Richard Wayne Leggett

Polonium-210 as a poison

The death of Alexander Litvinenko on 23 November 2006 has brought into focus scientific judgements concerning the radiotoxicity of polonium-210 ((210)Po). This paper does not consider the specific radiological circumstances surrounding the tragic death of Mr Litvinenko; rather, it provides an evaluation of published human and animal data and models developed for the estimation of alpha radiation doses from (210)Po and the induction of potentially fatal damage to different organs and tissues. Although uncertainties have not been addressed comprehensively, the reliability of key assumptions is considered. Concentrating on the possibility of intake by ingestion, the use of biokinetic and dosimetric models to estimate organ and tissue doses from (210)Po is examined and model predictions of the time-course of dose delivery are illustrated. Estimates are made of doses required to cause fatal damage, taking account of the possible effects of dose protraction and the relative biological effectiveness (RBE) of alpha particles compared to gamma and x-rays. Comparison of LD(50) values (dose to cause death for 50% of people) for different tissues with the possible accumulation of dose to these tissues suggests that bone marrow failure is likely to be an important component of multiple contributory causes of death occurring within a few weeks of an intake by ingestion. Animal data on the effects of (210)Po provide good confirmatory evidence of intakes and doses required to cause death within about 3 weeks. The conclusion is reached that 0.1-0.3 GBq or more absorbed to blood of an adult male is likely to be fatal within 1 month. This corresponds to ingestion of 1-3 GBq or more, assuming 10% absorption to blood. Well-characterised reductions in white cell counts would be observed. Bone marrow failure is likely to be compounded by damage caused by higher doses to other organs, including kidneys and liver. Even if the bone marrow could be rescued, damage to other organs can be expected to prove fatal.

Mayak Worker Study: An Improved Biokinetic Model for Reconstructing Doses from Internally Deposited Plutonium

Abstract Leggett, R. W., Eckerman, K. F., Khokhryakov, V. F., Suslova, K. G., Krahenbuhl, M. P. and Miller, S. C. Mayak Worker Study: An Improved Biokinetic Model for Reconstructing Doses from Internally Deposited Plutonium. Radiat. Res. 164, 111–122 (2005). The plutonium production facility known as the Mayak Production Association was put into operation in June 1948. A high incidence of cancer in the Mayak workers has been related to the level of exposure to plutonium, but uncertainties in tissue doses have hampered development of dose–risk relationships. As part of an effort to improve dose estimates for these workers, the systemic biokinetic model for plutonium currently recommended by the International Commission on Radiological Protection (ICRP) has been modified to reflect recently developed data and facilitate interpretation of case-specific information. This paper describes the proposed model and discusses its implications for dose reconstruction for the Mayak workers.

A physiologically based biokinetic model for cesium in the human body

A physiologically descriptive model of the biological behavior of cesium in the human body has been constructed around a detailed blood flow model. The rate of transfer from plasma into a tissue is determined by the blood perfusion rate and the tissue-specific extraction fraction of Cs during passage from arterial to venous plasma. Information on tissue-specific extraction of Cs is supplemented with information on the Cs analogues, K and Rb, and known patterns of discrimination between these metals by tissues. The rate of return from a tissue to plasma is estimated from the relative contents of Cs in plasma and the tissue at equilibrium as estimated from environmental studies. Transfers of Cs other than exchange between plasma and tissues (e.g. secretions into the gastrointestinal tract) are based on a combination of physiological considerations and empirical data on Cs or related elements. Model predictions are consistent with the sizable database on the time-dependent distribution and retention of radiocesium in the human body.

Fractional Absorption of Ingested Uranium in Humans

This paper provides a review and reanalysis of data relating to gastrointestinal (GI) uptake of uranium in humans. Estimates of GI uptake of uranium in adult humans have been derived from results of three controlled experimental studies involving short-term oral intake of an elevated quantity of uranium in fluids, from a controlled balance study conducted in a metabolic research ward of a hospital, and from a variety of environmental studies in which urinary uranium could be related to total intake or total excretion of this element in the same population. For controlled studies, uptake values range from less than 0.1% to about 6% for individual subjects, with central values for different studies falling in the range 1-2.4%. Environmental studies yield central estimates in the range 0.3-3.2%. Expressed as a percentage of total intake of uranium in food and fluids, average GI uptake of uranium in adult humans appears to be about 1-1.5%. Limited intake and excretion data for environmentally exposed human subjects > or = 5 y of age do not reveal important differences with age in uranium uptake, but more definitive information is needed for children. More information is also needed to determine whether fractional uptake of uranium increases with decreasing levels of intake and whether uptake from drinking water is substantially higher than uptake from food. Data for laboratory animals indicate that fractional uptake of uranium depends strongly on the chemical form ingested and the length of time since the last intake of food.

A model of the distribution and retention of tungsten in the human body

Expanding industrial and military uses of tungsten could result in substantially increased levels of this metal in the environment in the next few years. Although occupational experiences and available toxicological studies on laboratory animals suggest that tungsten may have a relatively low order of toxicity, the data are weak and inconclusive. There is a need not only for more systematic studies of the behavior and effects of tungsten in different animal species but also for a reliable, biologically realistic biokinetic model for tungsten in man that can be used to relate concentrations of this metal in environmental media to concentrations in tissues of exposed persons and translate results of experimental studies into terms of environmental exposures. This paper is intended as a first step toward development of such a biokinetic model. Information related to the biokinetics of tungsten in mammalian species is examined, a biologically meaningful compartmental model structure is proposed, provisional transfer rates between compartments are selected, areas are identified where additional biokinetic data on tungsten are most needed and suggestions are made for further research into the biokinetics of tungsten.

Prediction of renal concentrations of depleted uranium and radiation dose in gulf war veterans with embedded shrapnel

Mobilization of uranium (U) from embedded depleted uranium (DU) metal fragments in Gulf War veterans presents a unique exposure scenario for this radioactive and nephrotoxic metal. In a cohort of exposed veterans, urine U concentrations measured every two years since 1993 persistently range from 10 to over 500 times normal levels, indicating that embedded DU fragments give rise to chronic, systemic exposure to U. Health effects of this exposure are not fully known, but clinical surveillance of these soldiers continues in light of animal studies showing that U released from implanted DU pellets results in tissue accumulation of U. The biokinetic model for uranium recommended by the International Commission on Radiological Protection was used to predict kidney U concentrations and tissue radiation doses in veterans with DU shrapnel based on their urine U excretion. Results suggest that kidney U concentrations in some individuals reached their peak within six years after the war, while in others, concentrations continue to increase and are approaching 1 ppm after 10 y. These results are consistent with urine biomarker tests of renal proximal tubular cell function and cytotoxicity which have shown elevated mean urinary protein excretion indicative of functional effects in veterans with high urine U concentrations (≥0.10 &mgr;g g−1 creatinine). Predicted lifetime effective radiation dose from DU released to the blood for the highest exposed individual in this cohort was substantially less than the National Council on Radiation Protection (NCRP) limit for occupational exposure. These results provide further support for current health protection guidelines for DU, which are based on the metal’s chemical rather than its radiological toxicity. In light of the potential for continued accumulation of U in the kidney to concentrations approaching the traditional guidance level of 3 ppm U, these results indicate the need for continued surveillance of this population for evidence of developing renal dysfunction.

A systemic biokinetic model for polonium

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 210Po 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.

Strontium-90 in bone: a case study in age-dependent dosimetric modeling.

There is an increasing need for age-dependent dosimetric models, and it would be desirable to develop these models in such a way that the uniformity and basic features of the standard man models are retained. Unfortunately, available data concerning the age-dependent retention of nuclides would rarely permit the identification of compartments, uptake fractions, and clearance times using the empirical fitting methods that characterize the development of many adult models. However, in cases where compartments can be made to correspond to physically identifiable processes or subsections within an organ, it may be possible to combine relatively extensive information concerning the development of the human body with generally sparse nuclide-specific information to construct age-dependent compartmental models. In some cases there may be sufficient data to identify trends with age within compartments using empirical fitting techniques, provided the compartments have already been identified on physical bases. To obtain models that describe changes in a continuous manner from birth through adulthood, it may be necessary in many cases to modify existing adult models to consider fewer (or more easily identifiable) compartments. In this article we describe an age-dependent model for retention of ingested 90Sr in bone that exemplifies these concepts.

Mortality among Radiation Workers at Rocketdyne (Atomics International), 1948–1999

Abstract Boice, Jr., J. D., Cohen, S. S., Mumma, M. T., Ellis, E. D., Eckerman, K. F., Leggett, R. W., Boecker, B. B., Brill, A. B. and Henderson, B. E. Mortality among Radiation Workers at Rocketdyne (Atomics International), 1948–1999. Radiat. Res. 166, 98–115 (2006). A retrospective cohort mortality study was conducted of workers engaged in nuclear technology development and employed for at least 6 months at Rocketdyne (Atomics International) facilities in California, 1948–1999. Lifetime occupational doses were derived from company records and linkages with national dosimetry data sets. International Commission on Radiation Protection (ICRP) biokinetic models were used to estimate radiation doses to 16 organs or tissues after the intake of radionuclides. Standardized mortality ratios (SMRs) compared the observed numbers of deaths with those expected in the general population of California. Cox proportional hazards models were used to evaluate dose–response trends over categories of cumulative radiation dose, combining external and internal organ-specific doses. There were 5,801 radiation workers, including 2,232 monitored for radionuclide intakes. The mean dose from external radiation was 13.5 mSv (maximum 1 Sv); the mean lung dose from external and internal radiation combined was 19.0 mSv (maximum 3.6 Sv). Vital status was determined for 97.6% of the workers of whom 25.3% (n = 1,468) had died. The average period of observation was 27.9 years. All cancers taken together (SMR 0.93; 95% CI 0.84–1.02) and all leukemia excluding chronic lymphocytic leukemia (CLL) (SMR 1.21; 95% CI 0.69–1.97) were not significantly elevated. No SMR was significantly increased for any cancer or for any other cause of death. The Cox regression analyses revealed no significant dose–response trends for any cancer. For all cancers excluding leukemia, the RR at 100 mSv was estimated as 1.00 (95% CI 0.81–1.24), and for all leukemia excluding CLL it was 1.34 (95% CI 0.73–2.45). The nonsignificant increase in leukemia (excluding CLL) was in accord with expectation from other radiation studies, but a similar nonsignificant increase in CLL (a malignancy not found to be associated with radiation) tempers a causal interpretation. Radiation exposure has not caused a detectable increase in cancer deaths in this population, but results are limited by small numbers and relatively low career doses.

A physiological systems model for iodine for use in radiation protection.

Abstract This paper summarizes the biokinetic database for iodine in the human body and proposes a biokinetic model for systemic iodine for use in dose assessments for internally deposited radioiodine. The model consolidates and extends existing physiological systems models describing three subsystems of the iodine cycle in the body: circulating inorganic iodide, thyroidal iodine (trapping and organic binding of iodide and synthesis, storage and secretion of thyroid hormones), and extrathyroidal organic iodine. Thyroidal uptake of inorganic iodide is described as a function of stable iodine intake (Y, µg day−1) and thyroidal secretion of hormonal iodine (S, µg day−1). Baseline parameter values are developed for reference adults with typical iodine intake. Compared with the current systemic biokinetic model of the International Commission on Radiological Protection (ICRP) for occupational intake of radioiodine, the proposed model predicts higher absorbed doses to the thyroid per unit uptake to blood for very short-lived iodine isotopes, similar absorbed doses to thyroid for iodine isotopes with half-life of at least a few hours, and substantially higher estimates of absorbed dose to stomach wall, salivary gland and kidneys for most iodine isotopes. Absorbed dose estimates for intravenous administration of radioiodine-labeled thyroid hormones based on the proposed model differ substantially in some cases from current ICRP values.