Biomedical subjects

B G Miller

Publications and source records attributed to B G Miller.

At least 19 recordsLinked to original sources

PubMed2006

Dust related risks of clinically relevant lung functional deficits.

AIM: To quantify the risks of clinically important deficits of FEV1 in coal miners in relation to cumulative and average concentrations of respirable dust. METHODS: Data were studied from over 7000 men who had been surveyed in the late 1970s. Linear regression equations for the association between FEV1 and self-reported breathlessness on mild exertion were used to define clinically important levels of FEV1 deficit, and the probabilities that individuals with different dust exposures would experience these deficits were calculated. RESULTS: Levels of FEV1 were lower among breathless men than among others, with a large overlap of the distributions. The relations between standardised FEV1 and breathlessness were constant over all age and smoking groups. A decrease of 100 ml in FEV1 was associated with an increase of 1.12 in the odds of reporting breathlessness. FEV1 deficits of -0.367, -0.627, and -0.993 l (designated as "small", "medium", and "large" deficits) were, on average, associated with proportional increases of risks of breathlessness by factors of 1.5, 2.0, and 3.0 respectively. Cumulative respirable dust exposure ranged up to 726 gh/m3, mean 136 gh/m3 (British Medical Research Council measurement convention). An increase of 50 gh/m3 was associated with an increase of about 2% in the proportion of men with small deficits in FEV1. For medium deficits the increases ranged from 1.5% to 2%, depending on age. A similar pattern was seen for large deficits, but with smaller increases. CONCLUSIONS: In the unlikely event of continuous exposure at the proposed new maximum respirable dust limit for British mines of 3 mg/m3 (ISO-CEN measurement convention) for a working lifetime, the risk of a medium deficit of FEV1 for a non-smoker at age 60 would be estimated to be 34%, compared with 25% for zero dust exposure; for smokers, about 54% compared with 44%.

Adolescent↗

PubMed2005

Effects of insulation on the temperature within farrowing huts and the weaning weights of piglets reared on a commercial outdoor pig unit.

The air temperatures inside uninsulated and insulated huts were recorded on an outdoor pig unit in the south of England between September 1997 and September 1998, and the herd's production parameters were also recorded. During the summer the temperatures inside some of the uninsulated huts exceeded 45 degrees C, but the temperatures inside the insulated huts were lower and fluctuated less. Despite the high temperatures, the weaning weight of piglets reared in the uninsulated huts were often higher than those of the piglets reared in the insulated huts, possibly as a result of the higher mortality of small piglets in the uninsulated huts, especially during the winter. The weaning weights of the piglets were higher during the summer.

Animal Husbandry↗

PubMed2005

A comparison of fibre counting across three European national proficiency testing schemes.

Proficiency testing (PT) schemes seek to improve and maintain consistency in asbestos fibre counting by circulating mounted samples to laboratories, which return counts for comparison with consensus reference values. This study compares the level of these consensus values in three (Spanish, Belgian and UK) national PT schemes. It also assesses the effect of the imminent change in the European standard rules for counting asbestos fibres, to the new rules from the World Health Organisation (WHO), which will include more fibres. Forty samples from the three schemes were circulated to six laboratories, two in each national scheme. The UK and Spanish laboratories counted using both the ERM and the WHO method. Belgian laboratories already use the WHO method, and they counted only by this method. Densities from counts in this sample exchange served as a common basis against which we compared the national reference values (R). This produced a geometric overall mean ratio of R to exchange mean density of 0.94 for the UK scheme, 1.01 for the Spanish and 0.97 for the Belgian scheme, and thus indicated remarkably similar levels. Nevertheless, non-trivial systematic inter-laboratory differences confirmed the need for regular PT and international inter-laboratory comparisons. Examination of previous data from the national PT schemes and from an international scheme (AFRICA) provided further comparisons for the same laboratories (either comparing the laboratory's data with R values or making direct comparisons between laboratories) that are consistent with those from this special exchange. The change in fibre counting rule (to include fibres apparently touching particles with diameter >3 microm) produced mean increases in reported densities that ranged among samples from 0 to 70% (highest individual estimate 170%); the effect was broadly similar for the three schemes. The laboratories gave mostly similar estimates of percentage increase; however, one laboratory occasionally produced high estimates indicating a possible need for training for using the new method.

Air Pollutants, Occupational↗

PubMed2005

Trichinella spiralis: enteric mucin-related response to experimental infection in conventional and SPF pigs.

Duodenal and jejunal responses to infection with Trichinella spiralis were compared in weaned piglets with a "normal dirty" vs. a "clean SPF" gut flora. Histochemical staining of neutral, acidic, sialylated, and sulphated residues was used to assess biosynthetic responses in mucin-secreting goblet cells. Peanut and Ulex lectins were also used to assess responses within the intestinal glycocalyx. Histomorphometric analysis was undertaken to evaluate the distribution and staining patterns of goblet cells in villi and crypts. Our analysis showed that stored mucin within goblet cells increased more in the infected conventional animals than in the infected SPF group. This was accompanied by changes in the pattern of sulphation and sialylation in the duodenum and jejunum. The thickness of the glycocalyx was increased in both duodenum and jejunum in both infected groups. However, this effect was greater for the infected SPF animals than the infected conventional animals. No significant differences were observed between uninfected conventional and uninfected SPF pigs.

Animal Husbandry↗

PubMed2004

Dust concentrations and respiratory risks in coalminers: key risk estimates from the British Pneumoconiosis Field Research.

To help inform the setting of dust control standards in coalmines, this brief review summarises the most recent and reliable exposure-response relations, for damaging respiratory effects, derived from the Pneumoconiosis Field Research (PFR). Collecting data over 38 years in the British coal industry, this was a programme of prospective research on the respiratory health of coal miners, characterised by regular health surveys and detailed measurements of dust and silica concentrations in the workplace. Exposure-response relations are presented for coal workers' simple pneumoconiosis category II, progressive massive fibrosis, defined deficits of lung function (FEV1), and category II silicosis. This simplified overview provides a guide to the most recent and most reliable estimates from the PFR of dust-related risks of substantial pulmonary disease, and to the magnitude of the effects. Control of dust sufficient to prevent category II simple pneumoconiosis should prevent most cases of progressive massive fibrosis and most dust related large lung function deficits. Where the dust contains high proportions of silica, control to low levels is essential, and even quite brief excursions of silica to high levels must be avoided.

Adult↗

PubMed2003

Modeling the retention and clearance of manmade vitreous fibers in the rat lung.

A mathematical model describing the dissolution and disintegration of long fibers and the clearance of short fibers is developed. For short fiber clearance, the model is based on previous modeling of the retention and clearance of particles, and most model parameters are taken from that particulate model. In addition to modeling the disappearance of long fibers, the present study includes a quantitative measure of goodness of fit of the model to observed data. Data from chronic inhalation experiments with insulation glass wools (MMVF10 and MMVF11) and rockwool (MMVF21) were provided for this study. These data comprised lung burdens at 10 time points at each of 3 concentrations for each fiber in inhalation experiments lasting up to 104 wk. At the two higher concentrations, the model had to take into account the effects of lung burden on macrophage-mediated clearance. The modeling shows that the overload dependence appears remarkably similar to that for low-toxicity particles in that the critical volumetric lung burden is similar to that for low toxicity dust. The model describes overload as leading to alveolar sequestration of short fibers or particles, and the estimated rate of alveolar sequestration for MMVF10 was similar to that for particles, but the estimated rate was lower for the other two fibers. Two alternative hypotheses to describe the process of the disappearance of longer fibers were tested by assessing their effect on a quantitative measure of fit of model predictions to the lung-burden data. These tests indicated that (a) dissolution leading to disintegration of long fibers into shorter fibers gave a much better fit than the alternative assumption that dissolution would leave only nonfibrous residue and (b) the relative rates of disintegration of the fibers in the lung appear to be directly dependent on their rates of in vitro dissolution and their diameters.

Administration, Inhalation↗

PubMed2003

Life table methods for quantitative impact assessments in chronic mortality.

Quantitative health impact assessments of chronic mortality, where the impacts are expected to be observed over a number of years, are complicated by the link between death rates and surviving populations. A general calculation framework for quantitative impact assessment is presented, based on standard life table calculation methods, which permits consistent future projections of impacts on mortality from changes in death rates. Implemented as a series of linked spreadsheets, the framework offers complete flexibility in the sex specific, age specific, and year specific patterns of baseline mortality death rates; in the predicted impacts upon these; in the weights or values placed on gains in life; and in the summary measures of impact. Impacts can be differential by cause of death. Some examples are given of predictions of the impacts of reductions in chronic mortality in the populations of England and Wales and of Scotland.

Adolescent↗

PubMed2003

Quantitative relations between exposure to respirable quartz and risk of silicosis.

AIMS: To reanalyse exposure-response data from a Scottish colliery to gain a more detailed knowledge of the relations between exposure to quartz and risks of silicosis in coal miners, and hence inform the debate on an appropriate occupational standard for respirable quartz. METHODS: Detailed data on working times at different quartz concentrations were combined to produce exposure profiles for miners who had provided a full chest radiograph at a follow up survey. Logistic regression methods were used to model profusion of radiographic abnormalities category 2/1+, and a general exposure index was used to compare different quartz exposure measures in these models. RESULTS: Results in 371 men aged 50-74 indicated that cumulative quartz exposure at higher concentrations resulted in proportionally greater risks of abnormalities. One g x h x m(-3) of cumulative exposure at quartz concentrations greater than 2 mg x m(-3) was estimated to have equivalent risks to 3 g x h x m(-3) at lower concentrations. The timing of exposure relative to follow up appeared less important, although the study had limited power to compare different lag periods between exposure and effect. CONCLUSIONS: Quantification of the risks of silicosis should take account of variations in quartz exposure intensity, particularly for exposure to concentrations of greater than 1 or 2 mg.m(-3), even if exposure is for relatively short periods. The risks of silicosis over a working lifetime can rise dramatically with even brief exposure to such high quartz concentrations. Risk estimates are given, to inform choice of control limits.

Aged↗

PubMed2002

Tumorigenicity of cellulose fibers injected into the rat peritoneal cavity.

Cellulose fibers, along with many other organic fibers, are durable. Therefore, if inhaled, they have the potential to persist within the lung, and may then cause disease. Here we report the effects of injecting high-purity cellulose fibers into the abdominal cavity of rats. A respirable fraction of cellulose fiber was collected from an aerosol of a thermo-mechanically-processed wood pulp. A sample of respirable crocidolite asbestos, known to produce mesotheliomas in rats, was used as a positive control. Total doses of 10(6), 10(7), 10(8), or 10(9) WHO fibers were injected intraperitoneally as 3 weekly aliquots. A negative control was provided by phosphate-buffered saline used to suspend the fibers for injection. There were 50 rats per treatment group except for the 10(8) and 10(9) fibers crocidolite groups which were reduced to 26 rats because of the expectation of high tumor incidence in these groups. The two higher doses of crocidolite asbestos caused greatly reduced survival compared to the saline controls. With cellulose there was a much less marked effect on survival. In the highest dose cellulose group, multiple large nodules (granulomas) and widespread adhesions (bands of new tissue connecting organs to each other and to the abdominal wall) were present in all animals. Granulomas were not observed in the 10(9) fibers crocidolite group. More than 80% of animals in the 10(8) and 10(9) crocidolite asbestos groups had mesotheliomas, a type of tumor sometimes observed in people exposed to asbestos. In contrast, there were only 2 animals in the cellulose groups with mesothelioma tumors, 1 in the 10(7) and 1 in the 10(8) groups. However, 9 (18%) of the 10(9) cellulose group had malignant tumors that, in contrast to the usual pattern of mesothelioma development following treatment with mineral fibers in rats, showed no obvious involvement of mesothelial tissues, were not associated with blood-stained ascites fluid, and were thus classified as sarcomas. This study has demonstrated that a high dose of cellulose fibers is capable of producing tumors when injected into the abdominal cavity of rats.

Air Pollutants, Occupational↗

PubMed2001

Role of enzyme-ribofuranosyl contacts in the ground state and transition state for orotidine 5'-phosphate decarboxylase: a role for substrate destabilization?

The crystal structure of yeast orotidine 5'-monophosphate decarboxylase (ODCase) complexed with the inhibitor 6-hydroxyuridine 5'-phosphate (BMP) reveals the presence of a series of strong interactions between enzyme residues and functional groups of this ligand. Enzyme contacts with the phosphoribofuranosyl moiety of orotidine 5'-phosphate (OMP) have been shown to contribute at least 16.6 kcal/mol of intrinsic binding free energy to the stabilization of the transition state for the reaction catalyzed by yeast ODCase. In addition to these enzyme-ligand contacts, active site residues contributed by both subunits of the dimeric enzyme are positioned to form hydrogen bonds with the 2'- and 3'-OH groups of the ligand's ribosyl moiety. These involve Thr-100 of one subunit and Asp-37 of the opposite subunit, respectively. To evaluate the contributions of these ribofuranosyl contacts to ground state and transition state stabilization, Thr-100 and Asp-37 were each mutated to alanine. Elimination of the enzyme's capacity to contact individual ribosyl OH groups reduced the k(cat)/K(m) value of the T100A enzyme by 60-fold and that of the D37A enzyme by 300-fold. Removal of the 2'-OH group from the substrate OMP decreased the binding affinity by less than a factor of 10, but decreased k(cat) by more that 2 orders of magnitude. Upon removal of the complementary hydroxymethyl group from the enzyme, little further reduction in k(cat)/K(m) for 2'-deoxyOMP was observed. To assess the contribution made by contacts involving both ribosyl hydroxyl groups at once, the ability of the D37A mutant enzyme to decarboxylate 2'-deoxyOMP was measured. The value of k(cat)/K(m) for this enzyme-substrate pair was 170 M(-1) s(-1), representing a decrease of more than 7.6 kcal/mol of binding free energy in the transition state. To the extent that electrostatic repulsion in the ground state can be tested by these simple alterations, the results do not lend obvious support to the view that electrostatic destabilization in the ground state enzyme-substrate complex plays a major role in catalysis.

Alanine↗

PubMed2001

Dissecting a charged network at the active site of orotidine-5'-phosphate decarboxylase.

The crystal structure of yeast orotidine-5'-phosphate decarboxylase in complex with the postulated transition state analog, 6-hydroxyuridine-5'-phosphate, reveals contacts between this inhibitor and a novel quartet of charged residues (Lys-59, Asp-91, Lys-93, and Asp-96) within the active site. The structure also suggests a possible interaction between O2 of the 6-hydroxyuridine-5'-phosphate pyrimidine ring and Gln-215. Here we report the results of mutagenesis of each of the charged active site residues and Gln-215. The activities of the Q215A and wild-type enzymes were equal indicating that any interactions between this residue and the pyrimidine ring are dispensable for efficient decarboxylation. For the D91A and K93A mutant enzymes, activity was reduced by more than 5 orders of magnitude and substrate binding could not be detected by isothermal calorimetry. For the D96A mutant enzyme, k(cat) was reduced by more than 5 orders of magnitude, and isothermal calorimetry indicated an 11-fold decrease in the affinity of this enzyme for the substrate in the ground state. For the K59A enzyme, k(cat) was reduced by a factor of 130, and K(m) had increased by a factor of 900. These results indicate that the integrity of the network of charged residues is essential for transition state stabilization.

Binding Sites↗

PubMed2001

The role of mucins in host-parasite interactions: Part II - helminth parasites.

Some parasites express mucin-like molecules. These have possible roles in attachment and invasion of host cells and in the avoidance of host immune processes. Enzymes of parasite origin might also facilitate infection, either by degrading host mucus barriers or by generating binding sites on host cells. Host mucins have roles in preventing parasite establishment or in parasite expulsion. They, in turn, might be exploited by parasites, either as sources of fuel or binding sites, or as host-finding targets. Here, we describe the biochemical properties of mucins and mucin-like molecules in relation to interactions (established and putative) between helminth parasites and their hosts.

Animals↗

PubMed2001

Effects of stressors on immune parameters and on the faecal shedding of enterotoxigenic Escherichia coli in piglets following experimental inoculation.

The study examined the effects of stressors on the responses of 3 and a half-week old piglets that had been given an oral dose of enterotoxigenic Escherichia coli (ETEC) and a novel harmless antigen (ovalbumin). Removal from the sow (WEAN), a short-term cold stressor (12;C for 48 hours) (TEMP) and mixing with non-littermates (MIX) were assessed in terms of the effects on faecal shedding of ETEC, immune responses, weight gain and an ACTH stimulation test. WEAN and TEMP reduced weight gain and all stressors increased faecal shedding of ETEC. All stressors increased the IgG responses to F4(K88)ac antigens and WEAN and TEMP increased the IgA responses to the same antigens, probably as a result of increased intestinal proliferation of ETEC. None of the stressors, however, had significant effects on antibody responses to ovalbumin or on lymphocyte proliferation assays. The results indicate that stressors influence the faecal shedding of ETEC in young piglets by a mechanism that may not involve modulation of immune responses.

Adrenocorticotropic Hormone↗

PubMed2001

An epidemiological study of the respiratory health of workers in the European refractory ceramic fibre industry.

OBJECTIVES: To investigate possible relations between respiratory health and past airborne exposure to refractory ceramic fibres (RCFs) and respirable dust in workers at six European factories, studied previously in 1987. METHODS: The target population comprised all current workers associated with RCF production, plus others who had participated in 1987 "leavers". Information was collected on personal characteristics, chest radiographs, lung function, respiratory symptoms, smoking, and full occupational history. Regression analysis was used to study relations between indices of health of individual workers and of cumulative exposure to airborne dust and fibres, and likely past exposure to asbestos. RESULTS AND DISCUSSION: 774 workers participated (90% of current workers, 37% of leavers). Profusion of small opacities in exposed workers (51% 0/1+; 8% 1/0+) was similar to that among an unexposed control group but higher than in new readings of the 1987 study films (11% 0/1+, 2% 1/0+). The large difference between 1987 and recent films may be, at least in part, a reading artefact associated with film appearance. Small opacities of International Labour Organisation (ILO) category 1/0+ were not associated with exposure. An association of borderline significance overall between 0/1+ opacities and exposure to respirable fibres was found for some exposure periods only, the time related pattern being biologically implausible. Pleural changes were related to age and exposure to asbestos, and findings were consistent with an effect of time since first exposure to RCFs. Among men, forced expired volume in 1 second (FEV(1)) and forced vital capacity (FVC) were inversely related to exposure to fibres, in current smokers only. FEV(1)/ FVC ratio and transfer factor (TL(CO)) were not related to exposures. The estimated restrictive effect was on average mild. Prevalence of respiratory symptoms was low. Chronic bronchitis and its associated symptoms (cough, phlegm) showed some association with recent exposure to respirable fibres. This could be due to an irritant effect of RCFs.

Adult↗

PubMed2000

Contribution of enzyme-phosphoribosyl contacts to catalysis by orotidine 5'-phosphate decarboxylase.

The crystal structure of the complex formed between recombinant yeast orotidine 5'-phosphate decarboxylase and the competitive inhibitor 6-hydroxyuridine 5'-phosphate reveals the presence of four hydrogen bonds between active site residues Tyr-217 and Arg-235 and the phosphoryl group of this inhibitor. When Tyr-217 and Arg-235 are individually mutated to alanine, values of k(cat)/K(m) are reduced by factors of 3000- and 7300-fold, respectively. In the Y217A/R235A double mutant, activity is reduced more than 10(7)-fold. Experiments with highly enriched [(14)C]orotic acid show that when ribose 5'-phosphate is deleted from substrate orotidine 5'-phosphate, k(cat)/K(m) is reduced by more than 12 orders of magnitude, from 6.3 x 10(7) M(-1) s(-1) for OMP to less than 2.5 x 10(-5) M(-1) s(-1) for orotic acid. Activity toward orotate is not "rescued" by 1 M inorganic phosphate. The K(i) value of ribose 5'-phosphate, representing the part of the natural substrate that is absent in orotic acid, is 8.1 x 10(-5) M. Thus, the effective concentration of the 5'-phosphoribosyl group, in stabilizing the transition state for enzymatic decarboxylation of OMP, is estimated to be >2 x 10(8) M, representing one of the largest connectivity effects that has been reported for an enzyme reaction.

Binding, Competitive↗

PubMed2000

Anatomy of a proficient enzyme: the structure of orotidine 5'-monophosphate decarboxylase in the presence and absence of a potential transition state analog.

Orotidine 5'-phosphate decarboxylase produces the largest rate enhancement that has been reported for any enzyme. The crystal structure of the recombinant Saccharomyces cerevisiae enzyme has been determined in the absence and presence of the proposed transition state analog 6-hydroxyuridine 5'-phosphate, at a resolution of 2.1 A and 2.4 A, respectively. Orotidine 5'-phosphate decarboxylase folds as a TIM-barrel with the ligand binding site near the open end of the barrel. The binding of 6-hydroxyuridine 5'-phosphate is accompanied by protein loop movements that envelop the ligand almost completely, forming numerous favorable interactions with the phosphoryl group, the ribofuranosyl group, and the pyrimidine ring. Lysine-93 appears to be anchored in such a way as to optimize electrostatic interactions with developing negative charge at C-6 of the pyrimidine ring, and to donate the proton that replaces the carboxylate group at C-6 of the product. In addition, H-bonds from the active site to O-2 and O-4 help to delocalize negative charge in the transition state. Interactions between the enzyme and the phosphoribosyl group anchor the pyrimidine within the active site, helping to explain the phosphoribosyl group's remarkably large contribution to catalysis despite its distance from the site of decarboxylation.

Amino Acid Sequence↗

PubMed2000

Epidemiological evidence on the carcinogenicity of silica: factors in scientific judgement.

In view of the extended debate and differing opinions on whether crystalline silica is a human carcinogen, we have reviewed a selection of epidemiological reports, to identify the areas of uncertainty and disagreement. We have chosen to examine the papers which in a recent review were considered to provide the least confounded examinations of an association between silica exposure and cancer risk. We also refer to a study of the mortality of coalminers very recently reported by ourselves and colleagues. We find that parts of the evidence are coherent but there are contradictions. On examination this resolves mostly into differences between types of studies. The three types of epidemiological study included are: (i) exposure-response studies, the most powerful for the confirmation of a relationship between a specific exposure and a health effect; (ii) descriptive studies in which incidence of disease in an exposed population is compared with that in a reference population; and (iii) studies of incidence of disease in subjects on silicosis case-registers. Descriptive studies frequently though not invariably suggest an excess lung cancer risk in silica-exposed workers compared with the general population, but exposure-response studies consistently fail to confirm that the cause is exposure to quartz. A single exposure-response study of cristobalite suggests a positive relation. Both sets of evidence have weaknesses. There are uncertainties on whether the excess risks in the descriptive studies are related to silica exposure or to lifestyle, including smoking habits. There are doubts on whether the exposure estimates in some of the exposure-response studies were sufficiently reliable to detect a small risk or weak association, though they are unlikely to have missed a strong effect. Studies of subjects on silicosis case registers consistently show an excess of lung cancer, but it is not clear to what extent these increased risks represent a direct effect of silica exposure, a secondary effect of the silicosis, preferential inclusion of subjects suffering from the effects of smoking, or bias in diagnostic accuracy. This not unnaturally leads to differences in opinion, exacerbated by variations in the strength of proof required by different experts. The main scientific uncertainties in the evidence are: 1. Whether, in the descriptive studies, the excess lung cancer rates in silica-exposed workers are explicable in terms of smoking habits, socio-economic class differences and inappropriate comparison populations. Better smoking information and more carefully chosen comparison populations are needed; 2. Whether the exposure-response studies could have missed a real relationship between silica exposure and lung cancer, if one exists. Many of the exposure-response studies were conducted with great care, but weaknesses, in the available data on which the exposure estimations were based, could have caused a real relationship of lung cancer and silica exposure to be missed. These studies were sufficiently powerful to demonstrate relationships of silica exposure with silicosis and silico-tuberculosis, so it is unlikely that they would have missed any but a small risk, or weak relationship, for lung cancer. Our own recent study of coalminers used uniquely detailed and reliable exposure data, and failed to demonstrate convincingly an increased risk. This negative finding, though, applies only to a dust in which the proportion of quartz in the dust is usually less than 10%. Exposure-response studies are needed, with high quality exposure estimates, in populations exposed to respirable dust of which crystalline silica comprises more than 10%; 3. Whether the excess cancer risks in subjects on silicosis registers are the result of selection and diagnostic bias. Given these difficulties, case-register studies may not be capable of giving a reliable answer to the central question, though they have been useful in pointing to the possibility of a can

Carcinogens↗

PubMed2000

Pathogenicity of a special-purpose glass microfiber (E glass) relative to another glass microfiber and amosite asbestos.

This article describes the activity of an E-glass microfiber (104E) during chronic inhalation and intraperitoneal injection studies in rats. Results are compared with another microfiber of similar dissolution rate (k(dis)), code 100/475, and the more durable amosite asbestos, both of which we had previously used in similar experiments (Davis et al., 1996). Rats were exposed to aerosol concentrations of 1000 fibers (longer than 5 microm)/ml, as measured by optical microscopy, for 7 h/day, 5 days/wk. Subgroups of rats were followed for mean lung burden, early and late signs of fibrosis, and tumor incidence. At the end of 12 mo of exposure, the mean number of 104E fibers of all lengths in the lungs was approximately double that for amosite but two-thirds of that for 100/475. For fibers longer than 15 microm, the mean 104E burden was similar to that for the amosite and more than twice that of the 100/475. After a 12-mo recovery period, the retained lung burdens (of fibers of all lengths) were approximately 30% of those at 12 mo for both microfibers, and somewhat higher (approximately 44%) for amosite. Amosite and 100/475 fibers longer than 15 microm were more persistent in the lungs than 104E fibers. The chemical composition of 104E fibers did not appear to have been significantly altered by up to 24 mo of residence in lung tissue, whereas the composition of 100/475 was substantially altered over the same time period. From the inhalation study, out of the pathology subgroup of 43 animals exposed to 104E microfibers, 10 had lung tumors (7 carcinoma, 3 adenoma) and 2 had mesotheliomas, whereas in 42 rats exposed to amosite asbestos, there were 16 lung tumors (7 carcinoma, 9 adenoma) and 2 mesotheliomas. The 104E- and amosite-treated animals had similar levels of fibrosis. In contrast, 38 animals treated with 100/475 had little fibrosis, 4 lung tumors (adenomas), and no mesotheliomas. The greater pathogenicity of the 104E fibers, compared to 100/475 fibers, might be partly explained by the greater numbers of long fibers retained in the lung after 12 mo of inhalation. However, we speculate that modification of surface properties by extensive selective leaching of some glass components reduces the toxic potential of 100/475. In a parallel intraperitoneal injection study, 104E caused considerably more mesotheliomas (21 rats out of 24) than 100/475 (8 rats out of 24). In addition, 104E appeared to be more active than amosite asbestos, since mesotheliomas appeared much more quickly in the 104E-treated animals. In conclusion, we have shown that two microfiber types, 100/475 and 104E, of similar dissolution rates, had markedly different pathogenicity in rats. We believe that this contrast is only partly due to differences in numbers of long fibers and that differences in surface properties of the fibers, possibly due to proportionately greater leaching of 100/475 fibers, play an important role.

Administration, Inhalation↗