Biomedical subjects

R B Richardson

Publications and source records attributed to R B Richardson.

At least 19 recordsLinked to original sources

PubMed2001

Review of the ICRP tritium and 14C internal dosimetry models and their implementation in the Genmod-PC code.

Biokinetic models for tritium and 14C compounds, as described by various ICRP publications, have been incorporated into the Genmod-PC internal dosimetry code. This work reviews the models for tritium and 14C labeled compounds that the ICRP has formulated over several decades. The ICRP dosimetry prescribed for hydrogen and carbon radionuclides is fundamentally different from that recommended for other elements in that it is based on retention functions for whole body activity instead of compartmental biokinetic models. The ICRP recommends dosimetric methods for tritium and 14C compounds, ten of which are coded in Genmod-PC as compartmental models, namely, five tritium compounds, e.g., tritiated water, tritium gas, and five 14C compounds, e.g., carbon dioxide, carbon-labeled methane. The values of the Genmod-PC calculated dose coefficients were compared with the ICRP's values. It is shown how the dose coefficients for intakes of tritium and 14C compounds are affected by different interpretations of the methods recommended by the ICRP for two of the three classes of vapors and gases. Some aspects of the ICRP models, such as the percent oxidized, would benefit from reconsideration so as to produce tritium and 14C biokinetics that are less dependent on the radionuclide.

Carbon Radioisotopes↗

PubMed2001

Influence of gender differences in the carbon pool on dose factors for intakes of tritium and 14C-labeled compounds.

The ICRP's biokinetic models for five tritium-labeled and five 14C-labeled compounds (not including radiopharmaceutical compounds and excepting carbon monoxide) incorporate a compartment representing the body carbon pool. Using the ICRP models, as coded into the Genmod-PC internal dosimetry code, higher dose coefficients are calculated for females than for ICRP's Reference Man. The ICRP's committed effective dose coefficients for the ingestion of tritiated water and organically bound tritium by the adult male are 1.8 x 10(-11) and 4.2 x 10(-11) Sv Bq(-1), respectively. Using the Genmod-PC code, the corresponding dose coefficients for the adult female are 2.2 x 10(-11) and 6.2 x 10(-11) Sv Bq(-1), which are 25% and 46% greater than the adult male's. Similarly, the ICRP's dose coefficient is 5.8 x 10(-10) Sv Bq(-11) for an intake of organically bound 14C by the adult male, and the estimated dose coefficient using Genmod is 54% greater for the adult female. The carbon retention half-time for an average adult female is calculated as 51 d and that for an average adult male, 38 d; the latter is similar to the carbon half-time of 40 d recommended by International Commission on Radiological Protection (ICRP). The longer turnover time of whole body carbon in females is one factor that causes the dose coefficients for females to be higher than those of males; a second factor is the smaller whole body mass of ICRP's Reference Woman compared to Reference Man.

Carbon Radioisotopes↗

PubMed2001

Dose to lung from inhaled tritiated particles.

Tritiated particulate materials are of potential hazard in fission, fusion, and other tritium handling facilities. The absorbed fractions (fraction of energy emitted that is absorbed by the target region) are calculated for tritiated particles deposited in the alveolar-interstitial (AI) region of the respiratory tract. The energy absorbed by radiologically sensitive tissue irradiated by tritiated particles, in regions of the lung other than in the AI region, is negligible. The ICRP Publication 71 assumes the absorbed fraction is unity for tritium deposited in the AI region. We employed Monte Carlo methods in a model to evaluate the energy deposition in the wall of the alveolar sac from particles of tritiated beryllium, tritiated graphite, titanium tritide, tritiated iron hydroxide and zirconium tritide. For the five materials examined, the absorbed fraction in alveolar tissue ranged from 0.31 to 0.61 for particles of 1 microm physical diameter and 0.07 to 0.21 for 5 microm diameter particles. The dose to alveolar tissue, for an acute inhalation of tritiated particles by an adult male worker, was calculated based on the ICRP 66 lung model and the particle dissolution model of Mercer (1967). For particles of 5 microm activity median aerodynamic diameter (AMAD), the committed equivalent dose to alveolar tissue, calculated for the five materials, ranged from 32-42%, respectively, of the committed equivalent dose derived assuming the absorbed fractions were unity.

Administration, Inhalation↗

PubMed2000

Dose to the cell nucleus from exposure to tritiated pump oil or formaldehyde.

A Monte Carlo simulation of tritium decays in a cell composed of two parts, a nucleus and surrounding cytoplasm, was developed to evaluate the beta-radiation dose to the nucleus. A dose modifying factor (DMF), which is a ratio of the average nuclear dose to the whole-tissue dose, after skin-contact exposure of rats to tritiated pump oil or tritiated formaldehyde was estimated. Biokinetic data characterizing the retention of tritium in liver were available in the form of tritium-specific activities and biological half-times for tritiated water and five macromolecular species (DNA, RNA, acid-soluble fraction, acid-insoluble protein, and lipids). The spatial distribution of tissue-free water and macromolecular species in the nucleus and cytoplasm of rat liver cells was based on published data. In the case of exposure to tritiated pump oil, tritium incorporated into lipids provides the largest percentage (60%) of the absorbed dose to the nucleus. For the tritiated-formaldehyde exposure, the tritium dose to the nucleus is overwhelmingly contributed by tritiated water (58%) and in acid-insoluble proteins (40%). For both these tritiated organic exposures, the tritium-labeled DNA has a negligible effect on the DMF. The DMF for the tritiated pump oil and formaldehyde exposures was estimated as 0.81 and 1.05, respectively: the DMF of both exposures was close to unity. Given the other uncertainties in tritium dosimetry, our results suggest that for these skin-contact exposures a uniform distribution of tritium in tissue is an adequate assumption for dosimetry.

Animals↗

PubMed1998

Computer simulation of inspiratory nasal airflow and inhaled gas uptake in a rhesus monkey.

There is increasing evidence that inspiratory airflow patterns play a major role in determining the location of nasal lesions induced in rats by reactive, water-soluble gases such as formaldehyde and chlorine. Characteristic lesion patterns have also been seen in inhalation toxicity studies conducted in rhesus monkeys, the nasal anatomy of which resembles that of humans. To examine the hypothesis that regions of high airflow-dependent uptake and lesions occur in similar nasal locations in the primate, airflow and gas uptake patterns were simulated in an anatomically accurate computer model of the right nasal airway of a rhesus monkey. The results of finite-element simulations of steady-state inspiratory nasal airflow for the full range of resting physiological flow rates are reported. Simulated airflow patterns agreed well with experimental observations, exhibiting secondary flows in the anterior nose and streamlined flow posteriorly. Simulated airflow results were used to predict gas transport to the nasal passage walls using formaldehyde as an example compound. Results from the uptake simulations were compared with published observations of formaldehyde-induced nasal lesions in rhesus monkeys and indicated a strong correspondence between airflow-dependent transport patterns and local lesion sites. This rhesus computer model will provide a means for confirming the extrapolation of toxicity data between species by extrapolating rat simulation results to monkeys and comparing these predictions with primate lesion data.

Air Movements↗

PubMed1997

Correlation of regional formaldehyde flux predictions with the distribution of formaldehyde-induced squamous metaplasia in F344 rat nasal passages.

Squamous epithelium lines the nasal vestibule of the rat, rhesus monkey, and human. Respiratory, transitional, and olfactory epithelia line most areas posterior to the nasal vestibule. Inhaled formaldehyde gas induces squamous metaplasia posterior to the nasal vestibule and does not induce lesions in the nasal vestibule in rats and rhesus monkeys, indicating that squamous epithelium is resistant to irritant effects of formaldehyde and that squamous metaplasia may be an adaptive response. If squamous metaplasia is determined by formaldehyde dosimetry rather than by tissue-specific factors, squamous epithelium may be protective by absorbing less formaldehyde than other epithelial types. In a previous study, a three-dimensional, anatomically accurate computational fluid dynamics (CFD) model of the anterior F344 rat nasal passages was used to simulate inspiratory airflow and inhaled formaldehyde transport. The present study consisted of two related parts. First, the rat CFD model was used to test the hypothesis that the distribution of formaldehyde-induced squamous metaplasia is related to the location of high-flux regions posterior to squamous epithelium. Regional formaldehyde flux into nonsquamous epithelium predicted by the CFD model correlated with regional incidence of formaldehyde-induced squamous metaplasia on the airway perimeter of one cross-sectional level of the noses of F344 rats exposed to 10 and 15 ppm formaldehyde gas for 6 months. Formaldehyde flux into nonsquamous epithelium was estimated to vary by an order of magnitude depending on the degree of formaldehyde absorption by squamous epithelium. These results indicate that the degree to which squamous epithelium absorbs formaldehyde strongly affects the rate and extent of the progression of squamous metaplasia with continued exposure to formaldehyde. In the second part of this study, the CFD model was used to predict squamous metaplasia progression. Data needs for verification of this model prediction are considered. These results indicate that information on the permeability of squamous epithelium in rats, monkeys, and humans is important for accurate prediction of uptake in regions posterior to the nasal vestibule.

Administration, Inhalation↗

PubMed1997

Computer simulation of inspiratory airflow in all regions of the F344 rat nasal passages.

Data from laboratory animal experiments are often used in setting guidelines for safe levels of human exposure to inhaled materials. The F344 rat has been used extensively in laboratory experiments to determine effects of exposure to inhaled materials in the nasal passages. Many inhaled materials induce toxic responses in the olfactory (posterior) region of the rat nasal passages. The location of major airflow routes has been proposed as playing a dominant role in determining some olfactory lesion location patterns. Since nasal airflow patterns differ significantly among species, methods are needed to assess conditions under which these differences may significantly affect extrapolation of the effects of local dose in animals to potential disease outcome in humans. A computational fluid dynamics model of airflow and inhaled gas uptake has been used to predict dose to airway walls in the anterior F344 rat nasal passages (Kimbell et al., Toxicol. Appl. Pharmacol., 1993; 121, 253-263). To determine the role of nasal airflow patterns in affecting olfactory lesion distribution, this model was extended to include the olfactory region. Serial-step histological sections of the nasal passages of a F344 rat were used to construct the computer model. Simulations of inspiratory airflow throughout the rat nasal passages were consistent with previously reported experimental data. Four of the five major simulated flow streams present in the anterior nose (dorsal lateral, middle, ventral lateral, and ventral medial streams) flowed together to exit ventrally at the nasopharyngeal duct, bypassing the ethmoid recesses. The remaining dorsal medial stream split to flow both medially and laterally through the olfactory-epithelium-lined ethmoid recesses in a Z-shaped pattern when viewed sagitally. Simulated flow in the ethmoid recesses was more than an order of magnitude slower than flow in the anterior and ventral parts of the nasal passages. Somewhat higher volumes of flow were predicted in the dorsal medial stream when the nasal vestibule was reshaped to be upturned, and more flow was allocated to the dorsal medial stream with increased inspiratory airflow rate, suggesting that rats may be able to allocate more airflow to this stream by both modifying the shape of the nasal vestibule and increasing inhaled air velocity during sniffing. The present study provides the first description of flow in the complex olfactory region of the nose of the F344 rat. This model will be used to evaluate the role of airflow patterns in determining the distribution of xenobiotically induced olfactory mucosal lesions. This information, combined with models of disposition in the airway lining, will provide comprehensive dosimetry models for extrapolating animal response data to humans.

Animals↗

PubMed1997

Dose contribution from metabolized organically bound tritium after acute tritiated water intakes in humans.

Urine samples from eight male radiation workers who had an unplanned acute tritiated water intake were measured for tritium-in-urine up to 300 d post-exposure. During the first month or so post-exposure, these individuals increased their fluid intakes to accelerate the turnover rate of tritium in the body for dose mitigation. Their daily fluid intakes reverted to normal levels in the latter period of the study. A non-linear regressional analysis of the tritium-in-urine data showed that the average biological half-life of tritium in body water, with standard deviation, was 6.3 +/- 1.0 d (range, 5.0-8.1 d) and 8.4 +/- 2.0 d (range, 6.2-12.8 d) during the respective periods of increased fluid intake and the later period of normal fluid intake. A longer term component of tritium excretion was also observed with average biological half-life of 74 +/- 18 d (range, 58-104 d), indicating the incorporation of tritium, and its retention, in the organic fractions of the body. A mathematical model was developed and used to estimate the dose increase from the metabolized organically bound tritium on the basis of the kinetics of tritium-in-urine. The model accounts for a change in the rates of urinary excretion caused by variable fluid intakes. The average dose to the body, for the eight male workers, due to the metabolized organically bound tritium was estimated to be 6.2 +/- 1.3% (range, 3.5% to 8.9%) of the committed effective dose due to tritium in the body water. This value for the dose increase from organically bound tritium is in the range of the current recommendations of the International Commission on Radiological Protection, i.e., organically bound tritium incorporated into the body contributes about 10% of the dose to the body water following tritiated water intakes.

Adult↗

PubMed1995

Reconstruction of complex passageways for simulations of transport phenomena: development of a graphical user interface for biological applications.

Flow of fluids, such as blood, lymph and air, plays a major role in the normal physiology of all living organisms. Within individual organ systems, flow fields may significantly influence the transport of solutes, including nutrients and chemical toxicants, to and from the confining vessel walls (epithelia and endothelia). Computational fluid dynamics (CFD) provides a potentially useful tool for biologists and toxicologists investigating solute disposition in these flow fields in both normal and disease states. Application of CFD is dependent upon generation of accurate representations of the geometry of the system of interest in the form of a computational reconstruction. The present investigations, which were based on studies of the toxicology of inhaled reactive gases in the respiratory tract of rodents, provide computer programs for the generation of finite element meshes from serial tissue cross-sections. These programs, which interface with a commercial finite element fluid dynamics simulation package (FIDAP 7.05, Fluid Dynamics International, Evanston, IL), permit simulation of fluid flow in the complex geometries and local solute mass flux to the vessel walls of biological systems. The use of these programs and their application to studies of respiratory tract toxicology are described.

Algorithms↗

PubMed1995

Mortality of iron foundry workers: IV. Analysis of a subcohort exposed to formaldehyde.

In the final phase of the mortality study of workers at an automotive iron foundry, a subset (N = 3929) of the original cohort of 8147 men, consisting of those exposed to formaldehyde during the period from January 1960 through May 1987, was analyzed. In addition to the external US population, an internal population (N = 2032), consisting of men who had worked in the same foundry during the same time period but not in formaldehyde-exposed jobs, was also used as a referent. Follow-up continued through December 31, 1989. Smoking status was ascertained for 65.4% of the exposed and for 55.1% of the unexposed cohorts. Detailed work histories and evaluation of occupational exposures by an industrial hygienist enabled us to categorize cumulative formaldehyde and silica exposures. Standardized mortality ratios were used to compare the mortality experience of the exposed cohort with the US population and, because of concerns about the healthy worker effect, with an occupational referent population. Relative risks for race, formaldehyde exposure status, smoking status, and silica exposure level were estimated by fitting a Poisson regression model to four causes of death: cancers of the buccal cavity and pharynx, lung cancer, diseases of the respiratory system, and emphysema. No association between formaldehyde exposure and deaths from malignant or nonmalignant diseases of the respiratory system was found. Cigarette smoking and silica exposure were found to be significantly associated with deaths attributed to lung cancer and disease of the respiratory system.

Adolescent↗

PubMed1994

Mortality of iron foundry workers. III. Lung cancer case-control study.

A nested case-control study was undertaken to identify the determinants of lung cancer mortality in a cohort of 8147 foundry men among whom an excess of lung cancer deaths was previously observed. The present study consisted of all lung cancer deaths (N = 220) that occurred within this cohort between 1950 and 1989. both living and dead controls, matched on race and attained age, were selected in the ratio of 10:1 (N = 2200) by means of the incidence density sampling procedure. All cases and two controls per case, randomly selected from each case's 10 controls, were included in a smoking history survey. Basic smoking history information was obtained for about 71% of these study subjects. For the purpose of this study, formaldehyde exposure levels were categorized as high, medium, low, and none. Airborne silica exposure was categorized only as high, medium, and low levels, because all foundry workers were known to be exposed to silica. Conditional logistic regression analyses indicated that cigarette smoking was a strong predictor of lung cancer mortality in this cohort. Neither exposure to formaldehyde nor silica exposure level, nor employment in any of the six major work areas within the foundry, showed an association with lung cancer.

Aged↗

PubMed1992

Mortality of iron foundry workers. II. Analysis by work area.

Plantwide analyses of the mortality experience of 8147 foundrymen revealed excesses for several diseases including lung cancer. Using indirect measures of smoking, it appeared that most, if not all, of the excess of lung cancer deaths could be explained by smoking habits. To explore further the possible association between these mortality excesses and foundry exposures, jobs were grouped into six work areas on the basis of similarities in production processes. The findings of analyses by work areas support the inferences from plantwide observations. No evidence was found of a relationship between lung cancer and foundry exposures. The pattern of mortality from emphysema and cerebrovascular disease in the different work areas paralleled that of lung cancer, suggesting that mortality from these diseases may have been influenced by a common etiologic agent, probably tobacco smoke. The data also reveal possible associations between metal pattern-making and colon cancer, silica or metal dust and stomach cancer, and carbon monoxide and ischemic heart disease.

Adult↗

PubMed1991

Dose to red bone marrow from natural radon and thoron exposure.

The age-dependent radiation dose to the haematopoietic tissue of bone marrow has been calculated for exposure to radon, thoron and their daughter products. The component of dose due to pure radon is dependent on the fat content of the marrow, since the solubility of radon in fat is about 16 times that in tissue. The mean dose equivalent muSv to the total active marrow is estimated for a range of fat cell diameters from 25 to 200 microns, taking account of the percentage cellularity and distribution of active marrow as a function of age. Similarly, the dose due to the inhalation of short-lived radon daughters was estimated, based on measurements in blood and marrow, modified to allow for the greater deposition of daughter products expected in children. An estimate of the age-dependent dose from long-lived radon daughters was made from uranium miner and natural exposure data. Dose estimates were made for the average UK indoor exposure to radon gas of 20 Bq/m3 and an equilibrium equivalent thoron concentration of 0.3 Bq/m3. The annual radon and thoron derived dose to the active marrow of the newborn was calculated as 30 and 40 muSv, respectively. For a 10-year-old child, the radon and thoron derived annual dose are 70 and 40 muSv, and for a 40-year-old adult 90 and 30 muSv, respectively. The above values exhibit wide range limits due principally to uncertainties in the accumulation of 210Pb in bone, and 210Po in marrow. These data indicate that at the average UK exposure, the alpha-particle dose to active marrow is dominated by that derived from inhaled radon and thoron compared with dietary intake. In infants the dose is dominated by thoron daughters. At the UK radon Action Limit of 200 Bq/m3, the radon and associated thoron derived dose is similar to that from all low LET sources. This work shows that the dose to red bone marrow from radon and thoron is significant, and that the possibility of leukaemia induced by these radiation sources warrants further investigation.

Adipose Tissue↗

PubMed1990

Radon as a causative factor in induction of myeloid leukaemia and other cancers.

The international incidence of myeloid leukaemia, cancer of the kidney, melanoma, and certain childhood cancers all show significant correlation with radon exposure in the home. For myeloid leukaemia, analysis suggests that in the UK 6-12% of incidence may be attributed to radon. In Cornwall, where radon levels are higher, the range is 23-43%. For the world average radon exposure of 50 Bq.m-3, 13-25% of myeloid leukaemia at all ages may be caused by radon.

Adult↗

PubMed1990

Dosimetry of intrathecal iodine131 monoclonal antibody in cases of neoplastic meningitis.

Radioiodinated monoclonal antibodies (MCA) were administered by the lumbar route into the cerebrospinal fluid (CSF) of four patients with malignant leptomeningeal disease. Evidence suggesting uptake of 131I-MCA by tumour sites was seen in scintigrams. Dosimetry calculations were carried out, assuming that a proportion of the administered radionuclide was bound as a thin layer on the CSF surfaces of the meninges. The percentage injected dose and the clearance curves for the head and four spinal segments were obtained by scintigraphy after administration of tracer amounts of 131I-MCA (7-18 MBq). Although radioisotope levels in the central nervous system (CNS) fell, as determined by both external scintillation counting and direct CSF sampling, a marked difference in the measurements developed with respect to time. The ratio of these two measurements reached a maximum of 49:1, 7 days after monoclonal antibody administration. Patients subsequently received therapeutic amounts (870-1600 MBq) of 131I-MCAs, resulting in clinical remissions and prolonged survival. The mean absorbed radiation dose was estimated as 3.9 cGy.MBq-1 to the thoraco-lumbar region of the spine and 0.51 cGy.MBq-1 to the outer surface of the brain. The maximal dose delivered to the surface of the CNS in the region of the spine and brain was 5800 and 600 cGy, respectively.

Adult↗

PubMed1990

Intrathecal administration of 131I radiolabelled monoclonal antibody as a treatment for neoplastic meningitis.

Fifteen patients with neoplastic meningitis received a single intrathecal injection of between 11 and 60 mCi of a 131I radiolabelled monoclonal antibody (MoAb), chosen for its immunoreactivity to tumour. Major toxicity was manifest as nausea, vomiting and headache (7/15 patients), reversible bone marrow suppression (3/8 patients) and seizures (2/15 patients). Nine patients were evaluable for either a tumour or clinical response. Six of these demonstrated an event-free response that was maintained for periods of between 7 and 26 months.

Antibodies, Monoclonal↗

PubMed1990

Assigning race to occupational cohorts using census block statistics.

Race is an important determinant of disease frequency, yet the race of subjects in retrospective epidemiologic studies is frequently unknown. If addresses are available, the race of study subjects may be estimated from the racial composition of the blocks on which they have resided. Such information can be obtained from census block statistics for Standard Metropolitan Statistical Areas and, with the 1990 Census, probably for the entire United States. The authors assigned black race to persons on blocks with greater than 60% black residents and white race to those residing on blocks containing less than 40% blacks. The validity of the procedure was tested on 341 decedents of known race who resided at the time of death within the Detroit, Michigan, Standard Metropolitan Statistical Area. Thirteen individuals who lived on blocks with 40-60% blacks were excluded from analysis, as well as 18 others for whom racial composition of blocks could not be ascertained. In 293 (94%) of the remaining 310 persons, race assigned on the basis of census information agreed with race obtained from death certificates. This method should prove useful for assigning race to study subjects lacking racial identification.

Black or African American↗

PubMed1990

Mortality of iron foundry workers: I. Overall findings.

A retrospective cohort mortality study was conducted among 8147 men and 627 women employed in a gray iron foundry for at least 6 months between 1950 and 1979. More than 1700 deaths occurred during a 35-year period of observation. Standardized mortality ratios (SMRs) for all causes were close to expected values based on the US general population as the standard. The mortality of nonwhite men was significantly increased for lung cancer (SMR 132) and ischemic heart disease (SMR 126). Other moderate, but nonsignificant excesses were noted among nonwhite men for cancers of the stomach, pancreas, and prostate, for diabetes mellitus and pulmonary emphysema, and among white men for cancers of the lung and stomach, gastric and duodenal ulcers, pulmonary emphysema, and suicide. Small mortality increases were observed in both racial groups for cerebrovascular disease. The lack of a trend with time since hire and duration of foundry employment suggests that lung cancer mortality may not be associated with exposure to the foundry environment. Utilizing indirect measures of smoking, it appears that virtually all excess lung cancer deaths among whites and at least some of the excess among nonwhites could be explained by smoking habits. Similarly, smoking may have been responsible for the mortality excesses from emphysema, cerebrovascular diseases, and ischemic heart disease.

Adult↗