0.0003

Rats Rats Rats

4-6 mo adult adult

citrate chloride nitrate

-

0.50 <0.001 0.015 0.03

Rats Dogs Swine Sheep

2y 20 d

chloride chloride chloride chloride

<0.001
Sheep

180 d

chloride

O.ogO9

Sheep

550 d

chloride

0.0003

Referonce

Matsusaka et al. (1969) Matsusaka et al. (1969) Naharin et al. (1969) Inaba and Lengemann (1972) Inaba and Lengemann (1972) Inaba and Lengemann (1972) Inaba and Lengemann (1972) Shiraishi and Ichikawa (1972) Shiraishi and Ichikawa (1972) Shiraishi and Ichlkawa (1972) Dwbin et al. (1956a) Hamilton (1947) Sagan and Lengemann (1973) Moskalev et al. (1970) Moskalev et al. (1970) McClellan et al. (1965) Buldakov and Burov (1967) Buldakov and Burov (1967) Buldakov and Burov (1967)

"Fractional absorption values were taken directly or estimated from data presented in the cited references. Animals received cerium by suckling from mothers previously injected with cerium citrate.

transfer coefficient of by two orders of is lower than that of magnitude and lower than those of I3lI and 13'Cs by three orders of magnitude. Contamination of aquatic foodstuffs by the radiocerium in fallout from weapons tests and effluents from nuclear power facilities is well documented. The concentrations of '14Ce in clam muscle and cuttlefish in Japan in 1960 exceeded those of "Sr by one to two orders of magnitude and were somewhat greater than those measured in food crops (Nezu et al., 1962). Radiocerium was detected in only a few samples of aquatic foods monitored in the Central Pacific during nuclear device testing there in 1962 (Welander and Palumbo, 1963;

2.2 PATHWAYS TO MAN

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19

TABLE 11-Equilibrium concentration ratios"for cerium-144in aquatic foodstuffsh Minimum

Maximum

Kcference

Averwe -

Seawater Plants

700 300

900

100 2000

Crustaceans Molluscs 200

2000

Fish

1.0

Mauchline & Templeton (1963) Bryan et al. (1966) Bryan et al. (1966) Mauchline & Templeton (1963) Bryan et al. (1966) Bryan et aL (1966) Mauchlie & Taylor (1964)

Freshwater Plants Crustaceans Molluscs Fish

MOO

1600 37

loo00 6500 720 1.0

Bryan et al. (1966) Polikarpov (1966) Polikarpov (1966) Polikarpov (1966) --

' Activity per gram wet weight/activity per milliliter water. " Adapted

from Thompson el al.(1972).

Palumbo et al., 1963). Cerium-141 from fallout was measured in invertebrates (euphausids) off the Oregon coast in 1962 (Osterberg et aL, 1964). The nuclide was concentrated by primary producers and filter-feeding herbivores but not by carnivores (lantern fish and carid prawns). Cerium-144 from Windscale Works, United Kingdom, has been monitored in seaweed, invertebrates, and fish (Mauchline and Templeton, 1963). Here, the concentration factor was defined as activity per gram of wet tissue divided by activity per milIiliter of water. Table 11, adapted from Thompson et al. (1972) summarizes the available data on concentration factors for 144Cein aquatic foodstuffs derived from field studies of the organisms in their natural environments. These authors also reported concentration factors that were derived from stable-element distributions in biota and water for edible freshwater and marine organisms. Under field conditions, processes such as adsorption onto suspended particles, which sediment and exchange with bottom materials, tend to decrease the radiocerium concentration in water. For example, field studies in natural ponds with low water-renewal rates showed removal of about 0.9 of the radiocerium (Beninson et al., 1966). Reports of radiocerium in human populations from fallout showed this radionuclide to be measurable in the tissues of the lungs and lymph nodes. The concentration of 14'Ce + 14Ce in ashed lung in 1963 was comparable to those of I o 3 ~ + u lo6Ruand of 9 5 ~ r(Wegst el al., 1964). In an earlier study, the concentration of '44Ce in pulmonary lymph nodes was one to two orders of magnitude greater than that in the remainder of the lung (Liebscher et al., 1961).

3. Metabolism of Cerium in Mammalian Species Cerium can enter the human body by ingestion, inhalation, or absorption through wounds. Aside from evaluating the irradiation of the gastrointestinal tract during passage of ingested radiocerium, it is important to determine the fraction of ingested radiocerium that may be absorbed into the systemic circulation. Gastrointestinal absorption has been shown to be minimal in adult mice, rats, dogs, sheep, and cattle, being about 0.0005 of the ingested amount for soluble chemical forms. In newborn mice and rats, absorption is as high as 0.2 to 0.5 for soluble forms; however, this high absorption ceases beyond about 20 days of age. There are no measurements of gastrointestinal absorption of cerium in humans and no evidence that this should be substantially different from what has been observed in animals. Deposition of inhaled cerium-containing aerosols in the respiratory tract is related to their aerodynamic particle sizes as described by the ICRP Task Group on Lung Dynamics (ICRP, 1966). Clearance of particles from the respiratory tract depends upon the site of deposition and their solubility in biological fluids. Deposited particles will be mechanically cleared to the gastrointestinal tract or pulmonary lymph nodes. Absorption of radiocerium into the systemic circulation depends upon the particle dissolution rates in relation to the rates a t which the deposited cerium may be cleared to the gastrointestinal tract. Solubility rate functions are described for inhaled cerium chloride, cerium oxide, and cerium in fused aluminosilicate particles. These should provide lung clearance information covering the range of solubilities for particles that might be expected to be accidentally inhaled by humans. Radiocerium absorbed into the systemic circulation will be transported by blood proteins and be deposited predominantly in liver and bone. Deposition fractions will be about 0.45 for liver, 0.35 for bone, and 0.1 for other soft tissues with the remainder excreted in urine and feces. The retention times in liver and bone are long compared to the radioactive half-lives of the cerium isotopes. Therefore, their effective biological half-times in these organs wilI be approximately equal to their physical half-lives. Experimental data on internal organ distri20

3. METABOLISM OF CERIUM IN MAMMALLAN SPECIES

/

21

butions of intravenously injected radiocerium have often been difficult to interpret. This is due to the ease with which cerium compounds hydrolyze a t the blood pH and form radiocolloids. Radiocolloids deposit mainly in tissues rich in reticuloendothelial cells or with restrictive capillary circulation. These distribution patterns are typical of finely divided solids and may be similar to radiocerium contamination through puncture wounds, but they bear little resemblance to those for radiocerium absorbed through biological membranes. Injecting low mass, high specific activity cerium solutions of chlorides or citrates results in internal organ distribution patterns that are more similar to those from inhaled and absorbed radiocerium. Variations in radiation doses to individuals within exposed populations also occur. Based upon previous exposures of people to Pu and Sr in fallout and exposures of laboratory animals to Ce, the dispersion of individual doses in a population is expected to be significant and should be considered in the formulation of population exposure guidelines.

3.1 Gastrointestinal Absorption of Ingested Cerium Cerium, like other members of the lanthanide series of elements, is poorly absorbed from the gastrointestinal tract in adult mammals. Almost all of the information available on gastrointestinal absorption of cerium is derived from studies in laboratory animals. There have been few accidental exposures of humans that could provide this information directly for people. One man was accidentally contaminated with l4'Ce and 14Ce in the area of the nose and the mouth (Sill et al., 1969). More than 0.997 of the initial total body burden was eliminated within 4 days, but no radioactivity was found in any urine sample. The feces contained all of the recovered radiocerium aside from that removed from external surfaces in the initial area of contamination. The exposure probably involved both inhalation and ingestion of radiocerium. Some of the retained radioactive material may have been in the pulmonary spaces; however, less than 0.01 of the cerium passing through the gastrointestinal tract could have been absorbed. A summary of information on gastrointestinal absorption of radiocerium in laboratory studies with animals is given in Table 10. In adult animals, absorption was between 0.0001 and 0.001 of the administered radioactivity when given in relatively soluble chemical forms. This range of absorption values applies to adult and young adult swine, sheep, dogs, mice, and rats over 14 days of age. Radiocerium administered to mice or rats between birth and 14 days of ,age was absorbed

22

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

by the gastrointestinal tract to a much greater degree. These fractional absorption values were between 0.01 and 0.5 with the highest values observed in the youngest animals. Only 0.0015 of the orally administered cerium chloride given to 20-day-old sheep was absorbed (Buldakov and Burov, 1967). This was similar to absorption of soluble farms of radiocerium in rats of the same age. There are no data available for gastrointestinal absorption of less soluble forms of cerium such as the oxides or hydroxides. Absorption of these compounds, however, should be considerably less than for the chlorides and nitrates, so that these experimental measurements would be extremely difficult to carry out. Matsusaka et al. (1969) reported that mice that were less than 7 days old at the time of administration retained 0.7 to 0.8 of an oral dose of IMCeCl3for more than 7 days. Only 0.5 of the administered radioactive material was eventually absorbed and deposited in internal organs. The remainder was lost by fecal excretion between 7 and 14 days after administration. This '%e had either been retained in the intestinal cavity or the intestinal wall before excretion. Both the retention of cerium in the intestines and its internal absorption were markedly decreased in 14- and 21-day-old mice. Sim* retention patterns for radiocerium were seen in newborn rats by Inaba and Lengemann (1972) and Shiraishi and Ichikawa (1972) after oral administration of '"Ce chloride and 14'Cenitrate, respectively. Radioanalyses of the intestinal tracts of these rats by Inaba and Lengemann (1972) revealed that the radiocerium was retained in the digestive tract and did not enter the body. Autoradiographs showed the l4'Ce to be in the intestinal cells particularly those of the jejunum and ileum. Little of the radiocerium incorporated into these cells was able to move into the rest of the body and eventually was lost when the epithelial cells were sloughed from the tips of the villi. This high retention of cerium was affected by both animal age and diet. The younger animal groups had higher and more prolonged retention of cerium than the older groups of animals even when all groups were fed a milk diet. Milk fed rats of several age groups retained more cerium than other rats of similar ages that were fed a grain based diet. The retention of radiocerium by suckling rats decreased abruptly when the animals started consuming a solid diet. The uptake of radiocerium by intestinal lining cells is not unique but may be expected to occur in similar chemical compounds that form colloids or large complexes within the intestine (Sullivan, 1966). Macromolecules are known to be easily absorbed by the intestinal cells of newborn animals through the process of pinocytosis (Clark, 1959). Polyvinylpyrrolidone (PVP) has been shown to be taken into the intestinal cells of rats less than 18 days old (Clarke and Hardy, 1969).

3.1 GASTROLNTESTMAL ABSORPTION OF INGESTED CERIUM

/

23

The PVP accumulated in large supranuclear vacuoles and, like immune globulins, remained there until the cells were sloughed. This pattern bears a marked similarity to radiocerium uptake in the intestinal cells of suckling rats. Radiocerium is so poorly absorbed in mature sheep, goats, and cattle that it is recommended as a nonabsorbable marker for digestion studies (Ekman and Aberg, 1961; Chandler and Cragle, 1962; Garner et al., 1960; Miller et al., 1967; 1969; 1971). In studies by Ellis and Huston (1968) the average retention time in the gastrointestinal tract for 14%e that had been previously adsorbed onto alfalfa and fed to sheep was the same as that for the residues derived from the feed stuff. The radiocerium remained in close physical association with indigestible residues during transit or was continually readsorbed onto other nonabsorbed particles. These observations were supported by additional in vitro studies of cerium adsorption onto partially digested particles under conditions simulating the intraruminal environment (Huston and Ellis, 1968). Between 1 hour and 24 hours were required to bring about maximum adsorption of cerium onto the food particles. Changing the mixtures from pH 3 to pH 6 or changing the electrolyte concentrations had little influence on the rate, degree, or tenacity of cerium binding to food particles. Miller et al. (1967) reported similar results from dairy cattle that were given 144Cechloride daily. More than 0.9 of the radiocerium was adsorbed onto undigested residues that moved rapidly through the gastrointestinal tract. In other studies, Miller and Byrne (1970) observed that absorption of orally administered cerium chloride was increased in calves when accompanied by large quantities of EDTA administered simultaneously; however, less than 0.01 was detected in the internal organs. Urinary excretion was increased slightly but no change in endogenous fecal excretion was noted. 'In studies with normal adult animals, orally administered radiocerium moves rapidly through the gastrointestinal tract. About 0.96 of a cerium nitrate solution administered orally to rats was excreted within 24 hours (Sagan and Lengemann, 1973). However, external irradiation of the gastrointestinal tract with a 137Cssource (800 R) delayed excretion of the radiocerium. Only about 0.85 of the administered cerium was excreted by 3 days; but 0.992 was excreted by 4 days. In swine, 0.98 of an oral dose of radiocerium was excreted by 3 days (Miller et al., 1969); while in cattle, radiocerium placed in the rumen required 3.7 days for 0.9 of the dose to be excreted. Fecal excretion of the cerium still occurred after 4 days. When radiocerium was placed in the abomasum of cattle, it was almost entirely voided in 1.2 days. Irradiation of the gastrointestinal tract itself due to passage of radiocerium will not be considered in detail in this report. Possibilities

24

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

for human exposures in which sigmficant gastrointestinal irradiation would occur are extremely remote. In such analyses, however, the gastrointestinal tract model proposed by Eve (1966) and Dolphin and Eve (1966) is recommended for the required transit times and organ masses. Further consideration should be given to the potential for exposures to newborn infants in large population exposures and their possible increased gastrointestinal absorption of cerium. The actual doses to intestinal crypt cells resulting from the ingestion of radiocerium should also be evaluated.

3.2

Deposition and Retention of Inhaled Cerium

The deposition of inhaled material in the respiratory tract was reviewed by an ICRP Task Group (ICRP, 1966) and more recently by Lippmann (1975) and Mercer (1975). The ICRP Task Group considered the respiratory tract to be composed of 3 major segments: (1) the nasopharynx (N-P); (2) the tracheobronchial region (T-B); and (3) the pulmonary region (P). The N-P region begins with the anterior nares and descends to the level of the larynx. The T-B region continues through the tracheobronchial tree to the terminal bronchioles. The P region consists of the remainder of the respiratory tract beginning with the respiratory bronchioles and including the alveoli. Respiratory tract deposition fractions were calculated for aerosols with different aerodynamic particle sizes. A respiratory rate of 15 breaths per minute was assumed for these calculations and tidal volumes were varied between 750 and 2150 cm3.The particle sizes were considered to be log-normally distributed with geometric standard deviations (%) between 1.2 and 4.5. The log-normal distribution is. a skewed positive distribution in which the logarithms of the values are normally distributed. This distribution has been suitable for describing the particle sizes in many of the aerosols found in nature. An example of the Task Group deposition fractions related to aerosol particle size is given in Figure 1. The more recent summaries of deposition data by Lippmann (1975) and Mercer (1975) tend to validate the ICRP lung model although the recent experimental data indicate that the model slightly overestimates pulmonary deposition and underestimates deposition in the tracheobronchial region. It is, however, recommended that the ICRP model be used for predicting the deposition of inhaled cerium aerosols in humans. The ICRP Task Group on Lung Dynamics (ICRP, 1966) also reviewed the available literature and developed a model to describe the clearance of materials from the respiratory tract to the gastrointestinal

3.2 DEPOSITION AND RETENTION OF INHALED CERIUM

/

25

tract, blood, and lymph nodes. They separated the various materials by chemical element and type of compound into three general categories that depend upon their clearance half-times from lung: D (rapid, within days); W (moderate, within weeks); and Y (slow, within years). The original lung model has been revised slightly in the ICRP Publication 19 (ICRP, 1972) and these revisions will be considered as part of the Task Group model in this report. The classification of cerium compounds by the Task Group (ICRP, 1966) is shown in Table 12. Clearance of particles from the nasopharynx to the gastrointestinal tract is predicted by the model to occur with a 15 min half-time for

MASS MEDIAN DIAMETfR-MICRONS

Fig. 1. Deposition of inhaled particles of different s k (mass median aerodynamic diameters) in the three regions of the respiratory tract. Each shaded area indicates the variabilityof depositionwhen the aerosol distribution parameter, aR(geometricstandard deviation) was varied from 1.2 to 4.5. The assumed tidal volume was 1450 cm3. (Reproducedfrom Health Physics, vol. 12, pp. 173-207,1966 by permission of the Health Physics Society). TABLE12-Classification

of compounds of cerium according to the Task Croup on Lung Dynamics (ICRP, 1966)

Class Y-Avid Retention: cleared slowly (years) (1) Carbides (2) Oxides (3) Hydroxides (4) Fluorides Class W-Moderate Retention: intermediate clearance rates (weeks) (1) Carbonates (2) Phosphates (3) Halides (except fluorides) (4) Nitrates Class D-Minimal Retention: rapid clearance (days) (1) Sulfides 12) Sulfates

26

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3. METABOLISM OF CERIUM I N MAMMALIAN SPECIES

Class D substances and with a 10 h half-time for Class W and Class Y substances. Absorption of material directly into blood is predicted to occur with a 15 min half-time for all compounds. Direct absorption is predicted for 0.5 of the Class D material, for 0.1 of the Class W material, and for 0.01 of the Class Y material. Cuddihy and Ozog (1973) studied direct absorption of '44CeC13solutions deposited in the nasal region of Syrian hamsters. About 0.04 of the deposited radiocerium was absorbed through the nasal membranes into the blood. This is about one-half of that predicted by the Task Group Model for nasal absorption of Class W compounds in humans. Clearance of particles from the tracheobronchial region to the gastrointestinal tract is predicted to occur with a half-time of 5 h. Absorption of material from the tracheobronchial region into blood is predicted to occur with a half-time of 15 min and amount to 0.95,0.5,and 0.01 of the deposited Class D, W, and Y substances, respectively. There are no experimental studies that provide measurements of these clearance pathways that can be compared to these model predictions for inhaled radiocerium. Particles depositing in the pulmonary region can be cleared to the gastrointestinal tract or pulmonary lymph nodes or be dissolved and absorbed into the blood. For Class D material in the pulmonary region, 0.2 is predicted to be cleared to lymph nodes with a 12 h half-time and 0.8 absorbed with a 20 h half-time. For Class W material, the model predicts that 0.4 will be cleared to the gastrointestinal tract with a 1 d half-time. The remaining material is cleared with a 50 d half-time with 0.4 going to the gastrointestinal tract, 0.15 going to blood, and 0.05 going to the pulmonary lymph nodes. For Class Y material, 0.4 is predicted to be cleared to the gastrointestinal tract with a 1 d halftime. The remaining material is cleared with a 500 d half-time with 0.4 going to the gastrointestinal tract, 0.05 going to blood, and 0.15 going to the pulmonary lymph nodes. Lymph node deposits are cleared to blood with 0.5, 50, and 1000 d half-times for Class D, W, and Y substances, respectively. All of this material is predicted to clear for Class D and W substances, but only 0.9 of the lymph node burdens for Class Y substances. The uptake of cerium by internal organs after its absorption into the systemic circulation was projected by the ICRP Committee I1 to occur principally in bone and liver (ICRP, 1959). Bone was projected to retain 0.3 of the absorbed cerium with a biological half-life of 1500 d and liver was projected to retain 0.25 of the absorbed cerium with a biological half-life of 293 d. Gastrointestinal absorption of cerium was thought to be negligible, less than of the ingested amount. The overall uptake and retention of inhaled cerium as predicted by the Task Group on Lung Dynamics and ICRP Committee

3.2

DEPOSITION AND RETENTION OF INHALED CERIUM

/

27

models for cerium metabolism is shown in Figure 2. These functions are for D, W, and Y class compounds of cerium inhaled in aerosols of 1p activity median aerodynamic diameter (AMAD).Data contained in the following review of literature on the metabolism of cerium compounds will be compared to these early projections of the ICRP Committees. The experiments that are most easily reviewed relative to the ICRP models for retention of inhaled radiocerium aerosols have involved serial observations on large groups of dogs exposed to '44CeCLrrs a contaminant in CsCl particles (Boecker and Cuddihy, 1974; Cuddihy

Pulmonary R s ~ i m f

l

o

.

o

[

hlmonory

0

Lymph Nodes

I-0

,

,

Clors w

1

Y LL

O.ceI0

1000

2000

DAYS AFTER INHALATION

Fig. 2a. Pulmonary and lymph node burdens of inhaled radioactive particles for Class W and Class Y compounds (no radioactive decay) a s projected from the TGLD clearance model.

DAYS AFTER INHALATION

Fig. 2b. Bone and liver uptake of inhaled cerium in Class D, W and Y compounds (no radioactive decay) as projected from the TGLD model coupled with the ICRP committee I1 model for radiocerium.

28

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

et al-, 1975; 1976), '44Ce oxides (Stuart et al., 1964; Stuart and Gaven, 1967; 1968), and 14%e entrapped in fused aluminosilicate particles (Boecker and Cuddihy, 1979). Boecker and Cuddihy (1974) developed

a model for describing the retention of inhaled '44CeCL?in the respiratory tract of beagles, Figure 3. This also included a description of the distribution of absorbed 14'Ce in other internal organs. For the analysis that follows, the respiratory tract and lymph node portions of this model were simplified a s shown in Figure 4. Then the model was used to estimate the rates of absorption of cerium from the lungs of dogs used in several studies with inhaled aerosols containing '44Cein different chemical forms. The lung and lymph nodes were taken to be single compartments. Clearance of lung was considered to result from mechanical movement of material toward upper ainvays and the Respiratory

Environment

Initial

Tranefer Rote Conrtonh Eapmswd as Fractionof Compar?menlalContent

Fig. 3. Kinetic model of the retention and tissue distribution of IUCe CL in CsCl a e m l particles. Interorgan exchange rates are expressed as fractions of the compartmental contenta transferred each day or for rates greater than unity, the number of times the contenta are cleared per day.

3.2 DEPOSITION AND RETENTION OF INHALED CERIUM

Pulmonory Rmgion

--/

Mechonicol ~learonce Processes

/

29

h /

Dissolution 'S(U and Absorotion

\

Fig. 4. Simplified rearrangement of the pulmonary clearance features of the kinetic model for retention and organ distribution of inhaled '"Ce.

gastrointestinal tract as well as to lymph nodes. Dissolution of material and absorption into blood was considered to be in competition with mechanical clearance in lung but as the sole clearance process in lymph nodes. This was not taken to occur at a constant rate but at a rate that could vary with time as indicated by S(t) in Figure 4. The remainder of the model describing the blood, liver, skeleton, and other soft tissue portions was not changed in simulating the retention patterns for the aerosols of '"CeCb in CsCl particles, '"Ce oxide, and I4%e in fused alurninosilicate particles. In addition to direct measurements of lung radioactivity, the buildup of 14Ce in the internal organs along with its endogenous excretion in urine and feces provided additional measures of the rate of lung clearance and particle solubilization. This model gave good reproductions of the experimental data of each study. Also, because the internal organ transfer rates were the same in describing the overall retention of radiocerium from the three aerosols, absorbed '"Ce was probably metabolized in a similar manner regardless of the chemical form inhaled. The observed patterns of retention of inhaled 144Cein lung, liver, and skeleton are shown in Figure 5 for the relatively soluble chloride aerosols and in Figures 6 and 7 for the relatively insoluble oxide and alurninosilicate aerosols. The data are presented as fractions of the initial pulmonary activities because most of the '44Ce found in the internal organs a t later times comes from material originally deposited in the lung. Most of the material deposited in the upper respiratory tract was rapidly cleared to the gastrointestinal tract and excreted in the feces due to its very low absorption. Therefore, this fraction of the initial body burden was of little consequence and has not been included in the data presentation. The solid lines in Figures 5, 6, and 7 were

30

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

produced from computer simulation of the model for cerium metabolism shown in Figures 3 and 4. In the studies conducted by Stuart et al. (1964),Stuart and Gaven (1967; 1968) the beagles inhaled lC4Ceoxide aerosols formed by high temperature calcination (400°C) or peroxide precipitation. The high

10-31

0

I

100

I

200 300 DAYS AFTER W L A l W N

400

500

Fig. 5. Retention of '"Ce in lung, liver, skeleton, and soft tissue remainders of Beagle dogs after inhalation of '&Ce chloride in Cs chloride aerosol particles. Average values and total ranges of data are shown in the upper figure along with solid line curves which were projected from the biological model, all of which include physical decay. The lower figure shows the same model projections only corrected for physical decay.

3.2 DEPOSITION AND RETENTION OF INHALED CERIUM

/

31

temperature calcined material was shown by x-ray diffraction to be crystalline whereas the peroxide precipitated material was amorphous. The whole-body retention patterns for both materials were similar with very long biological half-times. There was virtually no biological elimination after about one year following a single intake. Pulmonary

100

200 300 400 OAYS AFTER I N W T I O N

500

800

Fig. 6. Retention of '"Ce in lung:liver, skeleton, and tracheobronchial lymph nodes after inhalation of '"Ce in fused aluminosilicate particles in Beagle dogs. The upper figure shows average data points and total ranges with solid line curves projected from the biological model, a l l of which include physical decay. The lower figure shows the same model projections only corrected for physical decay.

32

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

I

I

500

1000 DAYS AFTER IWLATON

1500

500

lo00 DAYS AFTER INHbJATIW

1500

10-41

I 2000

I

0

2000

Fig. 7. Ftetention of '"Ce in lung, liver, and skeleton after inhalation of IUCe oxide in Beagle dogs. Upper figure shows data points and solid line curves projected from the radiocerium model, all of which include physical decay. The lower figure shows the same model functions only corrected for physical decay.

retention of '44Cein the calcined oxide aerosol appeared to be slightly greater than that for 144Ce in the aerosol prepared by peroxide precipitation. Translocation and retention of '44Cein the pulmonary lymph nodes resulted in between 0.006 and 0.08 of the sacrifice body burdens being in these nodes between 900 and 1700 d after inhalation. The

3.2 DEPOSITION AND RETENTION OF INHALED CERIUM

/

33

value predicted by the model was about 0.01 over this time period. Projections of the metabolic model generally overestimated the observed 144Cepulmonary lymph node contents for peroxide precipitated material and underestimated those from the calcined aerosols. The contrasting patterns of pulmonary retention for the three forms are shown in Figure 8 along with the pulmonary retention curves projected by the Task Group on Lung Dynamics model for Class W and Class Y compounds of '"Ce. Estimates of the time varying absorption rates of 144Ce from the lung after inhalation of the chloride, oxide, and fised alurninosilicate aerosols are shown in Figure 9. These studies show lung clearance rates characterized by a rapid initial dissolution and absorption into blood followed by a more prolonged, slower absorption. The clearance rates for Class W and Class Y compounds of the Task Group Model are also shown in Figure 9. These are represented by horizontal dashed lines since they are taken to be constants in time. The time varying absorption rates were also used for material translocated to lymph nodes. This precluded the need to specify an infinite retention time in lymph nodes for a fraction of accumulated radioactivity as is done in the Task Group Model. Clearance of material to the gastrointestinal tract was handled with a mechanical clearance function. For the inhalation studies in dogs, this resulted in a simple fractional transfer rate of 0.001 per day.

16 1 0

I

500

I

1000 I500 DAYS AFTER INHALATION

I

2000

Fig. 8. Summary of pulmonary retention of '"Ce in Beagle dogs after inhalation of labeled chloride, oxide, and alurninosilicate particles (heavy lines) as compared to Class W and Y compounds of '"Ce (light Lines). These include radioactive decay.

34

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3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

h

0.00011 0

CHLORIDE

sLt)

= o.we-."'

+ 0.02e-"~' + 0.0012

OXlOE l i t 1 = 0 . 0 1 5 i . ~ t" 0 . 0 0 0 9 FUSE0 ALUMINOSILICATE

I

100

I

PPRTlCLeS

sit)

= 003Se-"'

I

200 300 DAYS, AFTER INWLATlON

0.0009

I

400

500

Fig. 9. Rate of solubilization and absorption of '"Ce from lung after inhalation of three forms of cerium.

The functions for 144Cein the lung, liver, and skeleton given in Figures 5, 6, and 7, when integrated in time, provide a measure of the radiation doses to the organs.,These are given in Table 13 along with integrals of the functions for organ concentrations resulting from the combined Task Group on Lung Dynamics and ICRP Committee 11 models for 144Cein D, W, and Y class compounds. In general, the previous ICRP models tend to underestimate most organ doses, especially those to liver and bone. In the studies with beagles, there was always a soluble component of each aerosol which contributed to higher absorption of 144Cefrom the lung at early times and less overall clearance of Id4Ceto the gastrointestinal tract. Clearance of 144Ce from the liver of the beagles was also markedly less than projected by ICRP Committee 11. Boecker et al. (1969) studied the retention of two different size distributions of heat-treated 144Ceoxide aerosols. For the smaller particle size distribution (0.88-1.1 pm), they observed a pulmonary retention that could be approximated with an effective half-time of 140 d; the larger particle size distribution (1.8-2.3 pm) had a pulmonary retention that could be approximated with a half-time of 185 d.

/

3.2 DEPOSITION AND RETENTION OF INHALED CERIUM

35

Clearance of cerium via the lymphatics to the tracheobronchial lymph nodes (TBLN) is one of the more important avenues by which insoluble forms of lUCe may leave the pulmonary region of the respiratory tract. Boecker and Cuddihy (1979) observed that the tracheobronchial lymph node content of 14Ce continuously increased for 250 d following a single inhalation of '44Cein fused aluminosilicate particles and then slowly decreased (Figure 6). Boecker et al. (1969) observed similar results with 144Ce oxide. Because of the high solubility of the chloride, the accumulation of I4Tein TBLN was negligible and is not shown in Figure 5. Also, the insolubility of the fused alurninosilicate particle form of lUCe resulted in negligible translocation to the remaining soft tissue and thus these data are not shown in Figure 4. Stuart et al. (1964) observed a marked difference in the TBLN accumulation of '44Cefor the high temperature calcined versus the peroxide precipitated '44Ceoxide; the calcined material was retained much more avidly in the tracheobronchial lymph nodes. There are also significant species differences in respiratory tract deposition and clearance of inhaled particles (Thomas, 1972). Data from a number of studies are summarized in Table 14 to assist in evaluating the several factors that influence the retention of inhaled materials. In studies with rats, Syrian hamsters, Chinese hamsters, and mice, the '44Cewas generally lost a t a more rapid rate from the pulmonary region than was noted for the dog. A major factor in this difference may be differences in initial deposition sites and perhaps TABLE13-Tim integrated '"Ce activity in lung, liver, and skeleton after inhalation of class D, W, and Y compoundsnand after inhalation of chloride, oxcde and fused alwn~nosilicatepa~icles, FAP, by bkaglesb Integrated o an burdens (@Ci.days/pCi init3 pulmonary IUCe)

TGLD Model Lung Pulmonary lymph nodes Bone Liver

Class D

Class W

0.7 0.1 150 80 Chloride

40 3 35 20 Oxide

Class Y

Beagle Derived Model Lung Pulmonary lymph nodes Bone Liver "Organ burden functions were developed by combining the ICRP Task Group on Lung Model with the ICRP Committee Il Model for the metabolism of '"Ce. Organ burden functions were those given in Figures 5,6,and 7.

36

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

the size of the particles deposited in the pulmonary region (Thomas, 1971). Even with a single animal species, lung retention of I4'Ce and the related irradiation of lung tissues are highly dependent upon the solubility of the deposited particles in lung fluids (Cuddihy et al., 1975). This is also true for buildup of 144Ce in internal organs. Large variations in lung retention patterns have been reported even for two aerosols both described as CeCls particles in the same animal, beagles. In studies by Cuddihy et al. (1975) that used aerosols of '4"CeCls in very soluble CsCl particles, lung retention was only 0.04 of the initial lung burdens a t 32 days after inhalation. When aerosols of 144CeC12 in CeCb particles were used, lung retention was 0.25 of the initial lung burdens after 32 d. These aerosols were generated from solutions of 0.1 N HCI. In a study with aerosols containing I4'Ce, Morrow et al. (1968) reported the retention of inhaled I4'CeCl3 in CeCb aerosol particles to have a biological half-time greater than 170 d in the thorax for 0.6 of the initial thorax burden. Thus, about 0.5 of the initial thorax burden remained after 32 d. This aerosol was generated from solutions that had been vacuum distilled to remove excess acid. Thus, the solubility of the vector aerosol, if not completely composed of a single compound, may greatly alter its behavior in biological systems. For easily hydrolyzable compounds such as CeCb, that have low solubilities of the hydroxides, the acidity of the aerosol particles may also influence lung retention soon after inhalation. Thus, it is necessary to have detailed information regarding the composition of an inhaled aerosol before radiation dose estimates can be applied accurately. It is not sufficient merely to refer to inhaled cerium chloride or oxide aerosols to specify a clearance rate from the lung. The pulmonary retention patterns given in Figure 8 indicate ranges or boundary clearance patterns that might be expected for inhaled lace. Aerosols encountered in industrial or environmental releases may not be of uniform or easily definable composition such as those used in these studies. However, their clearance patterns from lung should fall within the specified ranges. There are only limited data available on the retention of inhaled 14%e in humans. Rundo (1965) followed the retention of radiocerium in an individual accidentally exposed while grinding and polishing uranium metal. On the sixth day after the accident, the subject contained 16.5 nCi of I4'Ce and 29 nCi of "%e. After the shorter-lived 141 Ce had decayed, the remaining I4'Ce appeared to decrease with a n effective half-time of approximately 280 d, essentially the same as the physical half-life. Rundo suggested that some translocation to liver and skeleton may have occurred over the 850 d of measurement.

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3.2 DEPOSITION AND RETENTION OF INHALED CERIUM

-

'

4

;. 0

e a

d. &

37

38

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3. METABOLISM O F CERIUM IN MAMMALIAN SPECIES

However, most of it was still in the thorax (either in lung or lymph nodes). The I4"Ce in this case may have been serving only as a tracer for the vehicle, uranium, as did the 144Cein fused aluminosilicate particles. Liebscher et al. (1961) reported on the concentrations of I4%e in thoracic lymph nodes and lungs from five residents of Vienna, Austria who ranged from 58 to 81 years of age. Presumably most of their radioactivity resulted from the weapons tests of 1957-1958. The I4%e concentrations in their thoracic lymph nodes were 12, 19 (a composite of samples from three individuals), and 64 times those in their lungs. If it is assumed that most of the I4%e was inhaled one to three years prior to their deaths, the ratio of radioactive material in the lymph nodes to that in the lung would appear to be slightly greater than that observed for the beagles that inhaled the more insoluble forms, 144Ce oxide or lMCein fused aluminosilicate particles.

3.3

Internal Organ Distribution of Absorbed or Injected Cerium

Studies of lanthanide retention patterns after intramuscular or intravenous injection are summarized in Tables 15 through 20. Many of these data have been recalculated from the originally reported values

TABLE 15--Uptake of IMCe,15'. Is4Eu,lWTband 17"Tmor 171Tmin female rats I and 24 hours after . -. injection -

Nuclide chemical form and mute of administration 144Ce

citrate, im.

'"ML~. p~ = 3.0, i.v. '152,"1%~Eup~ bcitrate, = 3.5, i.v. im. 1 5 4 ~ U p~ ~ b= , 3.5, i.v. I 5 ( ~ u c k i.v. , citmte, i.m. p~ = 3. i.v. pH = 3.5, i.v. (+ 6 Tb/kg body art) 17% . cltrate, im. 171 TmCb in 0.5 N HCI, i.v.

,'51 I%

'Ml.bcb, '%b,

<

Radionuclide content (fraction of injected activity) Liver

Skeleton

Reference

Durbin et al. (19568)' Moakalev (1961al M a g n m n (1963) Durbin et al. (195611)' Berke (1968) Stepanov et al. (1970) Durbin et a1. (1956n)' ZaWlin and Tmnova (1969) M a g n w n (1963) Durbin et al. (1956a)' Thomas and Kingsley (1969)

,L = LM + (G.1. contents)* - F u r where b and (G.I. contents)* are the amounts of nuclide in Liver and G.I. contents 4 days after injection, and Few is the cumulative fecal excretion at 4 days. Calculated horn data for humerus and femur.

3.3 INTERNAL ORGAN DISTRIBUTION OF CERIUM

39

/

to reduce variability caused by differences in material recovery, incomplete absorption into blood, and variations in endogenous excretion. High-specific-activity lanthanides were injected intramuscularly and intravenously as citrate complexes and intravenously in chloride solutions (Tables 15and 16).Tissue distributions in the liver and skeleton 24 h after administration were similar. The similarity of deposition patterns of high-specific-activity lanthanides introduced directly into the circulation and those introduced by infiltration into extracellular fluid (intramuscular injection) suggests that in both cases the lanthanides were not present in colloidal form, and that they were probably transported as complexes with either small molecules or serum proteins. Although the protein concentration of lymph and extracellular fluid, exclusive of blood, is low, it is not zero, and in man about onehalf of the body transferrin is believed to be located in extracellular fluid. TABLE 16--Uptake of various lanthanide and actinide preparations in liver and skeleton at 1 and 24 hours and excretion in urine and fecesa at 3 or 4 hours after intrauenous injection in female rats Radionuclide content (fraction of injected activity) Liver 1h

Skeleton

24 h

1h

High-Specific-Activity Citrale Complexes '"ce(~n)~ 15=, '5LEu0ll)~ 9 ' ~ ( ~ ~ ~ ) c 17"Tm(~11)b 299F'u(1~)c ~igh-S~~cific-Activity Chloride Solutions, pH = M . 5

Radionuclide and Stable Carrier in Chloride Solution, pH = 3-3.5 IM ~ b ( l 1 1+ ) ~0.6 pM Th/Kg body weight 'bBHo(11l)~+ 0.6 pm Hontg body weight ' % ( ~ n ) ~+ ~2 ,M n n t g bodv weinht

'P w e d feces and gastrointestinal

contentp. Data of Durbin el aL (19568). ' Data of Schubert el al. (1950). *Data of Magn-n (1963). Data of Belyaev (1969). 'Data of Zalikin and Tronova (1969) corrected to total material recovery.

24 h

Excreted Urine

Feces'

40

/

METABOLISM OF CERIUM IN MAMMALIAN SPECIES

3.

I

I

I

1

I

'%GI,

1

-

A 0

E

0

A~9~"~l,(15p~) 0 2'2~m (NO,), (0.00151rp) 0 "'A~(NO,),

(0.03-1.5p9)

0 P ' 2 ~ m ( ~ ~ a )+, LO carrier

ConhnldaqI-t0

-2 0.011 LL

-

(0.0003pq)

24'Am~l, (0.03~)

0

I

50

I

I

100 150 200 DAYS AFTER INJECTION

I

250

I

300

Fig. 10. Clearance of lanthanides and actinides from intramuscular injection sites.

Data on the absorption of simple salts of the lanthanide elements injected intramuscularly into rats are summarized in Figure 10.~The dependence of the fraction remaining at the injection site on the administered mass is apparent. When the amount injected was less than 0.01 pg, about 0.5 was absorbed in the first few days; another 0.4 was absorbed with a half-time of about 25 days; and the remaining 0.1 left the injection site with a half-time of 100 to 200 days. As the total mass injected was increased, the fraction absorbed in the first few days declined, and the amounts associated with the lower absorption rates increased. If 100 pg or more were injected, only 0.05 to 0.1 was absorbed during the first few days, and absorption was very slow thereafter. Absorption of intramuscularly injected lanthanides (Durbin et al., 1956a) is greatly accelerated if they are administered as citrate complexes. However, the fractional absorption rate is still a function of the amount injected. One day after injection of s 1 pg of the lanthanide citrates, 0.95 had been absorbed; 0.75 was absorbed in the first day if the amount of stable lanthanide administered was 1 to 5 pg. After 256 ~ 5 pg EU remained unabdays, only 0.05 of the injected 152, 1 5 4 Eplus "he curves in Figure 10 were drawn from a composite of many observations made in the course of metabolic studies including radioisotopes of yttrium and the 14 lanthanide elements administered as chlorides. These experiments were performed at the Crocker Laboratory, University of California, in the years 1943 to 1957 under the general direction of J. G. Hamilton, K. G. Scott, and P. W. Durbin. Some of the information was presented in Laboratory Progress Reports, but much is unpublished.

3.3 INTERNAL ORGAN DISTRIBUTION OF CERIUM

/

41

sorbed and only 0.06 of '60Tb remained at the intramuscular site under similar conditions. If the excess of lanthanide is sufficiently great, overloading of the transport system occurs and colloidal aggregates of large size are formed by hydrolysis. The interstitial or intracavitary formation of immobilized lanthanide colloids labeled with relatively short-lived radioisotopes was the basis for the attempted use of radioactive lanthanides as internal sources of therapeutic radiation (Kyker, 1962a, 1962b). The overall distribution of lanthanides in bone may be influenced by the reactions between trivalent cations and bone surfaces. Bone surfaces accumulate many poorly utilized or excreted cations present in the circulation. The mechanisms of accumulation in bone may include reactions with bone mineral such as adsorption, ion exchange, and ionic bond formation (Neuman and Neuman, 1958) as well as the formation of complexes with proteins or other organic bone constituents (Taylor, 1972). The uptake of lanthanides and actinides by bone mineral appears to be independent of the ionic radius. Taylor et al. (1971) have shown that the in vitro uptakes on powdered bone ash of "'Arn(II1) (ionic radius 0.98 A) and of 239P~(IV) (ionic radius 0.90 A) were 0.97 f 0.016 and 0.98 0.007, respectively. In vitro experiments by Foreman (1962) suggested that Pu(IV) accumulated on powdered bone or bone ash by adsorption, a relatively nonspecific reaction. On the other hand, reactions with organic bone constituents appear to depend on ionic radius. The complexes of the smaller Pu(1V) ion and any of the organic bone constituents tested thus far were more stable (as determined by gel filtration) than the complexes with Am(II1) or Cm(II1) (Taylor, 1972). The major sites of deposition of 14Teand other lanthanides in bones of rats injected with high specific activity preparations were described by Hamilton (1947; 1948a; 1949) and Durbin (1962). In these studies, cerium and other lanthanides and several tripositive actinide elements were deposited in identical anatomical locations. These included surfaces of trabeculae, the periosteum and endosteurn, the articular cartilage, and those surfaces in the neighborhood of blood vessels in the compact bone of the diaphysis. It was noted by Hamilton that these deposits did not change significantly over approximately one year of observation. In this regard, cerium and other lanthanide elements are considered to be initially deposited as "bone surface seekers" rather than being distributed uniformly throughout bone volumes. However, with the passage of time, some of these surfaces will be buried, a process that is more pronounced in immature individ-

+

42

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

uals than in adults. The mechanisms by which the liver accumulates noncolloidal trivalent cations are not yet understood. Deposition in the liver and skeleton of cerium absorbed into the general circulation is also of major importance after inhalation (Figures 5, 6, and 7). The metabolic model applied to the inhalation studies shown in Figure 3 indicated little clearance from these organs after deposition. In the dog, the effective half-life for '44Ce in liver was indistinguishable from its physical half-life. This will also be true for the other radioactive isotopes of cerium since their physical half-lives are even shorter than '"Ce. Rodents such as rats and mice show more rapid liver clearance than observed in dogs or hamsters (Boecker and Cuddihy, 1974; Morgan et al., 1970; Sturbaum et al., 1970; and Castellino et al., 1962). This has been attributed to more rapid excretion in feces via the bile and gastrointestinal tract. Stover et al. (1971)reported the biological half-time for Pu(1V) retention in the liver of beagles injected with 2 3 9 Pcitrate ~ to be about 10 y. Lloyd et al. (1970) reported half-times of 7 to 8 y for Am(II1) in dog livers after injection of 24'Am citrate. The dose levels used in both studies were low enough so that the radiation damage to liver probably did not influence the retention of Pu(1V) or Am(II1). It is likely that the biological half-time for Ce(II1) in dog liver would be similar to that for other heavy metal cations (about 10 y). In the absence of data on liver clearance in man, it is considered appropriate to use values derived from studies in dogs wherein the retention of '"Ce was indistinguishable from the physical half-life. This indicates a biological half-time in man of thousands of days. Additional internal organ distributions for injected ld4Cein several animals are given in Tables 17 and 18. The cat and dog always had larger quantities and concentrations of injected '"Ce in liver than in skeleton. The mouse, rat, and guinea pig showed marked clearance of 14Ce from the liver between 2 and 32 d after injection. Skeletal '44Ce increased over this same period of time, resulting in a substantial change in the liver to skeletal ratios of lace in these animals. After intraperitoneal injection of W e , the surfaces of abdominal organs may be artificially contaminated. This difficulty is apparent in the data presented in Tables 18 and 19. For example, the mouse spleen had inordinately high concentrations of I4Ce following intraperitoneal injection in comparison to the I4Ce concentrations in rat spleen following intramuscular injection. Concentrations of "14Ce in the pancreas of these mice were also higher than observed in other studies. Data for organ distributions of '44Cein minature swine after intravenous injection of '"Ce citrate are given in Table 20. Again, liver, skeleton, kidney, and spleen showed the highest concentrations of

TABLE 17-De~osition of IUCein the tissues and o r ~ a n of s adult mammals after injection of carrier-free '44CeC13(pH = 3)'.

hr

Content (fraction of administration activity) after injection

Tissue

Mouse (i.p.)" dav 2

dav a2

Rat (i.v.)' day 2

dav 32

Guinea pig (i.p.)"

dav 2

dav 32

Rsbbit (i.p.)" dsv 2

Cnt (ip.)" dav 2

dav 32

Dog (i.pJh dav 2

dav 32

Blood Liver Kidneys Spleen Lungs Heart G.I. Tract Pancreas Testes

Brain Muscle Pelt Femur x 20 Thyroid AdrenaLs Ovaries Data of Moskalev (1959); intravenous (i.v.). Data of Moskalev and Kulikova (1961);intraperitoneal (i-p.). ' Values of IUCe content of whole organs and times were transcribed from the author's original tables,". I, whenever such values were available and were calculated for the remaining tissues. a

TABLE18-Concentration of "'Ce in the tissues of a d d t mammals after injection of carrier-free "'CeCl3 @H = 3)-

A A

Concentration (percent of activity/g fresh weight) after injection Rat 6v.Y

Tipsue

day 2

Blood Liver Kidneys Spleen Lung Heart Small Intestine Pancreas Testes Brain Muscle Pelt Femur Thyroid Adrenals Ovaries Lymph Nodes Abdominal Cervical Body Weight

1.1 32 9.9 7.0 5.9 1.7

-

3.0

0.11 0.49 8.4

day 32

0 2.2 0.51 1.4 0.51

-

0.29 a31

-

0.30 0.50 14.2

-

-

30

8.4

-

-

-

-

25

-

25

Guinea pig (i.p.)" day 2

day 32

0.02 1.2 0.19 0.18 0.04 0.01 0.03 0.10 0.01 0.002 0.003 0.004 0.03 0.02 0.03 0.57'

0.001 0.23 0.03 0.06 0.03 0.01 0.02 0.09 0.005 0.001 0.001 0.002 0.16

0.20 1.9 0.29

0 0.67 0.27 0.45 0.05 O.Old 2.5 0.03 0.82 0.15

0.16 156

0.03 (190)B

0.12 0.008 450

0.004e 0.006' 450

day 2

0.006 9.6 0.43 1.5 0.14 0.01 0.05 0.02' 0.003 0.01 1.8

day 32

0.00s.

0.003 0.05e

Rabbit (ip.)" day 2

0.0004 0.36 0.19 0.14 0.0068 0.0046 0.017

Cat (i.p.)" day 2

("O4. i.~.) day 2

0.0004 0.073 0.0016 0.069 0.0024 0.0013 0.0017 0.006 0.0001 0.0006 0.0002 0.0009 0.012 0.0031 0.0058

0.035' 0.0036 0.0058 11,000 11,000

-

0.014 0.43 0.15 0.29 0.027 0.012 0.027 0.025

0.0027 0.0002 0.0008 0.002 0.045 0.02 0.53 0.036'

0.0004 0.0008 0.0051 0.072 0.021 0.11 0.044

0 0.48 0.012 0.053 0.0088 0.0075 0.0043 0.0024 0.0019 0.0014 0.0058 0.0011 0.12 0.0075 0.0086 0.022

0.058 0.042 3400

0.013 3700

0.77 0.0048' 3000

-

\

day 32

-

day 32

0.0002 0.082 0.0078 0.022 0.0013 0.0009 0.0011 0.0006 0.0003 0.0001 0.0004 0.0005 0.016 . 0.0020 0.0048 -

" Moskalev (1959);intravenous (i.v.). Moskalev and Kulikova (1961);intraperitoneal (i.p.). ' 1 day. * 16 days. " 64 days. '4 days. Albino rats, 156 g in weight, estimated from growth curves of several strains to be about 60 days old; 30 days later their weights have increased to about 190 g.

W

5

4

c

g z

8 Q M

2

2 z" Bz z

$ F Z cn 6 '

E

!2

/

3.3 INTERNAL ORGAN DISTRIBUTION OF CERIUM

45

TABLE 19-Deposition and concentration of '44Cein the tissues of adult mice" and ratsh after injection of carrier-free '44CeC13 Mouse (ip.)'

Rat (i.m.)"

.

(frat- COncentrahon (frac- Organ content (frac- Concentration (fiac-

Organ tlon of activity) day I

day 30

tion of adivity/g wet wt) day 1

day 30

tion of absorbed ac- tion of absorbed activity) tivity/g wet wl) day 1

day 64

day l

day 64

Blood Liver Kidneys Spleen Lung Heart GI Tract Pancreas Testea Brain Muscle Pelt Skeleton Tbyroid Adrenals Ovaries

Lymph Node Mouse

Rat

Body Weinhl (pr) Data of Spode and Gensicke (1958);only intraperitoneal (i.p.) concentrations were published. Organ weighta have been used lo calculate organ content. Skeleton calculated using data from femur. Original data for 30 days post injection mmrned to >l00 percent and have been corrected to 100 percent. "Data of S m l t et al. (1947) and Durbin el aL (1%): intramuscular (i.m.). ' W e c ~ t r a l ewas injected. Bath experiments were balance studies. Data have been corrected to 100 percent recovery and are expressed es p e ~ e n t a g e of absorbed activity.

144

Ce. The lower concentrations in the adrenal gland, testicle, ovary, and pancreas compared to data presented in Tables 18 and 19 are typical of intravenous rather than intraperitoneal injection. There are no available human data for transfer of cerium from the pregnant mother to the fetus. In studies with pregnant mice, Naharin et al. (1969) found that about 0.006 of the lMCecitrate injected into the mother was transferred to the fetus. These studies were in agreement with those of Sternberg (1962) in which 0.003 to 0.03 of the cerium injected into guinea pig mothers was transferred to their fetuses after 24 hours. The gastrointestinal absorption of cerium in the adult human is so small that inhalation is generally the exposure route of major concern. The limited available data on human inhalation exposures have been presented above. Organ distribution data for 144Ceinhaled by beagles are given in Tables 21 and 22 (Cuddihy et al., 1976). Turbinate, lung, and pulmonary lymph node concentrations are followed by liver, thyroid, kidney, and skeleton. Reproductive organs and endocrine glands, except for thyroid, are generally more than one order of magnitude lower in concentration. The sigmficance for man of the

46

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

TABLE 2LDep0sition a n d concentration of "'Ce in the tissues of miniature swine 10 days after intravenous injection of carrier-free IUCe citrate" O q a n content (fractton of act~v~ty)

Tkue

-

Liver Kidneys Spleen Lungs Salivary Glands Heart Lymph Nodes Adrenals Testes Ovaries Thyroid G.I. TractC Pancreas Muscle Brain Skeleton Body Weight (kg)

Concentration" (fraction of activity/g wet wekht)

3 . 5 . ~lo-'" 4.2.x lo-" 1.2 X I O - : ~ 3.7 x lo-:"' 2.8 x 10-"' 1.9 x lo-" 2.3 x lo-:" 4.9 x lo-5c 1.7 x lo-"" 1.1 x 2.4 x lo-" 3.2 x lo-:" 2.1 x lo-'' 3.7 x lo-" ~ 1 . x3 lo-'' 3.95 x 10-ld 70

3x

lo-5

2.2 x lo-" 1.6 x

lo-"

1.3 x lo-" 1.0 x lo-" 7.9 x lo-" 9.3 x lo-" 9.3 x 105.7 x 10" 1 x lo-" 3.6 x 10" 2.1 2.1

x lo-" x lo-"

1.4 x lo-" t 1 . 4 x lo-" 3.4 x

" Data of McCleUan et al. (1965). Original concentrations (Co) were reported as Co = (pCi/g tisque)/(pCi adm/g body). Those values have been converted to C(Fractions of dose/g) using the relation, C = Co/700, assuming an average body weight of 70 kg for miniature swine. ' Based on concentration in small intestine. Reported by authors. " Calculated from concentration and assumed organ weights. '(Fraction of activity in total skeleton)/(.l@ x 70 kg).

high I4%e concentrations observed in dog's thyroid is unknown, particularly when it is recognized that the dog accumulatesother elements such as %'Am to a greater degree in its thyroid than do other animals (Taylor et ak, 1969). All of the longer-lived radioactive isotopes of cerium that are of significance for radiation protection (see Table 4) decay to isotopes of other lanthanide elements. Some of these daughter products are radioactive and have physical half-lives ranging up to 13.6 d. These other lanthanide nuclides are also retained for long times in the internal organs. For purposes of radiation dosimetry, it is reasonable to assume that all of the energy resulting from these decay chains will be deposited in the organs in which cerium decays. 3.4

Circulatory Transport of Radiocerium

Because of the small solubility products of their hydroxides, the lanthanides do not exist as ions even in dilute solutions.%t the pH of A solution of I pCi/ml of carrier-free IUCe is 2.2 x

lo-'

M.

TABLE 21-Tissue distribution of '4'Ce-'44Pr in beagle dogs after inhalation of '44CeC13 W

Percent sacrifice burden Tissue

2h

Male C.1. & Contents

U)

Lung Liver

31 0.54 0.1 0.045 0.m5 0.0020 0.0040 0.0007 0.0020 0.0025 0.0015

Skeleton Kidney Spleen Ti-acheobmnchial L.N.' Salivary Glands Thyroid Pancreav Prostate Testes

-

U ~ N S

2d

Female 24 20 0.14 0.12

0.05 0.002 0.001 0.0012 0.0011 0.0012 -

Poplitaal L.N. Adrenal Glands Hepatic L.N. Ovaries Pituitary Remaining Soft Tissue Exmral Nares and pelt

0.00002 4.8 27.0

O.M#Jl 0.m001 0.0002 0.0001 0.0001 0.00002 0.3 30.0

T

83.7

74.6

C

~

'L.N. indicates lymph nodes.

0.0004 0.0003 0.OOM -

Male 3.9 45 23 12 2.8 0.09 0.04 0.034 0.064 0.010 0.032 0.006

-

0.003 0.003 0.002

-

0.00012 2.6 4.4 94.0

B 8d

4d

Fede 2.3 40 24 10 1.8 0.17 0.06 0.04 0.062 0.015

-

0.0011 0.0000 0.0033 0.0045 0.0012 0.0002 1.3 5.4 85.2

Male 2 32

Female 3

35

23 1.6 0.14 0.07 0.047 0.032 0.010 0.011 0.0047 -

0.0071 0.0026 0.0004 -

0.00013 1.8 2.1 97.7

25 39 18 3.2 0.13 0.06 0.05 0.06 0.05 -

Male 1.4 21 43 29 2 0.13 0.084 0.042 0.040 0.017 0.019 0.010

0.003

-

0.006 0.007 0.002 0.0025 0.0002 3.5 5.0

0.M86 0 . W 0.0020

97.1

-

0.00023 2.0 3.2 102.0

32 d

Female 1.6 19 35 78

2.7 0.2 0.054 0.042 0.020 0.014

-

0.0022 0.0090 0.0053 0.0017 0.0022 0.00047 2.0 5.4 94.0

Male 0.4 14 58 24.2 0.70 0.062 0.070 0.033 0.0% 0.W 0.011 0.005 -

0.011 0.0034 0.0027 -

0.00014 1.2 1.3 100

.

Female 0.8 15 48 32 1.5

0.12 0.058

"lo 0.045

0.009 -

-

0.0016 0.014 0.005 0.003 0.0016 0.00021 1.6 1.7 101

E

4

8<

23 'd

2c3! 0 %I

EE; m0 ?2

TABLE22-Tissue concentrations of 'UCe-'uPrin beagles after inhalation of '44CeCla' Tissue

Nasal Turbinates Lung Tracheobronchial L.N.' Liver Thyroid Kidney Skeleton Sternal L.N. Popliteal L.N. Hepatic L.N. Salivary Glands Spleen Pituitary Adrenal Glands Ovaries Prostate Uterus Pancreas Testes

Aversge t i e Normal. weight at ne- izedh tinsue c r o w (g) weight (g)

1.5 73 0.8 250 0.7 43

1760 0.1 I

0.4 10 23 0.065 1.2 0.70 11

110 0.5 500 0.7 65 lo00

12 35

-

1.5 1.4

6

-

17 19

26 18

\

Percent of initial lung burden per gram of h u e

2h

Male

2d Female

3.8 21.6 0.85 0.90 0.012 0.009 0.003 0.014 0.003 0.007 0.002 0.004 0.001 0.001 0.0024 0.002 0.0013 0.0001 0.0013 0.0014 0.0009 0.0005 0.0003 0.0002 0.0008 0.0012 0.0006 0.0007 0.0003 0.0007 0.0006 0.0002 0.0002 0.0002 -

4d

Male

Female

Male

0.88 0.45 0.089 0.052 0.100 0.047 0.014 0.017 0.0032 0.0050 0.0032 0.0027 0.0021 0.0022

7.6 0.44 0.14 0.06 0.12 0.033 0.011 0.005 0.0020 0.0011 0.0038 0.0055 0.0035 0.0026 0.0011

3.4 0.30 0.14 0.071 0.047 0.022 0.022 0.0067 0.0075 0.0011 0.0039 0.0037 00021 0.0018 -

-

0.0032

-

0.0004 0.0004

8d

Female

Male

0.52 0.24 0.23 0.19 0.12 0.17 0.077 0.087 0.090 0.059 0.052 0.031 0.018 0.031 0.028 0.019 0.0058 0.0092 0.0058 0.0050 0.0044 0.0036 0.0039 0.0036 0.0033 0.0036 0.0052 0.0031 0.0020 0.0018 0.0025 0.0032 0.0008 0.0004 0.0018 0.0007 - 0.0003 - 0.0006

32 d

Female

Male

2.8 0.19 0.11 0.074 0.028 0.045 0.029 0.040 0.0099 0.0045 0.0037 0.0058 0.0074 0.0037 0.0016 0.0009 0.0006

0.71 0.11 0.12 0.10 0.044 0.010 0.019 0.0144 0.0100 0.0066 0.0025 0.0017 0.0019 0.0020 0.0009 0.0003 0.0002

-

" Data are not corrected for physical decay and are listed in approximate order of decreasing radioactivity concentrations. Tissue weights were normalized to a total body weight of 10 kg.

'L.N. indicates Lymph Nodes.

0

Female

3.4

CIRCULATORY TRANSPORT OF RADIOCERIUM

/

49

biological fluids, which is approximately 7, they will form insoluble aggregates or soluble complexes. Colloidal suspensions introduced into the mammalian circulation or the fluid of the peritoneal cavity are characteristically taken up in the liver, spleen, bone marrow, lymph nodes, and lung-tissues rich in reticuloendothelial cells or with a restrictive capillary circulation. This typical colloid distribution appears to depend chiefly, if not solely, on the size of the particles, and to be independent of their composition (Dobson et al., 1949; 1966; Dobson and Jones, 1951; Kyker, 1962a, 1962b). Inasmuch as the behavior of lanthanide colloid is a function of a common physical characteristic, namely, that of being finely divided solids, rather than of chemical properties, this discussion is relevant only to the interpretation of animal studies in which these elements were administered to animals as colloids and not to potential human exposures. The sedimentation of carrier-free '&Ce in different solutions or suspensions has been investigated (Aeberhardt, 1961; Aeberhardt et al., 1961). Radiocerium remained uniformly suspended and was presumably ionic in chloride solutions of pH < 4.5 and in nitrate solutions of pH < 3.5. Sedimentation was rapid and complete for '"CeCL in solutions of pH > 7.2 and lUCe(N03)3 in solutions of pH > 6. In chloride solutions (4.5 < pH < 7.2) and in nitrate solutions (3.5 c pH < 6) was partly ionic and partly colloidal. The sizes of the particles, calculated from sedimentation rates, were 0.1 to 0.3 pm. Cerium-144 settled rapidly and completely from phosphate solutions of pH > 6. In a sodium citrate solution (mol ratio, citrate: Ce = 1000: l), '"Ce was present as a soluble complex at pH < 8. The influence of the pH on the physical state of '"Ce in simple salt solutions can also be demonstrated biologically. The distribution of intravenously injected l4CeCl3in rats was typical of ionic material for injected solutions of pH = 3 and typically that of colloidal material for injected solutions of pH > 9 (Aeberhardt, 1961; Moskalev, 1961a). Stem (1956) reviewed the early investigations of the interactions of lanthanides with proteins. These studies showed stable binding of carrier-free 90Y to a protein or proteins in plasma or ascites fluid that was not disturbed by the addition of a small amount of NTA, but was partially broken by a small amount of EDTA. They were unable to demonstrate any association of 9 with commercial bovine albumin. Using crude protein separation techniques (salting-out and dialysis), Durbin et al. (1956a) obtained results that suggested '"Ce, 1527'ME~, and 17Tmbinding to globulins in rat plasma. Lanthanide binding did not appear to be prevented when the mixture of lanthanide and plasma was 0.003 M in sodium citrate.

50

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

Aeberhardt (1961) and Aeberhardt et al. (1961) demonstrated conclusively that canier-free '44Ceintroduced into rat or rabbit plasma as 144CeC4(pH = 4.5) or as 144Ce(N03)3 (pH = 3.5) either in vitro or in vivo was not colloidal, but was associated with protein. They concluded that the binding proteins were p2 and y-globulins. In other studies, depending upon the methods used, nearly all of the major proteins of plasma have been reported capable of binding lanthanide ions. Spencer and Rosoff (1963) and Puchkova (1969) implicated alpha and beta globulins. Ekman and Aberg (1961) reported binding to albumin and low molecular weight fractions in plasma. In one case, Kanapilly and Chimenti (1972) were unable to demonstrate any significant binding of the heavy lanthanide, 17'Tm, in their in vitro system, and the binding of "Y and of ' 9 was below expectation. To date, the only convincing demonstration of a genuine reaction between a nonessential multicharged cation and a specific serum constituent is that of Pu(1V) with transferrin, the betal globulin (molecular weight about 70,000~)that normally carries Fe(1II) in mammalian plasma (Popplewell and Boocock, 1967; Stover et al., 1968; Turner and Taylor, 1968a; 1968b; Stevens et al., 1968; Bruenger et al., 1969; 1971; Stevens and Bruenger, 1972). It is reasonable to suppose that the lanthanides may be bound to the same serum protein that binds Pu(IV) and which is also presumed to bind the trivalent actinides. In accord with theory (Martell and Calvin, 1952), several chelate compounds of the trivalent actinides (citrate, NTA, EDTA, DCTA) are somewhat more stable than the chelates formed by the lanthanides of the same ionic radius (Fuger, 1958; 1961; Krot et al., 1962; Mackey et al., 1962; Moeller and Hseu, 1962; Moeller and Thompson, 1962; Fuger and Cunningham, 1964; Sillen and Martell, 1964; Baybarz, 1965; 1966; Lebedev et al., 1968), and chelates of quadrivalent cations are much more stable than those of trivalent ions.of the same size (Fuger and Cunningham, 1 W ; Krot et al., 1962). Thus, one would expect the stability of protein binding of multicharged cations to be in the order of: Alkaline earths (11)<< Lanthanides (111) < Actinides (111) << Actinides (IV) It is likely that identification of lanthanide(II1)-protein complexes would be even more difficult than for the actinide-protein complexes because of their lower stability and greater tendency to dissociate during separation processes. The results of the lanthanide studies can be combined and surnmarized as follows: If a lanthanide is added in microgram amounts to "The molecular weight of transferrin is not known precisely. Different modern methods have yielded weights ranging h m 68,000to 89,000(Katz, 1970). .

3.4

CLRCULATORY TRANSPORT OF RADIOCERIUM

/

51

plasma in a noncolloidal form (as a weak complex or in a salt solution of low pH): (a) colloidal aggregation does not occur in uitro or in the circulation; (b) the lanthanide is bound to a nondialyzable entity, most likely protein; (c) the binding protein is not albumin but probably a globulin or globulins, most likely transferrin; and (d) based on their smaller ionic size, that leads to greater stability of complexes, the heavier lanthanides probably form more stable protein complexes than do the light lanthanides such as I4Ve. If account is taken of the technical difficulties inherent in protein separation methods and in handling lanthanides (without hydrolysis) at nearly neutral pH, most of the above cited studies fit these general conclusions. The rates at which lanthanides are cleared from the general circulation and the organs in which cleared elements are deposited are indicative of their state in the blood plasma. Intravenously injected colloids of medium size are rapidly removed by reticuloendothelial cells of liver, spleen, and bone marrow. Plasma clearance of soluble complexes, such as those of DTPA or simple anions, occurs more slowly after rapid equilibration with extracellular fluids (Foreman and Finnegan, 1957; Pluth et al., 1966; Gelhorn et al., 1944). Radionuclides that form stable protein complexes are largely restricted to the circulation until the complex is destroyed, because they cannot be excreted. Certain metal ions, such as calcium, form unstable protein complexes and are rapidly diluted in extracellular fluids and gradually deposited in specific internal organs. Plasma clearance curves for a number of radionuclides intravenously injected into rats are shown in Figure 11. Injection of 239P~(IV) citrate appears to lead to formation of the most stable protein complex and long plasma retention times. Protein complexes with lanthanide elements are weaker, especially with the lighter elements of the series. Clearance of 15**1 5 4 Eand ~ from plasma was similar to that of 45Caand indicates a relatively weak association with plasma proteins. The extent to which serum proteins can bind any metal is limited by the number of binding sites on each protein molecule and the total number of each kind of protein molecule. The total iron-binding capacity of human transferrin, for example, is about 6 fl/100 ml plasma (Katz, 1970) or 2.4 pM/kg of body weight. Normally, about 30 percent of the binding sites are occupied to leave a residual binding capacity of 1.6 pM/kg. By using the transferrin concentration of human plasma, the residual iron-binding capacity of dog plasma is calculated to be 1.8 pM/kg and of rat plasma, 1.2 pM/kg. The effect of protein saturation is shown in studies in which plutonium(1V)-transferrin binding was enhanced in iron-poor serum (0.2 saturated), suppressed in plasma of high iron saturation (0.5 saturated), and completely

52

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

0

I 2 TIME AFTER INJECTION (hours)

3

Fig. 11. Plasma clearance of selected lanthanides and plutonium compared to calcium.

eliminated in serum to which excess iron had been added (Stover et al., 1968). Even though the specfic protein that binds the lanthanides may or may not be transfenin, the behavior of high-specific activity Lanthanides (< 1 pM/kg7) compared with that of lanthanides administered with significant amounts of stable carrier strongly suggests the kind of "break-through" one would expect if a protein transport system were overloaded. As long a s the amount of lanthanide introduced into the The value of 1 a / k g was adopted for this discussion as the division between highand low-specific activity lanthanide tracers. It was c h k n partly as a compromise among several sets of data, and partly for simplicity. Up to 0.7 yM/kg of Pu(IV) citrate given intravenously to rats gave no indication of colloid formation (Langham, 1947). Durbin el al. (1956a) obtained evidence of significant colloid formation with l h 7 b injected intravenously with 1.6 yM/kg of T b citrate, and Magnusson (1963) obtained unusually large liver uptakes after intravenous injection of 0.6 pM/kg of '"WoCb or 1.2 pM/kg of Ib%c13. "he amount of lanthanide that can be administered without overloading the transport system is slightly greater if the injected compound is the citrate complex than if the compound is a simple salt.

3.4 CIRCULATORY TRANSPORT OF RADIOCERIUM

/

53

system is below the protein-binding capacitg, one expects: (a) that the eventual deposition will be characteristic of the particular element; and (b) that there will have been no colloidal aggregation because there was enough protein to bind all of the lanthanide. If the amount introduced exceeds the protein-binding capacity, the excess, having no complexing agel;t available to keep it in solution, will hydrolyze and aggregate. The eventual distribution of part of the radioactivity will be characteristic of colloids. When high-specific-activity, non-colloidal preparations are administered: (a) they are partitioned characteristically between liver and bone; (b) in rodents the rate of loss of the liver burden is high (halftime = 6.5 to 10.8 d) (Durbin, 1973); (c) the spleen content is low; and (d) autoradiographs show uniform distribution in hepatic cells rather than of phagocytosis of radioactive particles in the reticuloendothelial ceUs of the liver, spleen, and bone marrow, and there is deposition on bone surfaces. When lanthanides are injected, even in citrate solutions, with added stable carrier or as low-specific-activity reactor-produced tracers: (a) most of the activity, even of those lanthanides that usually deposit in bone, is shunted to liver and spleen; (b) in rodents the loss of the liver burden is delayed; (c) the deposition in spleen is high; and (d) autoradiographs demonstrate reticuloendothelial uptake in liver and spleen (Durbin et al., 1956a; Moskalev, 1961b; Thomas et al., 1971). 3.5

Variations in Deposition and Retention Patterns Among Individuals

Mathematical models for estimating the deposition and translocation of ingested and inhaled radionuclides are often used for radiological dose evaluations. Their use is also recommended in this report. However, some individuals within an exposed population of animals or people to which the model is applied may receive much higher or lower doses than the predicted average values. This biological variability is related to differences in exposure patterns or exposure modes, to differences in physiological clearance processes, or to differences in radionuclide metabolism among individuals. Therefore, it is of interest to estimate the magnitude of the range of doses that may be observed in such a population. Cuddihy et al. (1978) reviewed a set of experimental data on lung, liver, and skeletal radioactivity after inhalation of 144CeC4by beagles (Boecker and Cuddihy, 1974) to determine the possible range of individual organ burdens in the total population. A second study on variability of aerosol deposition patterns in dogs (Cuddihy and

54

/

3. METABOLISM OF CERIUM IN MAMMALIAN SPECIES

Boecker, 1973) exposed to other radioactive aerosols was also reviewed. An analysis of the data from both studies suggested that for beagles exposed by inhalation to radioactive 144Ceaerosols, individuals in the population would receive radiation doses to a given organ within a bgnormal distribution characterized by a geometric standard deviation of 2. Concentratons of "Sr in people living in New York City between 1953 and 1959 who were exposed to nuclear weapons fallout were reported by Kulp .and Schulert (1962). They suggested that the distribution of observed values was well fit by a log-normal distribution that had a geometric standard deviation of about 1.7. The Federal Radiation Council (FRC, 1961), after review of the accumulated data on "Sr in human bone, concluded that a log-normal distribution was the appropriate description of the distribution of this age-controlled, exposuretime controlled population. The main exposure to wSr fmm fallout was by way of ingestion. Other exposures of people to plutonium, aluminum, and titanium in the environment occur mainly by inhalation. Distributions of measured lung burdens of these elements in human populations were also analy7ed by Cuddihy et al. (1979). Assuming log-normal distributions for these measurements, the geometric standard deviations were approximately 3. Thus,more than 0.98 of the individuals in these populations had lung burdens less than 9 times the geometric means. However, 0.02 of the lung burdens were more than 9 times the geometric mean. These factors should be taken into account in establishing radiation exposure guidelines for populations and their individual members.

4.

Biomedical Effects of Radiocerium

The biological effects of internally-deposited '44Cehave been studied in several species of animals (Table 23). As expected, the observed effects were closely correlated with its mode of entry into the body and its chemical form. Because gastrointestinal absorption of cerium is low, major emphasis will be directed to inhalation studies and to injection studies as models for effects of the material after absorption from lung. The major effects have involved respiratory tract, liver, skeleton, and bone marrow. When relatively soluble forms of Id4Ceare inhaled, the 144Cetranslocates a t a sufficiently rapid rate from the lung to the liver and skeleton so that the dose to lung is substantially less than that to skeleton or liver. The effects on lung from such exposures are minimal. When large quantities of relatively soluble "We are inhaled, the dose to bone marrow may cause bone marrow damage with resultant pancytopenia and death. With lesser amounts of inhaled, relatively soluble lace, late occurring effects in the skeleton and liver are observed. These include myeloproliferative disease including leukemia, hepatic degeneration, hepatic neoplasms, osteosarcomas, and nasal cavity carcinomas. When relatively insoluble fonns of 14"Ce are inhaled, the primary effects are observed in the lungs and tracheobronchial lymph nodes. With large quantities of 14%e, animals die of radiation pneumonitis and pulmonary fibrosis. The tracheobronchial lymph nodes are atrophic and fibrotic. At lower exposure levels pulmonary neoplasms are a prominent finding. The effects of internally-deposited 144Ceare consistent with the more extensive literature on other low dose rate low-LET radiation. This more extensive literature on other low-LET radiation can be used in setting standards for radiocerium if it is recognized that most lMCe intakes are likely to result in low dose rate exposures. 4.1

Respiratory Tract, Tracheobronchial Lymph Nodes, and Heart

Several studies have been conducted in which animals have been exposed to aerosols of 14%e or have been given intratracheal injections 55

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59

of 144Ce(Cember, 1962; 1963; 1964a; 1964b; Cember and Sternmer, 1964; Thomas et al., 1972; Hahn et al., 1973a; 1973b, 1974, 1975a; 1975b; Benjamin et al., 1972a; 1972b,1975a; 1975b; 1975c,;Lundgren et al., 1975; Kurshakova and Ivanov, 1963; Boecker et al., 1974; 1975; McClellan, et al., 1970a; 1970b; 1971, 1972; Stuart et al., 1964). Pulmonary effects have been a prominent finding in all of these studies. The most comprehensive studies have been those conducted with beagles exposed to aerosols of either 14"CeCb,or 14%e in fused aluminosilicate particles (Benjamin et al., 1973; 1975b; 1975c; Hahn et al., 1975a; McClellan, et al., 1970a). A few animals exposed to l4CeCh and many animals exposed to 144Cein the fused aluminosilicate particles died a t the highest exposure levels a t times less than 2 y post-inhalation of '"Ce. The prominent findings were radiation pneumonitis and pulmonary fibrosis. The relationship between dose to lung and survival time of dogs that inhaled 144Cein the fused aluminosilicate particles is shown in Figure 12. Typically, the dogs with initial lung burdens greater than 30 pCi/kg showed progressive dyspnea, deep and rapid respiration, cyanotic mucous membranes, anorexia, electrocardiographic abnormalities, and an abnormal heart shadow upon radiographic examination related to developing pulmonary hypertension. A sequence of changes in pulmonary function indicative of pulmonary insufficiency related to ventilation-perfusion imbalance was observed (Mauderly and Pickrell, 1973). The earliest deaths due to radiation pneumonitis, occurring a t just over 100 days after inhalation of radiocerium, were observed in animals that inhaled sufficient activity to result in doses to lung of tens of thousands of rad. In general, animals that inhaled sufficient radiocerium to achieve cumulative doses to lung of 40,000 or more rad Surv/vo/ d Beog/e Dogs After Inho/otion d I

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th FAP P

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INITIAL LUNG BURDEN ( P C ~'44~e/kg Body Weight)

Fig. 12. Dose-response relationship for the effect of '"Ce on the lung and other organs after inhalation of labeled fused aluminosilicate particles (as of September, 1978)

60

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4.

BIOMEDICAL EFFECTS OF RADIOCERIUM

during the first year post-inhalation exposure died of radiation pneumonitis and/or pulmonary fibrosis. Primary lung cancers have been a prominent finding in dogs, rabbits, and rats that have died a year or more after having inhaled or received intratracheal injections of " Y e (Cember, 1963; 1964a; 1964b; Cember and Stemmer, 1964; Thomas et al., 1972; Hahn et al., 1973a; 1973b; Benjamin et al., 1972a; 1972b; Kurshakova and Ivanov, 1963). In rodent species a variety of lung neoplasms were observed, including pulmonary adenomas and carcinomas and sarcomas, including fibrosarcomas, adenocarcinoma, bronchiogenic carcinoma, and squamous cell carcinoma. Sixteen pulmonary neoplasms were observed in 13 dogs (Hahn et al., 1975a; Hahn et al., 1978a) after inhalation of 14Ce in fused alurninosilicate particles as young adults (initial lung burdens from 20 to 65 pCi/kg). These tumors included 8 hemangiosarcomas, I fibrosarcoma, 2 adenocarcinomas, 3 mixed tumors, and 2 bronchioalveolar carcinomas. The hemangiosarcomas were invasive with widely disseminated metastases. The fibrosarcoma was well differentiated, but did metastasize to the tracheobronchial lymph nodes. The bronchio-alveolar carcinomas were invasive neoplasms. Pulmonary hemangiosarcomas are rare neoplasms, especially in dogs. The predominance of endothelial tumors in these studies is in contrast to studies with inhaled plutonium where epithelial tumors predominated. The basis of this difference is not known. It is of interest to examine the data for '*Ce and =4pu induced lung neoplasms in beagles to estimate the relative biological effectiveness for the induction of pulmonary neoplasms with alpha versus beta radiation. Hahn et al. (1973b) made such an estimate comparing the first five dogs with 2 3 9 Pdying ~ of pulmonary neoplasms and the first five cases observed in the dogs with 144Ce.Their preliminary data analysis suggested that 239 Pu alpha irradiation was about 5 to 10 times more effective per rad than the 144Cebeta radiation for inducing pulmonary neopIasms, although the influence of dose rate was not taken into account. It is difficult to derive a quantitative dose-response relationship for the effect of inhaled '*Ce and induction of lung neoplasia because of the limited range of doses for which data are available on completed lifespan studies (Figure 13). This situation should .improve in the future when additional data are available from studies now in progress. A complication in evaluating the dose-response data for lung is that the information a t lower dose levels is exclusively from rats. Thomas et al. (1972) noted the extent to which many of the lungs of rats in their studies showed active typical murine pneumonia frequently involving areas of radiation fibrosis. Further, they noted the possibility that the presence of pneumonia concurrent with chronic irradiation of

4.1

RESPIRATORY TRACT,E X .

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61

Fig. 13. Relationship between incidence of lung cancer and radiation dose to lung from inhaled beta-gamma emitting radionuclides in experimental animals (Bair et al., 1974).

the lung may have been a factor in producing a high incidence of pulmonary neoplasms. Richter (1970) has also commented on the possible contributing role of infectious agents in the pathogenesis of pulmonary neoplasms. However, the lowest dose for which observations have been made is approximately 500 rad, which resulted in a 0.2 incidence of lung cancer in rats. Using the '44Cedata as well as more limited data on 51Cr,' q u , and lg8Au(allof which are beta emitters), Thomas and Bair (1976) derived equations relating lung cancer incidence and cumulative dose to lung (Figure 13).A linear equation was calculated that had an intercept of 10.7 percent + 6.4with a slope of 8.6 X lop4 4.5 percent X rad-' and a logarithmic probit form that had a slope of 0.55 i 0.29. These equations may be applied relating radiation dose to tissue response over the range of doses studied but they may have limited relevance for doses less than 500 rad. There are several mathematical forms that may be fitted to these data, each providing a different interpretation of dose-response relationships when extrapolated to lower doses. In the absence of additional information, it is not possible to select the unique relationship that exists at doses less than 500 rad. Other lesions of note that appear to be directly related to material

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BIOMEDICAL EFFECTS OF RADIOCERIUM

entering the body via the respiratory tract are observed in the nasal cavity, tracheobronchial lymph nodes, and the heart. Animals that inhaled large quantities of relatively insoluble material were observed to have tracheobronchial lymph nodes devoid of active germinal centers and most of them were completely depleted of lymphocytes. The nodes consisted mainly of connective tissue, sinusoids, and pigment laden phagocytic cells. Hemangiosarcomas involving the tracheobronchid lymph nodes have been reported in dogs that have balded radiocerium, Hahn et al., 1978a. Changes were also observed in the hearts of animals that inhaled large quantities of relatively insoluble radiocerium. The changes consisted of necrosis of the myocardium of the right auricle with areas of organizing connective tissue and scarring. There was also evidence of recent hemorrhage involving the endocardium, myocardium, and epicardium, both in areas of recent necrosis and of organizing scars. One hemangiosarcoma has been observed in the heart of a dog that inhaled radiocerium. Four dogs that inhaled '44CeC4as young adults (Benjamin et al., 1976a; 1976b) developed squarnous cell carcinomas of the nasal cavity. These neoplasms appear to arise fkom the turbinate epithelium. One dog also had a hemangiosarcoma of the nasal cavity. Age at exposure may have a significant influence on the effects of inhaled 'We. Unfortunately there is only limited information available in this area. Boecker et al. (1975), Boecker and Cuddihy (1978), and Hahn et al. (1975a; 1978b) have reported preliminary results from studies that are in progress with beagles exposed to 14%e in fused aluminosilicate particles a t 3 months of age or 8 to 10.5 years of age for comparison with studies that have been conducted with young adult dogs exposed a t 12 to 14 months of age. They observed that immature dogs with initial lung burdens generally higher than the young adult dogs survived the early acute effects. However, it was noted that the average dose to lung was actually less because of the rapid growth and enlargement of the young dogs' lungs. Several of the dogs exposed to very high levels of '44Cea t 3 months of age had severe congestive heart failure as a complicating lesion along with radiation pneumonitis. Congestive heart failure was not a prominent feature in dogs exposed as young adults. The aged dogs that inhaled '44Cewere more susceptible to radiation induced pneurnonitis than were the young adults; 11 of 13 dogs with initial lung burdens of 20 to 75 pCi 14Te/kg body weight died within 500 days after exposure with radiation pneumonitis. Only 10 of 26 young adult dogs with similar initial lung burdens died with radiation pneumonitis within 500 days. The disease pattern seen in both groups of dogs was similar. However, there was an increased incidence of congestive heart failure in the aged dogs. Two dogs

4.1 RESPIRATORY TRACT, ETC.

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63

exposed at 3 months of age died with hemangiosarcomas of the lung and one died with a hemangiosarcoma of the mediastinum. They died at an earlier time and with doses less than those dogs dying of similar malignant lung tumors after inhalation of 14Ce as young adults. Broncho-alveolar carcinomas have been observed in dogs exposed as aged individuals. The initial impression from these studies is that animals exposed as immature individuals are more susceptible to pulmonary neoplasia. However, these studies are still in progress and additional data are needed to determine the increased susceptibility.

4.2

Liver

Major alterations in liver have been a significant finding in animals that have been administered relatively soluble forms of '@Ce by inhalation or injection (Table 23) (Brooks et al., 1972; Benjamin et al., 1973; 1974; 1975a; 1976c; Benjamin and Brooks, 1977; Lebedeva, 1966; Strel'tsova, 1961; Strel'tsova and Moskalev, 1961; Moskalev et al., 1969; Fritz et al., 1970; Nonis et al., 1961; 1962). A number of beagle dogs given large quantities of '%e intravenously as a citrate (Fritz et al., 1970; Norris et al., 1961; 1962) or via inhalation as a chloride died a t early time periods (
64

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4. BIOMEDICAL EFFECTS OF RADIOCERIUM

1975a; 1975b; f i t z et al., 1967). Strel'tsova (1961) observed tumors of hepatic parenchymal, bile duct, and endothelial cell origin in rats injected with 0.25 to 2.14 pCi lMCe/g body weight. Tumor incidence was proportional to the quantity of 14%e injected and the time of appearance was inversely proportional to the radiation dose. Bile duct tumors were the most common. A mildly increased incidence of pituitary adenomas after '"Ce injection was also reported, although the significance of these was not clear and incidence was not related to dose. Brooks et al. (1972) observed hepatocellular neoplasms and one bile duct adenoma in Chinese hamsters given single intraperitoneal injections of lMCe(0.05 to 0.45 pCi lMCe/g body weight). In later studies (Benjamin et al., 1975a; Benjamin and Brooks, 1977) the effect of partial hepatectomy on tumor induction was studied. Up to one-third of the animals injected with activity levels of 0.05 to 0.25 pCi lMCe/g body weight and with cumulative doses ranging from 1000 to 14,000 rad to liver developed hepatic neoplqms. Partial hepatectomy after 144Ceinjection significantly increased liver tumor incidence. Most tumors were benign or malignant hepatocellular neoplasms although hepatic fibrosarcomas, hepatic hemangiosarcomas, and bile duct adenomas were also found. It is not possible with the limited data available to define a quantitative relationship between dose and response. The doses required to produce death due to liver disease in dogs are given in Table 23 and Figure 14. The three dogs dying a t the earliest times had severe liver

I [L m 3

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Fig. 14. Dose-response relationship for the effect of inhaled IUCe on liver (as of Sept. 1, 1978).

4.2 LIVER

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65

necrosis, the six dying later all had hepatic neoplasms. Both osteosarcomas and hemangiosarcomas were observed in dogs exposed to aerosols of IaCeCG. Of the six hemangiosarcomas noted in Figure 16, one w,as in bone and five were in liver. At the chromosomal level, dose-response data are available from the studies of Brooks et al. (1972) in Chinese hamsters on metaphase chromosomes in liver cells stimulated to divide by partial hepatectomy. They observed a linear increase in aberrations through 362 days after 144 Ce injection with a dose-response curve slope of 3.1 x aberrations per cell per rad. For doses up to 14,500 rad through 362 days, there were no signs of saturation or plateauing of the radiation dose response curve. At 720 days after lace injection, the slope of the doseresponse curve had decreased to 1.8 x aberrations per cell per rad and the aberration frequency in controls had more than tripled. Changing the dose rate over a range of 2 to 250 rad/day by varying the level of injected lMCe,had no effect on the frequency of aberrations per cell per rad. The efficiency of producing aberrations per rad of dose from lace was equal to that observed after protracted external 60Co gamma exposure (dose rates of 154, 95, 44, or 14 rad/day for 6, 15, or 42 days) and was about one-twentieth as effective as alpha irradiation from %'Am deposited in liver. Over the first 362 days after lace injection, a dose of 130 rad was required to produce a level of chromosome damage two standard deviations higher than observed in the controls. Figure 15 illustrates that intraperitoneal injection of 144Cecitrate produced the same amount of chromosome damage as a protracted whole-body exposure to 60Co on a per rad to liver basis in Chinese hamsters (Brooks et al., 1972). Acute exposure to '%o a t high dose rates produces a nonlinear increase in damage as a function of dose (Brooks et al., 1971).

4.3

Skeleton and Bone Marrow

Damage to the skeleton, hematopoietic tissue of the bone marrow, and epithelial tissues closely apposed to the skeleton has been noted in animals administered '44Cein relatively soluble forms by inhalation or injection. At relatively early times after exposure the major target organ has been the bone marrow while at later times all three tissues have shown effects of the radiation damage from the lUCe deposited in the skeleton. Moskalev et al. (1966a; 1966b) reported that rats injected with high levels of '%e citrate died with acute bone marrow damage a t relatively

66

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4.

BIOMEDICAL EFFECTS OF RADIOCERIUM

" I

CUMULATIVE DOSE TO LIVER (rad*)

Fig. 15. Effect of beta irradiation from '"Ce-"'Pr and gamma irradiation from W o on the production of liver chromosome damage.

early times after exposure. Fritz et al. (1970) observed severe bone marrow damage in dogs given intravenous injections of 50-250 pCi "'Te citrate/kg body weight with death occurring within 100 days of injection. Benjamin et al. (1973, 1975b) and McClellan et al. (1969) reported severe bone marrow damage and early deaths in dogs exposed to aerosols of '(4CeC13(Figure 16).Their LD50/60d, value corresponded to a 14 day retained burden of 171 f 20 pCi/kg. Moskalev et al. (1966a; 1966b) observed an increased incidence of leukemias of a generalized reticulosis type in rats injected with high levels of '"Ce citrate. Both Fritz et al. (1970) and Benjamin et al. (1973, 1975b) reported myeloproliferative disorders including myelogenous leukemia in the dogs they have studied. The most significant late effect observed from 14'Ce deposited in the skeleton has been the development of neoplasms of the skeleton. Moskalev et al. (1966a; 196613; 1969) noted the increased occurrence of osteosarcomas in rats injected intrapentoneally with either 144Cecitrate or chloride. The incidence was greater than in controls when the administered activity exceeded 20 pCi/kg. In rats injected with 750 pCi 144 Ce/kg body weight, a 0.65 incidence of osteosarcoma was seen in the animals at risk after 200 days. In dogs that survived more than two years after injection of ld4Cecitrate or inhalation of "VeCb, skeletal neoplasms (osteosarcomas) have been observed (Figure 16).

4.3 SKELETON AND BONE MARROW

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67

Survival d Beople Dogs After /nhololion o f ' 4 4 ~ e ~ l .

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4.4

Gastrointestinal Tract

Since absorption of '44Cefrom the intestine is very low (Table lo), the major effect observed following ingestion of large amounts of 144Ce results from direct beta and gamma irradiation of the gastrointestinal tract. When the total absorbed dose to the gastrointestinal tract was high, animals died of a typical gastrointestinal syndrome (Moskalev and Strel'tsova, 1956). Animals that survived the acute death phase and received doses of 24,000 rads to the intestine developed tumors of the gastrointestinal tract (Lebedeva, 1963). Most of the tumors were in the large intestine where the largest radiation dose occurred (Lebedeva, 1963; Moskalev and Strel'tsova, 1961).

4.5

Dose-Response Relationships

The available data for deriving dose-response relationships for 144Ce are relatively limited. A complicating feature is that the spectrum of diseases produced is dependent upon the form of the 14Te entering the body and the resultant radiation dose. This is apparent from data in Table 23 in which several different and competing diseases were produced by inhaled '44CeCL. Additional factors that confuse the interpretation of internal emitter dose-response studies in laboratory

68

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BIOMEDICAL EFFECTS OF RADIOCERIUM

animals include variability in the normal Lifespans and survival times in different species, the effect of dose protraction, and competing risks. For a given intake of 144Ce,longer-lived animals can withstand greater radiation doses than shorter-lived animals simply because of the slower development of age-related disease processes. The shorter-lived animal does not have the potential for receiving as great a fraction of the radiation dose as the long-lived animal after inhaling moderate- to long-lived radionuclides. Radiation doses are generally calculated to the time of death of the animal. This is done without knowledge of the influence of protracted doses, cell survival times for the injured cells, latent periods, and times over which the injuries develop during and after which further radiation may have no consequence. Competing risks may also confuse experimental interpretation, for death due to one injury may occur prior to full development or manifestation of other injuries. Thus, the significance of injuries present at the time of death as opposed to injuries causing death must be addressed. This is especially true for deaths in animals caused by naturally-occurring disease processes in which radiation related injury may also be present. In view of the limitations of the lMCedata and the findings of Brooks et al. (1972) noted earlier, it would seem appropriate to estimate any effects of internally deposited lMCefrom the more extensive literature on other low-LET radiation. However, in doing so it must be recognized that lMCeintakes are likely to result in low dose rate exposures and adequate consideration must be given to the reduced effectiveness of chronic low dose rate exposure versus acute high dose rate exposure as observed for 14%e by Brooks et al. (1972).

5. History of Radiation Protection Guidelines for Cerium Radionuclides Values of maximum permissible body burdens (q) and concentrawere published in tions in air (MPC), and water (MPC), for NCRP Report No. 11 (NBSHandbook 52) in 1953 (NCRP, 1953) and, in 1959,recommendations were made for I4'Ce, '%e, and I4Ce (NCRP, 1959). At that time, the biological information for cerium nuclides was extremely limited. Most of the available metabolic studies involved the intravenous, intramuscular, oral, or intraperitoneal injections of lace into rats. The levels of exposure ranged from tracer to toxic quantities. Cerium radionuclides were administered either as a citrate complex, trirnethylamine tricarboxylic acid complex, or in a saline solution isotonic with plasma. The rats were autopsied and in most cases about 20 tissues were analyzed for their cerium content. In the majority of cases, the liver was the most important initial site of deposition. Subsequently, there was a decrease in the liver concentration of cerium and an increase in the skeletal concentration (Durbin et al., 1956a; 1956b; Hamilton, 1947,1948b; 194&, 1948d, 1950; Anthony and Lathrop, 1947). Although the biological data for cerium radionuclides per se were limited, consideration was given to the metabolic characteristics within a chemical family. Other biological studies had been conducted with nuclides of the lanthanide series to which cerium belongs. Based upon that analogy, Dr. Joseph G. Hamilton (Personal Commdcation to K. Z. Morgan, February 19,1956) suggested a biological half-life of about 1500 days for cerium in the skeleton. AU of the lanthanides were absorbed poorly from the gastrointestinal tract, so that a value of was used for oral absorption. NCRP Scientific Committee 2 adopted the policy of expressing 69

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5. RADIATION PROTECTION HISTORY

retention as a single exponential function even though it was known that the early retention of most nuclides was multiexponential in character. This was a simplification adopted for convenience because the exponentials corresponding to early elimination added little to the annual dose estimate after long continued exposure. MPC's are conventionally based on the dose that the individual would receive after 50 years of exposure a t the level of the MPC, and thus the single exponential representing the slowest effective elimination rate largely determined the MPC. Using a simple model for retention in an organ, the amount deposited in the organ, f6, and its rate of elimination, A,R, must be determined. Translocation from one organ to another was rarely considered except for soluble activity initially present in the lung or in the GI tract. The radiation doses to internal organs from insoluble radionuclides deposited in the lung but later absorbed into the systemic circulation were actually ignored in the calculations of (MPC), values. Dose was averaged over each organ except the GI tract where the maximum dose at positions along the tract was estimated. The fraction of body burden, fi, present in an organ after 50 years of exposure a t a constant level was used to calculate the organ burden, i-e., the activity in in organ which would deliver the limiting dose rate for the organ by NCRP recommendations (NCRP, 1959; ICRP, 1959). From the biological data obtained by using cerium radionuclides and a comparative study with other members of the lanthanide family, the following biological parameters were selected and used in calculating q, (MPC),, and (MPC), values for cerium (ICRP, 1959): fi = (the fraction of ingested radionuclide reaching the blood): 0.0001 f2 = (the fraction of the body burden in the organ of reference): Total body = 1.0 Liver = 0.13 = 0.8 Kidney = 0.02 Bone f i = (fraction of the radionuclide reaching blood which deposits in the organ of reference): Total body = 1.0 Liver = 0.25 Bone = 0.3 Kidney .= 0.02 f, = flf2 = (fraction of the ingested radionuclide reaching the organ of reference) f. = (0.25 + 0.5fi)f2' =-(fraction of the inhaled radionuclide reaching the organ of reference) The dose to bone included a relative damage factor, n, in addition to the quality factor, QF (then termed RBE). The n factor represented the relative effectiveness of the dose from the radionuclide as compared with the dose equivalent from 226Ra.The assumptions used by both NCRP and ZCRP in making this comparison of bone seeking radio'

5. RADIATION PROTECTION HISTORY

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71

nuclides are set forth in the following passage quoted from ICRP Publication 2 (ICRP, 1959): "In the case of a- and P-emitting radionuclides that localize in the bone, the maximum permissible body burden, q, is determined from a direct comparison with Ran6. In 1941 an advisory committee to the National Bureau of Standards first established the maximum permissible body burden for radium at 0.1 pg (= 0.1 pc). Man has had years of experience with radium, which is the basis of reference in choosing the maximum permissible body burden of similar radionuclides that are deposited in the bone. The radium dial painters, patients treated medically with radium, and persons using public water supplies relatively rich in radium have furnished the best source of continuous human exposure from which to observe the effects of an internally deposited radionuclide. From autoradiographic studies of human autopsy material, radium is known to be unevenly distributed in the bone, but other bone-seeking radionuclides may be even less uniformly distributed. From animal experiments it is known that some bone-seeking radionuclides produce greater damage to the bone than Ra226for the same RBE dose. This greater damage is attributed to several factors, some of which are (a) nonuniform distribution, (b) greater radiosensitivity of the portion of bone in which the isotope is deposited, and (c) greater essentialness of the damaged tissue. Therefore a relative damage factor, n, is introduced into the MPC calculation to make some allowance both for the greater relative effectiveness of some radionuclides as well as for the fact that many have a more heterogeneous distribution in bone than radium. The relative damage factor, n, in the formula for effective energy, 2 Eifi (RBE)ini is taken as 1 i

provided (a) the parent element of the chain considered is an isotope of radium or (b) the energy component considered originates as Xor y-radiation. The relative damage factor is taken as 5 in all other cases, i.e., if the parent element of the chain is not an isotope of radium and if the energy component considered originates as a-, 8--, Pi-, e--radiation or from a recoil atom." Since 141Ce, 143Ce,and '%e are beta and gamma emitters, the n factor of 5 was used in calculating the effective energy for these nuclides. Details for calculating the effective energy may be found in ICRP (1959). The (MPC), values were calculated by using the assumption that the radioactive material is taken into the body at a constant rate each day and that biological elimination from the lung follows a simple exponential law. In a 24-hour day, the ICRP standard man, now called

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5. RADIATION PR(YIXCTION HISTORY

TABLE 24-Retention of particulate matter in the respiratory tract of standard man Readii soluble compounds

Distribution

Exhaled Deposited in upper respiratory passages and subsequently swallowed Deposited in the lungs (lower respiratory passages)

Other cornpounds

0.25 0.50

0.25 0.50

0.26 (this is taken up into the bodv)

0.25"

" Of this, half is eliminated from the lungs and swallowed in the first 24 hours, making a total of 0.625 swallowed. The remaining 0.125 is retained in the lungs with a biological half-life of 120 days, it being assumed that this portion is taken up into body fluids. TABLE 2 b C r i t i c a l organs for 14'Ce,Id3Ce,and '"Ce Publication 2 (ICRP, 1959)

as specified in ICRP

Soluble

"'Ce '"Ce '"Ce

Insoluble

Ingestion

Inhalation

LLI' LLI LLI

Liver LLI Bone Liver

Ingestion

LLI LLI LLI

inhalation

Lung LLI Lung

" Lower large intestine.

reference man, breathes 2 x lo7 ml of air. Because of his greater activity during an 8-hour work day, it was assumed that half of this intake occurs during the work period, i.e., 10" ml of air. The reference man works 5 days a week and 50 weeks per year. Table 24, quoted from ICRP Publication 2 (ICRP, 1959), specifies the constants used for the lung model in calculating values of (MPC).. The portion absorbed into the systemic circulation and deposited in internal organs was apparently not considered in calculating the (MPC),. Doses to sections of the GI tract were calculated according to the model presented in ICRP (1959). The critical organ for each of these nuclides is indicated in Table 25 for each solubility class and for the two modes of exposure considered in that publication.

6. Considerations for Establishing New Radiation.Protection Guidelines for Radionuclides of Cerium The following physical, chemical, and biological factors related to the metabolism of inhaled and ingested radiocerium are recommended for establishing radiation protection guidelines: a. Plants grown in soils contaminated with radiocerium could have concentration ratios (activity per gram dry plant material/activity per gram of dry soil) as high as 0.1 (see Tables 6,7, and 8). The high values for this ratio were observed in plant leaves and probably included a substantial amount of plant surface contamination. With other plant parts not having surface contamination, the concentration ratios are expected to be less by a factor of 10 or more. b. Transfer of cerium from forage to meat (see page 16) will be negligible because of extremely low gastrointestinal tract absorption and low deposition of absorbed cerium in muscle. The total animal muscle mass should reach an equilibrium level of 14%e of about 0.02 of the daily ingested radiocerium after several hundred days (see page 17). c. Transfer of cerium from forage to milk (see page 17) will be about 2 x of the daily intake secreted per liter of milk at equilibrium. d. Uptake of cerium from freshwater and seawater in aquatic food stuff (see Table 11) will result in the following range of concentration factors (activity per gram net weight/activity per ml water):

Fish Crustaceans Molluscs Plants

Fresh Water -1.0 1600-6500 40-720 2000-10000 73

Sea Water -1.0 -100 200-2000 300-900

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6. CONSIDERATIONS FOR GUIDELINES

e. Fractional absorption of soluble forms of cerium from the gasIn newborns, trointestinal tract in adults should be taken as 5 x this factor may be as high as 5 x lo-' for certain dietary modes. However, this higher absorption rate is assumed to decline within a few weeks after birth and only very low levels of radiocerium can reach milk of dairy cows. Insoluble forms such as cerium oxide should have even less absorption than observed with the more soluble citrate, chloride, and nitrate forms. These values are estimated from studies in experimental animals (Table 10) since no human data are available. f. Absorption through intact skin is assumed to be negligible, but for wounds that disrupt the skin and result in cerium deposition in the subcutaneous tissues or in muscle, the more soluble forms of cerium may be assumed to be totally absorbed into the bloodstream within 24 hours (Table 16 and Figure 10). g. For inhalation, the deposition parameters recommended by the ICRP Task Group on Lung Dynamics (ICRP, 1966) are appropriate for cerium (Figure 1).These deposition fractions are not anticipated to change with age. h. Detailed knowledge of the physical-chemical characteristics of inhaled radiocerium is required to project its deposition, retention, and dosimetry accurately. Lacking such information, the general solubility characterizations and respiratory tract clearance model described by the ICRP Task Group on Lung Dynamics (ICRP, 1966) may be used for lung and internal organ radiation dosimetry. With additional information on the solubility of specific radiocerium compounds, further analyses are recommended using procedures described below. A comparison of the analyses for three inhaled cerium aerosols is given in Table 13. i. The projected clearance of radiocerium deposited in the respiratory tract of humans is indicated in Figure 17 which is adapted from the information presented in this report, especially Section 4, and the ICRP Task Group on Lung Dynamics (ICRP, 1966). Most of this information was derived from studies with laboratory animals, especially beagle dogs. This limitation of the model is unavoidable since no substantial data are available on the metabolism of cerium in humans. The similarities in initial deposition patterns for inhaled aerosols in these animals (especially dogs) and in people have been discussed by Cuddihy et al. (1973). Organ weights and other physiological pararneters needed for radiation dose calculations applied to humans should be taken from ICRP Publication 23 (ICRP, 1974). j. For cerium deposited in the nasopharyngeal region of the respiratory tract, it may be assumed that the most soluble forms (e.g., cerium chloride and cerium citrate) will be absorbed into the systemic

6. CONSIDERATIONS FOR GUIDELINES

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75

ATMOSPHERE

Fig. 17. Biological model recommended for describing the uptake and retention of cerium by humans after inhalation or ingestion. Numbers in parentheses give the fractions of the material in the originating compartments which are cleared to the indicated sites of deposition. Clearance from the pulmonary region results from competition between mechanical clearances to the lymph nodes and gastrointestinal tract and absorption of soluble material into the systemic circulation. The fractions included in parentheses by the pulmonary compartment indicate the distribution of material subject to the two clearance rates; however, these amounts will not be cleared in this manner if the material is previously absorbed into blood. Transfer rate constants or functions, S(t), are given in fractions per unit time. Dashed l i e s indicate clearance pathways which exist but occur a t such slow rates as to be considered insigxufmmt compared to radioactive decay of the cerium isotopes.

circulation to the extent of about 0.04 of the deposited amount. Less soluble forms of cerium (e.g., oxides) will have lower direct absorption as determined by the balance between the rates of dissolution and absorption and the rates of clearance to the gastrointestinal tract. k. For cerium deposited in the tracheobronchial and pulmonary regions of the respiratory tract, clearance rates to the gastrointestinal tract should be taken from the Task Group on Lung Dynamics (ICRP,

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6. CONSIDERATIONS FOR GUIDELINES

1966). Clearance to pulmonary lymph nodes will occur a t a fractional rate of 0.0001 per day. Dissolution of the deposited particles and absorption of cerium into the systemic circulation will occur a t rates that are between the extremes represented by CeC13 in CsCl particles and Ce oxide or Ce in fused aluminosilicate particles as given by the functions included in Figure 9. These rates should not be expected to be constant over the entire clearance period and will depend upon the overall composition of the bulk aerosol particles, which indude particle size, amount of stable lanthanide present, acidity, and the solubility of other components of the particles. The accuracy of predicting respiratory tract clearance and internal organ uptake of radiocerium will depend heavily upon adequate determination of the particle solubility characteristics. 1. Cerium reaching the tracheobronchial lymph nodes is likely to be absorbed into the bloodstream a t rates similar to the rates of absorption from lung. For insoluble materials, such as oxides, the cerium may be retained for several thousand days. More soluble forms clear more rapidly and lymph node deposition is less important. This result is due to the rapid clearance of the cerium from lung to the bloodstream that effectively bypasses the lymph nodes. m. Clearance of cerium in the bloodstream to tissues and excreta results in partitioning as follows (see pages 27-33):

Liver Skeleton Testes9 Ovariess

0.45 0.35

1x 3 x lo-s

Other Soft Tissue Urine Feces

0.10 0.02 0.08

Retention of cerium deposited in these tissues is generally considered to be very long, with a biological half-time in excess of a thousand days. Therefore, the effective half-time of retention in these internal organs will be approximately equal to the physical half-life. n. Transfer of cerium from the pregnant mother to the fetus (see page 45) should range from 0.003 to 0.03 of that portion of the mother's internal body burden that was received during the pregnancy exclusive of lung and gastrointestinal tract. o. The loss of cerium from liver to feces via the bile and gastrointestinal tract may be assumed to occur with a half-time of several thousand days. AU cerium isotopes discussed in this report will be lost Fractions of absorbed cerium depositing in gonads were calculated from data in Table 20 by taking average ratios of radioactivity in testes or ovaries to that in liver and skeleton and multiplying these by the above liver and skeletal deposition fraction.

6. CONSIDERATIONS FOR GUIDELINES

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from the liver at an assumed effective half-time equal to the physical half-life of the isotope. p. Cerium in the skeleton will preferentially be deposited on bone surfaces (see page 41). Even for the energetic beta emissions of the radionuclides of cerium, there will be greater irradiation of bone surfaces and adjacent tissues than for the average skeletal mass. Therefore, a model for deposition of cerium radionuclides on bone surfaces similar to those used for plutonium isotopes should be used for purposes of radiation dosimetry. q. Cerium inhaled and deposited in the lung will be nonuniformly distributed either because it will be inhaled as insoluble particles or because of the tendency of soluble forms to rapidly hydrolyze. This nonuniform distribution is expected to have minimal impact on the degree of uniformity of radiation because of the high energy of the P emissions and the low density of lung tissue. r. Biological variability in animal populations exposed to radioactive aerosols has produced distributions of organ dose values that have been characterized as log-normal with geometric standard deviations of about 2 (see page 53). Human populations may exhibit similar or greater variability such that a fraction of their members, 0.02, may receive radiation doses greater than 5 to 10 times that for the average member. s. The available data on 14%e indicate a dose-response relationship similar to that for other low-LET radiations that produce chronic irradiation of internal organs, especially the lung, liver, skeleton, and gastrointestinal tract.

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The NCRP The National Council on Radiation Protection and Measurements is a nonprofit corporation chartered by Congress in 1964 to: 1. Collect, analyze, develop, and disseminate in the public interest information and recommendations about (a) protection against radiation and (b) radiation measurements, quantities, and units, particularly those concerned with radiation protection; 2. Provide a means by which organizations concerned with the scientific and related aspects of radiation protection and of radiation quantities, units, and measurements may cooperate for effective utilization of their combined resources, and to stimulate the work of such organizations; 3. Develop basic concepts about radiation quantities, units, and measurements, about the application of these concepts, and about radiation protection; 4. Cooperate with the International Commission on Radiological Protection, the International Commission on Radiation Units and Measurements, and other national and international organizations, governmental and private, concerned with radiation quantities, units, and measurements and with radiation protection. The Council is the successor to the unincorporated association of scientists known as the National Committee on Radiation Protection and Measurements and was formed to carry on the work begun by the Committee. The Council is made up of the members and the participants who serve on the fifty-eight Scientific Committees of the Council. The Scientific Committees, composed of experts having detailed knowledge and competence in the particular area of the Committee's interest, draft proposed recommendations. These are then submitted to the full membership of the Council for careful review and approval before being published.

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The following comprise the current officers and members of the Council: Officers President Vice President Secretary and Treasurer Assistant Secretary A~sistantTreasurer Members

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Honorary Members LAURISTON S. TAYLOR, Hormmry President EDGARC. BARNES PAUL.C. HODGES EDITHH. QUIMBY JOHN H. RUST CARLB. BRAESTRUP GEORGEV. LEROY SHIELDS WARREN AUSTINM. BRUES KARLZ. MORGAN FREDERICK P. COWAN RUSSELLH. MORGAN HAROLD 0 . WYCKOFF ROBLEYD. EVANS HERBERTM. PARKER

Currently, the following Scientific Committees are actively engaged in formulating recommendations: Basic Radiation Protection Criteria Medical X-ray and Gamma-ray Protection up to 10 MeV (Equipment Design and Use) Incineration of Radioactive Waste X-ray Protection in Dental Offices Standards and Measurements of Radioactivity for Radiological Use Radionuclides and Labeled Organic Compounds Incorporated in Genetic Material Radiation Protection in the Use of Small Neutron Generators High Energy X-Ray Dosimetry Administered Radioactivity Dose Calculations Maximum Permissible Concentrations for Occupational and Non-Occupational Exposures Procedures for the Management of Contaminated Persons Waste Disposal Microwaves Biological Aspects of Radiation Protection Criteria Radiation Resulting from Nuclear Power Generation Industrial Applications of X Rays and Sealed Sources Radiation Associated with Medical Examinations Radiation Received by Radiation Employees Operational Radiation Safety Instrumentation for the Determination of Dose Equivalent Apportionment of Radiation Exposure Surface Contamination Radiation Protection in Pediatric Radiology and Nuclear Medicine Applied to Children Conceptual Basis of Calculations of Dose Distributions Biological Effects and Exposure Criteria for Radiofrequency Electromagnetic Radiation Bioassay for Assessment of Control of Intake of Radionuclides Experimental Verification of Internal Dosimetry Calculations Mammography Internal Emitter Standards Radioactivity in Water

In recognition of its responsibility to facilitate and stimulate cooperation among organizations concerned with the scientific and related

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aspects of radiation protection and measurement, the Council has created a category of NCRP Collaborating Organizations. Organizations or groups of organizations that are national or international in scope and are concerned with scientific problems involving radiation quantities, units, measurements and effects, or radiation protection may be admitted to collaborating status by the Council. The present Collaborating Organizations with which the NCRP maintains liaison are as follows: American Academy of Dermatology American Association of Physicists in Medicine American College of ~adiology American Dental Association American Industrial Hygiene Association American Insurance Association American Medical Association American Nuclear Society American Occupational Medical Association American Podiatry Association American Public Health Association American Radium Society American Roentgen Ray Society American Society of Radiologic Technologists Association of University Radiologists Atomic Industrial Forum College of American Pathologists Defense Civil Preparedness Agency Genetics Society of America Health Physics Society National Bureau of Standards National Electrical Manufacturers Association Radiation Research Society Radiological Society of North America Society of Nuclear Medicine United States Air Force United States Army United States Department of Energy United States Department of Labor United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission United States Public Health Service

The NCRP has found its relationships with these organizations to be extremely valuable to continued progress in its program.

T H E NCRP

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The Council's activities are made possible by the voluntary contribution of the time and effort of its members and participants and the generous support of the following organizations: Alfred P. Sloan Foundation Alliance of American Insurers American Academy of Dental Radiology American Academy of Dermatology American Association of Physicists in Medicine American College of Radiology American College of Radiology Foundation American Dental Association American Industrial Hygiene Association American Insurance Association American Medical Association American Nuclear Society American Occupational Medical Association American Osteopathic College of Radiology American Podiatry Association American Public Health Association American Radium Society American Roentgen Ray Society American Society of Radiologic Technologists American Veterinary Medical Association American Veterinary Radiology Society kssociation of University Radiologists Atomic Industrial F O N ~ BatteUe Memorial Institute College of American Pathologists Defense Civil Preparedness Agency Edward Mallinckrodt, Jr. Foundation Electric Power Research Institute Genetics Society of America Health Physics Society James Picker Foundation National Association of Photographic Manufacturers National Bureau of Standards National Electrical Manufacturers Association Radiation Research Society Radiological Society of North America Society of Nuclear Medicine United States Department of Energy United States Environmental Protection Agency United States Navy United States Nuclear Regulatory Commission United States Public Health Service

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To all of these organizations the Council expresses its profound appreciation for their support. Initial funds for publication of NCRP reports were provided by a grant from the James Picker Foundation and for this the Council wishes to express its deep appreciation. The NCRP seeks to promulgate information and recommendations based on leading scientificjudgment on matters of radiation protection and measurement and to foster cooperation among organizations concerned with these matters. These efforts are intended to serve the public interest and the Council welcomes comments and suggestions on its reports or activities from those interested in its work.

NCRP Publications NCRP publications are distributed by the NCRP Publications' office. Information on prices and how to order may be obtained by directing an inquiry to: NCRP Publications P.O. Box 30175 Washington, D.C. 20014 The extant publications are listed below. 7.

Lauriston S. Taylor Lectures

No.

Title and Author

1

The Squares of the Natural Numbers in Radiation Protection by Herbert M. Parker Why be Quantitative About Radiation Risk Estimates? by Sir Edward Pochin

2

NCRP Reports No.

Title

8

Control and Removal of Radioactive Contamination in Laboratories (1951) Recommendations for Waste Disposal of Phosphorus-32 and Iodine-131 for Medical Users (1951) Recommendations for the Disposal of Carbon-14 Wastes (1953)

Radioactive Waste Disposal in the Ocean (1954) Maximum Permissible Body Burdens and Maximum Pennissible Concentrations of Radionuclides in Air and in Water for Occupational Exposure (1959) [Includes Addendum 1 issued in August 19631 Measurement of Neutron Flux and Spectra for Physical and Biological Applications (1960) Measurement of Absorbed Dose of Neutrons and of Mixtures of Neutrons and Gamma Rays (1961) Stopping Powers for Use with Cavity Chambers (1961) 107

NCRP PUBLICATIONS

Safe Handling of Radioactive Materials (1964) Radiation Protection in Educational Institutions (1966) Medical X-Ray and Gamma-Ray Protection for Energies Up to 10 MeV-Equipment Design and Use (1968) Dental X-Ray Protection (1970) Radiation Protection in Veterinary Medicine (1970) Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides (1970) Protection against Neutron Radiation (1971) Basic Radiation Protection Criteria (1971) Protection Against Radiation From Brachytherapy Sources (1972)

Specification of Gamma-Ray Brachytherapy Sources (1974) Radiological Factors Affecting Decision-Making in a Nuclear Attack (1974) Review of the Current State of Radiation Protection Philosophy (1975) Krypton-85 in the Atmosphere-Accumulation, Biological Significance, and Control Technology (1975) Natural Background Radiation in the United States (1975) Alpha-Emitting Particles in Lungs (1975) Tritium Measurement Techniques (1976) Radiation Protection for Medical and Allied Health Personnel (1976) Structural Shielding Design and Evaluation for Medical Use of X Rays and Gamma Rays of Energies Up to 10 MeV (1976)

Environmental Radiation Measurements (1976) Radiation Protection Design Guidelines for 0.1-100 MeV Particle Accelerator Facilities (1977) Cesium-137 From the Environment to Man: Metabolism and Dose (1977) Review of NCRP Radiation Dose Limit for Embryo and Fetus in Occupationally-Exposed Women (1977) Medical Radiation Exposure of Pregnant and Potentially Pregnant Women (1977) Protection of the Thyroid Gland in the Event of Releases of Radioiodine (1977) Radiation Exposure From Consumer Products and Miscellaneous Sources (1977) Znstrumentation and Monitoring Methods for Radiation Protection (1978) A Handbook of Radioactivity Measurements Procedures (1978)

Operational Radiation Safety Program (1978) Physical, Chemical, and Biological Properties of Radiocerium Relevant to Radiation Protection Guidelines (1978)

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Binders for NCRP Reports are available. Two sizes make it possible to collect into small binders the "old series" of reports (NCRP Reports Nos. 8-31) and into large binders the more recent publications (NCRP Reports Nos. 32-60). Each binder will accommodate from five to seven reports. The binders carry the identification "NCRP Reports" and come with label holders which permit the user to attach labels showing the reports contained in each binder. The following bound sets of NCRP Reports are also available: Volume I. Volume 11. Volume 111. Volume IV. Volume V. Volume VI. Volume VII.

NCRP Reports Nos. 8,9, 12, 16, 22 NCRP Reports Nos. 23,25,27,30 NCRP Reports Nos. 32,33,35,36,37 NCRP Reports Nos. 38.39,40,41 NCRP Reports Nos. 42,43,44,45,46 NCRP Reports Nos. 47,48,49,50,51 NCRP Reports Nos. 52, 53, 54, 55, 56,57

(Titles of the individual reports contained in each volume are given above.) The following NCRP reports are now superseded and/or out of print: NCRP Report No.

Title

X-Ray Protection (1931). [Superseded by NCRP Report No. 31

Radium Protection (1934). [Superseded by NCRP Report No. 41

X-Ray Protection (1936). [Superseded by NCRP Report No. 61

Radium Protectwn (1938). [Superseded by NCRP Report NO. 131

Safe Handling of Radioactive Luminous Compounds (1941). [Out of print] Medical X-Ray Protection up to Two Million VoUs (1949). [Superseded by NCRP Report No. 181 Safe Handling of Radioactive Isotopes (1949). [Superseded by NCRP Report No. 301 Radiological Monitoring Methods and Instruments (1952). [Superseded by NCRP Report No. 571 Maximum Permissible Amounts of Radioisotopes in the Human Body and Maximum Permissible Concentrations in Air and Water (1953) [Superseded by NCRP Report No. 221

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Protection Against Radiations from Radium, Cobalt-60 and Cesium-137 (1954). [Superseded by NCRP Report No. 241 Protection Against Betatron-Synchrotron Radiations Up to 100 Million Electron Volts (1954). [Superseded by NCRP Report No. 511. Safe Handling of Cadavers Containing Radioactive Isotopes (1953). [Superseded by NCRP Report No. 211 Permissible Dose from External Sources of Ionizing Radiation (1954) including Maximum Permissible Exposure to Man, Addendum to National Bureau of Standards Handbook 59 (1958). [Superseded by NCRP Report No. 391 X-Ray Protection (1955). [Superseded by NCRP Report No. 261

Regulation of Radiation Exposure by Legislative Means (1955). [Out of print] Protection Against Neutron Radiation Up to 30 Million Electron Volts (1957). [Superseded by NCRP Report No. 381 Safe Handling of Bodies Containing Radioactive Isotopes (1958). [Superseded by NCRP Report No. 371 Protection Against Radiations from Sealed Gamma Sources (1960). [Superseded by NCRP Reports Nos. 33, 34, and 401 Medical X-Ray Protection Up to Three Million Volts (1961). [Superseded by NCRP Reports Nos. 33,34,35, and 361 A Manual of Radioactivity Procedures (1961). [Superseded by NCRP Report No. 581 Exposure to Radiation in an Emergency (1962). [Superseded by NCRP Report No. 421 Shielding for High Energy Electron Accelerator Installations (1964). [Superseded by NCRP Report No. 511 Medical X-Ray and Gamma-Ray Protection for Energies Up to 10 Me V-Structural Shielding Design and Evaluation (1970). [Superseded by NCRP Report No. 491

Statements T h e following statements o f t h e N C R P were published outside o f t h e NCRP Report series: "Blood Counts, Statement of the National Committee on Radiation Protection," Radiology 63, 428 (1954) "Statements on Maximum Permissible Dose from Television Receivers and Maximum Permissible Dose to the Skin of the Whole Body," Am. J . Roentgenol., Radium Ther. and Nucl. Med. 84, 152 (1960) and Radiology 75, 122 (1960) X-Ray Protection Standards for Home Television Receivers, Interim Statement of the National Council on Radiation Protection and Measurements (National Council on Radiation Protection and Measurements, Washington, 1968)

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Specification of Units of Natural Uranium and Natural Thorium (National Council on Radiation Protection and Measurernen'ts,Washington, 1973)

Copies of the statements published in journals may be consulted in libraries. A limited number of copies of the last two statements listed above are available for distribution by NCRP Publications.

Index Absorbed cerium (see also injected cerium), 38-46 Distribution in bone, 41 Distribution in liver, 42 High specific activity compounds, 39 Organ distribution, 38,43,44 Transfer to fetus, 45 Age, influence on effects of radiocerium, 62,63

Aged nnimnln, 62 Congestive heart failure, 63 Immature animals, 62 Pulmonary neoplasia, 63 Animal studies, uptake of cerium, 16-24 Aquatic animals, 18 Cerium in milk, 17 Concentration by tissue, 19 Gastrointestinal absorption, 17.21 Atomic structure of lanthanides, 2 Ionic radii, 2 Oxidation states, 2 Biomedical effects of radiocerium, 55-68 Dose-responserelationships, 67 Effects of age, 62 Gastrointestinal tract, 67 Heart, 55, 62 Liver, 63 Respiratory tract, 55-62 Skeleton and bone marrow. 65 Tracheobronchial lymph nodes, 55,61, 62

Bone marrow, effect of radiocerium on, 6567

Leukemias, 66 Chelating agents, 4, 5 Complexes with lanthanides, 4 Lanthanide analysis and preparation, role in, 4 Tissue removal of lanthanides, 4 Chromosomes, effect of radiocerium on, 65

Circulatory transport of cerium, 46,49-53 Colloidal cerium, 49 Plasma clearance of cerium, 51,52 Protein interaction of cerium, 49, 50 Class " D compounds (definition), 25 Class " W compounds (definition),25 Class 'Y" compounds (definition), 25 Clearance half-times for cerium, 26-38 Nasopharynx, 26 Pulmonary region, 26 Tracheobronchial region, 26,34 Decay schemes for cerium isotopes, 5-8 Half-lives, 6 Radiation emissions, 6, 7, 8 Deposition of inhaled cerium, 20,24, 25,35 Particle size, role of, 20.25 Species differences, 35 Dose-response relationships for radiocerium, 67,68 Chemical form of cerium, 68 Competing risks,role of, 68 Dose effect of, 68 Lifespan, importance of, 68 Survival time, importance of, 68 Environment, cerium in, 9-11 Aquatic systems, 10 Atmosphere, 9, 10, 11 Primary isotopes, 9 Fallout, cerium in 10-12 Chemical forms of cerium,10 Effect on food crops, 12 Food contamination by cerium, 10, 12, 16 Aquatic foodstuffs, 10 Crop inigation, role of, 16 Fallout. 10 Gastrointestinal absorption of cerium, 2124

Age, effect of. 22 Cerium transit time, 24

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Diet, effect of, 22 hadiation of gastrointestinal tract. 24 Retention of cerium, 22 Gastrointestinal tract, effect of radiocerium on, 67 Gastrointestinal syndrome, 67 Health effects of radiocerium (see Biomedical effects of radiocerium) Heart, effect of radiocerium on, 62-63 Congestive heart failure, 63 Infectious agents, 61 Pulmonary neoplasm, role in, 61 Inhaled cerium, 24-28,33-36,47-48,74-76 Absorption into blood, 26 Clearance to gastrointestinal tract, 26 Deposition model, 24 Deposition in respiratory tract, 24, 74 In man, 36,74-76 Organ radiation dases, 34 Retention model, 28 Species differences, 36, 36 Tissue distribution after inhalation, 47, 48

Translocation to lymph nodes, 33 Uptake by internal organs, 26,27 Injected cerium (see also absorbed cerium), 38,40,43-61

Intramuscular, 40 Organ distribution after injection, 43, 44 Quantity administered, importance of, 40 Isotopes of cerium, 1,5-7 Abundance, 1

Mass, 1 Naturally occurring, 1 Radioactive, 5 , 6 , 7 Lanthanide chemistry, 1-4 Atomic structures, 2 Complex stability, 4 Inorganic chemistry, 1,3 Ionic radii, importance of, 3 (lanthanide contraction) Periodic system, position in, 1 Radiochemistry, 1 Soluble complex formation. 3,4 Liver, effect of radiocerium on, 63-65 Biliary hyperplasia, 63 Chromosomal changes, 65 Cirrhosis, 63

Dose-response relationship, 64 Hepatic degeneration, 63 Necrosis, 63 Neoplasms (cancers), 63,64 Lung (see respiratory tract) Metabolism of cerium, 20-24,38,46,53 Circulatory transport of cerium, 46 Gastrointestinal absorption, 21 Inhaled cerium, 24 Internal organ distribution of cerium, 38 Variability among individuals, 53 Nasopharynx, 24 Nuclear explosive devices, 10 Nuclear Fuel repxceesing, 11 Nuclear power production, 11 Nuclear weapon tests, 9, 10 Cerium released to atmosphere, 10 Cerium released to aquatic environments, 10 Cerium isotope yield, 9 Pathways of cerium to man, 9-19 Atmospheric, 9,10, 11 Cerium in diet, 13 Food contamination, 12, 16, 18 Plant studies, uptake of cerium, 13, 14 Absorption, 13 Concentration by plants, 14 Root uptake, 13 Protection guidelines for radiocerium,establishing new, 73-77 Biological variability, 77 Cerium in aquatic foodstuffs, 73 Cerium in meat, 73 Cerium in milk, 73 Cerium in plants, 73 Cerium in skeleton, 76,77 Deposition parameters for respiratory tract, 74 Dose-response relationships, 77 Fetus, transfer of cerium to, 76 Gastrointestinal absorption, 74 Liver, loss of cerium from, 76 Lung deposition of inhaled cerium, 77 Physical-chemical characteristics, 74 Respiratory tract clearance, 74-76 Tracheobronchial lymph nodes, 76 Protection guidelines for radiocerium, history of, 69-72

INDEX Pulmonary region, 24 Respiratory tract, effect of radiocerium on, 55,59-60

Dose-response relationship, 60 Neoplasms, (cancers), 60 Pulmonary fibrosis, 59 Radiation dose effect, 59 Radiation pneurnonitis, 59 Retention of inhaled cerium, 27,29-32,35 Liver, 29-32 Lung, 29-32 Skeleton, 29-32 Soft tissue, 30 Species differences, 35 Tracheobronchial lymph nodes, 35 Skeleton, effects of radiocerium on, 66

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Neoplasms (cancers), 66 Solubility of lanthanide compounds, 3 Bond formation, role of, 3 Lanthanide contraction, role of. 3 Sources of environmental cerium, 9-11 Nuclear explosive devices, 10 Nuclear fuel reprocessing, 11 Nuclear power production, 11 Nuclear weapon testing, 9, 10 Tracheobronchial lymph nodes, effect of radiocerium on, 62 Tracheobronchial region, 24 Uptake of cerium (see plant studies. uptake of cerium and animal studies, uptake of cerium)