Biomedical subjects

K Donaldson

Publications and source records attributed to K Donaldson.

At least 37 records · Page 2Linked to original sources

PubMed2000

Asthma and PM10.

PM10 (the mass of particles present in the air having a 50% cutoff for particles with an aerodynamic diameter of 10 microm) is the standard measure of particulate air pollution used worldwide. Epidemiological studies suggest that asthma symptoms can be worsened by increases in the levels of PM10. Epidemiological evidence at present indicates that PM10 increases do not raise the chances of initial sensitisation and induction of disease, although further research is warranted. PM10 is a complex mixture of particle types and has many components and there is no general agreement regarding which component(s) could lead to exacerbations of asthma. However pro-inflammatory effects of transition metals, hydrocarbons, ultrafine particles and endotoxin, all present to varying degrees in PM10, could be important. An understanding of the role of the different components of PM10 in exacerbating asthma is essential before proper risk assessment can be undertaken leading to advice on risk management for the many asthmatics who are exposed to air pollution particles.

Air Pollution↗

PubMed2000

Effects of the aromatase inhibitor anastrozole on serum oestrogens in Japanese and Caucasian women.

PURPOSE: Substantial differences in plasma oestrogen disposition have been reported between Japanese and Caucasian women, but there are currently few data available on the relative endocrinological effects of aromatase inhibitors in these two groups. Hence, the effects of the nonsteroidal aromatase inhibitor anastrozole on serum oestrogen concentrations were compared in 24 healthy postmenopausal Japanese women and 24 healthy postmenopausal Caucasian women. METHODS: Anastrozole, 1 mg/day, was given once daily for 16 days. Serum oestradiol and oestrone sulphate levels were measured on three consecutive days beginning 2 days before the first dose, and on a further three consecutive days beginning on the penultimate day of dosing. Trough concentrations of anastrozole (measured 24 h after dosing) were also determined during the same periods. RESULTS: There were no substantial differences in plasma oestrogen concentrations between the Japanese and Caucasian women at baseline. On average, anastrozole suppressed serum oestradiol and oestrone sulphate levels by approximately 87% and 93%, respectively, for both Japanese and Caucasian women, and minimum plasma anastrozole concentrations at steady-state (anastrozole C(min)) were also similar in both groups. Statistical analysis of serum oestradiol and serum oestrone sulphate levels, and plasma anastrozole C(min) showed that there were no statistically significant differences between the Japanese and Caucasian women. CONCLUSION: Neither the pharmacodynamic effects of anastrozole on serum oestrogens nor the pharmacokinetics of anastrozole differ between postmenopausal Japanese and Caucasian women. Hence, these findings suggest that the therapeutic benefits of anastrozole in Caucasians will be predictive of the drug's effect in Japanese women and support the use of anastrozole in postmenopausal Japanese women with breast cancer.

Aged↗

PubMed2000

Release of TNFalpha in response to SiC fibres: differential effects in rodent and human primary macrophages, and in macrophage-like cell lines.

Asbestos has been implicated in the pathogenesis of several lung diseases, but its mechanism of action is not fully understood. However, asbestos-induced oxidative stress and production of inflammatory cytokines may play a significant role. TNFalpha is an inflammatory cytokine which has a central role in inflammation and fibrosis due to its ability to stimulate fibroblasts and collagen deposition. In this study, a panel of fibres designated either pathogenic or non-pathogenic in recent animal studies, were utilized. The amount of TNFalpha released after a 16-hour exposure to the panel of fibres was compared in four different cell types; two primary macrophage cell types and two cell lines. TNFalpha release by cells exposed to the panel did not equate to pathogenicity, although the most pathogenic fibre caused three out of the four cell types tested, to produce the greatest amount of TNFalpha. Primary rat cells and primary human cells behaved in a similar manner as regards to TNFalpha production; the cell lines behaved quite differently to their primary counterparts with regards to TNFalpha production in this study.

Animals↗

PubMed2000

Increased calcium influx in a monocytic cell line on exposure to ultrafine carbon black.

Ultrafine particles have been shown to induce pro-inflammatory effects both in vivo and in vitro. Increased expression of pro-inflammatory genes probably requires the activation of specific transcription factors such as nuclear factor kappa B (NF-kappaB) via a number of possible pathways including Ca2+ and reactive oxygen species. The fluorescent dye fura 2, was used to measure cytosolic Ca2+ in the human monocytic cell line, Monomac 6 on exposure to 66 microg x mL(-1) of either ultrafine carbon black (ufCB; diameter 14 nm), carbon black (CB; diameter 260 nm), quartz (diameter 1.45 microm), or medium alone. UfCB but not fine CB induced a 1.6-fold increase (p<0.01) in the resting cytosolic Ca2+ concentration of Monomac 6 cells. In addition ufCB induced a 2.6-fold increase (p<0.001) in the response to the endoplasmic reticulum Ca2+- adenosine triphosphatase (ATPase) inhibitor, thapsigargin, suggesting the Ca2+ release-activated Ca2+ current across the plasma membrane was enhanced. This response was inhibited by the removal of extracellular Ca2+ and by the Ca2+ channel blocker, verapamil. In addition, ufCB stimulated the entry of extracellular Mn2+. Finally, the antioxidants mannitol and nacystelin both inhibited the effects of ufCB on the response to thapsigargin. These data suggest that ultrafine carbon black particles stimulated an increase in cytosolic Ca2+, possibly through the entry of extracellular Ca2+ via Ca2+ channels in the plasma membrane. The particles may in part activate the opening of Ca2+ channels via a mechanism involving reactive oxygen species.

Calcium↗

PubMed2000

Inhalation of poorly soluble particles. I. Differences in inflammatory response and clearance during exposure.

Results from animal studies have indicated some uncertainties over the validity of a single general occupational control limit for all types of "particulates (insoluble) not otherwise classified" (PNOC) (ACGIH, 2000). Therefore, to examine the extent to which a given control limit may be valid for nontoxic dusts with different physical characteristics, this study compared the pulmonary effects in rats of inhalation exposure to two poorly soluble dusts of similar density and with relatively low toxicity: titanium dioxide and barium sulfate. The objectives were to compare the dusts in (a) their buildup and clearance in the lungs during inhalation; (b) their transfer to lymph nodes; (c) the changes, with time, in the lavageable cell population; and (d) the pathological change from histology. The exposure aerosol concentrations were selected to achieve similar mass and volume lung burdens for both dusts and to attain "overload" over the common exposure periods of about 4 mo and 7 mo. Despite obtaining similar lung burdens for both dusts, there was significantly more translocation of TiO(2) to the hilar lymph nodes than with BaSO(4). It was also found that clearance of TiO(2) was retarded whereas clearance of BaSO(4) was not. Trends in these data were clarified by the use of a simple model of particle clearance. Retardation of particle clearance and translocation to the lymph nodes are markers of the condition known as "overload" in which the alveolar macrophage-based clearance of particles from the deep lung is impaired. In addition, bronchoalveolar lavage showed that TiO(2) caused significantly more recruitment of inflammatory neutrophils to lungs than BaSO(4). These differences between the dusts were not due to differences in toxicity, solubility, or lung deposition. The explanation that the different responses are due to the different particle size distributions of the two dust types is examined in a companion paper (Tran et al., this issue).

Administration, Inhalation↗

PubMed2000

Inhalation of poorly soluble particles. II. Influence Of particle surface area on inflammation and clearance.

In this article the volumetric overload hypothesis, which predicts the impairment of clearance of particles deposited in the lung in terms of particle volume, is reevaluated. The degree to which simple expressions of retained lung burden explain pulmonary responses to overload was investigated using data from a series of chronic inhalation experiments on rats with two poorly soluble dusts, titanium dioxide and barium sulfate. The results indicated that the difference between the dusts in the level of inflammation and translocation to the lymph nodes could be explained most simply when the lung burden was expressed as total particle surface area. The shape of the statistical relationship for both lung responses indicated the presence of a threshold at approximately 200-300 cm(2) of lung burden. On the basis of this and other similar results, a hypothesis regarding a generic mechanism for the impairment of clearance and associated lung responses is proposed for such "low-toxicity" dusts.

Administration, Inhalation↗

PubMed2000

Increased inflammation and intracellular calcium caused by ultrafine carbon black is independent of transition metals or other soluble components.

OBJECTIVES: Particulate air pollution has been shown to cause adverse health effects, and the ultrafine particle component has been implicated. The aim of the present study was to investigate whether an ultrafine particle exerted its effects through transition metals or other soluble factors released from the surface of the particles. METHODS: Both in vitro and in vivo models were used to test the imflammogenicity of carbon black (CB) and ultrafine carbon black (UfCB) and the role of transition metals was investigated by treating the particles with desferrioxamine mesylate (desferal), a transition metal chelator. Rats were instilled with particles and the cell population assessed by bronchoalveolar lavage (BAL). Calcium homeostasis in macrophages was assessed with a fluorimetric technique. RESULTS: UfCB was inflammogenic compared with CB when instilled into Wistar rat lungs, an effect which could not be ameliorated by desferal treatment of the particles. Particle leachates produced no significant inflammation in vivo. In vitro experiments showed that the cytosolic calcium ion concentration in Mono Mac 6 cells was increased significantly after UfCB treatment and treatment of particles with desferal did not alter these effects. Particle leachates had no effect on cytosolic calcium ion concentration. Iron was not detected in leachates of the particles with the desferal assay, however, ng/mg of particles were detectable in citrate leachates with inductively coupled plasma-mass spectrometry (ICP-MS). CONCLUSIONS: The increased inflammogenicity of UfCB compared with CB cannot be explained by soluble transition metals released from or by accumulation of iron at the particle surface. Differences may be accounted for by increased surface area or particle number.

Air Pollutants↗

PubMed2000

In vitro toxicology of respirable Montserrat volcanic ash.

OBJECTIVES: In July 1995 the Soufriere Hills volcano on the island of Montserrat began to erupt. Preliminary reports showed that the ash contained a substantial respirable component and a large percentage of the toxic silica polymorph, cristobalite. In this study the cytotoxicity of three respirable Montserrat volcanic ash (MVA) samples was investigated: M1 from a single explosive event, M2 accumulated ash predominantly derived from pyroclastic flows, and M3 from a single pyroclastic flow. These were compared with the relatively inert dust TiO(2) and the known toxic quartz dust, DQ12. METHODS: Surface area of the particles was measured with the Brunauer, Emmet, and Teller (BET) adsorption method and cristobalite content of MVA was determined by x ray diffraction (XRD). After exposure to particles, the metabolic competence of the epithelial cell line A549 was assessed to determine cytotoxic effects. The ability of the particles to induce sheep blood erythrocyte haemolysis was used to assess surface reactivity. RESULTS: Treatment with either MVA, quartz, or titanium dioxide decreased A549 epithelial cell metabolic competence as measured by ability to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On addition of mannitol, the cytotoxic effect was significantly less with M1, quartz, and TiO(2). All MVA samples induced a dose dependent increase in haemolysis, which, although less than the haemolysis induced by quartz, was significantly greater than that induced by TiO(2). Addition of mannitol and superoxide dismutase (SOD) significantly reduced the haemolytic activity only of M1, but not M2 or M3, the samples derived from predominantly pyroclastic flow events. CONCLUSIONS: Neither the cristobalite content nor the surface area of the MVA samples correlated with observed in vitro reactivity. A role for reactive oxygen species could only be shown in the cytotoxicity of M1, which was the only sample derived from a purely explosive event. These results suggest that in general the bioreactivity of MVA samples in vitro is low compared with pure quartz, but that the bioreactivity and mechanisms of biological interaction may vary according to the ash source.

Adsorption↗

PubMed2000

Regulation of lipopolysaccharide-mediated interleukin-1beta release by N-acetylcysteine in THP-1 cells.

Increased levels of inflammatory cytokines such as interleukin (IL)-1 and IL-8 occur in the bronchoalveolar lavage fluid in various lung diseases. Cytokine gene expression is controlled by transcription factors such as nuclear factor-kappaB (NF-kappaB) which can be activated by a number of stimuli including the oxidants prevent. It was hypothesized that lipopolysaccharide (LPS)-induced IL-1beta secretion may be modulated by the intracellular thiol redox status of the cells. The effect of the antioxidant compound, N-acetyl-L-cysteine (NAC), on IL-1beta release and regulation of NF-kappaB in a human myelo-monocytic cell line (THP-1) differentiated into macrophages was studied. LPS (10 microg x mL(-1)) increased IL-1beta release at 24 h compared to control levels (p<0.001). NAC (5 mM) also enhanced LPS-induced IL-1beta release from THP-1 cells (p<0.001). In addition, treatment of cells with cycloheximide, an inhibitor of protein synthesis, inhibited the NAC-mediated IL-1beta release. Under the same conditions, NF-kappaB binding was activated by LPS and NAC increased this LPS-mediated effect. Western blot analysis revealed that NAC treatment leads to an increase in p50 and p65 protein synthesis. These data indicate that N-acetyl-L-cysteine modulates interleukin-1kappa release by increasing levels of the homo- and heterodimeric forms of nuclear factor-kappaB.

Acetylcysteine↗

PubMed2000

Exacerbations of COPD: environmental mechanisms.

Air pollution as a trigger for exacerbations of COPD has been recognized for > 50 years, and has led to the development of air quality standards in many countries that substantially decreased the levels of air pollutants derived from the burning of fossil fuels, such as black smoke and sulfur dioxide. However, the recent dramatic increase in motor vehicle traffic has produced a relative increase in the levels of newer pollutants, such as ozone and fine-particulate air pollution < 10 microm in diameter. Numerous epidemiologic studies have shown associations between the levels of these air pollutants and adverse health effects, such as exacerbations of airways diseases and even deaths from respiratory and cardiovascular causes. Elucidation of the mechanism of the harmful effects of these pollutants should allow improved risk assessment for patients with airways diseases who are be susceptible to the effects of these air pollutants.

Air Pollutants↗

PubMed2000

Depletion of glutathione and ascorbate in lung lining fluid by respirable fibres.

OBJECTIVE: The use of synthetic vitreous fibres has increased along with a decline in the utilisation of asbestos. There remains concern that these synthetic fibres pose a health risk to workers because of the generation of respirable fibres which can enter the lung and cause adverse health effects. An improved understanding of the mechanism of fibre pathogenicity should allow more rational short-term testing regimes for new fibres as they are developed. We hypothesised that carcinogenic fibres have greater free radical activity compared with non-carcinogenic fibres and that they contribute to disease by causing oxidative stress in the lung. We examined a panel of respirable fibres, designated as being carcinogenic or non-carcinogenic based on previous animal studies for ability to deplete antioxidants from lung lining fluid. METHODS: On the basis of inhalation studies, a panel of fibres was divided into three carcinogenic fibres-amosite asbestos, silicon carbide, and refractory ceramic fibre 1 (RCF1) and three non-carcinogenic fibres-man-made vitreous fibre 10 (a glass fibre MMVF10), Code 100/475 glass fibre, and refractory ceramic fibre 4 (RCF4). We measured the levels of glutathione (GSH) and ascorbate, two antioxidants present in lung lining fluid (LLF) after fibre treatment. All of the experiments were carried out at equal fibre number. RESULTS: Fibres had the ability to deplete both GSH and ascorbate from both LLF and pure solutions, an effect which was fibre number dependent. The greatest depletion of antioxidants was observed with the two non-carcinogenic glass fibres, and this effect was observed when A549 lung epithelial cells were treated with fibres. CONCLUSIONS: Our results show that antioxidant depletion in cell free solution and lung lining fluid solely is not a simple indicator of the ability of fibres to cause lung pathology and that other biological events in the lung are involved.

Analysis of Variance↗

PubMed2000

How can ultrafine particles be responsible for increased mortality?

The link between particulate air pollution at relatively low levels and adverse effects both in the lungs and of the cardiovascular system remains a puzzling event. The authors have developed a hypothesis which suggests that ultrafine components of particulate air pollution may result in local and systemic oxidative stress, which produces lung inflammation, but also the systemic effects, resulting in mortality in susceptible individuals from cerebrovascular disease. Preliminary data in vitro and in vivo suggest that both local and systemic oxidative stress occur in response to ultrafine particles and that the effects of such oxidative stress on pro-inflammatory gene regulation and changes in blood coagulation may result in the adverse effects of particulate air pollution. In this article, the evidence which supports this hypothesis is reviewed.

Air Pollutants↗

PubMed1999

Induction of nuclear translocation of NF-kappaB in epithelial cells by respirable mineral fibres.

A panel of mineral fibres has been studied for their ability to cause translocation of the transcription factor NF-kappaB to the nucleus in A549 lung epithelial cells. On the basis of inhalation studies, three fibres were designated as being carcinogenic-amosite asbestos, silicon carbide and refractory ceramic fibre 1 (RCF1)-or non-carcinogenic-man-made vitreous fibre (MMVF10), Code 100/475 glass fibre, and RCF4. The experiments were carried out at equal fibre number. It was hypothesized that carcinogenic fibres have greater free radical activity than non-carcinogenic fibres and that an oxidative stress produced in the lung after inhalation of fibres could cause translocation of the transcription factor NF-kappaB to the nucleus, where transcription of pro-inflammatory genes such as cytokines could occur. It was demonstrated that a simple oxidant, hydrogen peroxide, caused translocation in a time- and dose-dependent manner. The three carcinogenic fibres produced a significant dose-dependent translocation of NF-kappaB to the nucleus, whereas the non-carcinogenic fibres did not. Silicon carbide fibres were the most potent of the pathogenic fibres. MMVF10 was the most potent of the non-pathogenic fibres, causing significant nuclear translocation of NF-kappaB at high fibre number. Using three antioxidants, curcumin, pyrrolidine dithiocarbamate, and Nacystelin, translocation caused by carcinogenic fibres could be significantly reduced. The present study shows that a short-term in vitro assay can discriminate between pathogenic and non-pathogenic fibres in terms of a key pro-inflammatory event in epithelial cells. The mechanism of the activation of NF-kappaB by pathogenic fibres and its general applicability to other fibre types remain to be determined.

Antioxidants↗

PubMed1999

Mathematical modeling of the retention and clearance of low-toxicity particles in the lung.

A mathematical model has been formulated to describe the mechanisms that determine the retention or clearance of insoluble inhaled particles in the rat lung. The hypotheses underlying the model are described-for example, the phagocytosis of free particles by macrophages, the transport of particles in macrophages from the alveolar region, the effect of the life cycle of macrophages leading to the eventual release of phagocytosed particles, the effect of lung burden on the macrophage activity, the transport of particles into the interstitium, the role of interstitial macrophages, the formation of granulomata, and transport of interstitialized particles to the thoracic lymph nodes. With these hypotheses, the fate of particles is described mechanistically via the cellular response of the lung. The mathematical model expresses these particle transitions as differential equations quantifying the transport of particles from one compartment to another, where the compartments represent the alveolar surface, the alveolar macrophages, overloaded alveolar macrophages, the interstitium, interstitial macrophages, and the thoracic lymph nodes. A companion article describes the application of the model to a data set from rats exposed to a low-toxicity dust at several concentrations and for a range of exposure times.

Algorithms↗

PubMed1999

Exploration of the mechanisms of retention and clearance of low-toxicity particles in the rat lung using a mathematical model.

A mathematical model of the mechanisms of clearance or retention of inhaled particles in rat lungs is used to explore the extent to which a hypothesized sequence of events (including phagocytosis, macrophage-mediated clearance, transfer into the interstitium, transfer to lymph nodes, and overloading of the defense mechanisms) can account for data from a series of inhalation experiments with a low-toxicity, insoluble dust-titanium dioxide, TiO(2). These data include mean lung burdens and mean lymph-node burdens in groups of rats exposed to concentrations of 1, 10, 30, 50, and 90 mg m(-3), with exposure periods for as long as 2 yr (at 10 mg m(-3)), up to 7 mo at 50 mg m(-3), and 3.5 mo at 1 and 30 mg m(-3). The estimation of the parameters in the model is based mainly on information from other experimental studies or prior modeling. Values within the biologically plausible range were evaluated for the main parameters by inspection of predictions in comparison with data from the lowest concentration experiments. The suitability of the selected values was then confirmed by comparison of model predictions with data from the higher concentration experiments (at 30, 50, and 90 mg m(-3)). During inhalation, clearance rates are affected by translocation of dust and by overloading. The characterization of overload appears to describe these experiments well. Comparison with the effect of lung burden reported for other types of particles supports the hypothesis that overload is more dependent on the volume rather than the mass of the particles.

Air Pollutants↗

PubMed1999

Short-term inflammatory responses following intratracheal instillation of fine and ultrafine carbon black in rats.

Ultrafine carbon black (ufCB) 14 nm in diameter and fine carbon black (CB) 260 nm in diameter were instilled intratracheally in rats at mass of 125 microg, and the bronchoalveolar lavage (BAL) profile at 6 h was assessed. UfCB generated a 50% neutrophil alveolitis 6 h after intratracheal instillation compared to CB, which showed similar activity to the phosphate-buffered saline (PBS) vehicle control. UfCB instillation also produced a marked increase in lactate dehydrogenase (LDH) levels in BAL fluid, which was associated with increased epithelial permeability measured as total protein. In contrast, CB had much less of an effect in increasing BAL protein. Although both particle types caused a decrease in glutathione (GSH) in lung tissue compared to control, the greatest depletion was seen in ufCB-treated animals. To investigate time response, bronchoalveolar lavage was carried out at 6 h, 24 h, and 7 days after a single 125-microg instillation of ufCB. Neutrophil influx was relatively persistent and was still maintained 7 days later. Tumor necrosis factor (TNF) production by BAL leukocytes increased gradually postinstillation, whereas NO production became significantly higher at 24 h after instillation and remained at raised levels up to 7 days. Higher doses of CB caused more inflammation than the ufCB. Thus, in the instillation model, a localized dose of particle over a certain level causes the particle mass to dominate the response, rather than the surface area. In contrast to the effect of CB, which showed a dose-related increasing inflammatory response, ufCB at the highest dose caused less of a neutrophil influx than at the lower dose. Six hours after intratracheal instillation, the threshold dose for neutrophil influx occurred at 50 microg. Calculation of surface area of particles instilled suggested that this was likely to be an overload-inducing dose of particles, as gauged from recent experiments with inhaled particles. In summary, this study provides evidence in a rat instillation model that ufCB has greater ability than CB to produce lung inflammation and oxidant stress at a relatively low dose of 125 microg. At high doses, however, BAL is not a reliable indicator of pulmonary response, since the overall response seems to scale to mass or volume of instilled particulate without an influence of surface area.

Animals↗

PubMed1999

Chemical differences between long and short amosite asbestos: differences in oxidation state and coordination sites of iron, detected by infrared spectroscopy.

OBJECTIVES: Short fibres of amosite asbestos (SFA), obtained by ball milling of long fibres (LFA), have been shown to be less pathogenic than long fibres. Accumulating evidence suggests an important role for differences in surface chemistry between fibres. Iron has been implicated in the pathogenesis of asbestos fibres. In this study infrared (IR) spectroscopy was used to compare LFA and SFA in terms of the coordination and oxidation state of iron at the three cation sites (M1, M3, M1). METHODS: Infrared was used to examine LFA ad SFA, when dry and when hydrated in the presence and absence of the chelators desferroxamine and ferrozine. With appropriate software the proportions of iron and its oxidation states in the overlapping peaks were resolved and assigned, and the three coordination sites were identified. Data were obtained from 10 samples of both lengths of fibre for each of the four treatments. Iron release was also monitored. RESULTS: Iron was significantly more oxidised in LFA than SFA. Further oxidation of the dry fibres with water, ferrozine, or desferroxamine tended to abolish these differences. There were also significant differences between the proportions of iron held in the different coordination sites of the fibres. For LFA, a higher proportion of its iron was held in the cation sites coordinating less with iron and more with Mg. Interestingly, the sites coordinating single irons were significantly more oxidised than multiple sites. The single iron sites were more oxidised in LFA than SFA and were more readily oxidised by the treatments. CONCLUSIONS: Important chemical differences between LFA and SFA were found. There seemed to be some mobility of iron near the surface. Based on these data it is speculated that the 1 iron surface site may be important in pathogenesis.

Asbestos, Amosite↗

PubMed1999

Influence of fibre length, dissolution and biopersistence on the production of mesothelioma in the rat peritoneal cavity.

A range of respirable man-made mineral fibres were tested for evidence of carcinogenicity by injection into the peritoneal cavity of male SPF Wistar rats; and differences in carcinogenicity were related to the dimensions and biopersistence of the injected fibres. The fibres tested included an amosite asbestos, a silicon carbide whisker, a special purpose glass microfibre, and a range of other man-made vitreous fibres (MMVFs) and refractory ceramic fibres (RCFs) from the TIMA fibre repository. The injected dose of each was designed as the estimated mass required to contain 10(9) fibres > 5 microns in length, as determined by optical microscopy. The numbers of long fibres (> 15 microns) contained in these doses ranged across fibres from 0.1 x 10(9) to 0.8 x 10(9) fibres; the number of long fibres thinner than 0.95 micron ranged from 0.015 x 10(9) to 0.4 x 10(9). The treatment groups contained between 18 and 24 animals. Animals were killed when they showed signs of debilitation. At autopsy, the diagnosis of mesothelioma was usually obvious macroscopically. Otherwise, histological examination of peritoneal organs was used to search for early tumour development. Judged by median survival time, four of the fibre types, in the doses administered, presented higher mesothelioma activity than amosite asbestos. The other fibres tested were less carcinogenic than the amosite. Only a ceramic material derived by extreme heating to simulate the effect of furnace or oven conditions, produced no mesotheliomas. Attempts were made, using regression models, to relate these differences to fibre dimensions and to measures of durability from separate experiments. The results pointed principally to a link with the injected numbers of fibres > 20 microns in length and with biopersistence in the rat lung of fibres longer than 5 microns. Improved quantification of the relative importance of fibre dimensions and biopersistence indices requires experimentation with a range of doses.

Animals↗