Comparison between biokinetics of inhaled plutonium nitrate and gadolinium oxide in humans and animals

Journal of Radioanalytical and Nuclear Chemistry, Vol. 252, No. 2 (2002) 315–325

Comparison between biokinetics of inhaled plutonium nitrateand gadolinium oxide in humans and animals

N. Stradling,1 G. Etherington,1 A. Hodgson,1 M. R. Bailey,1 S. Hodgson,1 P. Pellow,1 A. L. Shutt,1

A. Birchall, 1 E. Rance,1 D. Newton,2 K. Fifield 3

1 National Radiological Protection Board, Chilton, Didcot, Oxon, UK2 AEA Technology, Harwell, Didcot, Oxon., UK

3 Australian National University, Canberra, Australia

(Received November 23, 2001)

Due to the paucity of human data after inhalation of different chemical forms of radionuclides, the implications for human exposure are oftenbased on animal studies. This paper describes biokinetic studies of plutonium nitrate and gadolinium oxide in human volunteers and rats. Theresults, together with information from other studies with radionuclides, suggests that animal studies can be used with advantage for assessing thebiokinetic behavior in humans, and for providing guidance on the assessment of intake and optimal monitoring regimens.

Introduction and man, (2) in animals, the absorption rates afterinhalation and intratracheal instillation of the materialssince either or both methods of administration could beused for animal studies depending on the amounts andexposure facilities available, and (3) the biokinetics inhumans predicted from animal studies with thoseobserved experimentally.

A wide variety of physical and chemical forms ofradionuclides can be inhaled as a consequence ofoccupational and environmental exposure. Human dataon the biokinetics of inhaled radionuclides are rarelyavailable, and, therefore, guidance on dose assessmentsand individual monitoring programmes are often basedon extrapolation from animal studies. An effectiveframework for this procedure is provided by the HumanRespiratory Tract Model (HRTM)1 and element specificsystemic models2,3 published by the InternationalCommission on Radiological Protection (ICRP). AtNRPB, the implications for human exposure are assessedby combining material-specific absorption rates fromanimal studies (rather than using default values) withparticle transport data from the HRTM (derived fromexperimental human data) and the appropriate humansystemic model for the radionuclide (either thatpublished by ICRP or obtained from independent humanstudies).

Experimental

The studies with human volunteers were undertakenwith the approval of independent ethical committees andappropriate certification for the administration ofradioactive products. All animal studies were conductedin accordance with national legislation.

Interspecies comparison of lung clearance of plutonium

The data presented here were determined fromexperiments involving the inhalation of 237,244Pu byhuman volunteers and the inhalation or intratrachealinstillation of 237Pu by rats.

At present, a major uncertainty in this approach is thepaucity of evidence to support, or contradict, theassumption concerning the species independence ofabsorption parameters. If appreciable differences shouldoccur, then it would question the justification of animalstudies for predicting biokinetics in humans.

Human studies

The 237Pu (T1/2 = 45 d) and 244Pu (T1/2 = 8.107 y)were obtained from the Joint Institute for NuclearResearch, Dubna, Russia, where mass-separationtechniques5 were used to remove isotopic impurities inorder to reduce doses to below the WHO Category 1limit of 0.5 mSv.6 The use of 237Pu, a photon emitter,enabled in vivo measurements of organ distribution andexcretion in humans to be made up to four months afterexposure. The use of 244Pu enabled long-term excretionmeasurements to be made by accelerator massspectrometry (AMS).7

In order to address this uncertainty, a largeprogramme of work involving five chemical compoundswas carried out under the European Union’s FourthFramework Programme, an overview of which has beenpublished elsewhere.4 This paper addresses only thosetwo projects in which human volunteers were used,namely the administration of plutonium nitrate(Pu(NO3)4) and gadolinium oxide (Gd2O3). In summary,the objectives of the work were to compare (1) theabsorption rates from lungs to blood in animal species

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N. STRADLING et al.: COMPARISON BETWEEN BIOKINETICS OF INHALED PLUTONIUM NITRATE AND GADOLINIUM OXIDE

The human volunteers were healthy, non-smokingadult males. The two volunteers in the Pu study hadparticipated previously in studies of the systemicbiokinetics of 237Pu administered as citrate byintravenous injection.8,9 To assist the interpretation ofthe retention data, individual liver phantoms wereconstructed. These phantoms and information on theindividual systemic biokinetics of 237Pu were madeavailable for this study.

group of 56 rats in order to develop a systemic model forthis species. This model would be used in conjunctionwith the inhalation and instillation data to calculate theabsorption parameter values. Groups of 4 animals werekilled on a similar time scale as the instillationexperiment.

Interspecies comparison of lung clearanceof gadolinium

A mixture of 237Pu and 244Pu generated from a 0.5%sodium nitrate solution containing about 0.01M nitricacid was inhaled by the volunteers. The aerosolgenerator and exposure apparatus used foradministration of the plutonium were essentially thesame as described elsewhere.10 Using this procedure, thenebulized droplets dried rapidly to produce an aerosol ofactivity median aerodynamic diameter (AMAD) of1.1 µm, with a geometric standard deviation (σg) of 1.2.The volunteers were exposed for about 30 minutes usinga breathing pattern designed to optimise deposition inthe alveolar-interstitial region of the lungs.11 The initiallung deposit (ILD) of 237Pu (8 kBq), obtained byexternal counting of the chest, was sufficient to enablethe amounts in the blood, liver, lungs and whole body tobe measured up to 14 days, 4 months and 7 months afterexposure, respectively. The amounts in urine and faecalsamples were measurable up to 4 months. The initiallung deposit of 244Pu (30 ng) will enable massspectrometric measurements of blood concentrations,urinary and faecal rates to be made for many years, ifconsidered appropriate. Information on the measurementprocedures is reported elsewhere.11

The experimental data presented here involved theinhalation of 153Gd2O3 by human volunteers and theinhalation or intratracheal instillation of 153Gd2O3 byrats. The results of supplementary intravenous injectionexperiments designed to develop systemic models for thespecies are also reported. Details of the dosimetric andtoxicological data for 153 Gd are included in thedocument on which ethical approval was obtained for thehuman studies.13 The implications of the results ofinhalation and instillation studies with dogs andprimates, reported elsewhere,4 are discussed later.

Human studies

Prior to the inhalation of Gd2O3, a pilot study with99mTc labeled polystyrene particles was carried out inorder to optimize the breathing pattern for maximumdeposition in the alveolar-interstitial region. Theprocedure used for exposing human volunteers to Gd2O3has been described elsewhere.11 Monodisperse,physically uniform particles of Gd2O3 (mass medianaerodynamic diameter 2.2 µm, σg 1.16) were preparedfrom 153Gd nitrate using a spinning top aerosolgenerator. The droplets of Gd nitrate generated weredried and heated at 800 °C to produce the oxide.Simultaneously with the oxide, the two volunteersinhaled 51Cr labeled insoluble polystyrene particles ofthe same aerodynamic size. The addition of 51Crparticles enabled particle transport rates from the deeplung to be determined, thus permitting the absorptioncharacteristics of the 153Gd oxide to be determined moreprecisely. External counting measurements of 153Gd inthe chest, liver, head and total body, and measurementsby gamma-spectrometry of urinary and faecal excretionhave been made up to about 30 days after exposure. It isexpected that such measurements will continue for about6 months.19

Rat studies

The rats used for the Pu and Gd studies were adultfemales of the HMT strain, about 3 months old andweighing about 180 g at the time of exposure.

An aerosol of 237Pu nitrate in 0.01M HNO3 wasadministered by inhalation to 64 rats. The inhalationfacility has been described previously.12 Groups of fourrats were killed at 10 minute intervals during theexposure and from 10 minutes to 84 days after exposure.To investigate absorption parameters after a differentmode of intake, and to extend the experimental period, asolution of 237,238Pu nitrate in 0.01M HNO3 was alsoadministered to 56 rats by intratracheal instillation, andgroups of 4 rats killed at intervals from 10 minutes to180 days. The Pu content of the lungs, liver, kidneys andthe remaining carcass were measured at all these times.Urine and faecal excretion were also measured in orderto determine excretion rates and cumulative excretion.

For the intravenous injection experiment, 153Gd(about 2 kBq) was administered as the citrate in sterileisotonic saline. The retention of 153Gd in the whole bodywas measured up to about 250 days after exposure andgamma spectrometric measurements of urinary andfaecal rates up to about 4 months. Blood concentrationswere only measurable for a few days.

In a supplementary study, 237,238Pu citrate, as a 1%solution at pH 6.5, was injected intravenously into a

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(2) a GI tract model, and (3) a systemic modeldescribing the organ distribution, retention and excretionof the Pu or Gd after entering the blood.

Hence a respiratory tract model was developed foreach species, based on the ICRP HRTM,1 but simplifiedto include only those compartments needed to describethe distribution and retention of most of the activity.Such a model has already been developed for the HMTrat,14 but corresponding models for man (and otherspecies) were developed as a part of this study. It wasassumed that the absorption rate over the period of eachexperiment could be represented by a fraction frdissolving relatively rapidly at a constant rate sr, and theremaining fraction (1-fr) dissolving more slowly at aconstant rate ss.

The GI tract model used to describe uptake to bloodand faecal excretion was based on the ICRP Publication30 model for humans.15,16 The results of the intravenousinjection experiments were used to develop a systemicmodel for each element and species. The faecal excretiondata were also used to set the parameters of the GI tractmodel.

Fig. 1. Predicting biokinetics in humans from animal studies

Rat studies

Values for the absorption parameters fr, sr and sswere derived using the program GIGAFIT (GraphicallyInteractive General Algorithm for FITting) developed atNRPB.14 GIGAFIT is a parameter-fitting program thatfits a function or model, with up to 30 variableparameters, to several data sets simultaneously. It shouldbe noted that the three parameters fr, sr and ss arecorrelated. Hence, it is possible to alter the value of oneparameter, and by varying the values of the others toobtain a fit to the data which is little different from theoriginal. Generally, the correlation becomes greater thecloser the values of sr and ss. Thus caution should beexercised in making comparisons based on the values ofan individual parameter, unless the values of the otherparameters are very different.

The Gd2O3 preparation was as described for thehuman study. The oxide was administered to 36 rats byinhalation. Groups of four animals were killed atintervals from 15 minutes to 182 days. A suspension ofthe oxide was also administered to rats by intratrachealinstillation, and groups of animals killed at intervalsfrom 15 minutes to 200 days. In both experiments, the153Gd contents of the lungs, liver, kidneys, remainingcarcass, urine and faeces were measured.

In a supplementary experiment, 153Gd citrate wasinjected intravenously in order to develop a systemicmodel for the rat. Tissues and excreta were measured ona similar time-scale as in the inhalation experiment.

Modeling proceduresIn order to compare the amounts of Pu and Gd

absorbed in the different species, the “fractionundissolved”, or the fraction of the initial lung depositthat would remain at time t in the absence of clearanceby particle transport, can be calculated using theexpression:

Whilst the human studies for Pu and Gd will “standalone”, the objectives of these, and allied studies, was tocompare the rates of absorption from lungs to blood ofthe same material in different mammalian species, and tocompare their biokinetics in humans when extrapolatedfrom animals with those actually observed.

Fu = fr exp(–srt) + (1–fr) exp(–sst)The derivation of the absorption rate, i.e., the fractionof the contemporary lung content that is absorbed intoblood per unit time, is not straightforward because itcannot be measured directly and has to be calculatedfrom measurements of retention and excretion underdynamic conditions. Hence to derive the absorption ratefrom the animal studies a compartmental model needs tobe developed which considers; (1) a respiratory tractmodel describing deposition in the respiratory tract,particle transport from the respiratory tract to thegastrointestinal (GI) tract and absorption to the blood,

For predicting the biokinetics of Pu and Gd inhumans, the absorption data from the animalexperiments is combined with human lung depositionand particle transport data from the HRTM and systemicmodels for Pu and Gd (Fig. 1). The computer codeLUDEP (LUng Dose Evaluation Program) developed atNRPB17 was used for this purpose. The systemic modelused for Pu was that published by ICRP;2 in the absenceof an ICRP systemic model for Gd, one was developedfrom the intravenous data reported here.

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Fig. 4. 237Pu concentration in blood after inhalation as nitrate (Man C)Fig. 2. Plutonium-237 lung retention and liver uptake after inhalation

as nitrate (Man C)

Fig. 3. Plutonium-237 excretion in urine and faeces after inhalation asnitrate (Man C)

Results Fig. 5. Activity balance for Pu measurements (Man C)

For clarity, the detailed experimental data fromwhich the absorption rates were calculated have not beenincluded here, and the biokinetic data should beconsidered an overview. However, this information willbe published elsewhere.18–21

Figures 2 and 6 show, for subjects Man C and ManD, respectively, the retention of 237Pu in the lungs anduptake and retention in the liver up to 120 days afterexposure. Figures 3 and 7 show the respective urinaryand faecal excretion rates, also up to 120 days afterexposure. The concentrations of 237Pu in the blood aregiven in Figs 4 and 8. The activity balances for themeasurements with Man C and Man D are given in Figs5 and 9, respectively.

Lung clearance of plutonium-human studies

The biokinetic data obtained from the two humanvolunteers are shown in Figs 2 to 5 (Man C) and in Figs6 to 9 (Man D). All the values are decay corrected to thetime of inhalation. Figures 2 to 4 and 6 to 8 also showpredictions for the retention and excretion quantitiesmeasured using the current best estimates of the absorptionparameters for the two subjects given in Table 1.

Lung clearance of plutonium-animal studies

The Pu contents of the lungs, remaining carcass,urine and faeces after the inhalation and intratrachealinstillation of Pu nitrate are given in Figs 10 and 11.

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In order to facilitate comparison between theadministration procedures, the inhalation data (Fig. 10)are expressed in terms of the initial lung deposit. Thisrepresented about 26% of the total radioactivityrecovered which included deposition in the upperairways and external contamination of the pelt. Theabsorption values obtained after inhalation are similar tothose for man, and Type M compounds. The appreciablygreater amounts of Pu absorbed after intratrachealinstillation may be due to the rapid absorption of theaqueous phase associated with this procedure.

An overview of the intravenous injection data used todevelop a systemic model for the rat is shown in Fig. 12.

Fig. 8. Plutonium-237 concentration in blood after inhalation asnitrate (Man D)

Fig. 6. Plutonium-237 lung retention and liver uptake after inhalationas nitrate (Man D)

Fig. 9. Activity balance for Pu measurements (Man D)

Lung clearance of gadolinium – Human studies

The lung retention of Gd2O3 particles and the 51Cr-labeled polystyrene aerosol up to 40 days after inhalationis shown in Fig. 13. Because the 51Cr-labeled aerosolwas insoluble, it can be assumed that over this timeperiod, Cr absorption was negligible. Thus the removalof Cr activity from the lung shown in the lung retentiondata must have occurred by particle transport only.Fig. 7. Plutonium-237 excretion in urine and faeces after inhalation

(Man D)

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Analysis of the Cr and Gd2O3 retention curves hasallowed preliminary estimates of absorption parametersto be derived for one of the subjects (Table 1). A fullanalysis will take account of the whole body, organretention and excretion data from the inhalation andinjection studies for both subjects. This work is currentlyin progress.

Lung clearance of gadolinium – Animal studies

The Gd contents of the lungs, remaining carcass,urine and faeces after the inhalation and intratrachealinstillation of Gd oxide into rats are given in Figs 15 and16. The inhalation data (Fig. 15) are expressed in termsof the initial lung deposit to allow comparison betweenthe two methods of administration. The initial lungdeposit constituted about 24% of the total recoveredradioactivity. The remaining activity was deposited inthe upper airways and on the pelt as externalcontamination. The absorption parameter valuesobtained after inhalation (Table 1) are very similar tothose for man, and more like an ICRP Type M defaultcompound than those for Type F and Type Scompounds.

Fig. 10. Biokinetics of Pu in rats after inhalation as nitrate

Absorption parameter values and dose coefficients

The absorption parameter values calculated for thehuman and animal studies described in this paper aresummarized in Table 1. Included for comparison are thevalues for the baboon and dog obtained from studiesdescribed elsewhere.4

The dose coefficients for inhaled 239Pu nitrate usingthe absorption parameter values derived for 237Punitrate, and 153Gd oxide, are given in Table 1.

Fig. 11. Biokinetics of Pu in rats after instillation as nitrate

Since the Cr-polystyrene and Gd2O3 particles had thesame aerodynamic diameter and were inhaledsimultaneously, it can be assumed that the Gd2O3particle transport rates were the same of those measuredfor the Cr-polystyrene aerosol. Thus, the cumulativeamount of Gd2O3 absorbed from the lung can bedetermined by subtracting the Gd2O3 lung retentioncurve from the Cr lung retention curve. Figure 14 showsthe cumulative amount of Gd2O3 absorbed as a fractionof the contemporary lung retention. The differenceincreases at early times as absorption proceeds, andincreases much more slowly at later times when particletransport becomes the dominant clearance mechanism.Fig. 12. Biokinetics of Pu in rats after intravenous injection as citrate

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Fig. 13. Lung retention of 153Gd2O3 and insoluble 51Cr-labeled polystyrene particles

Fig. 14. Cumulative Gd absorption from lungs as a fraction of contemporary lung retention (determined from lung retention data shown in Fig. 13)

Also included in the table are the values using ICRPdefault absorption parameter values.22,23 Thecalculations assume default parameters for particledeposition and transport for an aerosol of 5 µm AMADfor a Reference Worker,1 the ICRP human systemicmodel for Pu2 and the ICRP human systemic model forGd.3

the wide variety of chemical forms used in industry,reliable human data are not usually available and adviceon these matters is usually based on the results ofbiokinetic studies with laboratory animals. A crucialfactor in extrapolating the results of animal studies tohumans is the assumption that absorption rates arespecies independent. There is little information tosupport this hypothesis, particularly for importantradionuclides associated with the nuclear industry.Similar absorption of cerium from the lungs of dogs,mice, rats and hamsters has been reported afterinhalation as chloride and oxalate.24 Similar rates ofabsorption of 137Cs have been found after inhalation oflabeled fused aluminosilicate particles by dog, mice, ratsand guinea pigs.25 Similar solubility rates for cerium,americium, plutonium, curium and iron after inhalation

Results and discussion

The ICRP has recommended for many years thatwhenever possible, material specific data, includingabsorption rates, rather than default values should beused for assessing intakes and doses for inhaledradionuclides and interpreting bioassay data.15,16 Due to

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by hamsters, mice, rats and dogs have also been claimed,but no details were given.26 Comparison between thebiokinetics of uranium in humans after inhalation asoctoxide and dioxide, and those predicted fromexperimental studies with the rat suggested that theabsorption rates in the two species were similar.27,28 Acomprehensive interspecies study of absorption rates of57Co after inhalation as oxide by humans, baboons,dogs, guinea pigs, hamsters and rats showed a moderaterange in values, the highest being about 3 to 6 times thatof the lowest depending on particle size.29–31

Nevertheless, these studies provided good support forother HRTM assumptions, namely that particle transportand absorption are independent, and that particletransport rates are similar for different materials in thesame species.

Some of the experiments described in this paper areunique in that they involve the controlled exposure ofhumans by inhalation to an important industrial aerosol,Pu nitrate, and to a second material Gd oxide which isconsidered an appropriate surrogate for Am oxide.13,32

The studies permit direct comparison of the observedbiokinetic behavior in humans with that predicted fromanimal studies, particularly the rat, which is the speciesmost frequently used for such predictions.

Absorption parameter values and dose coefficients

The values obtained for fr and ss in man after theinhalation of Pu nitrate are in reasonable agreement withthose in the rat after the same route of intake (Table 1).The values for fr and ss are also similar to the referencevalues for a Type M compound recommended by ICRP.1

After inhalation, the values for sr in man, and to a lesserextent in the rat, are substantially lower than the HRTMdefault value1 of 100 d–1. Moreover, there areappreciable differences in the value of sr between thespecies. However, this does not appear to affect thebehavior of plutonium in man when predicted using theabsorption parameter values obtained from the animalstudy (Figs 17 and 18).

In the rat, fr was much greater after instillation thanafter inhalation possibly for the reason given above. Theresults suggest that for Pu nitrate the fr value obtainedafter instillation should not be used for radiologicalprotection purposes. However, the values for sr and ss inthe rat after the inhalation and instillation of Pu nitrateare reasonably similar.

Fig. 15. Biokinetics of 153Gd in the rat after inhalation as oxide

After administration of Gd oxide, the values derivedfor fr, sr and ss were similar for man, baboon, dog andrat. For rats instilled with Gd2O3, the value of sr wasconsiderably higher than after inhalation, but this wasoffset by a much lower value of fr. As for Pu nitrate, thevalue of sr was much lower than the default of 100 d–1.1

The data in Table 1 shows that the dose coefficientsfor Pu nitrate calculated after inhalation of thesecompounds by rat and man are closely similar; for Gdoxide the calculated values are similar for rat, man, dogand baboon.

Fig. 16. Biokinetics of 153Gd in the rat after instillation as oxide

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protocols for optimising monitoring procedures for theassessment of intake.

At this time, the human studies with Gd areinsufficiently advanced for similar deductions to bemade. However, the similarity between the absorptionparameters for the rat and human in the early lungclearance phase would appear to suggest that thepredicted and observed biokinetic data may again besimilar.

Conclusions

The human inhalation data reported here andelsewhere for plutonium are unique and provide specificdata for an important chemical form. The results showthat the biokinetics and dosimetry of inhaled plutoniumnitrate in man can be predicted reasonably accuratelyfrom inhalation, but not instillation, studies with rats.

Fig. 17. Predicted lung retention of Pu in man comparedwith volunteer data after inhalation as nitrate

Fig. 18. Predicted urinary excretion of Pu in man comparedwith volunteer data after inhalation as nitrate

Fig. 19. Predicted intake for man from long retention of 1 Bq usinghuman and rat absorption parameter values in conjugation with ICRP

HRTM and systemic model parameters

Comparison between predicted and observedbehavior of Pu and Gd

The methodology for predicting the biokinetics of Puin humans using biokinetic data from animal studies hasbeen described previously (Table 1 and modelingprocedures). Based on the absorption parameter valuesderived from the experimental studies, the predictedintake by man based on the measurement of either 1 Bqin the lungs or 1 Bq.d–1 in urine at given times afterexposure are shown in Figs 19 and 20, respectively. Inall cases, the intakes predicted from the rat studies weresimilar to those predicted for man. This would appear toconfirm that at least for Pu nitrate, and indeed the othermaterials referred to earlier in the discussion, thatexperimental studies with the rat can be used withadvantage as a basis for developing appropriateFig. 20. Predicted intake for man from urinary excretion of 1 Bq–1

using human and rat absorption parameter values in conjugation withICRP HRTM and systemic model parameters

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Table 1. Absorption parameter values and dose coefficients for Pu nitrate and Gd oxide

Species Intake Days Absorption parameter values†DoseCoefficient

fr sr (d-1) ss (x10-3d-1) (Sv.Bq)

Plutonium nitrateMan C Inhaled 0-120 0.20 0.48 2.7 2.1E-5Man D Inhaled 0-120 0.21 0.29 4.0 2.3E-5Rat Inhaled 0-84 0.09 20 5.5 2.6E-5Rat Instilled 0-84 0.68 18 2.9 5.3E-5Rat Instilled 0-180 0.68 18 2.2 5.2E-5

ICRPType F 1 100 – 1.4E-4Type M 0.1 100 5.0 3.3E-5Type S 0.001 100 0.1 8.4E-6Gadolinium oxideMan B Inhaled 0-40 0.49 0.10 <3.5* 1.1E-9

Rat Inhaled 0-180 0.47 0.08 8.3 1.0E-9

Rat Instilled 0-180 0.07 1.2 8.7 1.2E-9

Baboon** Instilled 0-180 0.26 0.06 5.0 1.2E-9

Dog** Inhaled 0-180 0.53 0.07 3.5 1.1E-9

ICRPType F 1 100 – 2.5E-9

Type M 0.1 100 5.0 1.4E-9

Type S 0.001 100 0.1 1.5E-9

†Dose coefficients for 239Pu calculated using absorption parameter values derived for 237Pu.*Based on lung data later than 40 days after intake.** Data from Reference 4.

Ongoing human studies with gadolinium oxide willagain provide important new data after inhalation of thischemical form. The early results also suggest that theabsorption parameter values in the human and rat aresimilar.

3. International Commission on Radiological Protection, Limits onIntakes of Radionuclides by Workers, Pergamon Press, Oxford,ICRP Publication 30, Part 3, Ann. ICRP, 6 (2/3), 1981.

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Comparison between biokinetics of inhaled plutonium nitrate and gadolinium oxide in humans and animals