Femoroacetabular impingement osteoplasty: is any resected amount safe? A laboratory based experiment with sawbones.

There is an increased risk of fracture following osteoplasty of the femoral neck for cam-type femoroacetabular impingement (FAI). Resection of up to 30% of the anterolateral head-neck junction has previously been considered to be safe, however, iatrogenic fractures have been reported with resections within these limits. We re-evaluated the amount of safe resection at the anterolateral femoral head-neck junction using a biomechanically consistent model. In total, 28 composite bones were studied in four groups: control, 10% resection, 20% resection and 30% resection. An axial load was applied to the adducted and flexed femur. Peak load, deflection at time of fracture and energy to fracture were assessed using comparison groups. There was a marked difference in the mean peak load to fracture between the control group and the 10% resection group (p < 0.001). The control group also tolerated significantly more deflection before failure (p < 0.04). The mean peak load (p = 0.172), deflection (p = 0.547), and energy to fracture (p = 0.306) did not differ significantly between the 10%, 20%, and 30% resection groups. Any resection of the anterolateral quadrant of the femoral head-neck junction for FAI significantly reduces the load-bearing capacity of the proximal femur. After initial resection of cortical bone, there is no further relevant loss of stability regardless of the amount of trabecular bone resected. Based on our findings we recommend any patients who undergo anterolateral femoral head-neck junction osteoplasty should be advised to modify their post-operative routine until cortical remodelling occurs to minimise the subsequent fracture risk.

Development of a Task-Exposure Matrix (TEM) for Pesticide Use (TEMPEST).

INTRODUCTION: Pesticides have been associated with increased risks for a range of conditions including Parkinson's disease, but identifying the agents responsible has proven challenging. Improved pesticide exposure estimates would increase the power of epidemiological studies to detect such an association if one exists. METHODS: Categories of pesticide use were identified from the tasks reported in a previous community-based case-control study in Scotland. Typical pesticides used in each task in each decade were identified from published scientific and grey literature and from expert interviews, with the number of potential agents collapsed into 10 groups of pesticides. A pesticide usage database was then created, using the task list and the typical pesticide groups employed in those tasks across seven decades spanning the period 1945-2005. Information about the method of application and concentration of pesticides used in these tasks was then incorporated into the database. RESULTS: A list was generated of 81 tasks involving pesticide exposure in Scotland covering seven decades producing a total of 846 task per pesticide per decade combinations. A Task-Exposure Matrix for PESTicides (TEMPEST) was produced by two occupational hygienists who quantified the likely probability and intensity of inhalation and dermal exposures for each pesticide group for a given use during each decade. CONCLUSIONS: TEMPEST provides a basis for assessing exposures to specific pesticide groups in Scotland covering the period 1945-2005. The methods used to develop TEMPEST could be used in a retrospective assessment of occupational exposure to pesticides for Scottish epidemiological studies or adapted for use in other countries.

Impact of diet composition on ileal digestibility and small intestinal morphology in early-weaned pigs fitted with a T-cannula.

Piglets, separated from their dam at 12 days of age and fed a milk substitute hourly, were used as a model for suckling. Animals were fitted with a terminal ileal T-cannula and a jugular vein catheter. At 28 days of age, half of the pigs had a dietary change to a cereal-based weaner diet fed as slurry, and the others remained on milk substitute. Animals were labelled by oral administration of 15N-labelled yeast for 10 days (days 15 to 25). Blood samples were taken twice a day to monitor 15N enrichment of the blood plasma. Diets included polyethylenglycol (PEG 4000) to allow calculation of apparent ileal digestibility of nitrogen and individual amino acids. Ileal bacterial nitrogen was calculated from D-alanine content of the digesta. Furthermore, small intestinal (SI) villus height and crypt depth were measured. Feed intake was increased by the dietary change. The total nitrogen flow was 3.2 ± 0.4 g/day and 5.9 ± 0.4 for the milk and weaner diet, respectively. Endogenous nitrogen flow at the terminal ileum was similar for both groups (milk diet 2.4 ± 0.4 v. weaner diet 2.2 ± 0.3 g/day), whereas the bacterial nitrogen content (0.08 ± 0.01 g/day milk diet v. 0.15 ± 0.01 g/day weaner diet, P < 0.01) and exogenous nitrogen flow (0.94 ± 0.16 g/day milk diet v. 3.29 ± 0.12 g/day weaner diet, P < 0.001) increased significantly in the weaner-diet group. The ileal apparent digestibility coefficient of protein was 0.81 ± 0.06 and 0.68 ± 0.01 for the milk replacer and the weaner diet, respectively. Morphology measurements made along the SI at 25%, 50% and 75% were similar between piglets fed milk replacer and those fed a cereal-based weaner diet. The only statistical effect (P < 0.01) of dietary change was an increase in crypt depth in the weaner-diet group. In conclusion, pigs, following a dietary change analogous to weaning, lack the capacity to fully digest a standard weaner diet. This may result in an increased nutrient content entering the large intestine and an altered microbiota. In the absence of a period of anorexia, often associated with traditional weaning, we saw no evidence of villous atrophy, but report here a significant crypt hyperplasia, especially at the 75% level, as a result of dietary change.

A review of the data quality and comparability of case-control studies of low-level exposure to benzene in the petroleum industry.

PURPOSE: Published case-control studies of risks of leukaemia following low exposures to benzene in the distribution of petroleum (gasoline) have not all identified the same level of risk, but the studies have had differences in cohort inclusion, case determination and availability of occupational and lifestyle data. We reviewed the quality and comparability of the data from three (of four) studies. METHODS: Through site visits, discussions with the investigators and reading study reports, we reviewed and audited the methods used for selecting cases and controls, for estimating individual exposures and for analysing and interpreting the data. Case-control comparisons of exposures were examined using customized graphs. RESULTS: We found that there were no issues of subject selection, methods or general data quality that were likely to have distorted their internal comparisons; we could not check in detail whether the metric for exposure assessments was the same across the studies; the exposure assessments for the Australian study required the least backward estimation, and the Canadian, which also had fewest cases, the most; evidence of an increased risk at higher exposures in Australia was convincing. CONCLUSIONS: The findings are consistent with some effect of benzene at higher lifetime exposures. A proposed pooled analysis should improve quantification of any exposure-response relationship.

Bar workers' health and environmental tobacco smoke exposure (BHETSE): symptomatic improvement in bar staff following smoke-free legislation in Scotland.

OBJECTIVE: To examine changes in the health of bar workers after smoke-free legislation was introduced. DESIGN: Longitudinal study following bar workers from before legislation introduction, at 2 months after introduction and at 1 year to control for seasonal differences. SETTING: Bars across a range of socio-economic settings in Scotland. PARTICIPANTS: 371 bar workers recruited from 72 bars. INTERVENTION: Introduction of smoke-free legislation prohibiting smoking in enclosed public places, including bars. MAIN OUTCOMES MEASURES: Change in prevalence of self-reported respiratory and sensory symptoms. RESULTS: Of the 191 (51%) workers seen at 1-year follow-up, the percentage reporting any respiratory symptom fell from 69% to 57% (p = 0.02) and for sensory symptoms from 75% to 64% (p = 0.02) following reductions in exposure, effects being greater at 2 months, probably partly due to seasonal effects. Excluding respondents who reported having a cold at either baseline or 1 year, the reduction in respiratory symptoms was similar although greater for "any" sensory symptom (69% falling to 54%, p = 0.011). For non-smokers (n = 57) the reductions in reported symptoms were significant for phlegm production (32% to 14%, p = 0.011) and red/irritated eyes (44% to 18%, p = 0.001). Wheeze (48% to 31%, p = 0.006) and breathlessness (42% to 29%, p = 0.038) improved significantly in smokers. There was no relationship between change in salivary cotinine levels and change in symptoms. CONCLUSIONS: Bar workers in Scotland reported significantly fewer respiratory and sensory symptoms 1 year after their working environment became smoke free. As these improvements, controlled for seasonal variations, were seen in both non-smokers and smokers, smoke-free working environments may have potentially important benefits even for smokers.

A panel study of air pollution in subjects with heart failure: negative results in treated patients.

OBJECTIVES: To investigate preclinical adverse effects of ambient particulate air pollution and nitrogen oxides in patients with heart failure. METHODS: A cohort of 132 non-smoking patients living in Aberdeen, Scotland, with stable chronic heart failure were enrolled in a repeated-measures panel study. Patients with atrial fibrillation or pacemakers were excluded. Participants were studied for 3 days every 2 months for up to 1 year with monitoring of pollutant exposure and concurrent measurements of pathophysiological responses. Measurements included daily area concentration of particulate matter with a median aerodynamic diameter of <10 micrometres (PM(10)), particle number concentration (PNC) and nitrogen oxides; daily estimated personal concentration of particulate matter with a median aerodynamic diameter of <2.5 micrometres (PM(2.5)) and PNC exposures; and 3-day cumulative personal nitrogen dioxide (NO(2)). Concurrent meteorological data were recorded. Blood was taken at the end of each 3-day block for assays of markers of endothelial activation, inflammation and coagulation. Cardiac rhythm was monitored by ambulatory Holter monitor during the final 24 h of each block. RESULTS: The average 24 h background ambient PM(10) ranged from 7.4 to 68 microg.m(-3) and PNC from 454 to 11 283 particles.cm(-3). No associations were demonstrated between the incidence of arrhythmias, heart rate variability or haematological/biochemical measures and any variations in pollutant exposures at any lags. CONCLUSION: Assuming that low-level pollution affects the parameters measured, these findings may suggest a beneficial effect of modern cardioprotective therapy, which may modify responses to external risk factors. Widespread use of such drugs in susceptible populations may in future reduce the adverse effects of air pollution on the heart.

A normative study of levels of uranium in the urine of British Forces personnel.

OBJECTIVES: The UK Ministry of Defence (MoD) controls a biological monitoring programme that includes testing for uranium in personnel who served in the conflict in Iraq in 2003. To help interpret the results, the MoD commissioned this study to quantify a normative reference distribution of urinary uranium concentrations in military personnel who had not served in that conflict. METHODS: The study selected and visited various military establishments to recruit a representative mix of ranks, genders and occupational groups (combat, support and auxiliary). A standardised protocol and recruitment questionnaire were used. The 125 ml spot urine samples collected were analysed for uranium and creatinine concentrations and (where possible) for uranium isotope (238)U/(235)U ratio. RESULTS: Samples from 732 eligible subjects were analysed. Adjusted uranium concentrations ranged up to 556 ng.g(-1) creatinine, somewhat higher than reference values quoted for the USA but much lower than recorded in granite areas such as Finland. Isotope ratio measurements were available for 125 samples (17%) with the highest concentrations; these all had a natural isotope signature and no evidence of depleted uranium (DU). On average, urinary uranium concentrations were somewhat lower in officers than in other ranks; they differed also across the services, the Navy being lowest and the Army highest. The levels give no concern regarding health risks in the personnel studied. CONCLUSION: Since even the highest values were from natural sources, we assume the differences represent differences in ingestion of natural uranium. Definition of a reference distribution or normal values will depend on the subpopulation of interest.

Changes in workplace concentrations of airborne respirable fibres in the European ceramic fibre industry 1987 1996.

As part of a wider epidemiological research programme, an occupational hygiene study was carried out during 1995-1996 to assess workers' current exposures to airborne materials in six European refractory ceramic fibre (RCF) plants. These plants had also participated in a cross-sectional occupational hygiene survey in 1987. The sampling strategy focussed principally on personal shift-average exposures of workers, by occupation, to respirable fibres. Monitoring was undertaken in two integrated phases: a 1-week cross-sectional survey followed by a prospective, and ongoing, programme by the RCF industry. Statistical (analysis of variance) analyses to identify patterns of variability by plant, occupational group (OG) and occupations within group were based on 464 individual shift samples, the greatest amount of data being available for production occupations. Concentrations of respirable fibres showed marked differences between plants and between OGs. Average respirable fibre concentrations among Primary and Secondary Production and Ancillary workers ranged from <0.1 f ml(-1) to up to 0.4 f ml(-1), depending on OG and plant. Individual shift-average measurements were almost invariably <1 f ml(-1). Within Secondary Conversion and Finishing, plant-specific averages ranged from 0.3 f ml(-1) to 1.25 f ml(-1). Respirable fibre concentrations were, in some plants, less than half those found in 1987. In other plants, mainly those where concentrations had been relatively low in 1987, the dust exposure had remained essentially unchanged or increased slightly. An ongoing programme of sampling is being carried out by the participating companies, generating additional information that could assist research in the long term and in improving control.

A normative value pilot study: levels of uranium in urine samples from UK civilians.

A normative study of the levels of urinary uranium in the general UK population is needed for comparison with levels in UK military and ex-military personnel who served where munitions containing depleted uranium (DU) were used. As preparation, this pilot study trialled the process of collecting 24-h samples from adult male civilians, and compared the measurements from 24-h samples with those from spot samples taken over the subsequent 24h. The purpose was to assess the relative utility of the two types of samples. Twenty-five convalescent hospital in-patients were recruited as participants. Uranium concentrations in the 24-h samples ranged from 1 to 10.6 ng l(-1); in the spots, from not detectable to 38.1 ng l(-1). Normalised to creatinine, concentrations in the 24h samples ranged from approximately 100 to 800 ng mol(-1) creatinine; in the spot samples, from not detectable to approximately 4000 ng mol(-1) creatinine. The ranges appear similar to those reported for residents of the US. The distribution of spot sample results indicated that 95% of a participant's creatinine-adjusted concentrations from spot samples would be within the range 40-250% of his mean. Adjusting for creatinine almost entirely eliminated a slight indication of diurnal variation in urinary uranium concentration in spot samples. All the 24-h samples and 131 out of the 133 spot samples showed ratios of isotopes (238)U to (235)U consistent with natural uranium (i.e. neither enriched nor depleted). Slightly elevated ratios in two spot samples were not supported by other samples from the same participants, indicating that slightly elevated ratios may be recorded on very low concentration (<1 ng l(-1)) samples. In the main, quantification of this isotope ratio from spot samples was only slightly more variable than from 24-h samples. Complete 24-h urine samples gave better precision than spot samples in estimating uranium concentrations at these low levels, but presented more logistic difficulties in the collection of the samples. Clarification of the relative merits of alternative sampling strategies enables the design of a wider study to be optimised.

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%.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.