The HATM and HRTM: their future together.
Explore the source record for details and available documents.
Digestive System Physiological Phenomena↗
Biomedical subjects
R W Leggett
Publications and source records attributed to R W Leggett.
A respiratory model for uranium aluminide based on occupational data.
As part of an epidemiological study, doses from intake of radionuclides were estimated for workers employed during a 52-year period at the Rocketdyne/Atomics International facility in California. The facility was involved in a variety of research programmes, including nuclear fuel fabrication, spent nuclear fuel decladding, and reactor operation and disassembly. Most of the documented intakes involved inhalation of enriched uranium (U), fission products, or plutonium (Pu). Highest doses were estimated for a group of workers exposed to airborne uranium aluminide (UAl(x)) during the fabrication of reactor fuel plates. Much of the exposure to UAl(x) occurred early in the fuel fabrication programme, before it was recognised that intake and lung retention were being underestimated from urinary data due to an unexpected delayed dissolution of the inhaled material. In workers who had been removed from exposure, the rate of urinary excretion of U increased for a few months, peaked, and then declined at a rate consistent with moderately soluble material. This pattern differs markedly from the monotonically decreasing absorption rates represented by the default absorption types in the Human Respiratory Tract Model (HRTM) of the International Commission on Radiological Protection (ICRP). This paper summarises the findings on the behaviour of UAl(x) in these workers and describes material-specific parameter values of the HRTM based on this information.
Air Pollutants, Radioactive↗
Mayak worker study: an improved biokinetic model for reconstructing doses from internally deposited plutonium.
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.
Bone and Bones↗
A biokinetic model for carbon dioxide and bicarbonate.
A systemic biokinetic model is presented for radiocarbon taken into the body as carbon dioxide or bicarbonate. Parameter values describing retention and excretion of carbon during the first few weeks after administration are based on studies of the fate of radiocarbon in human subjects after injection of labelled bicarbonate or inhalation of carbon dioxide. Data on laboratory animals administered labelled bicarbonate, carbonate or carbon dioxide provide information on the tissue distribution and long-term retention of carbon. Model predictions of the time-dependent distribution and retention of carbon differ considerably from those of models recommended by the International Commission on Radiological Protection.
Administration, Oral↗
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.
Cesium↗
The biokinetics of uranium migrating from embedded DU fragments.
Military uses of depleted uranium (DU) munitions have resulted in casualties with embedded DU fragments. Assessment of radiological or chemical health risks from these fragments requires a model relating urinary U to the rate of migration of U from the fragments, and its accumulation in systemic tissues. A detailed biokinetic model for U has been published by the International Commission on Radiological Protection (ICRP), but its applicability to U migrating from embedded DU fragments is uncertain. Recently, Pellmar and colleagues (1999) conducted a study at the Armed Forces Radiobiology Research Institute (AFRRI) on the redistribution and toxicology of U in rats with implanted DU pellets, simulating embedded fragments. This paper compares the biokinetic data from that study with the behavior of commonly studied forms of U in rats (e.g., intravenously injected U nitrate). The comparisons indicate that the biokinetics of U migrating from embedded DU is similar to that of commonly studied forms of U with regard to long-term accumulation in kidneys, bone, and liver. The results provide limited support for the application of the ICRP's model to persons with embedded DU fragments. Additional information is needed with regard to the short-term behavior of migrating U and its accumulation in lymph nodes, brain, testicles, and other infrequently studied U repositories.
Animals↗
A generic biokinetic model for predicting the behaviour of the lanthanide elements in the human body.
Information on the biokinetics of the 15 elements of the lanthanide series, 57La to 71Lu, is too sparse to permit individual development of meaningful biokinetic models to describe the behaviour of each of the elements in humans. The lanthanides show a regular gradation in chemical properties across the series, and animal studies indicate that this is reflected in regular differences in their deposition in tissues such as the liver and skeleton. These regular differences in chemical and biological behaviour have been utilised to construct a generic lanthanide biokinetic model and to define element-specific parameters for each element in the series. This report describes the use of the available biokinetic data for humans and animals to derive the parameters for each of the elements.
Animals↗
Reliability of the ICRP's dose coefficients for members of the public. III. Plutonium as a case study of uncertainties in the systemic biokinetics of radionuclides.
This paper is a case study of the validity of different data sources and modelling approaches commonly used to build biokinetic models for radionuclides. The paper examines the basis and apparent predictive accuracy of each of the biokinetic models for Pu used over the years by the International Commission on Radiological Protection (ICRP), in view of recent improvements in the database. The results of this study and similar retrospective studies for other elements suggest the following five points. (1) Extrapolation of biokinetic data from laboratory animals to man is particularly uncertain for the liver due to qualitative differences among species in the handling of many elements by this organ. (2) As a 'default' approach to biokinetic modelling or model assessment, biokinetic data for unhealthy human subjects should be given higher weight than information extrapolated across animal species or chemical families, but there are counter-examples. (3) Little confidence can be placed in biokinetic model predictions for long times after exposure based solely on curve fits to short-term biokinetic data. (4) Bioassay and dosimetry models for a radionuclide should not be developed separately. (5) Where feasible, the systemic biokinetic model for a radionuclide should be developed within a physiologically realistic model structure, because this allows biokinetic data from experimental studies to be supplemented with physiological information, provides a basis for extrapolation of data across animals species or chemical families, results in models that can be used for both bioassay interpretation and dosimetry, and provides a logical basis for extrapolation of data to subgroups of the population (e.g., various ages) or to times outside the period of observation.
Body Burden↗
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.
Air Pollutants, Occupational↗
Reliability of the ICRP's dose coefficients for members of the public. 1. Sources of uncertainty in the biokinetic models.
During the decade following the Chernobyl accident, the International Commission on Radiological Protection (ICRP) developed dose coefficients (doses per unit intake) for ingestion or inhalation of radionuclides by members of the public. The level of uncertainty in those coefficients varies considerably from one radionuclide to another, due largely to differences in the level of understanding of the biological behaviour of different elements in the human body. This paper is the first in a series that examines the sources and extent of uncertainties in the ICRP's biokinetic and dosimetric models for members of the public and the dose coefficients derived from those models. The present paper describes the different types of information generally used to develop biokinetic models for radionuclides, the main sources of uncertainty associated with each type of information, and the approach used in subsequent papers in this series to quantify the uncertainties in biokinetic and dosimetric estimates.
Age Factors↗
Reliability of the ICRP's dose coefficients for members of the public, II. Uncertainties in the absorption of ingested radionuclides and the effect on dose estimates. International Comission on Radiological Protection.
Data on the gastrointestinal absorption of 12 elements have been reviewed. In each case, absorption is expressed as the fraction of the ingested element absorbed to blood, referred to as the f1 value, applying to intakes of unspecified chemical form by average population groups. The level of confidence in individual absorption values has been estimated in terms of lower and upper bounds, A and B, such that there is judged to be roughly a 90% probability that the true central value is no less than A and no greater than B. Ranges are proposed for intakes by adults, 10-year-old children and 3-month-old infants. Uncertainty in f1 values (B/A) ranged from 10% to factors of 100-400. The lowest uncertainties were for the well absorbed elements, H, I and Cs, for which there are good data, and the greatest uncertainties were for less well absorbed elements for which few data are available, particularly Zr and Sb. Ranges were generally wider for children and infants than for adults because of the need to allow for the likelihood of increased absorption with only limited data in support of the proposed values. The largest ranges were for 3-month-old infants, reflective lack of knowledge on the time-course and magnitude of possible increased absorption in the first few months of life. For each age group, ICRP values of absorption tend towards the upper bound of the ranges, indicating a degree of conservatism in th calculation of ingestion dose coefficients. Examination of the effect of the proposed confidence intervals for f1 values on uncertainties in dose coefficients for ingested radionuclides showed that there was no direct relationship. For some radionuclides, uncertainties in effective dose were small despite large uncertainties in f1 values while for others the uncertainties in effective doses approached the corresponding values for uncertainty in f1 values. These differences reflect the relative contributions to effective dose from cumulative activity in the contents of the alimentary tract, which in many cases is insensitive to uncertainties in f1, and cumulative activity of the absorbed radionuclide in systemic tissues, which is proportional to f1. In general, uncertainties in effective close for children and infants exceeded those in adults as a result of greater uncertainties in f1 values for the younger age groups. However, this effect was reduced in some cases by shorter retention times of absorbed nuclides in body tissues and organs.
Adult↗
A model for the transfer of alkaline earth elements to the fetus.
A biokinetic model has been developed for the transfer of calcium, strontium, barium and radium to the human fetus. For the mother, ICRP models were adapted for pregnancy to include increases in gastrointestinal absorption, urinary excretion and bone turnover rates. The fetus was modelled with blood, soft tissue and bone compartments. Fetal requirements for Ca were determined by skeletal calcification, and recyling between fetal and maternal blood was inlcluded. Daily transfer of Sr, Ba and Ra to the fetus was taken to be lower than for Ca by factors of 0.6 for Sr and 0.4 for Ba and Ra. For acute intakes in late pregnancy at 35 weeks after conception, when maximum transfer occurs, the model predicts whole-body fetus:mother concentration ratios (C(F):C(M)) of 18 for Ca, 8 for Sr and 2 for Ba and Ra, respectively. Estimates of committed equivalent doses to the red bone marrow of offspring, including in utero and postnatal dose, after maternal ingestion in late pregnancy, were greater than corresponding doses in adults by factors of 20-31 for 45Ca, 2-3 for 90Sr and 3-4 for 226Ra but slightly lower (0.8-1.9) for 133Ba.
Barium↗
Proposed revision of the ICRP model for inhaled mercury vapor.
A critical review of the literature on the biokinetics of inhaled mercury vapor was performed as part of an accident analysis for the Spallation Neutron Source to be built at Oak Ridge National Laboratory. It was concluded that current models for inhaled mercury vapor do not accurately describe the distribution or residence time of mercury deposited in the respiratory tract. This paper proposes a model that is more consistent with collective information on the fate of inhaled mercury vapor in laboratory animals and human subjects. Compared with the model currently recommended by the International Commission on Radiological Protection (ICRP), the proposed model predicts lower deposition in the bronchi and bronchioles, greater deposition in the alveolar-interstitial region, and a different pattern of absorption to blood. The proposed model yields substantially reduced estimates of lung dose and effective dose for most radioisotopes of mercury inhaled as mercury vapor.
Animals↗
The ICRP age-specific biokinetic model for lead: validations, empirical comparisons, and explorations.
The objective of this manuscript is to provide a description of the International Commission for Radiation Protection (ICRP) model and a comparison to other models (the integrated exposure uptake biokinetic [IEUBK] and O'Flaherty models), including the software used with the models, and a comparison of the model predictions for selected situations. The ICRP biokinetic model for Pb is a multicompartmental model for Pb uptake and disposition in children and in adults. The model describes deposition and retention of absorbed Pb in numerous tissues, removal from tissues to plasma, and movement along various routes of excretion. Long-term skeletal behavior of Pb is described in terms of age-specific rates of restructuring of compact and trabecular bone. The ICRP model is more flexible and has wider applicability than the IEUBK model. The major disadvantages are that application of the computer model requires some basic computer skills, and the user must convert the Pb concentrations in food, air, soil, dust, paint, or other media to the amount of Pb ingested or inhaled per day. Direct comparisons between the ICRP model and the IEUBK model are provided by modeling blood Pb levels using the IEUBK v0.99d default Pb uptakes and intake values. The model is used to simulate occupational exposure cases and a controlled Pb inhalation experiment in adult humans. Finally, use of the model to explore situations with limited data is illustrated by simulating the kinetics and disposition of Pb during acute Pb poisoning and chelation therapy in a child.
Animals↗
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.
Environmental Exposure↗
Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity.
We have previously observed that Sp1, a ubiquitous zinc finger transcription factor, is phosphorylated during terminal differentiation in the whole animal, and this results in decreased DNA binding activity (Leggett, R. W., Armstrong, S. A., Barry, D., and Mueller, C. R. (1995) J. Biol. Chem. 270, 25879-25884). In this study, we demonstrate that casein kinase II (CKII) is able to phosphorylate the C terminus of Sp1 and results in a decrease in DNA binding activity. This suggests that CKII may be responsible for the observed regulation of Sp1. Mutation of a consensus CKII site at amino acid 579, within the second zinc finger, eliminates phosphorylation of this site and the CKII-mediated inhibition of Sp1 binding. Phosphopeptide analysis confirms the presence of a CKII site at Thr-579 as well as additional sites within the C terminus. No gross changes in CKII subunit levels were seen during de-differentiation associated with liver regeneration. The serine/threonine phosphatase PP1 was identified as the endogenous liver nuclear protein able to dephosphorylate Sp1 but again no gross changes in activity were observed in the regenerating liver. Okadaic acid treatment of K562 cells increases Sp1 phosphorylation and inhibits its DNA binding activity suggesting that steady state levels of Sp1 phosphorylation are established by a balance between kinase and phosphatase activities.
Amino Acid Sequence↗
Basis and implications of the ICRP's new biokinetic model for thorium. International Commission on Radiological Protection.
The International Commission on Radiological Protection (ICRP) has adopted a new, age-specific biokinetic model for thorium, along with new assumptions concerning the fate of radioactive progeny produced in the body after intake of thorium. This paper explains the basis for the model and assumptions and examines some of their implications with regard to radiation dosimetry and bioassay. The new model differs substantially from the ICRP's previous biokinetic model for thorium (introduced in 1979 in ICRP Publication 30) with regard to model structure, sources of data used to derive parameter values, predictions of integrated activities of long-lived thorium isotopes in some radiosensitive organs, and predictions of the rates of urinary and fecal excretion of thorium at times remote from exposure. For the case of injection of 232Th into blood of an adult, the new model and assumptions yield 4- to 8-fold decreases in predictions of 50-y committed equivalent doses to radiosensitive skeletal tissues but 7- to 55-fold increases in predictions of committed equivalent doses to extra-skeletal tissues, compared with the model and treatment of decay chain members recommended in ICRP Publication 30.
Adult↗
Sp1 is phosphorylated and its DNA binding activity down-regulated upon terminal differentiation of the liver.
Using nuclear extracts prepared from rat liver it was demonstrated that binding of a transcription factor to site II of the D-site binding protein promoter could be induced by dephosphorylation of these extracts. Competition band shifts and supershift assays reveal this protein to be the general transcription factor Sp1. Phosphorylation of Sp1 appears to occur as a result of terminal differentiation of the liver. Proteins from both 1-day-old rat liver and adult liver undergoing regeneration have less of the phosphorylated form of Sp1 present with consequent increased DNA binding activity. Sp1 is similarly phosphorylated in brain, kidney, and spleen with phosphatase treatment of the extracts significantly increasing the level of DNA binding activity. Dephosphorylation of Sp1 results in a 10-fold increase in the affinity of Sp1 for its cognate site. Two-dimensional gel electrophoresis reveals that approximately 20% of the detectable protein appears to be in the phosphorylated form in adult liver extracts. Another protein with similar characteristics also appears to be present in the liver. Decreasing Sp1 DNA binding activity by phosphorylation may be an important mechanism for regulating gene expression, and possibly bringing about growth arrest during terminal differentiation.
Animals↗