Carcinogenicity of radon/radon decay product inhalation in rats--effect of dose, dose rate and unattached fraction.

PURPOSE: The effects of inhalation of radon/radon decay products at different total doses, dose rates and 'unattached' fractions were investigated in a life span study in rats. MATERIALS AND METHODS: 1574 rats inhaled radon/radon decay products in a purpose-built recirculating exposure system that provided stable/reproducible exposure conditions. 501 were maintained as controls. RESULTS: Lung tumour incidences were significantly elevated in most exposed groups. The study power was insufficient to resolve the shape of the dose and dose rate response curves, but combination of this data with that from other studies demonstrated that for high cumulative exposures, the lifetime excess absolute risk increases with increasing exposure durations and for low cumulative exposures the opposite trend occurs. Exposure did not increase leukaemia incidences. A small number of non-lung tumour types including mammary fibroadenoma showed elevated incidences in some exposed groups, however not consistently across all exposure groups and showed no dose or dose rate relationship. CONCLUSIONS: Radon/radon decay product exposure caused excess lung tumours in rats along with limited non-lung effects. The results are consistent with the findings that at low cumulative exposures decreasing exposure concentrations or protracting the time over which the dose is delivered, reduces lung tumour risk. At higher levels, decreasing exposure concentrations or protracting exposure time increases lung tumour risk.

Lung tumour risk in radon-exposed rats from different experiments: comparative analysis with biologically based models.

Data sets of radon-exposed male rats from Wistar and Sprague-Dawley strains have been investigated with two different versions of the two-step clonal expansion (TSCE) model of carcinogenesis. These so-called initiation-promotion (IP) and initiation-transformation (IT) models are named after the cell-based processes that are assumed to be induced by radiation. The analysis was done with all malignant lung tumours taken to be incidental and with fatal tumours alone. For all tumours treated as incidental, both models could explain the tumour incidence data equally well. Owing to its better fit, only the IP model was applied in the analysis of fatal tumours that carry additional information on the time when they cause death. A statistical test rejected the hypothesis that a joint cohort of Wistar and Sprague-Dawley rats can be described with the same set of model parameters. Thus, the risk analysis has been carried out for the Wistar rats and the Sprague-Dawley rats separately and has been restricted to fatal tumours alone because of their similar effect in humans. Using a refined technique of age-adjustment, the lifetime excess absolute risk has been standardised with the survival function from competing risks in the control population. The age-adjusted excess risks for both strains of rats were of similar size, for animals with first exposure later in life they decreased markedly. For high cumulative exposure the excess risk increased with longer exposure duration, for low cumulative exposure it showed the opposite trend. In addition, high cumulative exposure exerted lethal effects other than lung cancer on the rats.

Carcinogenicity studies after intraperitoneal injection of two types of stone wool fibres in rats.

A summary is given of the pathology results after intraperitoneal (i.p.) injection in rats of insulation wool HT, representing the new biosoluble types. The pathology results are compared with a previously conducted i.p. study with traditional stone wool D6 (with similar chemical composition to MMVF21). The HT fibre is characterized by a relatively high content of aluminium and a relatively low content of silica compared to MMVF21. HT has a high in vitro dissolution rate at pH 4.5, a relatively low dissolution rate at pH 7.5 and is less biopersistent than the MMVF21 fibre. Female Wistar rats received a dose of 2 x 10(9) WHO HT fibres by i.p. injection. The fibres had been size-selected to be largely rat respirable. The negative control group was exposed to saline. Following exposure, the animals were maintained until survival in one group fell below 20%. At this time, all animals were killed. All animals were subjected to a necropsy examination; any gross abnormalities observed at necropsy were subjected to histopathological examination. In addition, histopathology was carried out on a predefined list of tissues. The incidences of lesions and survival in the control and fibre dosed animals were compared using appropriate statistical methods to determine whether the dosed animals showed adverse effects on survival or a positive carcinogenic response. The main protocol for the previously conducted study with D6 (MMVF21) was similar, but the animals were maintained as long as they survived, and the WHO fibre dose was lower. The results of the comparative study showed a marked difference in the i.p. pathogenicity of D6 (MMVF21) and HT in terms of their carcinogenic potential. D6 (MMVF21) caused a statistically significant increase of mesotheliomas in the peritoneal cavity compared to the negative control, but the HT fibre did not cause any mesotheliomas or any increase in other tumour types.

Developments in radar and remote-sensing methods for measuring and forecasting rainfall.

Over the last 25 years or so, weather-radar networks have become an integral part of operational meteorological observing systems. While measurements of rainfall made using radar systems have been used qualitatively by weather forecasters, and by some operational hydrologists, acceptance has been limited as a consequence of uncertainties in the quality of the data. Nevertheless, new algorithms for improving the accuracy of radar measurements of rainfall have been developed, including the potential to calibrate radars using the measurements of attenuation on microwave telecommunications links. Likewise, ways of assimilating these data into both meteorological and hydrological models are being developed. In this paper we review the current accuracy of radar estimates of rainfall, pointing out those approaches to the improvement of accuracy which are likely to be most successful operationally. Comment is made on the usefulness of satellite data for estimating rainfall in a flood-forecasting context. Finally, problems in coping with the error characteristics of all these data using both simple schemes and more complex four-dimensional variational analysis are being addressed, and are discussed briefly in this paper.

Revised organ partition of thorium-232 in thorotrast patients.

Risk estimates for internally deposited alpha particles in humans, such as those for alpha-particle-induced leukemia, have been derived from data on the toxicity of (232)Th in patients injected with Thorotrast. Their derivation requires both epidemiological data and organ doses calculated from the volume of Thorotrast injected and a knowledge of its pattern of deposition within the body. However, accumulating evidence suggests that the organ partition of (232)Th that has commonly been used for dosimetry (i.e. liver:spleen:red bone marrow: others tissues = 59:29:9:3) is inaccurate. In the present study, the organ distribution of (232)Th has been recalculated using a revised averaging method and both published data and our own unpublished data. For the three major organs of deposition (liver, spleen and bone marrow), activity concentration data were selected from 27 published papers and data sets including 140 newly compiled Japanese cases. For organs of minor storage, both published data for 38 German and 24 Japanese autopsy cases and new data were used. The revised estimate of the relative partition of (232)Th among the above organs was 53:14:25:8. It follows that doses calculated to date are essentially correct for the liver but are too high for the spleen and about three times too low for the red bone marrow. This suggests that the risk of alpha-particle-induced leukemia, per unit of alpha-particle dose, in Thorotrast patients is about three times lower than previously thought.

Effects of continuous inhalation exposure of rats to radon and its progeny at various levels of dose and dose rate: interim results.

Studies of rats at Harwell and CEA [Monchaux et al., Radiat. Res. 152 (Suppl.), S137-S140, 1999] are currently in progress to determine the factors affecting the risk of induction of lung tumors after exposure to radon and radon progeny. Knowledge of the effect of dose, dose rate and characteristics of the aerosol on lung tumor induction in rats may be used to improve estimates of risk from domestic exposure. At Harwell, three studies are in progress, studying the effect of dose, dose rate, and dose rate at low total exposures. Approximately 2000 adult male rats have been exposed. A small number of rats were taken to determine deposition in the respiratory tract and the early effects of exposure on cell proliferation and nuclear aberrations. The remaining animals have been held for their life span. To date 65% of the animals in the first study have been examined. Current results (for 421 rats) suggest that exposure to radon and radon progeny causes elevated incidences of both benign and malignant lung tumors. These findings are based on incomplete tumor incidences. Competing causes of death may affect the results, and full statistical analysis is required before firm conclusions can be drawn about the effect of dose and dose rate.

Thunderstorm-related asthma--the epidemic of 24/25 June 1994.

BACKGROUND: A large epidemic of asthma occurred following a thunderstorm in southern and central England on 24/25 June 1994. A collaborative study group was formed. OBJECTIVES: To describe the epidemic and the meteorological, aerobiological and other environmental characteristics associated with it. METHODS: Collation of data from the Meteorological Office, the Pollen Research Unit, the Department of the Environment's Automatic Urban Network, from health surveillance by the Department of Health and the National Poisons Unit, from clinical experience in general practice and hospitals, and from an immunological study of some of the affected cases from north east London. RESULTS: The thunderstorm was a Mesoscale Convective System, an unusual and large form of storm with several centres and severe wind gusts. It occurred shortly after the peak grass pollen concentration in the London area. A sudden and extensive epidemic occurred within about an hour affecting possibly several thousand patients. Emergency services were stretched but the epidemic did not last long. Cases had high serum levels of IgE antibody to mixed grass pollen. CONCLUSION: This study supports the view that patients with specific IgE to grass pollen are at risk of thunderstorm-related asthma. The details of the causal pathway from storm to asthma attack are not clear. Case-control and time series studies are being carried out.

Comparison of biopersistence of experimental glass fibres in the lung and peritoneal cavity.

Thirty three female Fischer-344 rats were intra-peritoneally (IP) injected with 5 mg of an experimental glass fibre designated X7753. This fibre type had an in vitro dissolution rate of 600 ng cm-2h-1. Groups of three rats were killed at various times up to one year after injection. The diaphragm and any fibre nodules were removed from the carcass and separately digested using hypochlorite solution, to recover the fibres. The number and morphometry of the fibres was measured using phase contrast optical microscopy (PCOM) and semi-automatic image analysis. The data obtained were compared to the previous studies of the durability of the X7753 fibres in the lung.

The durability and distribution of glass fibres in the rat following intra-peritoneal injection.

Intra-peritoneal (IP) injection is being recommended as a means of assessing potential carcinogenicity of MMF following inhalation. Little is known of the behaviour of fibres in the peritoneal cavity or its relevance to the lung. This study considered both the biopersistence and the distribution of dose following IP injection of fibres. Biopersistence of fibres in the peritoneal cavity has been compared with that observed previously in the lung. Marked differences were found, with long fibres (> 20 microns) being more durable in the peritoneal cavity than in the lung. Breakage could not account for this finding, whereas differences in dissolution could. The behaviour of fibres and powders and their distribution in the peritoneal cavity following injection of different masses is reported. Distribution of dose depended on injection mass, with masses of < 1.5 mg showing even uptake onto the surfaces of the peritoneal organs, and higher masses resulting in the development of nodules of injection material, free in the peritoneal cavity, or loosely bound to the peritoneum. With fine powder, some clearance was observed over the first 48 h after IP injection, but not with fibres. The findings on both durability and distribution of dose following IP injection have implications on the justification for the use of IP injections in assessment of potential carcinogenicity of fibres following inhalation.

Preliminary data from investigations of the in vivo biopersistence of three experimental glass fibres of varying chemical composition.

The durability of three experimental glass fibres (X7753, X7484, and X7779) was investigated in vivo. These fibres had in vitro dissolution rates of 600, 150, and 2 ng cm-2 hour-1, respectively. Three groups of female Fischer-344 rats were intratracheally instilled with a 1.2 mg suspension of one of each of the fibre types. All fibres had previously been neutron activated, to produce radioactive 24Na within the glass, which served as a radiotracer. At 2 days post instillation (PI) about 1 x 10(6) glass fibres were within the pulmonary region of the lung. Animals were killed at various time points from 2 to 360 days PI. Fibres were recovered from the animal lungs by hypochlorite digestion. The retention and morphometry of these fibres was investigated, and preliminary results are presented. After 360 days in the lung, the number of X7753 and X7484 fibres fell respectively to 10% and 50% of those present at 2 days PI. There was no detectable reduction in the number of X7779 fibres in the lung over this period. Morphometric analyses demonstrated a 53% and 22% reduction in the mean length of the X7753 and X7484 fibres, after 360 days in the lung. Reduction in diameter was apparent after only 28 days for the these fibre types. No change in the mean size of the X7779 fibres was observed during the study. The fibre morphometry data suggested that short fibres dissolved at a slower rate than long fibres. In general the in vivo fibre retention and morphometry data reflected the measured in vitro dissolution rate.

The behavior of glass fibers in the rat following intraperitoneal injection.

Potential carcinogenicity of fibers is believed to be determined by three factors: the dose, dimensions and durability of the fibers concerned. Currently there is considerable debate on the appropriateness of using results from intraperitoneal (i.p.) injection studies to predict the potential carcinogenicity of airborne fibers following inhalation. For ip results to have any significance to potential inhalation hazards, there should be some relation between the biopersistence, dose, and dose distribution of fibers in the serosal cavity and in the lung. Preliminary results on the durability of one experimental glass fiber in the peritoneal cavity suggest differences in dissolution when compared with durability in the lung. In the lung, the diameters of the long fibers (> 20 microns) were observed to decline at a rate consistent with their exposure to a neutral pH environment. The diameter of shorter fibers declined much more slowly, consistent with exposure to a more acidic environment such as is found in the phagolysosomes of alveolar macrophages. In the peritoneal cavity all fibers, regardless of length, dissolved at the same rate as short fibers in the lung. The effect of dose on the distribution of fibers in the peritoneal cavity was investigated using similar experimental glass fibers and compared with that of a powder made from ground fibers. For both materials at doses up to 1.5 mg, material was taken up by the peritoneal organs roughly in proportion to their surface area. This uptake was complete 1-2 days after injection. At higher doses, the majority of the material in excess of this 1.5 mg formed clumps of fibers (nodules) which were either free in the peritoneal cavity or loosely bound to peritoneal organs. These nodules displayed classic foreign body reactions with an associated granulomatous inflammatory response. The findings on both durability in the peritoneal cavity and the presence of two distinct populations of material following i.p. injection have implications for the justification of the use of i.p. injections to assess potential carcinogenicity of fibers following inhalation.

Changes in the rat lung after exposure to radon and its progeny: effects on incorporation of bromodeoxyuridine in epithelial cells and on the incidence of nuclear aberrations in alveolar macrophages.

The aim of this study was to investigate some responses of cells in the rat respiratory tract as a function of time after inhalation exposure to various levels of radon and its progeny. Rats were exposed to a constant concentration of radon and its progeny to give cumulative exposure levels of 120, 225, 440 and 990 working level months (WLM). An additional unexposed group of rats served as controls. The end points selected for investigation were (a) the incorporation of bromodeoxyuridine (BrdU) in epithelial cells of the conducting airways and of the alveolar region of the respiratory tract and (b) the incidence of alveolar macrophages with nuclear aberrations. After exposure, the incidence of epithelial cells incorporating BrdU--the labeling index--increased in all regions of the respiratory tract examined, but the increase occurred later in alveolar than in airway epithelial cells. The highest labeling index was found in bronchial epithelial cells, which probably received the highest radiation dose. After an initial induction period, the incidence of alveolar macrophages with nuclear aberrations also increased. The possibility of using the labeling index of alveolar and airway epithelial cells, and/or the incidence of nuclear aberrations in alveolar macrophages, to estimate the radiation dose to various regions of the respiratory tract after exposure of rats to radon and its progeny is discussed.

A radioactive tracer technique to determine in vivo the number of fibers in the lungs of rats following their administration by intratracheal instillation.

A radioactive tracer technique is described which enables the total number of fibers present in the lungs of rats to be estimated following administration of the fibers by intratracheal instillation. The glass fiber used in the study was irradiated with thermal neutrons to induce radioactive 24Na. A suspension of the radioactive fiber was administered to eight rats by intratracheal instillation and to two additional rats by intraesophageal instillation. The 24Na radioactivity in the rats was counted in vivo at 24 and 48 hr after administration, after which they were killed. The amounts of fiber in the lungs, in the gastrointestinal tracts, and excreted in feces were estimated radiometrically. On average 93% of the administered fiber was accounted for. The lungs were digested with sodium hypochlorite solution and aliquots of the resulting digest filtered through membrane filters which were clear for examination by phase-contrast optical microscopy (PCOM). The numbers of fibers in the lungs, estimated by PCOM, were well correlated with the in vivo counting rates at 48 hr, indicating that the latter can be used to provide an accurate index of the number of fibers retained in the lung at that time.

Distribution of glass fibers in the peritoneal cavity of the rat following administration by intraperitoneal injection.

The distribution of glass fibers in the peritoneal cavity of the rat was investigated at 2, 24, and 48 h following intraperitoneal injection of 1 mg of material using a radioactive tracer technique. At each time point the peritoneal cavities of the rats killed were lavaged with 20 ml of physiological saline to recover fibers not yet attached to tissue surfaces. At 2 h, 35% of the administered fiber could be recovered by lavage, but at 48 h this was reduced to 2%. At 48 h, the amount of fiber associated with the abdominal organs and the abdominal wall was roughly in proportion to their surface areas. The weight of fiber associated with the various tissues was in the following order: gastrointestinal tract > liver > carcass (abdominal wall) > diaphragm > urogenital tract > spleen > kidneys. Differential counts on cells recovered by lavage were made both on cytocentrifuge slides and by flow cytometry. Compared with controls, the numbers of cells recovered from treated rats at 24 and 48 h were increased by a factor of about 2, due mainly to an influx of neutrophils into the peritoneal cavity. There was a marked reduction in the proportion of mast cells compared to controls.

Radiological implications of inhaled 239Pu and 241Am in dusts at the former nuclear test site in Maralinga.

The biokinetics of 239Pu and 241Am present in three dust samples obtained from Maralinga were investigated after their deposition in the rat lung. Results were used as an experimental basis for assessing the radiological implications for human exposure. The transfer rates of these actinides to blood in the various dusts differed by 50-fold. The most transportable forms were compatible with a material that had 25% class W and 75% class Y characteristics. The doses per unit intake for adults, children, and infants exposed to an aerosol of 5 microns AMAD were calculated to be, respectively, 0.059, 0.076, and 0.140 mSv Bq-1. The corresponding doses for the least transportable forms were the same as those calculated for a class Y compound, namely 0.036, 0.049, and 0.096 mSv Bq-1. The behavior of the actinides in humans was predicted by combining the transfer rates to blood with mechanical clearance data obtained after volunteers had inhaled 85Sr or 88Y labeled fused aluminosilicate particles. The results suggested that monitoring of 241Am in the chest could be used to advantage for assessing intakes incurred by workers involved with any further decontamination procedures but would be of little practical value for assessing inadvertent public exposure. The paper includes comments on the relevance of the 1990 ICRP recommendations and the proposed new dosimetric model for the respiratory tract.

Factors affecting the in vitro dissolution of cobalt oxide.

In a recent interspecies comparison of the lung clearance of cobalt oxide (57Co3O4), differences of up to 4-fold were found in the translocation rates of 57Co to blood between seven different animal species, including man. This study investigated some factors that could influence the dissolution of this material in vitro. The effect of bicarbonate and citrate concentrations (over physiological ranges) and medium pH on in vitro dissolution of 57Co from 57Co3O4 particles was measured in a simple noncellular system. pH levels of 4.5, 6.1, and 7.2 were used to correspond to those in the alveolar macrophage lysosome, its cytoplasm, and the extracellular lung fluid. Measurements of the fractional dissolution rate were made weekly for 3 months. pH had the greatest effect on dissolution rates, with particles suspended in the lowest pH medium (4.5) dissolving at a significantly faster rate than at higher pH values. Increasing citrate concentrations resulted in slightly higher dissolution rates, but there was no effect of bicarbonate concentration. There was no evidence of synergism between the factors studied.

Weather conditions prior to major outbreaks of meningococcal meningitis in the United Kingdom.

Meningitis has been a notifiable disease in the United Kingdom for some 70 years. Only in recent years, stimulated by the work of the Meningitis Trust, has there been a more general awareness of the geographical distribution of cases, with certain locations being more prone than others to episodic outbreaks of the disease. In this paper we consider weather conditions prior to major outbreaks of meningitis in Hereford and Worcester, and Cleveland and the northwest Midlands. Possible causal links to air quality and large temporal changes of relative humidity are found from analysis of case data. However, whilst the diagnostic studies reported are encouraging, an independent test of the relative humidity gradient criterion using independent data for Gloucester was not successful. It is clear that meteorological and air quality data actually of the area from which the disease is reported must be analysed more fully to sustain or overrule the hypothesis proposed. In addition, the need for further clinical research into the likelihood of disease triggers generated by atmospheric smoke, dust and moisture is identified.