Treatment of accidental intakes of plutonium and americium: Guidance notes

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Applied Radiation and Isotopes 62 (2005) 829–846 www.elsevier.com/locate/apradiso

Treatment of accidental intakes of plutonium and americium: Guidance notes F. Me´ne´triera,,1, L. Grappina, P. Raynaudb, C. Courtayc, R. Woodd, S. Joussineaue, V. Listf, G.N. Stradlingg, D.M. Taylorh, Ph. Be´rarda, M.A. Morcilloi, J. Rencovaj a

Commissariat a` l’Energie Atomique, Paris, France b COGEMA, Marcoule, France c COGEMA, La Hague, France d United Kingdom Atomic Energy Authority, UK e Centrum fo¨r stra˚lningsmedicin, Stockholm, Sweden f Forschungszentrum GmbH, Karlsruhe, Germany g National Radiological Protection Board, Chilton, UK h School of Chemistry, Cardiff University, Cardiff, UK i CIEMAT, Madrid, Spain j National Institute of Public Health, Prague, Czech Republic Received 18 December 2004; received in revised form 17 January 2005; accepted 17 January 2005

Abstract The scientific basis for the treatment of the contamination of the human body by plutonium, americium and other actinides is reviewed. Guidance Notes are presented for the assistance of physicians and others who may be called upon to treat workers or members of the public who may become contaminated internally with inhaled plutonium nitrate, plutonium tributyl phosphate, americium nitrate or americium oxide. r 2005 Elsevier Ltd. All rights reserved. Keywords: Plutonium nitrate; Plutonium tributylphosphate; Americium nitrate; Americium oxide; Decorporation therapy; Radiation risk reduction

PART 1

1. Introduction

Principles underlying the treatment of accidental intakes of plutonium and americium by humans

The hypothesis underlying decorporation therapy is that acceleration of the natural rate of elimination of the contaminant will reduce the amount of radioactivity retained in the body, thus reducing the radiation dose received by sensitive tissues and producing an at least proportional reduction in the risks of induction of serious radiation effects such as cancer. Whether this hypothesis actually applies in humans is extremely difficult to answer because there are few human data

Corresponding author.

E-mail address: fl[email protected] (F. Me´ne´trier). Present address: Me´ne´trier F. - CEA – DSV/CARMIN – route du Panorama – BP6 – 92265 Fontenay-aux-Roses cedex, France. 1

0969-8043/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.apradiso.2005.01.005

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on the effectiveness of chelation therapy. The only human evidence to support this hypothesis comes from the well-documented Hanford Americium Accident (Breitenstein and Palmer, 1989) where it is believed that the early and prolonged treatment with trisodium calcium and/or zinc diethylenetriamine-pentaacetate (Ca- and/or Zn-DTPA) reduced the liver burden of 241 Am to a sufficient extent to prevent the victim’s early death from radiation-induced liver failure. The status of chelation research has been reviewed recently (HengeNapoli et al., 2000). The results of animal studies have been reviewed elsewhere (Henge-Napoli et al., 2000). A survey of lifespan studies in mice and rats given carcinogenic doses of 239 Pu has shown that treatment with Ca- or Zn-DTPA reduced both the retention of the radionuclide and the fraction of animals developing bone tumours. Similar studies in beagles injected with particulate 239Pu treated by either weekly injections of Ca-DTPA, or daily injections of Zn-DTPA (30 mmol/kg beginning 2 h after contamination) showed no decrease in the incidence of bone tumours in the treated animals, but in the animals receiving daily Zn-DTPA the mean survival time was increased from
4 years to
10 years (Henge-Napoli et al., 2000). Life-span studies in beagles given a carcinogenic dose of 241Am and treated with daily injections of Ca- or ZnDTPA, beginning at 14 days after 241Am injection showed that daily treatment for 2 to more than 6 years reduced both the average skeletal bone dose and the incidence of bone tumours to about one-third of those found in non-DTPA-treated 241Am-injected animals, and doubled the survival times (Henge-Napoli et al., 2000). The results of animal studies can only be extrapolated to humans with extreme caution, however, they do indicate either a reduction in bone tumour incidence and/or a significant increase in survival time and it appears reasonable to assume that appropriate decorporation therapy can reduce, or substantially delay, the risk of late effects occurring in humans following a serious contamination with 239Pu or 241Am (Breitenstein and Palmer, 1989). The Guidance Notes for the treatment of contamination of the human body with plutonium and americium, presented in Part 2, have been prepared by a consortium of scientists experienced in the development and testing of chelating agents in animals, and physicians experienced in their administration to workers who have been exposed occupationally, brought together under the sponsorship of the European Late Effects of Radiation Project (EULEP). The members of the consortium came from France, the United Kingdom, Sweden, Germany, Spain and the Czech Republic. Whilst the guidance notes are aimed principally at accidental industrial exposures by inhalation, since this

is considered the most likely route of intake, it is considered that the same principles concerning decision levels and treatment protocols are equally applicable to members of the public. The risk of deliberate release due to terrorist attack highlights the need to extend this guidance to include members of the public. The views expressed in these notes are not intended to be dogmatic since there will be different medical opinions on the instigation and extent of treatment. More emphasis is given to the range of options available and their likely efficacy so that individual physicians are more able to make informed judgements in specific cases whilst taking account of the health status of the individual. In all cases treatment should be based on an agreement between the physician and the patient. Apart from clinical experience, two major source documents have been used in their formulation. First a Guidebook for the Treatment of Accidental Internal Contamination of Workers, prepared for the Commission of the European Communities and the United States Department of Energy (Gerber and Thomas, 1992) and re-published in French (Bhattacharyya et al., 1995); second a collection of papers on Decorporation of Radionuclides from the Human Body which reviewed the current status of research and medical opinion, prepared by the European Late Effects Project Group (EULEP) for the Commission of the European Communities (Henge-Napoli et al., 2000). However, other references are included when considered appropriate. For human beings internally contaminated with plutonium and other transuranics, only Ca- and/or Zn-DTPA have been used. These substances have been used throughout the world but are not licensed everywhere in Europe. For the current status of their licensing the reader should refer to Appendix A. In the USA, the use of DTPA has recently been approved under the New Drug Applications (NDAs) by the Food and Drug Administration (FDA, 2003) (see Appendix A). In some countries, determination of its acceptable use is considered to be the responsibility of individual clinicians. Whilst animal experiments have demonstrated that other substances, particularly analogues of siderophores, can be appreciably more effective than DTPA (Henge-Napoli et al., 2000), they have as yet not been approved for administration to humans in any country, and hence are not discussed further in these guidance notes.

2. Radionuclide biokinetics In order to appraise the biokinetic behaviour of specific chemical forms, information is presented on their retention in body tissues with emphasis on the lungs, liver and skeleton, and the excretion in urine and faeces. In most cases the data are derived from ICRP

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publications and relate to the absorption type to which the compound is assigned. More reliable data will be obtained if the predicted behaviour of the radionuclide incorporates material-specific information on particle size, absorption parameter values etc, or if human data for a specific chemical form are available from research studies (ICRP, 2002). However, it should be recognised that in many circumstances there may be doubts about the precise chemical form of the radionuclides and conclusions drawn about the efficacy of treatment, or lack of it, may be misplaced. For example, in animal studies DTPA has been shown to be effective for plutonium nitrate when inhaled as the pure form, but poorly effective when the compound is adsorbed onto or intermixed with corrosion products or building dust (Henge-Napoli et al., 2000) In a similar way, DTPA is effective for inhaled americium dioxide, 241AmO2,, but not when the compound is present in a plutonium oxide matrix and formed from the decay of 241Pu (Gerber and Thomas 1992). Whilst DTPA is also partially effective for PuO2 with a high ultrafine (soluble) component, the efficacy for mixed oxide (MOX) fuel would be expected to be minimal (Henge-Napoli et al., 2000). For the purpose of orientating the reader with regard to the potential efficacy of DTPA, a brief overview of retention and excretion data is given with each chemical form considered.

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there are two alternative approaches involving decisions on treatment, which for convenience are termed urgent and precautionary. The urgent approach is recommended when an appreciable intake is most likely to have occurred, but it cannot be confirmed until the results of monitoring are obtained at a later date. In this approach, DTPA is administered as soon as possible, and decisions for continuation reviewed on the basis of individual monitoring data as it becomes available and appropriate consultations between physicians, health physicists and the patient have taken place. The advantage of this approach is that in most cases treatment will be optimised, but the disadvantage is that assessments of dose will be complicated by the subsequent enhanced urinary excretion over a period of several weeks and when all the data are available treatment may be deemed to have been unnecessary. In many cases, the uncertainty about magnitude of the assessed uptake may be considerable. In the precautionary approach, treatment is delayed until the magnitude of the uptake and dose is confirmed, and treatment if warranted can be based more reliably on the probable reduction in risk of late effects. The advantage of this approach is that if confirmed uptakes are low, then any risks associated with treatment will have been avoided. The disadvantage is that should assessed doses necessitate treatment, then the efficacy is likely to be reduced substantially.

3. DTPA pharmacokinetics Diethylenetriaminepentaacetic acid (DTPA) is an organic compound that forms water-soluble, chemically very stable, ring-shaped, complexes (chelates) with metals such as plutonium. The actinide DTPA chelates are generally much more stable than those formed with essential metals, and, since they are excreted readily in the urine, the spontaneous elimination of metals such as plutonium is preferentially enhanced. Following injection, DTPA distributes throughout the extracellular fluid space; however, it enters cells slowly and only to a limited extent. Chelation takes place predominantly in the extracellular fluids but mobilization of plutonium from cells, probably macrophages, in the lungs does occur (Henge-Napoli et al., 2000). Although non-chelated DTPA is excreted within about 12 h, the DTPA–Pu complex may be excreted over several weeks.

4. Decisions on treatment It is recognised that different organisations will have different strategies in place, and this document is not intended to over-ride these procedures. In broad terms,

5. Intake levels and corresponding effective doses In the publications for the Commission of the European Communities referred to above (HengeNapoli et al., 2000; Bhattacharyya et al., 1995), it was concluded that decision levels should be related to the committed effective dose. For intakes of soluble or moderately soluble chemical forms by adults, the following levels are proposed, namely that treatment:

 should not be considered when the assessed dose is less than 20 mSv

 should be considered for assessed doses between 20 and 200 mSv be implemented when the assessed dose exceeds 200 mSv.

 should

Even for a dose of less than 20 mSv, the urgent approach will increase the excretion rate of the contaminant. It is often easier to judge the desirability of treatment by comparison of assessed uptake with intakes that correspond to the doses listed above. For workers, intakes corresponding to doses of 20 and 200 mSv, based on values of the dose coefficient (dose per unit intake,

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Sv Bq1) recommended by ICRP in Publication 68, are given in Table 1 (ICRP, 1995). These dose coefficients have also been adopted by the European Union (OJEC, 1996), and by the International Atomic Energy Agency (IAEA, 1996). The intakes for members of the public, based on dose coefficients in ICRP Publication 72 (ICRP, 1996) are given in Table 2. These values have also been adopted by the European Union (OJEC, 1996) and the International Atomic Energy Agency (IAEA, 1996). After the inhalation of insoluble compounds such as 239 PuO2, bronchopulmonary lavage was recommended when the assessed dose to the lungs was likely to exceed 5 Sv within a few weeks (Henge-Napoli et al., 2000). Although this value may seem high compared with those above, it is because treatment in this case is intended to reduce deterministic rather than stochastic effects.

Whilst industrial accidents may result in appreciable over-exposure, the number of affected workers is likely to be small. However, accidental releases to the environment from whatever cause can affect substantial numbers of people. Rather than have different risk coefficients for different exposure groups, these guidance notes re-iterate the conservative approach, i.e. using the risk for members of the public (ICRP, 1996). It is assumed that the overall risk of health detriment from stochastic effects is 7.3  102 Sv1 or 7.3% Sv1. The probabilities of such effects are given in Table 3. As more information becomes available from the Atomic Bomb Casualty Commission life-span study, it should become clear whether or not these values are conservative for children. Since decisions on treatment should be based on net benefit to the patient, it is more appropriate to consider

Table 1 Dose coefficients for plutonium and americium following inhalation of specified activities by workers (aerosol size 5 mm AMAD) (ICRP, 1995) Nuclide

238

Pu

239

Pu

241

Pu

241

Am

Type

M S M S M S M Sa

Dose coefficient (Sv Bq1)

3.0  105 1.1  105 3.2  105 8.3  106 5.8  107 8.4  108 2.7  105 8.7  106

Intake (Bq) 20 mSv

200 mSv

670 1820 625 2410 34,480 238,095 740 2300

6700 18,200 6250 24,100 344,800 2,380,950 7400 23,000

f 1 ¼ 5  104 for Type M and 105 for Type S compounds of Pu. f 1 ¼ 5  104 for Type M and Type S compounds of Am. a Not listed in ICRP Publication 68 but calculated using current physiological models.

Table 2 Dose coefficients for plutonium and americium following inhalation of specified activities by adult members of the public (aerosol size 1 mm AMAD) (ICRP, 1995) Nuclide

238

Pu

239

Pu

241

Pu

241

Am

Type

M S M S M S M Sa

Dose coefficient (Sv Bq1)

5

4.6  10 1.6  105 5.0  105 1.6  105 9.0  107 1.7  107 4.2  105 1.6  105

f 1 ¼ 5  104 for Type M compounds and 1  105 for Type S compounds of Pu. f 1 ¼ 5  104 for Type M and Type S compounds of Am. a Not listed in ICRP Publication 68 but calculated using current physiological models.

Intake (Bq) 20 mSv

200 mSv

435 1,250 400 1,250 22,220 117,650 475 1,250

4,350 12,500 4,000 12,500 222,200 1,176,500 4,750 12,500

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Detriment for the public (102 Sv–1)

Fatal cancer Non-fatal cancer Severe hereditary effects Total

5.0 1.0 1.3 7.3

Table 4 Summary of risk factors (Henge-Napoli et al., 2000) Action

Risk of

Risk factor

Intravenous injection (mSv) E (50) 20

Air-bubble embolism

1 in 20,000

Fatal cancer (public) Total detriment (public) Fatal cancer (public) Total detriment (public) Fatal cancer (public) Total detriment (public)

1 1 1 1 1 1

E (50) 200 E (50) 1000

in in in in in in

1000 685 100 69 20 14

E(50) is the estimated Committed Effective Dose over a 50-year period.

the overall risk rather than only death arising from fatal cancers. There are also other risk factors that may influence a physician’s decision to treat on the basis of risk, e.g. the risk from the anaesthetic prior to bronchopulmonary lavage or air-bubble embolism during intravenous injection of DTPA. These risk factors are summarised in Table 4 (Henge-Napoli et al., 2000).

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7. Treatment protocols Depending on the chemical form and route of intake, treatment for soluble or moderately soluble plutonium and americium may involve administration of DTPA by inhalation, or intravenous injection; occasionally it has also been used orally (Largerquist et al., 1967). The most common route is by slow intravenous injection or infusion in isotonic saline. Most recommendations suggest that Ca-DTPA is used for the initial administration, and Zn-DTPA for subsequent administrations should these be deemed necessary (Henge-Napoli et al., 2000). Nevertheless Zn-DTPA is not authorized for use everywhere in Europe. The dosage is usually 30 mmol kg1 body mass, or 1 g for a 70 kg adult, although it has been reported that 0.1 g is equally effective (Schofield, 1969). Intermediate dosages of 0.5 and 0.25 g have also been used (Schofield, 1969; Schofield et al. 1974; Blanchin et al., 2004; Piechowski et al., 2003). An example of treatment options is given in Appendix B. Historically, the preferred method of administration is intravenous injection, but a promptly administered DTPA aerosol would have the advantage that Pu would be chelated in the respiratory tract, thus minimising subsequent deposition in systemic tissues, and that lower dosages are required than after the other methods of administration. In principle the most rapid, and potentially most efficient, means of administration is as an aerosol using a ‘turboinhalator’ or similar device. However, it is doubtful whether the particles are of sufficiently small size to deposit in the deep lung. The oral administration of DTPA would be advantageous where large numbers of people may require to be treated for a long period.

8. Assessment of treatment 6. Assessment of intake Decisions on treatment will in some circumstances depend on the high probability, or confirmation, that the assessed dose meets the criteria referred to above. This may depend on data from static or personal air samplers, nose blows, facial contamination, or the results of whole body or chest monitoring and the analysis of excreta. It is not the purpose of this document to set reference levels for these procedures, but comments are made on the effectiveness of individual monitoring when deemed appropriate. However, it should be recognised that lung monitoring will measure the amounts present in the bronchiolar and alveolar regions. For workers and members of the public this represents only an initial deposition of about 8% (5 mm) and 15% (1 mm) of the total intake (ICRP, 1991).

Judgements on the likely efficacy of DTPA after accidental exposures are often extremely difficult due to insufficient information being available on important factors, for example the precise chemical form incorporated, the pattern of exposure, problems in assessing body retention or uncertainties about whether the optimal regimen has been used. Nevertheless, for large intakes early excretion analysis will provide a reliable indication of the likely effectiveness of treatment and indicate whether or not it should continue. In this respect, it is important to recognise that the elevation of urinary excretion above background levels is only important if it represents a significant fraction of the suspected or confirmed intake. However, it is essential that patients who receive DTPA therapy are followed up to establish the efficacy of the treatment regimen (Appendix C). This should be based on the fraction of

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the incorporated activity which is removed from the body by the treatment (and hence the assessed dose reduction), and not on the initial enhancement of excretion or the magnitude of the excretion rate. This fraction can only be assessed on a case by case basis. In practice, the results obtained from animal studies are considered a most useful component of the decisionmaking process since in such cases known amounts of radionuclides as specified chemical forms have been administered under controlled conditions. Hence, the efficacy of treatment based on a known regimen and measurements of tissue retention and excretion are readily assessed.

occurred in mice when similarly high doses were given throughout gestation. As a precaution, Ca-DTPA is contraindicated for persons with serious kidney disease or depressed myelopoietic function. DTPA therapy should be discontinued if diarrhoea occurs. DTPA treatment is not recommended during pregnancy. Animal studies indicate that Zn-DTPA is less toxic than Ca-DTPA (Gusev et al., 2001) and while Zn-DTPA is recommended for long term treatment, Ca-DTPA is more effective than Zn-DTPA for initial chelation. For this reason, Ca-DTPA is preferred for use during the first day or two of treatment. By 24 h after exposure, ZnDTPA is as effective as Ca-DTPA. PART 2: THE GUIDANCE NOTES

9. Toxicity of DTPA When DTPA is administered by infusion, blood pressure should be monitored. Because of potential damage to the kidneys, liver and gastrointestinal tract, patients treated with DTPA especially for prolonged periods should be monitored for kidney function, liver enzymes and symptoms of intestinal disorders. If the zinc salt of DTPA is administered for prolonged periods as an aerosol, the patient should be monitored for the possible onset of metal fume fever. However, considerable human experience indicates that no serious side effects have occurred even after prolonged administration. It is noteworthy that in the Hanford americium accident, about 580 g of DTPA, primarily as the Zn salt was administered to the patient over a 4-year period without any observed toxicological effects (Breitenstein and Palmer, 1989). In France, over 600 workers have been given a single injection of DTPA, and over 200 workers multiple injections without sideeffects other than transitional depletion of Cu and Zn in some of the latter cases. One of these patients received 120 g of DTPA over a period of more than 4 years (Giraud, 2001). Other information on DTPA treatment is available from the Oak Ridge Associated Universities (ORAU) DTPA Registry. In the period 1958 to 1987, 485 patients received a total of 3077 doses of DTPA, about twothirds as the Ca salt. Minor transient effects were observed in 12 patients, but no short- or long-term effects had been reported by the end of 1987 (Breitenstein et al., 1987). In one reported accident, 250 g of the free acid was administered orally to the patient over a period of 16 weeks without side effects (Largerquist et al., 1967). In animals given high doses of Ca-DTPA, toxicity has been observed due to chelation and excretion of essential trace metals, such as zinc and manganese. Doses 200 times or more larger than that used in humans caused severe lesions of the kidneys, intestinal mucosa and liver (Gusev et al., 2001). Teratogenesis and fetal death

2. The treatment of inhaled plutonium nitrate 2.1. Introduction This guidance note is confined to pure chemical forms 238 Pu, 239+240Pu (referred to hereafter as 239Pu), and 241 Pu which occur in industry. In some industrial situations plutonium nitrate may be absorbed onto, or become intermixed with corrosion products or other particulate matter. The limited evidence available suggests that the efficacy of DTPA in these circumstances will be low. Hence a clear distinction should be made between these different physical characteristics of the nitrate. For the purpose of this guidance note, it is assumed that the pure chemical form has been inhaled. of

2.2. Biokinetics Plutonium nitrate is assigned to absorption type M (ICRP, 1994) i.e. it is moderately absorbed into blood after inhalation. The time-dependent retention of plutonium in the lungs, liver and skeleton is shown in the upper part of Fig. 1 and the excretion in urine and faeces is shown in the lower section of this figure. Also shown are the biokinetic data obtained from human volunteers, Men C and D, who inhaled 237+244Pu (Etherington et al., 2002; Hodgson et al., 2003). The retention curves indicate that early treatment is important, since plutonium is not readily mobilized after deposition in the liver and bone. Lung monitoring, particularly when 241Am is present as a decay product of 241 Pu, and the assay of urinary and faecal samples are important considerations in the assessment of intake. 2.3. Treatment considerations As noted in the preface, it is proposed that treatment should be:

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10 -1

Lung retention

Type M

Systemic retention

Type S 10 -2

ICRP default Man C Man D

10 -2

Fraction of i

ICRP default Man C Man D

10 -3

Type M

Type S

Fraction of inhaled Pu

10 -3

10 -4 100

200

0

300

100

Days

200

300

Days

10 0

10 -3

Faecal excretion rate

Urinary excretion rate

ICRP default Man C Man D

10 -4

10 -5

ICRP default Man C Man D

10 -1

10 -2

10 -3

Type M

10 -4

Fraction 10 -6 of inhaled Pu

Type S

Fraction of inhaled Pu

Type S

10 -5

21

Type M 10 -6

10 -7 0

100

200

300

0

100

Days

200

300

Days

Fig. 1. Predicted biokinetics of plutonium after inhalation as nitrate.

 considered for assessed doses between 20 and 200 mSv 

and implemented when the assessed dose exceeds 200 mSv.

If a serious injury has occurred, appropriate medical care should be given to the victim regardless of contamination and the incorporation of radioactivity. Decontamination and decorporation measures can be initiated only when the health status of the patient permits. 2.4. Assessment of intake Lung monitoring can be used with some advantage for 238Pu and 239Pu, but not for 241Pu which emits only non-penetrating radiation. However, the limits of detection are high and hence monitoring data should only be used for judgements on the necessity of treatment and not for the purpose of recording doses. Typically, the limit of detection for pure 239Pu in the

lungs is about 3 kBq, but this value may vary appreciably depending on the chest wall thickness. Hence for workers, the minimum detectable intake is likely to be at least 24 kBq and the corresponding dose at least 800 mSv. Hence should any 239Pu be identified in the lungs, treatment should commence as soon as possible. If for example the aerosol contains say 10% of 241Am by radioactivity, then the sensitivity of lung monitoring is increased substantially. If the detection limit for 241Am in the lungs is 10 Bq, then the corresponding limit for 239Pu is 90 Bq. For practical purposes the dose coefficients for 241Am and 239Pu can be considered the same. Hence in this case, intakes of about 1220 Bq can be detected soon after exposure. This corresponds to a dose of about 40 mSv, greatly facilitating decisions on treatment. Treatment decisions may also be based on the prompt assay of urine, faecal and or nose blow samples, and information from static or personal air samples. It is assumed that appropriate action levels will form part of the local rules.

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2.5. Treatment regimens and likely efficacy of treatment

treatment commences promptly;

 after inhalation, the overall efficacy of treatment will Based on animal studies (Henge-Napoli et al, 2000) it can be expected that, compared with the absence of treatment:

 the prompt and repeated administration of DTPA as  

an aerosol (2 mmol kg1 body weight) can reduce the lung and body content of Pu by up to about 50- and 13-fold, respectively, by 28 d after exposure; the prompt and repeated intravenous injection of DTPA (30 mmol kg1) can reduce the lung and body content of plutonium by up to 23- and 17-fold, respectively, by 28 d after exposure; the prompt and repeated oral administration of DTPA (95 mmol kg1 d1 in water) can reduce the lung and body content of plutonium by up to 45- and 13-fold, respectively, by 21 d after exposure.

Delayed treatment will also be effective for removing Pu from the lungs. However, the overall efficacy will be reduced owing to the amounts that will have been absorbed into the blood and deposited in the liver and bone meanwhile. Thus, all methods of administration can be effective. The choice will be determined by the facilities available, the numbers of people potentially exposed, and most importantly the opinion of the clinician, and the agreement of the patient(s). The evidence for these conclusions is given in Appendix D.

  

decrease with increasing delays between exposure and administration of Zn-DTPA due to increased absorption into the blood and deposition in systemic tissues, principally bone and liver. However, the available evidence suggests that almost all of the contemporary lung deposit can still be chelated despite the delay in administration; the repeated administration of the ligand will be more effective than a single administration; the preferred dosage by injection is 30 mmol kg1 although some clinicians may prefer lower dosages; the administration of a Zn-DTPA aerosol should be considered due to its high efficacy at lower dosages than injection.

If large numbers of people are potentially exposed and repeated intravenous injection is impracticable or undesirable, the development of regimens concerning the oral administration of Zn-DTPA should be considered. However no protocol for oral treatment with DTPA is at present available.

3. The treatment of inhaled Plutonium Tributylphosphate 3.1. Introduction

Based on studies with laboratory animals it is concluded that for humans:

The biokinetics of plutonium and the efficacy of treatment will depend on the mass of the element inhaled. In the examples given in Appendix E, the masses of plutonium simulate realistic accidental exposures even though they are still considered high.

 the

3.2. Biokinetics

2.6. Conclusions

Fraction of inhaled Pu

administration of Zn-DTPA by injection or infusion, as an aerosol, or in drinking water can be an effective form of treatment for persons who have inhaled pure chemical forms of plutonium nitrate, if

The biokinetics of plutonium- tributylphosphate (PuTBP) are consistent with that for default Type M as

0.06

10 0

0.05

10 -1

0.04

Faeces Urine

10 -2 Lungs Systemic

0.03

10 -3

0.02

10 -4

0.01

10 -5

0.00

10 -6 0

60

120

180

240

Days after exposure

300

360

0

60

120

180

240

Days after exposure

Fig. 2. Biokinetics of default Type M plutonium after inhalation.

300

360

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defined by ICRP. The time-dependent retention of plutonium in the lungs, liver and skeleton, and the excretion of plutonium in urine and faeces are shown below (Fig. 2). The retention curves indicate that early treatment is important, since plutonium is not readily mobilized after deposition in the liver and bone (Fig. 2). 3.3. Treatment considerations

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about 3- and 5-fold, respectively, by 7 d after exposure: Treatment delayed for 1 d will also be effective for removing plutonium from the lungs. However, the overall efficacy will be reduced owing to the amounts that will have been absorbed into the blood and deposited in the liver and bone meanwhile. The evidence for these conclusions is given in the Appendix E.

As noted in the preface, it is proposed that treatment should be:

3.6. Conclusions

 considered for assessed doses between 20 and 200 mSv

Based on studies with laboratory animals it is concluded that for humans inhaling Pu-TBP:

and

 implemented

when

the

assessed

dose

exceeds

200 mSv. If a serious injury has occurred, appropriate medical care should be given to the victim regardless of contamination and incorporation of radioactivity. Decontamination and decorporation measures should be initiated only when the health status of the patient permits.

 the overall efficacy of all treatments must be expected



3.4. Assessment of intake

 Lung monitoring is of little practical value for assessing intakes and doses. Typically, the minimum detectable amount (MDA) for pure 239Pu in the lungs is about 3 kBq, but this value will vary depending on the chest wall thickness. For workers, the minimum detectable doses for default Type M from measurements made during the first week after acute exposure are between 1700 and 1900 mSv (Stradling et al., 2003). Hence should any 239Pu be identified in the lungs, treatment should commence as soon as possible. Treatment decisions may also be based on the assay of urine, faeces nose blow samples, and information from static or personal air samples. For MDAs of 0.1 and 1 mBq d1 in urine and faeces, respectively, doses of less than 1 mSv can be assessed for several months after exposure (Stradling et al 2003).

to decrease with increasing delays between exposure and administration of DTPA due to increased absorption into the blood and deposition in systemic tissues, principally bone and liver. However, the available evidence suggests that most of the contemporary lung deposit can still be chelated despite the delay in administration; the administration of DTPA by injection should be effective for inhaled plutonium tributylphosphate if treatment commences promptly; the repeated administration of the ligand should be more effective than a single administration.

4. The treatment of inhaled americium nitrate 4.1. Introduction These notes are confined to a pure chemical form of Am nitrate which may or may not be present with a pure chemical form of plutonium nitrate. The efficacy of treatment for plutonium nitrate has been described previously. In some industrial situations 241Am nitrate will be absorbed onto, or become intermixed with corrosion products or other particulate matter. Under these conditions the efficacy of treatment may be lower than described here. 241

3.5. Treatment regimens and likely efficacy of treatment 4.2. Biokinetics Compared with untreated controls, studies with rats (Henge-Napoli et al., 2000), indicated that for humans:

 the 

prompt and repeated injection of DTPA could reduce the lung and body content of plutonium by up to about 40- and 6-fold, respectively, by 28 d after exposure; a single administration of DTPA could reduce the lung and skeletal content of plutonium by up to

Americium nitrate is assigned to default Type M (ICRP, 1994) i.e. it is moderately absorbed into blood after inhalation. The time-dependent retention of americium in the lungs, liver and skeleton and the excretion in urine and faeces for default Type M is shown below (Fig. 3). The retention curves indicate that early treatment is important, since americium is not readily mobilized after deposition in the liver and bone.

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Fraction of inhaled Am

838

0.06

10 0

0.05

10 -1

Faeces Urine

10 -2

0.04 Lungs Systemic

0.03

10 -3

0.02

10 -4

0.01

10 -5

0.00

10 -6 0

60

120

180

240

300

360

0

Days after exposure

60

120

180

240

300

360

Days after exposure

Fig. 3. Biokinetics of default Type M americium after inhalation.

Lung monitoring and the assay of urinary and faecal data are important in the assessment of intake and dose for treatment considerations.

1 mBq d1 in urine and faeces, respectively, doses of less than 1 mSv can be assessed for several months after exposure.

4.3. Treatment considerations

4.5. Treatment regimens and likely efficacy of treatment

As noted in the preface, it is proposed that treatment should be:

In a human accident case, involving inhalation and cutaneous implantation of contaminated glass, the repeated intravenous administration of Ca- and ZnDTPA reduced the body content and potential life- threatening doses substantially (Breitenstein and Palmer, 1989). Compared with untreated controls, studies with rats (Henge-Napoli et al., 2000), indicated that for humans:

 considered for assessed doses between 20 and 200 mSv and

 implemented when the assessed dose exceeds 200 mSv. If a serious injury has occurred, appropriate medical care should be given to the victim regardless of contamination and incorporation of radioactivity. Decontamination and decorporation measures can be initiated only when the health status of the patient permits. 4.4. Assessment of intake Lung monitoring can be used with some advantage for pure chemical forms of 241Am; the MDA is about 10 Bq. The minimum detectable doses from lung counting measurements made within the first week after exposure, about 6 mSv, are 300 times less than for 239Pu nitrate (Stradling et al., 2003). For aerosols containing 239 Pu and 241Am, the minimum dose will depend on the relative amounts present; when this ratio by radioactivity is for example 9:1, the minimum detectable dose will be about 60 mSv. Hence, lung monitoring can be used with advantage for judgements concerning treatment. Treatment decisions may also be based on the assay of urine, faeces, nose blow samples, and information from static or personal air samples. With MDAs of 0.1 and

 the prompt and repeated administration of Zn-DTPA

  

as an aerosol (2 mmol kg1 body weight) can reduce the lung and body content of americium by up to about 45- and 30-fold, respectively, by 28 d after exposure; the prompt and repeated intravenous injection of ZnDTPA (30 mmol kg1) can reduce the lung and body content of americium by up to about 25- and 30-fold, respectively, by 28 d after exposure; the prompt and repeated oral administration of ZnDTPA (95 mmol kg1 d1 in water) can reduce the lung and body content of americium by up to about 30- and 20-fold, respectively, by 21 d after exposure; delayed treatment should also be moderately effective for removing 241Am from the lungs (see Table 4). However, the overall efficacy will be reduced owing to the amounts that will have been absorbed into the blood and deposited in the liver and bone before treatment was commenced.

Thus, administration of DTPA as an aerosol, by intravenous injection or infusion and by oral

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administration should be effective for humans. The choice will be determined by the facilities available, the numbers of people potentially exposed, and most importantly the opinion of the clinician, and the agreement of the patient(s). The evidence for these conclusions is given in the Appendix F. 4.6. Conclusions Based on human experience: intravenous administration is the most effective treatment regimen for internal contamination. From studies with laboratory animals it is concluded that for humans:

 administration of Zn-DTPA by injection or infusion,  



as an aerosol, or orally can be an effective treatment for inhaled pure chemical forms of 241Am nitrate if treatment commences soon after exposure; administration of a Zn-DTPA aerosol should be considered due to high efficacy at lower dosages than injection; for inhaled americium nitrate, the overall efficacy of treatment will decrease with increasing delays between exposure and administration of Zn-DTPA due to increased absorption into the blood and deposition in tissues, principally in the liver and bone. However, the available evidence suggests that most of the contemporary lung deposit can still be chelated despite the delay in administration; repeated administration of DTPA commencing soon after exposure will be more effective than a single administration.

839

Type M in the lungs, liver and skeleton and the excretion in urine and faeces are shown in Fig. 3. The retention curves indicate that early treatment is important, since americium is not readily mobilized after deposition in the liver and bone. Lung monitoring and the assay of urinary and faecal samples are important considerations in the assessment of intake. Whilst these data are similar to those given for americium nitrate, it should be recognised that the dissolution and absorption mechanisms are quite different (Stradling et al., 1980). After inhalation of 241 Am nitrate, the element is amenable to chelation in the lungs, whilst for 241AmO2, the efficacy of treatment depends mainly on chelation of 241Am absorbed into the blood; hence protracted treatment is likely to be needed. 5.3. Treatment considerations As noted in the preface, it is proposed that treatment should be

 considered for assessed doses between 20 and 200 mSv and

 implemented when the assessed dose exceeds 200 mSv. If a serious injury has occurred, appropriate medical care should be given to the victim regardless of contamination and incorporation of radioactivity. Decontamination and decorporation measures should be initiated only when the health status of the patient permits. 5.4. Assessment of intake

If large numbers of people are potentially exposed and repeated intravenous injection is impracticable or undesirable, the development of regimens concerning the oral administration of Zn-DTPA should be considered. However no protocol for oral treatment with DTPA is at present available. DTPA will be more effective for americium nitrate than for the dioxide.

These notes are confined to a pure chemical forms of americium dioxide, 241AmO2, and not as the oxide present in a 239PuO2 matrix due to the decay of 241Pu.

Lung monitoring can be used with advantage for 241Am. Typically the MDL for 241Am in the lungs is about 10 Bq, about 300 times less than that for 239Pu. Hence for workers, the minimum detectable dose from measurements made during the first week after exposure will be about 6 mSv. This value is sufficiently low for any decisions on treatment to be evaluated. For mixtures of 241Am and 239 Pu, the minimum detectable doses will increase, e.g. to about 60 mSv when the ratio by activity is 1:9. Treatment decisions may also be based on the assay of urine, faeces, nose blow samples, and information from static or personal air samples. With MDAs of 0.1 and 1 mBq d1 in urine and faeces, respectively, doses of less than 1 mSv can be assessed for several months after exposure.

5.2. Biokinetics

5.5. Treatment regimens and likely efficacy of treatment

Americium dioxide is assigned to absorption type M (ICRP, 1994) i.e. it is moderately absorbed into blood after inhalation. The time-dependent retention of default

Compared with untreated controls studies with rats and dogs indicate that after inhalation of americium dioxide by humans:

5. The treatment of inhaled americium dioxide 5.1. Introduction

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 the delayed (4 d) and repeated injection of Zn-DTPA  

(200 mmol kg1) could reduce the lung and body content of americium by up to about 7-fold by 74 d after exposure (see Table 13). the prompt and repeated injection of DTPA (30 mmol kg1) should reduce the lung and body content of americium by up to about 2- and 3-fold, respectively, by 64 d after exposure (See Table 2). the prompt injection of Ca-DTPA (30 mmol kg1) and subsequent subcutaneous infusion of Zn-DTPA (30 mmol kg1 d1) can reduce the lung and body content of americium by up to 3- and 10-fold, respectively, by 64 d after exposure. It is noteworthy that the liver and bone contents were reduced by about 200 and 60 times, respectively (see footnote to Table 14).

Appendix A. The status of authorisation of DTPA for human use A.1. Introduction For humans internally contaminated with plutonium and other transuranics, only the trisodium calcium or zinc salts of diethylene-triamine-penta-acetic acid (Caor Zn-DTPA) have been used, either as a regular drug or permitted under some form of investigational new drug procedure. This appendix summarises the present regulatory situation relating to the human use of Caor Zn-DTPA in several European countries and the USA.

 In The evidence for these conclusions is given in the Appendix G. Thus, the repeated infusion of Zn-DTPA (30 mmol kg1 d1) would appear to be the most effective method of treatment. Whilst, DTPA is unlikely to enhance the dissolution of 241Am in the lungs, the experimental data suggest that it will chelate the dissolved fraction, and importantly, inhibit the deposition of the radionuclide in systemic tissues.



5.6. Conclusions Based on studies with laboratory animals it is concluded that for humans:



 administration 

of DTPA by repeated injection, infusion or aerosol, should be a moderately effective treatment for inhaled 241Am dioxide; Infusion of DTPA in particular should inhibit the deposition of 241Am in systemic tissues, particularly liver and bone.



Acknowledgements

 The authors wish to thank the European Late Effects of Radiation Project Group (EULEP) for their encouragement and financial support (under EU Contract FIR1-CT-2000-20034) of this work. They also thank Dr. Alan Hodgson (NRPB—UK) for constructive discussions and exchange of useful information. Notice: The views and opinions expressed in these Notes for Guidance are those of the authors and are offered in good faith. However, neither the authors, nor their employing organisations, nor the European Union can be held responsible for any adverse effects arising from the information presented.



France—Although more than 700 workers have been treated with a single or multiple dosages of DTPA, the substance has not been yet authorised as a medical drug but a registration process has been begun by AFSSAPS. The substance is available commercially from the Army Central Pharmacy, Orle´ans. In Great Britain—Ca- and Zn-DTPA are not authorised for human use. But the compound is used by physicians as an experimental substance in workers under the ‘named patient’ rule. The substance is bought from Germany. In Sweden—DTPA is a licensed drug but has been used on rare occasions for heavy metal intoxication, but not, so far, for plutonium. In an emergency, it could be dispensed by the National Emergency Pharmacy Apoteket Scheele (Stockholm) as Ca-DTPA solution in an ampoule for injection. The substance is bought from Germany. In Germany—Ca- and Zn-DTPA have been authorised for medical use, with a specified protocol. The substance is available commercially from Heyl Chemisch-pharmazeutische Fabrik GmbH, (Goerzallee 253, 14167 Berlin, Germany). It has been used for workers, and treatment is not yet authorised for members of the public. In Spain—DTPA has been approved for medical use although it has never been used to treat contamination by transuranics. The Center of Radiopathology and Radioprotection, Gregorio Maran˜o´n Hospital, is the only authorised centre for the treatment of accidental internal radionuclide contamination (Dr Rafael Herranz, personal communication). The substance is bought from Germany. In the Czech Republic—DTPA has not been licensed for human use. Only the Clinic for Occupational Diseases may use it on the basis of a special permit from the Ministry of Health. The substance is bought from Germany.

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 In the USA—calcium DTPA has been used to treat, primarily actinide (especially plutonium and americium), internal radionuclide deposition since the 1960s. Ca- and Zn-DTPA have recently been approved under the New Drug Applications (NDAs) procedure by the FDA. Up to now, Oak Ridge Associated Universities, through a contract with the US Department of Energy (DOE), provided Ca & Zn DTPA to physicians (mostly employed at DOE contractor sites) for use in treating workers who sustain intakes of radionuclides, again, especially plutonium and americium. In the period 1958 to 1987, 485 patients received a total of 3077 doses of DTPA, about two-thirds as the Ca-salt in the USA. Since there was no commercial market for DTPA, it always remained in an Investigational New Drug (B. Breitenstein, pers. comm.). However, in September 2003, the Federal Register of FDA published a notice with guidance for industry on the use of Caand Zn-DTPA for treatment of internal contamination with plutonium, americium and curium (FDA, 2003).

Appendix B. Administration and dosage: an example of current practice B.1. Introduction Decisions to treat with DTPA should be made as early as possible, whatever the route of contamination, because the effectiveness of treatment can drop dramatically within a few hours. It is the physician’s responsibility to decide on the dosage and the administration protocol, having considered all relevant information such as the circumstances of the incident, the nature of the contaminant, route of intake, the results of atmospheric and nose blow sampling, plutonium in lung measurement and the time elapsed since the intake occurred. B.2. Systemic administration Calcium-DTPA (0.25–1 g) may be administered by slow intravenous injection (over 3–4 min) or by intravenous infusion diluted with isotonic saline or 5% glucose solution. This dose is equivalent to 30 mmol kg1 body mass for a 70 kg person. B.3. Administration by inhalation In the case of a possible intake by inhalation, an aerosol of Ca-DTPA may be rapidly self-administered directly at the workplace using a ‘turboinhalator’ or similar device. This treatment may be repeated. Administration by inhalation seems to be less effective than

841

intravenous injection, this is due probably to the low deposition of the DTPA particles in the deep lung. Depending on the level of intake, an intravenous injection of DPTA can follow in the medical department. B.4. Local infiltration Local infiltration of wounds using Ca-DTPA may be effective. The physician’s first consideration should be for the patient’s general condition and emergency procedures to control haemorrhage would be the first priority. Depending on the location of the wound and on the level of contamination, wound toilet, washing with Ca-DTPA solution, and wound excision may be appropriate. Ca-DTPA may also be administered systemically. B.5. Cutaneous administration In case of possible skin contamination, to prevent or reduce percutaneous absorption, the skin may be washed with Ca-DTPA solution and simultaneously the chelating agent may also be administered systemically. B.6. Prolonged treatment For large intakes, administration may be repeated. The dose should not exceed 1 g per day for prolonged treatment.

Appendix C. Case management including monitoring: an example of current practice C.1. Introduction When it is confirmed that a potential internal contamination incident involving transuranics has occurred, dosimetric monitoring is necessary to establish the level of uptake and the following procedures should be adopted: 1. Inform the patient of the situation, 2. Administer Ca-DPTA by the most appropriate route, 3. Collect 24 urine and faecal samples for bioassay for 3–5 days or longer if necessary 4. Carry out whole body and chest monitoring if necessary, 5. In case of prolonged treatment, monitor serum zinc, magnesium and manganese concentrations, kidney and liver function, and for symptoms of intestinal disorders, 6. In prolonged treatment give zinc supplements if necessary,

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842

7. Monitor the patient’s condition and order further investigation as indicated.

Table 5 Effect of aerosol and IP injected Zn-DTPA on retention of 238 Pu in rats

To assess the initial enhancement of excretion following DPTA administration, 24 h urine samples should be collected:

Treatmenta

A. 24 h before the administration of DPTA if possible, B. during the initial phase of treatment commencing at the time of administration, C. 24 h after the administration. This is the minimum requirement for assessment of an enhanced intake and investigations may need to continue for much longer. The need for continuing investigation must be assessed on a case-by-case basis.

Appendix D The information in Section 2 is based on a recently published review on decorporation (Henge-Napoli et al., 2000). The animal data, summarised in Table 5, show that inhaled DTPA at concentrations appreciably below the usual human equivalent dosage of 30 mmol kg1 removed almost all the plutonium from the lungs. The small amounts of the element present in other body tissues result primarily from absorption to blood before the commencement of treatment. It is noteworthy that the inhalation of DTPA is as effective as repeated injection of the ligand. Other work has shown that Pu can be nearquantitatively removed from the lungs of hamsters when treatment with inhaled (2 mmol kg1) and injected (30 mmol kg1) DTPA was delayed for 11 d after exposure and the ligand was then administered weekly. The amounts retained in the lungs and total body at 74 d Table 7 Effect of oral and IP injected Zn-DTPA on retention of Mode of Intake

d

Oral IP Injectione

% controls at 28 d (Mean  SE; N ¼ 5)b

Aerosolc Aerosolc + IP injectiond IP Injection onlyd

Lungs

Total body

2.171.1 1.170.1 4.472.4

7.671.2 4.270.7 5.771.4

Initial lung deposit (ILD): 505  37 Bq; 0.78 ng Pu. Equivalent intake of 239Pu by workers 1:13  104 ng or effective dose of 840 mSv. a DTPA administration at 30 min, 6 h, 1 d, 2 d, 3 d, 5 d and then twice weekly to 27 d. b % ILD in controls at 28 d: lungs, 29:3  1:8; total body 45:1  5:8: c Inhalation administration: 2 mmol kg1. d Intra-peritoneal injection (IP): 30 mmol kg1. Table 6 Effect of IP injected DTPA on retention of Treatmenta

c

Single Repeatedd

238

Pu in rats

% controls at 7 d (Mean  SE; N ¼ 4)b Lungs

Total body

1672 1271

1872 4.570.4

Initial lung deposit (ILD) : 600  25 Bq; 0.92 ng Pu. Equivalent intake of 239Pu by workers 1:34  104 ng or effective dose of 980 mSv. a 30 mmol kg1 administered by IP injection; first administration Ca-DTPA, then Zn-DTPA. b % ILD in controls at 7 d: lungs, 64.674.4; total body 86.374.8. c 30 min only. d 30 min, 6 h, 1 d, 2 d, 3 d.

238

Pu in rats

% controls at 21 da,c

% controls at 28 db,c

Prompt treatment (1 h)

Delayed treatment (7 d)

Lungs

Total body

Lungs

Total body

2.270.3 1.770.3

7.870.8 5.270.7

6.270.3 1171

1772 2574

Initial lung deposit (ILD): 676796 Bq, 1.04 ng Pu. Equivalent intake of 239Pu by workers—1.5  104 ng or effective dose of 1120 mSv. a % ILD in controls at 21 d: lungs, 41.073.6; total body 63.974.7. b Mean7SE, 4 animals per group. c % ILD in controls at 28 d: lungs, 30.772.7; total body 60.074.9. d 95 mmol kg1 per day administered in drinking water for 21 d. e 30 mmol kg1 administered by intraperitoneal injection twice weekly for 21 d.

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after exposure were 1% and 20% of controls, respectively. The greater efficacy of repeated injection over single injection is illustrated in Table 6. Animal studies have also shown that the administration of Zn-DTPA in drinking water is also an effective treatment regimen (Table 7). Indeed with delayed treatment it appears to be more effective than repeated injection of the ligand.

Appendix E The information in Section 3 is based on a recent review on decorporation (Henge-Napoli et al., 2000). The data obtained from animal studies, summarised in Table 8, show that injected DTPA at the usual human equivalent dosage of 30 mmol kg1 removed almost all the plutonium from the lungs. The amounts of the element present in other body tissues result primarily from absorption to blood before the commencement of treatment. In another study with rats (Henge-Napoli et al., 2000) involving a higher lung deposit of plutonium (8.1 ng) and a single IV administration of Ca-DTPA after 1 h, the plutonium contents of the lungs and skeleton were 30% and 22%, respectively, of controls by 7 d after exposure.

Appendix F The most compelling data for the efficacy of DTPA is that published by Breitenstein and Palmer, 1989 following inhalation and wound contamination by a worker. Table 9 Summary of the tissue contents and excretion of Time

Day 0 Day 3 Day 10 Day 60 1 year 2 years 5 years 7 years 10 years 11 years

843

The intravenous administration of Ca-DTPA during the first month and Zn-DTPA thereafter reduced substantially the body content. Without treatment the doses were considered to have been life threatening. The animal data in this appendix are taken from a recent review on decorporation (Henge-Napoli et al., 2000) (Table 9). It should be noted that in the experimental procedures used, the intakes and doses are substantially in excess of those likely in human accidents. Thus for humans it might be expected that the efficacy of treatment would be at least that shown below. The data obtained from animal studies, summarised in Table 10, show that after the inhalation of 241Am, inhaled DTPA at concentrations appreciably below the

Table 8 Effect of injected DTPA on retention of Treatment

Ca-DTPAb Zn-DTPAb Zn-DTPAc

238

Pu in rats

% controls at 28 d (Mean  SE; N ¼ 5)a Lungs

Total body

4.370.7 2.570.6 4.270.8

1672 1572 2672

Initial lung deposit (ILD): 384737 Bq 238Pu, 0.59 ng Pu. Equivalent intake of 239Pu by workers: 0.86  104 ng, or a committed effective dose of 640 mSv. a % ILD in controls at 1 d: lungs, 23.171.8; total body 62.073.0. % ILD in controls at 28 d: lungs, 9.571.0; total body 43.172.7. b 30 mmol kg1 Ca-DTPA or 200 mmol kg1 Zn-DTPA injected IP at 30 min, 6 h, 1 d, 2 d, 5 d and then twice weekly to 26 d. c Treatment regimen as (b), but delayed for 1 d.

241

Am in the Hanford Americium case

Organ content (kBq)

Cumulative (kBq)

Excretion

Skin

Lungs

Bone

Liver

Urine

Faeces

185,000 26,000 14,000 5,500 1,300 740 196 190 110 NM

960 290 74 74 55a ND ND ND AS

480 320 250 230 220 280 NM 350 NM

1400 590 150 150 ND 9.6b 17 19 23 (AS)

4800 5000 22,000 31,000 33,000 34,000 34,000 5.4c 4.8c NM

0 4700 6800 7000 7000 7000 7000 1.4c 0.036c NM

ND, not detectable; NM, not measured; AS, measured in autopsy sample. a Not detected at 3 years. b Increase in liver content due to reduction in DTPA treatment. c Values per year based on 1–2 assays per year.

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Table 10 Effect of aerosol and IP injected DTPA on retention of in rats Treatmentb

241

Am

% controls at 28 d (Mean  SE; N ¼ 5)a

Aerosolc Aerosolc7IP injectiond IP Injection onlyd

Lungs

Total body

2.370.5 1.670.3 5.072.1

3.770.6 2.970.5 3.670.9

Initial lung deposit (ILD) : 350725 Bq, 2.8 ng Am. Equivalent intake of 241Am by workers 4.05  104 ng or committed effective dose of 137 Sv. a DTPA administration at 30 min (Ca-DTPA), 6 h, 1 d, 2 d, 3 d, 5 d and then twice weekly to 27 d (Zn-DTPA). b % ILD in controls at 28 d: lungs, 14.371.8; total body 30.974.1. c Inhalation administration: 2 mmol kg1. d intra-peritoneal injection (IP): 30 mmol kg1. Table 11 Effect of IP injected DTPA on retention of Treatmentb

Singlec Repeatedd

241

Am in rats

% controls at 7 d (Mean  SE; N ¼ 4)a Lungs

Total body

2172 1372

1571 971

Appendix G

Initial lung deposit (ILD) : 623725 Bq, 4.97 ng Am. Equivalent intake of 241Am by workers—7.22  104 ng, equivalent to a committed effective dose of 244 Sv. a 30 mmol kg1 administered by IP injection; first administration Ca-DTPA, then Zn-DTPA. b % ILD in controls at 7 d: lungs, 40.473.7; total body 71.574.4. c 30 min only. d 30 min, 6 h, 1 d, 2 d, 3 d.

Table 12 Effect of oral and IP injected Zn-DTPA on retention of Mode of intake

d

Oral IP Injectione

usual human equivalent dosage of 30 mmol kg1 removed almost all the 241Am from the lungs. The small amounts of 241Am present in other body tissues result primarily from absorption to blood before the commencement of treatment. It is noteworthy that a single inhalation of 2 mmol kg1 DTPA is as effective as repeated injection of the ligand (30 mmol kg1). Other work has shown that 241Am can be nearly quantitatively removed from the lungs of hamsters when treatment with inhaled (2 mmol kg1) Zn-DTPA was delayed for 4 d after exposure and the ligand was then administered weekly. The amounts retained in the lungs and total body at 74 d after exposure were 3% and 54% of controls, respectively. The greater efficacy of repeated injection over single injection is illustrated in Table 11. Animal studies have also shown that the oral administration of Zn-DTPA is also an effective treatment regimen if commenced early (Table 12). Indeed with delayed treatment it appears to be more, or at least as, effective as repeated injection of Zn-DTPA, as judged by the total body content at 28 d.

The information in Section 5 is based on a recent review on decorporation (Henge-Napoli et al., 2000). The data from studies with the hamster, summarised in Table 13, showed that despite the delay in commencement of treatment, both injected and inhaled Zn-DTPA removed appreciable amounts of 241Am from the lungs and injected Zn-DTPA prevented most of the 241Am being deposited in systemic tissues. The efficacy of repeated injection or infusion of Ca-DTPA on the retention of 241Am in dogs after the inhalation of much higher amounts of 241AmO2 is shown in Table 14.

241

Am in rats

% controls at 21 da,b

% controls at 28 db,c

Prompt treatment (1 h)

Delayed treatment (7 d)

Lungs

Total body

Lungs

Total body

3.270.3 1.770.6

4.870.5 2.570.4

3.270.3 1.770.6

2073 2974

Initial lung deposit (ILD): 354749 Bq, 2.82 ng Am. Equivalent intake of 241Am by workers 4.1  104 ng equivalent to a committed effective dose of 139 Sv. a % ILD in controls at 21 d: lungs, 20.1 71.6; total body 51.774.3. b Mean7SE, four animals per group. c % ILD in controls at 28 d: lungs, 14.871.0; total body 51.373.8. d 95 mmol kg1 per day administered in drinking water for 21 d. e 30 mmol kg1 administered by intraperitoneal injection twice weekly for 21 d.

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b

Injection Aerosolc

% controls at 74 d (Mean  SE; N ¼ 5)a Lungs

Total body

1472 2774

1672 5674

Initial lung deposit (ILD): 80 Bq, 0.64 ng Am. Equivalent intake of 241Am, by workers 0.93  104 ng, or a committed effective dose of 31 Sv. a % ILD in controls at 74 d: lungs, 25.272.4; total body 58.673.1. b Zn-DTPA administered IP at weekly intervals from 4 to 67 d at a dosage of 200 mmol kg1. c Zn- DTPA inhaled at weekly intervals from 4 to 67 d at a dosage of 2 mmol kg1.

Table 14 Effect of injected or infused Ca-DTPA on retention of 241Am in dogs Treatment

Ca-DTPA injectionb,c Ca-DTPA infusiond,e

% controls at 64 d (Mean  SD; N ¼ 2)a Lungs

Total body

63725 3079

29710 1173

a Initial lung deposit (ILD): 17–39 kBq,. % ILD in controls after 64 d: lungs 24.572.5; liver, 25.173.4; bone, 21.874.2; total body, 76.777.8. b Ca-DTPA IV (30 mmol kg1) after 1 h, 1 d, 2 d, 3 d, 4 d and Zn-DTPA (30 mmol kg1) twice weekly thereafter. c Liver and bone content reduced to 4.773.2% and 1874% of controls. d Ca- DTPA (30 mmol kg1) IV after 1 h, then subcutaneous infusion with Zn-DTPA (30 mmol kg1 d1) from 1 d. e Liver and bone content reduced to 0.4370.28% and 1.770.7% of controls.

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