A systemic biokinetic model for polonium

The Science of the Total Environment 275 Ž2001. 109᎐125

A systemic biokinetic model for polonium 夽 R.W. LeggettU , K.F. Eckerman Life Sciences Di¨ ision, Commerce Park, Building 1060COM, MS6480, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA Received 25 July 2000; accepted 20 October 2000

Abstract Although the biokinetics of polonium has been studied extensively, interpretation of the data is complicated by potential differences with species and route of exposure and the questionable reliability of much of the reported excretion data for man. A study was undertaken to identify the data that are most likely to represent the typical behavior of polonium and apply those data to construct an improved, physiologically realistic systemic biokinetic model for polonium in man. Such a model is needed for interpretation of urinary excretion data for workers exposed to 210 Po and reconstruction of the radiation doses received by those workers. This paper reviews the database on the biokinetics of polonium and describes a new systemic biokinetic model for polonium in man. 䊚 2001 Elsevier Science B.V. All rights reserved. Keywords: Polonium; Urinary excretion; Systemic biokinetic model; Database

1. Introduction The biological behavior of polonium has been investigated extensively in laboratory animals. Information is also available from controlled studies on human subjects who were administered 210 Po by ingestion or intravenous injection, and much 夽

The submitted manuscript has been authored by a contractor of the US Government under contract No. DE-AC0500OR22725. Accordingly, the US Government retains a nonexclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for US Government purposes. U Corresponding author. Tel.: q1-865-576-2079; fax: q1-865574-1778. E-mail address: [email protected] ŽR.W. Leggett..

bioassay data have been gathered for subjects exposed to 210 Po in the work place. Despite this relatively large database, some important aspects of the biokinetics of polonium in man have not been characterized with much certainty. Of particular importance for purposes of reconstructing radiation doses to workers exposed to 210 Po are uncertainties concerning the rate of urinary excretion of internally deposited polonium. Interpretation of much of the available urinary data is complicated by the questionable accuracy of a widely used technique for measuring 210 Po in urine ŽFink, 1950; Spoerl, 1950; EML, 1983; Fellman et al., 1989.. It is not evident whether values based on that technique should be adjusted for underestimates of recovery, and in

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many cases it is not evident whether the questionable technique was applied. Characterization of the biokinetics of polonium in man is also hampered by additional weaknesses in nearly all of the data sets for human subjects as well as difficulties in extrapolation of data from laboratory animals to man. The most detailed data from controlled studies on human subjects are for seriously ill persons whose conditions may have affected the biokinetics of polonium. Data on occupationally exposed subjects generally are difficult to interpret due to uncertainties in the time course and level of exposure. Interpretation of data on laboratory animals is complicated by indications that the biokinetics of polonium may vary with species, route of exposure, and the chemical form of polonium taken into the body. The purposes of this paper are to review information on the biokinetics of polonium, identify the portions of the database that seem most appropriate for application to man, and apply those data to construct a physiologically realistic systemic biokinetic model for polonium. Such a model is needed for interpretation of urinary excretion data for workers exposed to 210 Po and reconstruction of the radiation doses received by those workers.

2. Summary of the database 2.1. General types of information a¨ ailable on the biokinetics of polonium Information on the biokinetics of polonium includes: bioassay data on human subjects exposed to 210 Po in the work place ŽSilverman, 1944; Naimark, 1948, 1949; Spoerl, 1951; Foreman et al., 1958; Sheehan, 1964; Testa, 1972; Scott and West, 1975; Wraight and Strong, 1989. results of controlled studies on human subjects receiving 210 Po by intravenous injection or ingestion, including autopsy data on one subject ŽSilberstein et al., 1950; Hunt and Allington, 1993.; data on environmentally exposed human subjects ŽHill, 1965; Yermolayeva-Makovskaya et al., 1969; Landinskaya et al., 1973.; and results of controlled studies on baboons ŽCohen et al., 1989;

Fellman et al., 1989, 1994., tamarins ŽCohen et al., 1989; Fellman et al., 1989., marmosets ŽNaylor et al., 1991., dogs ŽSmith et al., 1961; Parfenov and Poluboyarinova, 1969., guinea pigs ŽHaines et al., 1993., rats ŽBerke and Dipasqua, 1964; Casarett, 1964a,b,c; Stannard, 1964a,b; Stannard and Baxter, 1964; Stannard and Smith, 1964; Thomas and Stannard, 1964; Naylor et al., 1991; Haines et al., 1993., mice ŽSoremark and Hunt, 1966., and rabbits ŽMorrow and Della Rosa, 1964; Parfenov and Poluboyarinova, 1973. receiving 210 Po by injection, ingestion, or inhalation. Limited information is also available on the physiological behavior of polonium, including its broad similarities to sulfur and its affinity for certain amino acids and proteins ŽThomas, 1964; Yermolayeva-Makovskaya et al., 1969; Lanzola et al., 1973; Aposhian and Bruce, 1991.. The latter information provides some understanding of the qualitative behavior of polonium in the body but does not appear to be useful for purposes of quantifying the time-dependent distribution and excretion of polonium. Quantitative data on the biological behavior of polonium may be divided into two categories: Ž1. inhalation data; and Ž2. data for all other routes of exposure Žingestion, injection, puncture wounds and absorption through intact skin.. Information on the fate of inhaled polonium may be used to constrain predictions of combined respiratory and systemic biokinetic models and, because of the enormous amount of inhalation data available for man, to study the variability in the biokinetics of polonium in man. For purposes of constructing a systemic biokinetic model for polonium, however, the most easily interpreted data are for exposure modes other than inhalation because such data generally are not complicated by extended retention at sites of entry into the body. For example, available evidence indicates that absorption of polonium from a puncture wound to blood usually occurs over a period that is short compared with the residence time in systemic tissues. 2.2. Data on the fate of inhaled polonium 2.2.1. Human subjects Bioassay data, mainly in the form of urinary

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excretion measurements, are available from a number of follow-up studies of workers exposed to polonium by inhalation. The data are complicated by uncertainties in the time-course and level of exposure and by suspected recovery problems with a widely applied technique for measuring polonium in urine ŽFink, 1950; Spoerl, 1950; EML, 1983.. The latter problem is addressed in a later section. Briefly, the difficulty is that 210 Po excreted in urine may not be recovered to the same extent as 210 Po added to urine unless there is acid digestion of the urine prior to spontaneous deposition of 210 Po onto the metal disc from which decays of 210 Po are estimated ŽFellman et al., 1989.. The most easily interpreted inhalation data generally come from cases of acute exposure which occurred at reasonably well determined times and for which urinary measurements were supplemented with measurements of polonium in feces or blood. Results for several reported cases are summarized below. Foreman et al. Ž1958. reported urinary and fecal excretion data for two physicists who were exposed to 210 Po for at most a few minutes after the rupture of a Po-Be source. Both urinary and fecal excretion showed two phases. The estimated biological half-time of the first Žrapid. urinary component, representing approximately 6% of total urinary excretion, was 0.75 days. The estimated biological half-time of the first fecal component, representing roughly 60% of total fecal excretion, was approximately 0.6 days. Urinary as well as fecal data for times greater than a few days after exposure indicate a biological half-time of approximately 40 days, based on re-evaluation of the plotted data. The estimated ratio of total fecal excretion to total urinary excretion ŽF:U. was approximately 70. Ratios of F:U based on inhalation data generally overestimate the fecal to urinary excretion ratio for systemic polonium because much of the inhaled polonium is transported from the lungs to the gastrointestinal tract to feces without being absorbed to blood. The technique used by Foreman and co-workers to measure 210 Po in urine was not described. Sheehan Ž1964. analyzed blood, urine and feces of a worker who inhaled 210 Po in acid vapors.

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Measurements apparently started several days after exposure. Urine and blood both showed a biological half-time of 43 days. Total urinary and fecal excretion determined for days 47᎐52 postexposure indicated a F:U ratio of 6.5. Sheehan’s technique for measuring 210 Po in urine did not involve wet-ashing of samples and thus could have underestimated urinary excretion of 210 Po ŽFellman et al., 1989.. Scott and West Ž1975. measured excretion of 210 Po in urine and feces of a worker following accidental inhalation of material thought to consist of small particles of 210 Po oxide. Urine sampling began approximately 2 days after the exposure, and fecal sampling began 2 days later. The authors estimated a biological half-time of approximately 33 days from the urinary excretion data, but the data are highly variable and not closely represented by a single half-time. For example, there was a roughly 15-fold increase in the urinary excretion rate after approximately 1 month, followed by a decline to relatively low levels with a half-time of a few days. After this decline, the urinary excretion rate remained low but variable. Fecal excretion was less variable and, according to the authors, followed a twocomponent exponential curve with biological half-times of 2.4 and 52 days. The ratio of cumulative feces to cumulative urine, F:U, was initially approximately 65 but dropped to approximately 20 by 3 weeks after exposure and then showed a gradual increase. The estimated overall F:U ratio was 29. The technique for measuring 210 Po in urine was not described by the investigators. Follow-up data for many other cases of apparently acute inhalation of 210 Po by workers have been reported Že.g. see Naimark, 1948, 1949; Spoerl, 1951; Jackson and Dolphin, 1966.. Estimated biological half-times for individual subjects, based on urinary excretion data for the most part, usually fall in the range 20᎐60 days. Central estimates for relatively large groups of workers usually are in the range 30᎐50 days. These half-times reflect combined retention times in the respiratory tract and systemic tissues. Typical urinary excretion data for acutely exposed workers are shown in Fig. 1. We examined urinary excretion records for ap-

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proximately 1500 former polonium workers. Urine samples typically were collected and analyzed for 210 Po at 1-week intervals throughout the period of employment, but more frequent sampling was done if elevated exposure to 210 Po was suspected. Records for many of the subjects showed one or more sudden increases in urinary 210 Po, usually followed by a gradual, roughly exponential decline in the excretion rate. Effective half-times were estimated for such periods, excluding periods in which the roughly exponential decline represented fewer than five measurements. Subjective judgments had to be made concerning the appropriate starting and ending times to be used in an exponential fit to the data. In many cases, a rapid decline over a few days was followed by a slower, roughly exponential decline; in such cases, the second component was used. The distribution of the ‘long-term’ half-times determined in this way is shown in Fig. 2. Approximately 95% of the derived effective half-times were in the range 8᎐52 days, corresponding to a range of biological half-times of 8.5᎐83 days. The mean, median and mode of the effective half-times were approximately 30, 30 and 34 days, corresponding to biological half-times of 38, 38 and 45 days, respectively. 2.2.2. Laboratory animals Smith et al. Ž1961. studied the time-dependent distribution and excretion of 210 Po following acute

Fig. 1. Urinary excretion data for three chemists accidentally exposed to polonium ŽNaimark, 1948.. The exposure was thought to be mainly by inhalation and probably occurred a few days before the initial measurements.

Fig. 2. Distribution of effective half-times derived from urinary excretion records for a large number of polonium workers Žbased on unpublished data..

exposure of dogs to an atmosphere containing 210 Po chloride carried on an aerosol of count median diameter 0.04 ␮m. Approximately 63% Ž55᎐77%. of the inhaled 210 Po was deposited in the respiratory tract. The lung content in dogs sacrificed at 28, 29, 116, 131, 146 and 149 days was, respectively, 48.8%, 31.5%, 6.5%, 5.3%, 4.6% and 3.7% of the deposited amount. Fecal excretion accounted for more than 84% of total urinary plus fecal excretion during the first month and 90% or more of the total after 131 days. The ratio of total fecal excretion to total urinary excretion for four dogs sacrificed at 28᎐131 days was 5.4᎐8.5 Žmean, 7.2" 1.4. and for two dogs sacrificed at 146᎐149 days was 24.7᎐31 Žmean 27.9" 4.5.. A rapid phase of urinary excretion was evident, with the urinary excretion rate being as much as 1.9% of the deposited amount per day during the first 3 days. The biological half-times of the rapid and slow phases of urinary excretion were approximately 3 and 38 days, respectively. The systemic distribution of absorbed polonium was generally similar to that observed in injection studies on laboratory animals. Casarett Ž1964b,c. conducted a detailed study of the biological behavior of polonium following ‘nose only’ inhalation by rats. The inhaled material had an estimated count median diameter of approximately 0.05 ␮m. As determined by autoradiography, the primary sites of deposition were the alveoli and alveolar ducts. Smaller amounts

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were deposited in the terminal and respiratory bronchioles. Initially, polonium was removed from the body with a half-time of 1.5 days, primarily by fecal excretion. From 3 to 30 days the biological half-time for removal from the lungs was approximately 30 days. Three reasonably clear phases of lung clearance were observed: some absorption or removal to the gastrointestinal tract; a sharp decrease in body burden due to fecal excretion from 12 to 72 h after inhalation; and, from 3 to 30 days, a decrease in lung burden relative to the totalbody burden. During the third phase, the excretion rate remained relatively constant, and the relative time-dependent contents of the lungs and systemic organs indicated mobilization of polonium to other tissues of the body. Approximately 20% of the initial deposit was absorbed by 1 h after exposure, and as much as 4% of the total deposit appeared in the urine by 12 h after exposure. The rapidity with which this fraction left the lungs and was found in the carcass and urine indicated that this was a highly soluble form of polonium. Polonium remaining in the lungs after several hours may have been in a less soluble, colloidal form. Besides the possible movement of particles in cells, there appeared to be solubilization of particles and probably continued absorption from the interstitial tissues. It appeared that there was no long-term storage of polonium in lymphoid tissue and that polonium was released from lymphoid tissue to blood in a relatively soluble form. Peak concentrations in the gastrointestinal tract were reached in the esophagus and stomach at 4 h, in the small intestine at 8 h, and in the large intestine at 12 h. After 6᎐12 h, the amount entering the gastrointestinal tract was reduced considerably but was still significant. At 30 days, cumulative fecal and urinary excretion were approximately 76% and 6% of the initial deposit. After the first 3 days, the fecal-to-urine ratio at any time was approximately 10. For comparison, Silberstein et al. Ž1950. determined a fecal-to-urine ratio of 6.5 for rats after inhalation of volatilized polonium. In other studies of the inhalation of polonium by rats, the biological half-time for the slower phase of clearance from the respiratory tract has been estimated as 18 to 35 days ŽICRP Task

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Group on Lung Dynamics, 1966; Moroz and Parfenov, 1971.. After inhalation of 210 Po chloride carried on a NaCl aerosol, fractional lung retention of inhaled 210 Po was approximately 30% at 30 days ŽBerke and Dipasqua, 1964; Casarett, 1964b.. A similar result was obtained in a study involving intratracheal instillation of 210 Po chloride in acid solution ŽThomas and Stannard, 1964.. The studies on rats indicate that the systemic behavior of polonium absorbed from the respiratory tract to blood is broadly similar to that of intravenously injected polonium. Inhalation and intratracheal injection studies on rabbits have yielded half-times of 6᎐30 days for the slower phase of removal from the lungs ŽMorrow and Della Rosa, 1964; ICRP Task Group on Lung Dynamics, 1966; Parfenov and Poluboyarinova, 1973.. As observed in studies on rats, the systemic distribution of polonium after inhalation or intratracheal injection was broadly similar to that observed after intravenous injection. 2.3. Data on the fate of polonium taken in by other routes 2.3.1. Human subjects Silverman Ž1944. reported data for a male worker who apparently was exposed to 210 Po via absorption through the skin while handling a foil containing 44.4 GBq of 210 Po. Daily urine sampling and weekly fecal sampling began immediately and continued for 64 days. Biological halftimes of 34.9 and 29.3 days were derived from urinary and fecal excretion data, respectively. A solution containing 210 Po was accidentally splashed on the face of a female technician ŽCohen et al., 1989.. Measurements of 210 Po in urine, feces and blood over several months indicate biological half-times of 13.1, 28.6 and 20.3 days, respectively. Sheehan Ž1964. described a case in which a worker punctured his finger with a wire contaminated with 210 Po. Daily urinary excretion of 210 Po decreased by approximately a factor of four during the first 2 to 3 days after the incident and then decreased with a biological half-time of approximately 29 days over the next 14 weeks.

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Fig. 3. Urinary excretion of 210 Po following a puncture wound of the thumb ŽWraight and Strong, 1989.. The indicated single exponential curve was fit by the original investigators, but at least two phases of excretion are apparent.

Wraight and Strong Ž1989. described a case in which a worker was exposed to 210 Po through a puncture wound of the thumb. The authors derived biological half-times of 35, 40 and 26 days from measurements of 210 Po in urine, feces and blood, respectively. Fecal excretion of 210 Po was highly variable, and only one fecal measurement was made beyond 1 month after the incident. Urinary data for this subject may be more accurately described in terms of two excretion phases with biological half-times of approximately 5 days Žrepresenting approx. 30% of total urinary excretion. and 42 days ŽFig. 3.. Such multiple excretion phases are often apparent when measurements are started soon after exposure. Testa Ž1972. described a case in which a 59year-old woman contaminated her hands by cleaning a chemical hood where a 210 Po nitrate solution had been handled. The author conjectured that there was some absorption of 210 Po through the skin, plus some ingestion due to a habit of finger sucking. Urinary excretion measurements were initiated approximately 1 week after the incident. These data indicated a biological half-time of 29 days, but an early, rapid component may have been missed since the first measurement was at day 7 or 8, and the urinary excretion rate fell by more than a factor of two between the first measurement and the second, which was made approximately 10 days later. Silberstein et al. Ž1950. measured 210 Po in the

urine, feces and blood of four volunteers ŽSubjects 1᎐4. who were administered 210 Po chloride by intravenous injection and in a fifth volunteer ŽSubject 5. who ingested 210 Po chloride. Subject 1 was suffering from generalized lymphosarcoma, Subject 2 from acute lymphatic leukemia, and Subjects 3᎐5 from chronic myeloid leukemia. Observations on Subjects 1, 2, 3, 4 and 5 were continued for up to 43, 6, 71, 13 and 228 days, respectively. Biological half-times fitted to the time-dependent concentration of 210 Po in urine, feces, or blood of these subjects varied somewhat with the observation period and also showed considerable intersubject variability. For the subjects who were followed for several weeks or months ŽSubjects 1, 3 and 5., urinary excretion data indicate half-times of 30᎐50 days for the period starting 1 week after exposure; fecal excretion data indicate half-times of 33᎐52 days for this period; and data for red blood cells indicate half-times of 12᎐48 days for this period. Urinary excretion data for the first week after administration yield biological half-times as short as 3 days. Excretion data for the subject of Silberstein et al. who ingested 210 Po chloride ŽSubject 5. were reanalyzed in an attempt to determine fractional absorption from the GI tract. Under the assumption that all fecal excretion at times greater than 1 week after ingestion was due to secretion of systemic 210 Po into the GI tract, it is estimated that endogenous fecal excretion represented at least 14% of ingested 210 Po. Measurements of urinary excretion indicate that approximately 0.5% of the ingested amount was removed in urine. Thus, it appears that at least 14.5% of the ingested amount was absorbed to blood. The estimate of 0.5% for urinary excretion may be an underestimate due to problems with the measurement technique ŽFellman et al., 1989.. Subject 2 of Silberstein et al. died of acute lymphatic leukemia 6 days after injection of 210 Po. The distribution of 210 Po was determined from tissue samples taken approximately 1 h after his death. The usefulness of the data for this subject are limited not only by the fact that he was terminally ill but also because estimated recovery of polonium was substantially greater than 100%, probably due to overestimates of the mass of

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some tissues. For example, skin was estimated to represent 18% of body weight, which is approximately fourfold greater than the relative mass of skin given in the ICRP’s Reference Man document ŽICRP, 1975.. For purposes of the present study, the distribution of polonium in the human subject has been recalculated on the basis of current information on typical organ weights and by constraining organ contents to achieve mass balance. Hunt and Allington Ž1993. determined urinary 210 Po in six subjects who had ingested crab meat containing elevated concentrations of this radionuclide. Urinary excretion rates were determined for periods of 9᎐21 days in five of the subjects. Biological half-times of 3᎐8 days are indicated by these short-term data. Comparison of fecal excretion data with the ingested amounts indicates that fractional absorption to blood ranged from approximately 0.6 to more than 0.9 in the six subjects. Urinary excretion over the first 7 days represented 0.4᎐1.1% of the absorbed amount in four of the subjects and 5.1% in a fifth subject. It is not evident whether these data for ingestion of biologically incorporated polonium are pertinent to occupational exposures to 210 Po, but the data demonstrate the potentially high absorption of some forms of polonium from the GI tract and the potentially high variability in the biokinetics of absorbed polonium. 2.3.2. Laboratory animals Although the model was based as far as practical on data for human subjects, it was necessary to fill gaps in such data with findings for laboratory animals. The animals given highest weight in the selection of parameter values generally were primates and dogs, in part because these animals have proved to be useful models for the biokinetics of many elements in man and in part because some of the most detailed data on the biokinetics of polonium come from studies on baboons and dogs ŽParfenov and Poluboyarinova, 1969; Cohen et al., 1989; Fellman et al., 1989, 1994.. As indicated in Fig. 4, the initial distribution of polonium appears to be fairly similar in man, baboons and dogs. The baboon may excrete polonium at a higher rate than man or dog, but

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Fig. 4. Comparison of initial distribution of polonium in baboons ŽCohen et al., 1989; Fellman et al., 1994., dogs ŽParfenov and Poluboyarinova, 1969., and a human subject ŽSilberstein et al., 1950.. Data for the human subject have been re-evaluated. Kid, kidney; Liv, liver; Spl, spleen; Lng, lung; Bld, blood; Mus, muscle; Sk, skeleton.

differences in retention times in the three species may not be great. Comparison of data for baboons, tamarins and man indicate that man could be closer to the tamarin than the baboon with regard to the rate of excretion of polonium, but strong conclusions cannot be drawn from the limited data. Data for rats, mice, guinea pigs and rabbits were used as supporting information and to fill some gaps in the data for man, non-human primates, and dogs but were applied with caution because of potential qualitative differences between these species and man in the handling of polonium. For example, the blood cells of rats appear to have an unusually high affinity for polonium absorbed after ingestion, and rabbits show an unusually high rate of loss of polonium from the body.

3. The systemic biokinetic model 3.1. Model structure A schematic of the model structure is given in Fig. 5. This shows the compartments of the systemic model, paths of movement of polonium between compartments, and connections between

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the systemic model and models of the respiratory tract, gastrointestinal tract and wounds. The systemic model may be used in conjunction with essentially any intake or absorption model that predicts the time-dependent rate of absorption of deposited polonium into blood. 3.2. Summary of parameter ¨ alues Transport of polonium between compartments is assumed to follow first-order kinetics. Parameter values are expressed as transfer coefficients Žunits, dayy1 . between compartments. The term ‘transfer coefficient’ indicates fractional transfer per unit time from one compartment to another. The ‘total transfer coefficient’ from a compartment refers to the sum of transfer coefficients describing translocation from that compartment to all destinations. Transfer coefficients for the systemic model are given in Table 1. The basis for each of the values in Table 1 is discussed later. Most of the derived transfer coefficients are secondary values calculated from selected ‘removal half-times’ and ‘deposition fractions’. The

Fig. 5. Compartments of the systemic model, paths of movement of polonium between compartments, and connections between the systemic model and user-supplied models of the respiratory tract, gastrointestinal tract, and wounds.

Table 1 Transfer coefficients Ždayy1 . for absorbed polonium Plasma 2 to Plasma 1 Plasma 2 to Kidneys 1 Plasma 1 to Plasma 3 Plasma 1 to RBC Plasma 1 to Liver 1 Plasma 1 to Liver 2 Plasma 1 to Kidneys 1 Plasma 1 to Kidneys 2 Plasma 1 to Skin Plasma 1 to Red marrow Plasma 1 to Bone surface Plasma 1 to Spleen Plasma 1 to Testes Plasma 1 to Ovaries Plasma 1 to Other Plasma 3 to Plasma 1 RBC to Plasma 1 Liver 1 to GI tract Liver 2 to Plasma 1 Kidneys 1 to Urinary bladder Kidneys 2 to Plasma 1 Skin to Plasma 1 Skin to Excreta Red marrow to Plasma 1 Bone surface to Plasma 1 Spleen to Plasma 1 Gonads to Plasma 1 Other to Plasma 1

800 200 4.0 6.0 17.5 17.5 5.0 5.0 5.0 4.0 1.5 2.0 0.1 0.05 32.35 0.099 0.099 0.139 0.099 0.173 0.099 0.00693 0.00693 0.099 0.0231 0.099 0.0139 0.099

‘removal half-time’ from a compartment refers here to the biological half-time that one would observe, theoretically, if outflow from that compartment continued while feeds from all other compartments were stopped. The removal halftime as used here generally is shorter than the apparent half-time Ži.e. the externally viewed half-time. because the latter reflects any feedback of material to a compartment. The ‘deposition fractions’ in this model are used to describe the division of polonium that leaves the plasma compartment named Plasma 1 ŽFig. 5.. Deposition fractions are used mainly to translate experimental data into transfer coefficients. These fractions are approximately the portions of administered polonium that can be found in the compartments a few hours after injection or absorption of polonium into blood. As discussed later, the total transfer coefficient from Plasma 1 is set at 100 dayy1 , corresponding

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to a removal half-time of 10 min. The transfer coefficient corresponding to a given deposition fraction D is D = 100 dayy1 . For example, a deposition fraction of 0.05 for skin means that skin is assumed to receive 5% of polonium leaving Plasma 1, and the transfer coefficient from Plasma 1 to Skin is 0.05= 100 dayy1 s 5 dayy1 . 3.3. Basis for parameter ¨ alues 3.3.1. Blood Data on non-human primates indicate that there is a rapid phase of removal of polonium from blood, followed by one or more slower phases of removal ŽCohen et al., 1989.. The rapid phase represented approximately 80᎐90% of intravenously injected polonium and had a half-time on the order of 10᎐40 min. The remainder was removed with a half-time of approximately 8᎐19 days in the baboon and approximately 37 days in the tamarin. The slower phase of removal appears to be associated with attachment of polonium to red blood cells and plasma proteins ŽThomas, 1964; Cohen et al., 1989.. The relative quantities of polonium associated with red blood cells and plasma proteins varies with species, but in all species the total amount of polonium in red blood cells exceeds that in plasma at most times after absorption or injection of polonium into blood ŽSilberstein et al., 1950; Smith et al., 1961; Thomas, 1964; Cohen et al., 1989.. There was considerable inter- and intrasubject variability in the relative quantities of 210 Po in red blood cells and plasma determined in human subjects administered 210 Po by intravenous injection or ingestion, but the content of red blood cells averaged approximately 1.5 times that of plasma ŽSilberstein et al., 1950.. The initial behavior of polonium in blood appears to depend to some extent on the route of exposure. After exposure by inhalation or wounds there is generally an early, rapid loss of polonium in urine ŽForeman et al., 1958; Smith et al., 1961; Casarett, 1964b,c; Wraight and Strong, 1989. that appears to be absent or less pronounced after exposure by other routes. The model for blood has been designed to depict rapid and slow phases of removal such as

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those observed in non-human primates ŽCohen et al., 1989.; to approximate blood retention data for human subjects ŽSilberstein et al., 1950., non-human primates ŽCohen et al., 1989; Fellman et al., 1994., and dogs ŽParfenov and Poluboyarinova, 1969.; and to depict a higher rate of urinary excretion of polonium after exposure through inhalation or wounds than after exposure by other routes. Variation in the rate of urinary excretion with route of exposure is modeled by using different receptor compartments in plasma with different rates of transfer to the urinary excretion pathways. Specifically, a compartment called Plasma 2 is assumed to receive inflow to blood from the respiratory tract or wounds, and a compartment called Plasma 1 is assumed to receive inflow to blood from all other sources, including polonium that returns from systemic tissues to blood. Outflow from Plasma 2 is assumed to be rapid Žhalf-time of 1 min, corresponding to a transfer coefficient of 1000 dayy1 . and is divided between Plasma 1 and a kidney compartment ŽKidneys 1. that feeds the urinary bladder contents. This scheme yields an initially higher rate of urinary excretion for exposure by inhalation or wounds than for other routes. As default values, 80% of outflow from Plasma 2 is assigned to Plasma 1 and 20% is assigned to Kidneys 1. Assignment of a higher percentage to Kidneys 1 may be indicated in cases where the observed urinary excretion rate falls rapidly during the first few days after acute intake of polonium. This is because an unusually rapid decline in the urinary excretion rate may indicate that an unusually high fraction of the amount entering the systemic circulation was rapidly cleared by the kidneys. A third plasma compartment, called Plasma 3, is used to represent protein-bound, or non-diffusible polonium in plasma. Red blood cells are represented by a single compartment, called RBC. The removal half-time from Plasma 1 is assumed to be 10 min, corresponding to a total transfer coefficient from Plasma 1 of 100 dayy1 . Plasma 3 is assumed to receive 4% and RBC is assumed to receive 6% of the polonium atoms that leave Plasma 1 Ži.e. the deposition fractions for Plasma 3 and RBC are 0.04 and 0.06, respectively.. The removal half-time from either RBC or

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Fig. 6. Observations Žsymbols. and model predictions Žcurve. of retention of polonium in blood as a function of time after intravenous injection or ingestion. Different open symbols represent different human subjects. Data for man from Silberstein et al. Ž1950., for baboons and tamarins from Cohen et al. Ž1989., and for dogs from Parfenov and Poluboyarinova Ž1969..

Plasma 3 back to Plasma 1 is assumed to be 7 days. Recall that the term half-time, as used here, refers to the estimated half-time that would be seen if there were no recycling of polonium between compartments, and that the ‘apparent’ or ‘externally viewed’ half-time in blood will be greater than 7 days due to recycling of polonium. Note that, for most practical purposes, the model could be simplified by combining Plasma 3 and RBC into a single compartment that receives 10% of polonium leaving Plasma 1 and loses polonium to Plasma 1 with a half-time of 7 days. Model predictions of total retention in blood as a function of time after introduction of polonium to blood are compared in Fig. 6 with observed retention of polonium in blood of human subjects, non-human primates, and dogs exposed to 210 Po by intravenous injection or ingestion. 3.3.2. Li¨ er and fecal excretion Data for laboratory animals ŽSmith et al., 1961; Parfenov and Poluboyarinova, 1969; Fellman et al., 1994. and one human subject ŽSilberstein et al., 1950. indicate that a substantial portion of injected or absorbed polonium deposits in the liver. Much of the initial uptake by the liver may be removed with a half-time of a few days, and the remainder may be lost over a period of weeks. Endogenous fecal excretion of polonium appears

to arise mainly from biliary secretion from the liver ŽSilberstein et al., 1950; Fellman et al., 1994.. In this model the liver is assumed to consist of two compartments, called Liver 1 and Liver 2. Liver 1 represents polonium that is removed to the intestines by biliary secretion. Liver 2 represents polonium that is returned to blood after residence in the liver. The total liver is assumed to receive 35% of the outflow from Plasma 1, with half of this amount depositing in Liver 1 and half depositing in Liver 2. Polonium is assumed to be removed from Liver 1 to the contents of the small intestine with a half-time of 5 days and from Liver 2 to Plasma 1 with a half-time of 7 days. Passage from Plasma 1 to Liver 1 to the contents of the small intestine is assumed to be the sole source of endogenous fecal excretion of polonium. The structure and parameter values for liver were selected mainly to reproduce data on liver retention in man, baboons and dogs ŽFig. 7., and data on endogenous fecal excretion of polonium by man after intravenous injection or ingestion ŽFig. 8.. The fecal excretion curve for man shown in Fig. 9 is a least-squares fit to the data in Fig. 8, excluding subjects who ingested an organic form of polonium. Although the fitted curve is changed little by inclusion of ingestion data for organic polonium, the latter data were excluded from the fit due to the possibility of different biokinetics for polonium ingested in organic and inorganic forms. 3.3.3. Kidneys and urinary excretion In this model the kidneys are assumed to consist of two compartments, called Kidneys 1 and Kidneys 2. Kidneys 1 represents polonium that is eventually removed to the urinary bladder contents after filtration at the glomerulus and deposition in the renal tubules. Kidneys 2 represents polonium that is eventually returned to blood after entering kidney tissue, either from nutrient blood or the tubular lumen. For simplicity, polonium entering either Kidneys 1 or Kidneys 2 is assumed to transfer directly from Plasma 1. Also, there is assumed to be no direct transfer of filtered polonium into the urinary bladder con-

R.W. Leggett, K.F. Eckerman r The Science of the Total En¨ ironment 275 (2001) 109᎐125

Fig. 7. Observations and model predictions of retention of polonium in liver as a function of time after intravenous injection. Data for man from Silberstein et al. Ž1950., for baboons from Fellman et al. Ž1994., and for dogs from Parfenov and Poluboyarinova Ž1969..

tents. That is, filtered polonium is assumed to reside temporarily in kidney tissue before being transferred to the urinary bladder contents. Parameter values describing renal retention of polonium were chosen to fit retention data for man, baboons and dogs ŽFig. 10.. Kidneys 1 and Kidneys 2 are each assumed to receive 5% of polonium atoms that leave Plasma 1. The removal half-time from Kidneys 1 to bladder urine is assumed to be 4 days, and the removal half-time from Kidneys 2 to Plasma 1 is assumed to be 7 days. After parameter values describing fecal excretion of polonium had been selected, parameter

Fig. 8. Estimated endogenous fecal excretion rates for humans subjects exposed to known amounts of polonium. Data from Silberstein et al. Ž1950. and Hunt and Allington Ž1993..

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Fig. 9. Comparison of model predictions with endogenous fecal excretion rates determined for humans exposed to known amounts of 210 Po by injection or ingestion ŽSilberstein et al., 1950..

values describing urinary excretion were set, in part, to yield a Žcumulative. fecal-to-urinary excretion ratio, F:U, of approximately 3. The typical value of F:U for man has not been established. The selected value of 3 is a compromise, based on a fairly wide range of values determined for human subjects and non-human primates. The selected value is slightly lower than the value determined for tamarins ŽCohen et al., 1989; Fellman et al., 1989. and higher than the value determined for baboons ŽFellman et al., 1989.. The true ratio seems likely to be lower than the values of 10 or more determined by Silberstein et al.

Fig. 10. Observations and model predictions of retention of polonium in kidneys as a function of time after intravenous injection. Data for man from Silberstein et al. Ž1950., for baboons from Fellman et al. Ž1994., and for dogs from Parfenov and Poluboyarinova Ž1969. and Bruenger et al. Ž1990..

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Ž1950. for human subjects, in view of findings of Fellman et al. Ž1989. that the measurement technique of Silberstein substantially underestimates the concentration of polonium in urine, at least in baboons and tamarins. Results of a modern study on a human subject exposed through a puncture wound seem consistent with the relatively low urinary-to-fecal excretion ratio determined by Silberstein and co-workers ŽWraight and Strong, 1989.; however, the technique for measuring urinary polonium was not described, and conclusions concerning F:U were based on an uncertain curve fit to scattered fecal excretion data. Reported ratios F:U for human subjects exposed to 210 Po by inhalation are in the range 6.5᎐70 but provide only upper-bound estimates of F:U for systemic polonium, for two reasons: Ž1. a substantial portion of 210 Po found in feces may have been transported from the lungs to the gastrointestinal tract without having been absorbed to blood; and Ž2. at least some of the reported values were based on a measurement technique that may substantially underestimate the concentration of 210 Po in urine. The measurement technique used by Silberstein et al. Ž1950. and some later investigators involved spontaneous deposition of 210 Po from raw urine onto a suitable metal disc. Recovery was estimated by plating 210 Po from samples that had been spiked with known amounts of 210 Po. There is evidence from studies on laboratory animals, however, that 210 Po excreted in urine is not plated with the same efficiency as 210 Po added to urine, unless the samples have been digested with acid prior to deposition ŽFellman et al., 1989.. Although it is tempting to adjust older urinary excretion data for human subjects to account for potentially low recovery of 210 Po as indicated by results for laboratory animals, such adjustments would involve substantial uncertainties because recovery of metabolized 210 Po from raw urine appears to depend on species as well as time since exposure ŽFellman et al., 1989., and because there is some question as to whether inaccuracies in older methods are as great as indicated by modern reconstructions of those methods. Moreover, reported data on urinary excretion of 210 Po

often have not been accompanied by a description of the measurement technique. 3.3.4. Spleen In this model, the spleen is represented as a single compartment in exchange with Plasma 1. It is assumed that the spleen receives 2% of the outflow from Plasma 1 and that the removal half-time from spleen to Plasma 1 is 7 days. Model predictions are compared in Fig. 11 with observations of retention of polonium in the spleen for a human subject, baboons and dogs. It is not known which, if any, of the indicated data are most applicable to occupational exposures to humans. The value for the human subject may overestimate typical retention at 6 days due to the possibility of formation of polonium aggregates in the injected material and, subsequently, elevated uptake by the spleen. Interspecies extrapolation of kinetic data for the spleen is always questionable because the function of the spleen varies from one species to another, and it has been found that the kinetics of radionuclides in the spleen often varies substantially from one species to another. 3.3.5. Skin Data on laboratory animals and man indicate that skin initially takes up a few percent of the

Fig. 11. Observations and model predictions of retention of polonium in the spleen as a function of time after intravenous injection. Data for man from Silberstein et al. Ž1950., for baboons from Fellman et al. Ž1994., and for dogs from Parfenov and Poluboyarinova Ž1969..

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Fig. 12. Observations and model predictions of retention of polonium in skin as a function of time after intravenous injection. Data for man from Silberstein et al. Ž1950. and for baboons from Fellman et al. Ž1994..

polonium that enters plasma ŽFig. 12. but retains polonium more tenaciously than most other tissues. At times remote from acute intake, skin may contain half or more of the systemic burden ŽFig. 13.. Much of the skin content is found around hair follicles ŽSoremark and Hunt, 1966.. Hair has a relatively high polonium content at times remote from exposure ŽMayneord and Hill, 1964.. In this model, skin is represented as a single compartment that receives 5% of polonium that leaves Plasma 1. The removal half-time from skin is assumed to be 50 days. Half of polonium leaving skin is assumed to be lost in excreta Žhair,

Fig. 13. Observations and model predictions of the polonium content of skin as a percentage of the systemic burden. Data for man from Silberstein et al. Ž1950., for baboons from Fellman et al. Ž1994., for marmosets from Naylor et al. Ž1991., and for dogs from Smith et al. Ž1961..

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skin, sweat. and the other half is assumed to return to Plasma 1. Model predictions of polonium retention in skin as a percentage of the injected amount are compared in Fig. 12 with data for baboons and recalculated data for a human subject wbased on the weight of skin as given in ICRP Publication 23, ŽICRP, 1975., rather than on an apparently erroneous skin weight originally used by Silberstein et al. Ž1950.x. In baboons, pelt contained 53% of the body content at 91 days post-injection ŽFellman et al., 1989.. In dogs, the pelt contained 44%, 43%, 54% and 51% of total-body polonium at 116, 131, 146 and 149 days after inhalation ŽSmith et al., 1961.. Model predictions are reasonably consistent with these data ŽFig. 13.. 3.3.6. Skeleton Experimental data on laboratory animals indicate that approximately 5% of the injected or absorbed amount deposits in the skeleton ŽFig. 14.. Soon after exposure, most of the skeletal deposition is found in the marrow spaces and appears to be associated primarily with active marrow ŽICRP, 1993.. A smaller amount found in the mineralized skeleton may be associated with organic material in bone. The bone deposit may be retained longer than most soft-tissue polonium. In this model, the skeleton is represented as two compartments, identified with red marrow and bone surface. It is assumed that these com-

Fig. 14. Observations and model predictions of the polonium content of skeleton as a percentage of the systemic burden. Data for baboons from Fellman et al. Ž1994. and for dogs from Parfenov and Poluboyarinova Ž1969..

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partments receive, respectively, 4% and 1.5% of polonium leaving Plasma 1, and that both compartments lose polonium to Plasma 1. The removal half-time from red marrow is assumed to be 7 days, and the removal half-time from bone surface is assumed to be 30 days. Model predictions of polonium retention in the total skeleton are compared in Fig. 14 with observations for baboons and dogs. Although one data point Žat 6 days. is available for a human subject ŽSilberstein et al., 1950., the estimate is based on a sample of rib, which is likely to contain an atypically large portion of the heterogeneously distributed skeletal polonium.

3.3.7. Gonads Data on uptake and retention of polonium by testes or ovaries are variable but indicate elevated concentrations compared with most tissues ŽSilberstein et al., 1950; Blanchard and Moore, 1971; Cohen et al., 1989; Naylor et al., 1991.. In this model, the testes and ovaries are each considered as a single compartment that exchanges polonium with Plasma 1. These compartments are assumed to receive, respectively, 0.1% and 0.05% of polonium leaving Plasma 1. The removal halftime from each of these compartments is assumed to be 50 days.

3.3.8. Remaining tissue (Other) All remaining tissues and fluids are lumped together in a compartment called Other that is assumed to exchange polonium with Plasma 1. Other is assumed to receive 32.35% of polonium that leaves Plasma 1. This is the amount that remains after subtraction of the deposition fraction for all explicitly identified compartments. The removal half-time from Other to Plasma 1 is assumed to be 7 days. The best available data for retention in the tissues representing Other come from a study on baboons. These data are compared with model predictions in Fig. 15. The observations for baboons are based on data given in Tables 4.2 and 4.3 of Cohen et al. Ž1989..

Fig. 15. Observations and model predictions of the polonium content of Other as a percentage of the systemic burden. Data for baboons from Cohen et al. Ž1989..

4. Discussion and conclusions

Although there is a relatively large database on the biological behavior of polonium in man and laboratory animals, some important aspects of the biokinetics of polonium in man have not been characterized with much certainty. A central problem is that a substantial portion of the data on urinary excretion of 210 Po by human subjects may not be reliable. Although relatively detailed data are available from a controlled study on human subjects, these data are limited not only by potential errors in the urinary excretion data but also by the fact that the state of health of the subjects could have affected the biokinetics of polonium. Most occupational data on 210 Po are difficult to use in the construction of a biokinetic model due to uncertainties in the time course and level of exposure, in addition to uncertainties in measurements of 210 Po in urine. Interpretation of data on laboratory animals is complicated by indications that the biokinetics of polonium may vary with species, route of exposure, and the chemical form of polonium taken into the body. The questionable reliability of much of the reported urinary excretion data for 210 Po stems from the possibility that recovery of 210 Po may have been overestimated by some investigators. The problem is that 210 Po excreted in urine may not be recovered to the same extent as 210 Po

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added to urine unless there is acid digestion of the urine prior to spontaneous deposition of 210 Po onto the metal disc from which decays of 210 Po are estimated. This phenomenon appears to have been recognized by the mid-1950s, although the potential magnitude of the problem may not have been appreciated at the time. Black Ž1956. found that recovery of 210 Po was increased by roughly 20% by wet ashing samples of urine from 210 Poinjected rats, compared with unashed portions of the same samples. A more dramatic difference in recovery of 210 Po from ashed and unashed samples was observed by Sedlet and Robinson Ž1971., who studied elimination of 210 Po in human subjects who accidentally inhaled neutron-irradiated bismuth; however, it has been suggested that the discrepancy in 210 Po values in ashed and unashed samples may have resulted from differences in the extent of decay of excreted 210 Bi in the two cases ŽBale et al., 1975.. In the late 1980s, investigators at New York University ŽNYU. studied the biokinetics of 210 Po in intravenously injected baboons and tamarins ŽCohen et al., 1989; Fellman et al., 1989, 1994.. As part of the study, the investigators compared measurements of 210 Po in urine based on various techniques and found that ashing of samples yielded a dramatic increase in recovery of metabolized polonium compared with recovery from unashed samples. The ratio of values for ashed and unashed samples varied with time after injection but was sometimes 10 or more in baboons. The authors suggested that the results for baboons could be used to correct urinary excretion data for workers at Mound Laboratory, where a nonashing technique had been used to measure 210 Po in urine. However, the recovery ratios determined by the NYU researchers were much higher for baboons than tamarins, and ratios for both of these primates were much higher than had been determined for rats ŽBlack, 1956.. Thus, substantial uncertainties are involved in extrapolating ratios for ashed and unashed samples across species. Another limitation of the NYU data is that the results are for intravenously injected 210 Po. Exposures to most polonium workers has been mainly through inhalation. With regard to dose recon-

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struction from urinary excretion data, there may be important differences with route of exposure. For example, available experimental data on inhalation of 210 Po indicate that there may be an early, rapid phase of removal in urine that accounts for a sizable portion of the total urinary excretion of inhaled 210 Po. Activity removed in this early phase may not be attached to the same material that interferes with recovery of later urinary 210 Po, and it is conceivable that this portion of urinary 210 Po may be recovered efficiently by non-ashing methods such as the analytical procedure used at Mound Laboratory. With regard to construction of a biokinetic model for polonium, the questionable accuracy of reported urinary excretion data complicates the selection of parameter values describing urinary excretion of polonium but does not significantly hamper the selection of other parameter values. For example deposition fractions for internal organs may be estimated with reasonable confidence because the internal distribution of polonium appears to be reasonably well established by data on man and laboratory animals. Even though relative losses in urine and feces have not been established with much certainty for man, the evidence points to fecal excretion as the main route of loss of polonium from the body. Therefore, despite the uncertainty in the urinary excretion rate, one should be able to estimate the total retention time of polonium in the human body reasonably well on the basis of fecal excretion data. Moreover, even though the urinary excretion rate is not known precisely in an absolute sense, the relative time-dependent urinary excretion rates measured in human subjects usually indicate approximately the same total-body retention times as do fecal excretion data for the same subjects. Finally, relative retention times in different organs Že.g. relatively long retention in skin and bone. can be estimated from broadly consistent data for different species. Parameter values describing urinary excretion were set, in part, to yield a Žcumulative. fecal-tourinary excretion ratio of approximately 3, based on the following considerations. Ž1. Taken at face value, data from controlled studies on human subjects receiving 210 Po by intravenous injection

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indicate that losses in feces are an order of magnitude greater than losses in urine ŽSilberstein et al., 1950.. In view of current information on the low recovery of 210 Po by the analytical techniques used at that time, it seems likely that urinary excretion in these subjects was underestimated. More recent data for a subject exposed to 210 Po through a wound ŽWraight and Strong, 1989. seem broadly consistent with the findings of Silberstein and co-workers, but the technique for measuring urinary polonium was not described, and conclusions concerning F:U were based on an uncertain curve fit to scattered fecal excretion data. Ž2. Reported ratios of F:U for human subjects and laboratory animals exposed to 210 Po by inhalation have been as low as 6᎐7 at some times after exposure. Fecal-to-urinary ratios determined in inhalation studies may substantially overestimate the typical fecal-to-urinary ratio for systemic 210 Po, because urinary excretion of 210 Po could have been underestimated in some or all of these studies and because a large portion of the 210 Po deposited in the respiratory tract is likely to be lost in feces without entering the systemic circulation. Ž3. F:U ratios of approximately 1.5 and 3.5 were determined in baboons and tamarins, respectively, after intravenous injection with 210 Po ŽCohen et al., 1989.. It is not known which of these non-human primates may be the better laboratory model of urinary excretion of 210 Po in man.

Acknowledgements This work was sponsored by MJW Corporation, Inc., under DOErWFO Project Number ERD9801684, under contract DE-AC0584OR21400 with Lockheed Martin Energy Research Corporation. The authors are grateful to David A. Dooley of MJW Corporation, Inc., for his support and encouragement; to Alan Fellman and Lowell Ralston for helpful discussions of their excellent studies of the behavior of polonium in non-human primates and the potential limitations of older techniques for measuring 210 Po in urine; and to Joseph Moon for providing labora-

tory reports and useful background information on the measurement of 210 Po in workers. References Aposhian HV, Bruce DC. Binding of polonium-210 to liver metallothionein. Radiat Res 1991;126:379᎐382. Bale WF, Helmkamp RW, Hrynyszyn V, Contreras MA. The determination of 210 Po in urine. Health Phys 1975; 29:663᎐671. Berke HL, Dipasqua AC. Distribution and excretion of polonium-210. VIII. After inhalation by the rat. Radiat Res 1964;5ŽSuppl..:133᎐147. Black SC. Low level polonium determination of tissue and urine, Report UR-463. Rochester: University of Rochester Atomic Energy Commission, 1956. Blanchard RL, Moore JB. Body burden, distribution and internal dose of Pb-210 and Po-210 in a uranium miner population. Health Phys 1971;21:499᎐518. Bruenger FW, Lloyd RD, Taylor GN, Miller SC, Mays CW. Kidney disease in beagles injected with polonium-210. Radiat Res 1990;122:241᎐251. Casarett LJ. Distribution and excretion of polonium-210. V. Autoradiographic study of effects of route of administration on distribution of polonium-210. Radiat Res 1964a;5ŽSuppl..:93᎐105. Casarett LJ. Distribution and excretion of polonium-210. IX. Deposition, retention, and fate after inhalation by nose-only exposure. Radiat Res 1964b;5ŽSuppl..:148᎐165. Casarett LJ. Distribution and excretion of polonium-210. XII. Autoradiographic observations after inhalation of polonium-210 in rats. Radiat Res 1964c;5ŽSuppl..:187᎐204. Cohen N, Fellman AL, Hickman DP, Ralston LG, Ayres LS. Primate polonium metabolic models and their use in estimation of systemic radiation doses from bioassay data. Mound Laboratory, 1989. Environmental Measurements Laboratory ŽEML.Volchok HL, de Planque G, editors. Radiochemical determination of polonium. HASL procedures manual, E-Po-02-01. 26th ed New York: HASL-300, 1983. Fellman A, Ralston L, Hickman D, Ayres L, Cohen N. The importance of acid digestion of urine prior to spontaneous deposition of 210 Po. Health Phys 1989;57:615᎐621. Fellman A, Ralston L, Hickman D, Ayres L, Cohen N. Polonium metabolism in adult female baboons. Radiat Res 1994;137:238᎐250. Fink RM, editor. Biological studies with polonium, radium, and plutonium. New York: McGraw-Hill, 1950. Foreman H, Moss W, Eustler BC. Clinical experience with radioactive materials. Am J Roentgenol Radium Therapy Nucl Med 1958;79:1071᎐1079. Haines JW, Naylor GPL, Pottinger H, Harrison JD. Gastrointestinal absorption and retention of polonium in adult and newborn rats and guinea pigs. Int J Radiat Biol 1993; 64:127᎐132. Hill CR. Polonium-210 in man. Nature 1965;208:423᎐428.

R.W. Leggett, K.F. Eckerman r The Science of the Total En¨ ironment 275 (2001) 109᎐125 Hunt GJ, Allington DJ. Absorption of environmental polonium-210 by the human gut. J Radiol Prot 1993; 13:119᎐126. ICRP Task Group on Lung Dynamics. Deposition and retention models for internal dosimetry of the human respiratory tract. Health Phys 1966;12:173᎐207. ICRP. International Commission on Radiological Protection. Report of the Task Group on Reference Man. ICRP Publication 23. Oxford: Pergamon Press, 1975. ICRP. International Commission on Radiological Protection. Age-dependent doses to members of the public from intake of radionuclides, part 2. ICRP Publication 67. Oxford: Pergamon Press, 1993. Jackson S, Dolphin GW. The estimation of internal radiation dose from metabolic and urinary excretion data for a number of important radionuclides. Health Phys 1966; 12:481᎐500. Landinskaya LA, Parfenov YD, Popov DK, Federova AV. 210 Pb and 210 Po content of air, water, foodstuffs, and the human body. Arch Environ Health 1973;27:254᎐258. Lanzola EE, Allegrini ME, Taylor DM. The binding of polonium-210 in rat tissues. Radiat Res 1973;56:370᎐384. Mayneord WV, Hill CR. Total counting and spectroscopy in the assessment of alpha activity in human tissues. Assessment of radioactivity in man, 1. Vienna: International Atomic Energy Agency, 1964:291᎐309. Moroz BB, Parfenov YuD. Effects of polonium-210 on the organism, AEC-tr-7300, Moscow: Atomizdat, 1971. Morrow PE, Della Rosa RJ. Distribution and excretion of polonium-210. VII. Fate of polonium colloid after intratracheal administration to rabbits. Radiat Res 1964;5 ŽSuppl..:124᎐132. Naimark DH. Acute exposure to polonium Žmedical study of three human cases., Mound Laboratory report MLM-67, 1948. Naimark DH. Effective half-life of polonium in the human, Mound Laboratory report MLM-272, 1949. Naylor GPL, Bonas HE, Haines JW et al. The gastrointestinal absorption and tissue distribution of alpha-emitting actinide isotopes and polonium-210. The British Nuclear Energy Society Conference: Occupational Radiation Protection, Guernsey. London: Thomas Telford, 1991:291᎐296. Parfenov YuD, Poluboyarinova ZI. Dynamics of polonium-210 exchange in dogs after a single subcutaneous administration. In: Moskaleve YuI, editor. Radioactive isotopes and the body, AEC-tr-7195. Moscow: Izdatel’stvo Medisina, 1969:128᎐135. Parfenov YuD, Poluboyarinova ZI. Polonium-210 metabolism in rabbits after a single intravenous and intratracheal injection. Int J Radiat Biol 1973;23:487᎐493. Scott LM, West CM. Excretion of 210 Po oxide following accidental inhalation. Health Phys 1975;28:563᎐565. Sedlet J, Robinson JJ. Elimination of polonium-210 following accidental inhalation of neutron-irradiated bismuth wabstr. Pr121x. Health Phys 1971;21:62.

125

Sheehan WE. Effective half-life of polonium. Proceedings of the 10th Annual Bioassay and Analytical Chemistry Meeting Conference 727, 1964:32᎐38. Silberstein HE, Valentine WN, Minto WL, Lawrence JS, Fink RM. Studies of polonium metabolism in human subjects. Intravenous studies, comparison of intravenous studies, oral administration. In: Fink RM, editor. Biological studies with polonium, radium, and plutonium. New York: McGraw-Hill, 1950:122᎐148. Silverman LB. Excretion activity analyses as a monitor for postum exposures. Final Report No. 10, Report MLM-M1443. Nov. 30, 1944. Smith FA, Morrow PE, Gibb FR et al. Distribution and excretion studies in dogs exposed to an aerosol containing polonium-210. Am Ind Hyg Assoc J 1961;22:201᎐208. Soremark R, Hunt VR. Autoradiographic studies of the distribution of polonium-210 in mice after a single intravenous injection. Int J Rad Biol 1966;11:43᎐50. Spoerl ES. Urine assay procedure at the Mound Laboratory. MLM-460. Mound Laboratory, 1950. Spoerl ES. A derived biological half-life of polonium in humans, MLM-626. Report for biological research. Mound Laboratory, 1951:72᎐76. Stannard JN. Distribution and excretion of polonium-210. I. Comparison of oral and intravenous routes in the rat. Radiat Res 1964a;5ŽSuppl..:49᎐59. Stannard JN. Distribution and excretion of polonium-210. III. Long-term retention and distribution in the rat. Radiat Res 1964b;5ŽSuppl..:67᎐79. Stannard JN, Baxter RC. Distribution and excretion of polonium-210. IV. On a multiple dose regimen. Radiat Res 1964;5ŽSuppl..:80᎐92. Stannard JN, Smith FA. Distribution and excretion of polonium-210. X. Species comparison. Radiat Res 1964;5ŽSuppl..:166᎐174. Testa C. Indirect methods used at CNEN for the evaluation of internal contamination. Assessment of radioactive contamination in man. IAEA-SM-150r18. Vienna: International Atomic Energy Agency, 1972:405᎐421. Thomas RG. The binding of polonium by red cells and plasma proteins. Radiat Res 1964;5ŽSuppl..:29᎐39. Thomas RG, Stannard JN. Distribution and excretion of polonium-210. VI. After intratracheal administration in the rat. Radiat Res 1964;5ŽSuppl..:106᎐123. Wraight JC, Strong RA. Case study on the retention and excretion of internally deposited polonium. Radiation protection ᎏ theory and practice. Proceedings of the 4th International Symposium, Malvern, June, 1989:227᎐230. Yermolayeva-Makovskaya AP, Pertsov LA, Popov DK. Polonium-210 in the human body and the environment. USSR reports on natural fallout radioactivity. AEC-tr-7030, 1969:163᎐167.