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Biomedical subjects

A D McDonald

Publications and source records attributed to A D McDonald.

At least 19 recordsLinked to original sources
PubMed2001

Cohort mortality study of North American industrial sand workers. I. Mortality from lung cancer, silicosis and other causes.

BACKGROUND: In 1997 a Working Group of the International Agency for Research on Cancer changed an earlier classification of crystalline silica as a human carcinogen from Group 2A to Group 1, though commenting that the carcinogenicity might vary with industrial circumstances and depend on additional factors affecting biological activity, including the distribution of its polymorphs. OBJECTIVE: We aimed to determine whether pure quartz exposure uncomplicated by the presence of other contaminating carcinogens, as experienced by workers in the production of high-grade industrial sand, was causally related to an increased risk of lung cancer. METHODS: A cohort of 2670 men employed before 1980 for 3 years or more in one of nine North American sand-producing plants and a large associated office complex was selected for study. Of the cohort, 2644 (99%) were traced through 1994, and certificated cause of death ascertained for 1025 (99%) of the 1039 men known to have died. Standardised mortality ratios (SMRs) were calculated for the main causes of death, using both US and state or provincial male mortality rates for reference. FINDINGS: The main analyses of deaths, 20 or more years after first employment against regional rates, gave the following SMRs: all causes 109, lung cancer 139, other malignancies 98, non-malignant respiratory disease 161, and nephritis/nephrosis 244. There were, in total, 37 deaths from silicosis or silico-tuberculosis, with one or more death at least in all nine production plants. Analyses failed to show any relation between lung cancer risk and duration of employment. The increased SMR for lung cancer was wholly due to high rates in four plants in two states, whereas no increase was found in the remainder of the cohort. CONCLUSION: In the absence of information on smoking histories and risk in relation to estimated exposure, the increased SMR for lung cancer (139), although statistically significant, cannot be attributed confidently to crystalline silica. An answer to the question of attributability must await the findings of the nested case-control study, in which level of exposure and smoking habits were ascertained for cases and matched controls. The strong indication in this cohort of excess mortality from non-malignant renal disease deserves further investigation.

Adult↗
PubMed2001

Cohort mortality study of North American industrial sand workers. II. Case-referent analysis of lung cancer and silicosis deaths.

BACKGROUND: A cohort mortality study of 2670 men in nine North American industrial sand plants resulted in 83 deaths from lung cancer 20 or more years after hire (standardized mortality ratio 139) and 37 deaths from silicosis (including seven from silico-tuberculosis). The lung cancer excess was unrelated to duration of employment and not found in all plants. OBJECTIVES: The primary aim was to determine whether lung cancer risk among these employees was related to quantitative estimates of crystalline silica exposure, after allowance for cigarette smoking. A secondary aim was to do the same for silicosis mortality, partly as a means of validating the estimated levels of exposure. METHODS: A nested case-referent study was undertaken with cases matched with up to two controls on plant, age and date of first employment from men who survived the case. Exposures were estimated by linking work histories to a job-exposure matrix, undertaken separately. Cigarette smoking information was obtained from medical records and other sources, blind as to case-control status. Matched statistical analyses were conducted using conditional logistic regression. FINDINGS: Odds ratios for silicosis mortality were significantly related to cumulative silica exposures and tended to a relationship with category of average crystalline silica concentration, but inconsistently with length of employment. After accounting for a strong effect of cigarette smoking, odds ratios for lung cancer were related to cumulative crystalline silica exposure and to average silica concentration, but not to length of employment. CONCLUSION: These findings support a causal relationship between lung cancer and quartz exposure after allowance for cigarette smoking, in the absence of cristobalite or other known occupational carcinogens.

Aged↗
PubMed2001

Cohort mortality study of North American industrial sand workers. III. Estimation of past and present exposures to respirable crystalline silica.

BACKGROUND: Lung cancer and silicosis mortality were examined longitudinally and by a case-referent analysis in a cohort of workers selected from the North American industrial sand industry. Date of hire in the case-referent sub-cohort extended as far back as the second decade of the twentieth century. OBJECTIVE: The aim of this study component was to develop estimates of average and cumulative exposure to respirable crystalline silica for the 342 selected cases and referents. METHODS: Process and dust control histories were developed for each plant, and quantitative exposure data obtained from each of them and from a trade organization. An algorithm was developed to convert historical exposures reported in particle count concentrations to modern measures of mass concentration of respirable crystalline silica. Personal exposures were adjusted for use of protective equipment based on frequency of use and type of protection. FINDINGS: Between 1974 and 1998, a total of 14249 exposure measurements had been taken using a cyclone and membrane filter and gave an overall geometric mean of 42 microg/m3. The only exposure data identified earlier were based on approximately 500 samples collected across the industry between 1947 and 1955 using the Greenburg-Smith impinger, with analysis by microscopy. These data were converted to modern measures using a factor of 1 mppcf = 276 microg/m3 respirable dust and then adjusting for percentage silica. In general, the highest exposures occurred in bagging and bulk-loading operations and the lowest in wet processing of sand. CONCLUSIONS: There has been a substantial decline in exposure levels in this industry over time. The decline was rapid between the 1940s and 1970s and current exposures are, on average, less than 50 microg/m3. The use of personal protective equipment was judged to have had little impact on exposure before the 1970s.

Air Pollutants, Occupational↗
PubMed2000

Focal modification of electrical conduction in the heart by viral gene transfer.

Modern treatment of cardiac arrhythmias is limited to pharmacotherapy, radiofrequency ablation, or implantable devices. Antiarrhythmic medications suppress arrhythmias, but their systemic effects are often poorly tolerated and their proarrhythmic tendencies increase mortality. Radiofrequency ablation can cure only a limited number of arrhythmias. Implantable devices can be curative for bradyarrhythmias and lifesaving for tachyarrhythmias, but require a lifetime commitment to repeated procedures, are a significant expense, and may lead to severe complications. One possibility is the use of gene therapy as an antiarrhythmic strategy. As an initial attempt to explore this option, we focused on genetic modification of the atrioventricular node. First, we developed an intracoronary perfusion model for gene delivery, building on our previous work in isolated cardiac myocytes and hearts perfused ex vivo. Using this method, we infected porcine hearts with Adbetagal (recombinant adenovirus expressing Escherichia coli beta-galactosidase) or with AdGi (adenovirus encoding the Galphai2 subunit). We hypothesized that excess Galphai2 would mimic the effects of beta-adreneric antagonists, in effect creating a localized beta-blockade. Galphai2 overexpression suppressed baseline atrioventricular conduction and slowed the heart rate during atrial fibrillation without producing complete heart block. In contrast, expression of the reporter gene beta-galactosidase had no electrophysiological effects. Our results demonstrate the feasibility of using myocardial gene transfer strategies to treat common arrhythmias.

Adenoviridae↗
PubMed1999

Chrysotile, tremolite and fibrogenicity.

Recently published analyses have shown that the risks of mesothelioma and lung cancer in Quebec chrysotile miners and millers were related to estimated level of fibrous tremolite in the mines where they had worked. An analysis has therefore been made of radiographic changes in men who in 1965 were employed by companies in Thetford Mines where the same question could be examined for fibrogenicity. Of 294 men who met the necessary requirements, 129 had worked in six centrally located mines, where the tremolite content was thought to be high, 81 in 10 peripheral mines where it was thought to be low and 84 in both. The median prevalence of small parenchymal opacities (> or = 1/0) in chest radiographs read by six readers was higher among men ever than never employed in the central mines (13.6% against 7.4%), despite the fact that the mean cumulative exposure was lower in the former (430 mpcf.y vs 520 mpcf.y). After accounting by logistic regression for cigarette smoking, age, smoking-age interaction and cumulative exposure, the adjusted odds ratio for central mine employment was 2.44 (95% lower bound: 1.06). Together with other surveys of asbestos miners and millers, this study suggests that amphibole fibres, including tremolite, are more fibrogenic than chrysotile, perhaps to the same extent that they are carcinogenic, though the data available were not sufficient to address the latter question.

Aged↗
PubMed1998

Dust exposure and lung cancer in Quebec chrysotile miners and millers.

A large cohort of men born between 1891 and 1920 and employed for at least a month in the chrysotile producing industry of Quebec has been under study since 1966. These men were followed from first employment (the earliest in 1904) to 1992, by which time over 8000 had died, 657 from lung cancer. The current study is of 488 cases of lung cancer formerly employed at three places, viz. a major complex, here called Company 3, in the region of Thetford Mines (243 cases), the mine and mill in the town of Asbestos (206) and a small asbestos-products factory in the same town (39). For each case, four referents were sought by random selection from among survivors to a greater age, after matching on place of employment, age of starting work, smoking habit and date of birth. This process was highly successful, although six cases had less than four referents. For each man (the 488 cases with 1941 referents) and for each calendar year of employment, we obtained the fraction of the year worked at various levels of intensity, assessed in 13 'dust categories' of mpcf (million particles per cubic foot). We then calculated how many years each man spent at these various levels; these years, adjusted for the length of the working week (66 h until 1937; 48 h 1938-1949; and 40 h 1950-1985), were accumulated up to ten years before the death of the case. The men were classified according as they were non- or ex-smokers, or smokers, of cigarettes. For each man at Company 3 and one referent for each, his years of work in a central area of five mines and in a peripheral area of ten mines were differentiated; contamination of the chrysotile by fibrous tremolite was known to be much greater in the central than in the peripheral area. Case-referent comparisons, within place of employment, were made by conditional logistic regression. As anticipated from earlier subject-years analyses, lung cancer risks were found to be negligible for years worked in dust categories 1 and 2 (averaging 0.5 and 2 mpcf), regardless of place; as the upper limit of category 1 is considerably higher than permitted nowadays, the lung cancer risk from exposure to chrysotile at permitted levels can be taken as extremely small. Patterns of exposure-response for higher categories were irregular. At Company 3, some risks appeared elevated for years spent in the higher dust categories: 3-4, 5-7, 8-10 and 11-13, with averages around 9, 20, 36 and 92 mpcf, respectively. For categories 3-4 and 8-10, the odds ratios were high for some or all work in the central area, but minimal for years spent in the peripheral area only. Odds ratios were fairly low for cigarette smokers who worked in categories 5-7 and also for years spent in the highest categories (11-13). At the mine and mill in Asbestos, all risks were low except for years worked by non- and ex-smokers in categories 7-13 (ca. 40 mpcf). There were no increased risks at the factory. It was known from the subject-years analyses that most of the excess had occurred at Company 3, but it is now clear that for all practical purposes it was confined to the central area there, probably due largely to fibrous tremolite and in dust conditions of at least dust category 3. The average of this category was 7 mpcf or very roughly 24 fibres/ml, about two orders of magnitude higher than today's hygiene standards.

Aged↗
PubMed1997

The 1891-1920 birth cohort of Quebec chrysotile miners and millers: development from 1904 and mortality to 1992.

This paper draws together the mortality experience for a cohort of some 11000 male Quebec Chrysotile miners and millers, reported at intervals since 1971 and now again updated. Of the 10918 men in the complete cohort, 1138 were lost to view, almost all never traced after employment of only a month or two before 1935; the other 9780 men were traced into 1992. Of these, 8009 (82%) are known to have died: 657 from lung cancer, 38 from mesotheliona, 1205 from other malignant disease, 108 from pneumoconiosis and 561 from other non-malignant respiratory diseases (excluding tuberculosis). After early fluctuations. SMRs (all causes) against Quebec rates have been reasonably steady since about 1945. For men first employed in Asbestos, mine or factory, they were very much what might have been expected for a blue collar population without any hazardous exposure. SMRs in the Thetford Mines area were almost 8% higher, but in line with anecdotal evidence concerning socio-economic status. At exposures below 300 (million particles per cubic foot) x years, (mpcf.y), equivalent to roughly 1000 (fibres/ml) x years-or, say, 10 years in the 1940s at 80 (fibres/ml)-findings were as follows. There were no discernible associations of degree of exposure and SMRs, whether for all causes of death or for all the specific cancer sites examined. The average SMRs were 1.07 (all causes), and 1.16, 0.93, 1.03 and 1.21, respectively, for gastric, other abdominal, laryngeal and lung cancer. Men whose exposures were less then 300 mpcf.y suffered almost one-half of the 146 deaths from pneumoconiosis or mesothelioma; the elimination of these two causes would have reduced these men's SMR (all causes) from 1.07 to approximately 1.06. Thus it is concluded from the viewpoint of mortality that exposure in this industry to less than 300 mpcf.y has been essentially innocuous, although there was a small risk or pneumoconiosis or mesothelioma. Higher exposures have, however, led to excesses, increasing with degree of exposure, of mortality from all causes, and from lung cancer and stomach cancer, but such exposures, of at least 300 mpcf.y, are several orders of magnitude more severe than any that have been seen for many years. The effects of cigarette smoking were much more deleterious than those of dust exposure, not only for lung cancer (the SMR for smokers of 20+ cigarettes a day being 4.6 times higher than that for non-smokers), but also for stomach cancer (2.0 times higher), laryngeal cancer (2.9 times higher), and-most importantly-for all causes (1.6 times higher).

Aged↗
PubMed1997

Mesothelioma in Quebec chrysotile miners and millers: epidemiology and aetiology.

In a cohort of some 11,000 men born 1891-1920 and employed in the Quebec chrysotile production industry, including a small asbestos products factory, of 9780 men who survived into 1936, 8009 are known to have died before 1993, 38 probably from mesothelioma--33 in miners and millers and five in factory workers. Among the 5041 miners and millers at Thetford Mines, there had been 4125 deaths from all causes, including 25 (0.61%) from mesothelioma, a rate of 33.7 per 100,000 subject-years; the corresponding figures for the 4031 men at Asbestos were eight out of 3331 (0.24%, or 13.2 per 100,000 subject-years). At the factory in Asbestos, where all 708 employees were potentially exposed to crocidolite and/or amosite, there were 553 deaths, of which five (0.90%) were due to mesothelioma; the rate of 46.2 per 100,000 subject-years was 3.5 times higher than among the local miners and millers. Six of the 33 cases in miners and millers were in men employed from 2 to 5 years and who might have been exposed to asbestos elsewhere; otherwise, the 22 cases at Thetford were in men employed 20 years or more and the five at Asbestos for at least 30 years. The cases at Thetford were more common in miners than in millers, whereas those at. Asbestos were all in millers. Within Thetford Mines, case-referent analyses showed a substantially increased risk associated with years of employment in a circumscribed group of five mines (Area A), but not in a peripherally distributed group of ten mines (Area B); nor was the risk related to years employed at Asbestos, either at the mine and mill or at the factory. There was no indication that risks were affected by the level of dust exposure. A similar pattern in the prevalence of pleural calcification had been observed at Thetford Mines in the 1970s. These geographical differences, both within the Thetford region and between it and Asbestos, suggest that the explanation is mineralogical. Lung tissue analyses showed that the concentration of tremolite fibres was much higher in Area A than in Area B, a finding compatible with geological knowledge of the region. These findings, probably related to the far greater biopersistence of amphibole fibres than chrysotile, have important implications in the control of asbestos related disease and for wider aspects of fibre toxicology.

Aged↗
PubMed1997

Chrysotile, tremolite and carcinogenicity.

It has been suspected for many years that amphibole fibres in the tremolite series, a low level contaminant of chrysotile asbestos, may contribute disproportionately to the incidence of mesothelioma and perhaps other exposure-related cancers. A cohort of some 11,000 Quebec chrysotile workers, 80% of whom have now died, provided the opportunity to examine this hypothesis further. An analysis was made of deaths from mesothelioma (21), cancers of the lung (262), larynx (15), stomach (99), and colon and rectum (76), in men employed by the largest company in Thetford Mines, with closely matched referents. Risks were estimated by logistic regression for these five cancers in two groups of mines--five mines located centrally and ten mines located peripherally; tremolite contamination had been demonstrated to be some four times higher in the former than in the latter. Odds ratios for work in the central mines were raised substantially and significantly for mesothelioma and lung cancer, but not for the gastric, intestinal or laryngeal cancer sites. In the peripheral mines, there was little or no evidence of increased risk for any of the five cancers. The hypothesis that, because of the difference in distribution of fibrous tremolite, cancer risks in the central area would be greater than in the periphery was thus substantiated. That the explanation may lie in the greater biopersistence of amphibole fibres than chrysotile is important in framing policies for the use and control of asbestos and is directly relevant to the selection of man-made mineral fibre substitutes.

Aged↗
PubMed1996

The epidemiology of mesothelioma in historical context.

Primary malignant mesothelial tumours were recognized by pathologists before asbestiform minerals (chrysotile, crocidolite and amosite) were mined commercially. The discovery, 40 yrs ago, of a causal link with crocidolite and the wide-ranging epidemiological studies which followed are the subject of this review. Early case-control and descriptive surveys, supplemented by cohort studies in insulation workers and chrysotile miners, quickly demonstrated major occupational and geographical differences, with high risk in naval dockyard areas and in the heating trades. In the 1980s, reliable cohort surveys showed that in mining and in the manufacture of asbestos products the mesothelioma risk was much higher when exposure included crocidolite or amosite than chrysotile alone. However, qualitative and quantitative information on exposure was too often inadequate for this evidence to be conclusive. Well-controlled lung fibre analyses have reduced these deficiencies and demonstrated the probable implications of the greater biopersistence of amphibole fibres. Chrysotile for industrial use often contains low concentrations of fibrous tremolite, which may well explain the few cases of mesothelioma associated with this type of asbestos. Progress in this field has been much retarded by controversy, for which the 20 year gap between the availability of reliable estimates of risk for the mining of chrysotile and that for crocidolite or amosite may have been largely responsible.

Asbestos↗
PubMed1995

The Poisson process as a model for compartment digesta flow in ruminants.

The Poisson process, the simplest stochastic flow process, was used to develop a multicompartment model of ruminant digesta flow with Gamma distributed retention times. Although mathematically the model is a generalization of many previously published models, the physiological model differs substantially in asserting that the distributed delay time and the exponential rate (scale) parameters, including the scale parameter of the Gamma distribution, are determined by total digesta flow, and thus invariant with respect to the fraction marked. The shape factor of the Gamma distribution is shown to be sufficient to explain the difference between markers in rate of marker excretion. Consequently, the parameters of multiple markers can be simultaneously estimated with the constraint that the exponential scale parameters and the delay time are invariant with respect to marker. This constraint leads to a measure of pure error to strengthen statistical tests for model rejection. Steady-state digesta retention time is estimated from the transient marker retention parameters, eliminating the necessity of speculating on what fraction of digesta the marked fraction represents. Tests of various models, using simulations and animal experiments indicate that, even if a model is correct, it is not possible to obtain reliable parameter estimates by fitting to a single marker. Even with multiple markers some caution must be used in interpreting parameter estimates derived from least squares fitting.

Animals↗
PubMed1994

Therapeutic drugs in early pregnancy and congenital defects.

In a study of occupation and pregnancy outcome, information was collected on certain non-occupational factors including therapeutic drugs taken in the first trimester, reported by some 17% of women. A case-referent analysis was made of data from pregnancies leading to 787 major (class 1) and 2386 miscellaneous minor (class 2) congenital defects compared with pregnancies without defects, matched for hospital, maternal age and educational level. In pairs discordant for one of seven drug groups, ratios of positive pairs (case with drug) to negative pairs (referent with drug) were for class 1 defects 164:148, relative risk (RR) 1.11 and for class 2 defects 433:383, RR 1.13. Only anti-infective drugs showed an increased RR: 1.70 (p = 0.06). This was mainly with nervous/sensory defects (10:2; RR 5.0, p = 0.04) but no one type of defect or type of drug was identified; the infections for which the drugs were given might have been responsible. For class 1 defects two pairs were positive for anti-convulsant drugs and two negative; no increase in risk was found for any specific drugs including doxylamine succinate (Bendectin).

Abnormalities, Drug-Induced↗
PubMed1993

The 1891-1920 birth cohort of Quebec chrysotile miners and millers: mortality 1976-88.

A cohort of some 11,000 men born 1891-1920 and employed for at least one month in the chrysotile mines and mills of Quebec, was established in 1966 and has been followed ever since. Of the 5351 men surviving into 1976, only 16 could not be traced; 2508 were still alive in 1989, and 2827 had died; by the end of 1992 a further 698 were known to have died, giving an overall mortality of almost 80%. This paper presents the results of analysis of mortality for the period 1976 to 1988 inclusive, obtained by the subject-years method, with Quebec mortality for reference. In many respects the standardised mortality ratios (SMRs) 20 years or more after first employment were similar to those for the period 1951-75--namely, all causes 1.07 (1951-75, 1.09); heart disease 1.02 (1.04); cerebrovascular disease 1.06 (1.07); external causes 1.17 (1.17). The SMR for lung cancer, however, rose from 1.25 to 1.39 and deaths from mesothelioma increased from eight (10 before review) to 25; deaths from respiratory tuberculosis fell from 57 to five. Among men whose exposure by age 55 was at least 300 million particles per cubic foot x years (mpcf.y), the SMR (all causes) was elevated in the two main mining regions, Asbestos and Thetford Mines, and for the small factory in Asbestos; so were the SMRs for lung cancer, ischaemic heart disease, cerebrovascular disease, and respiratory disease other than pneumoconiosis. Except for lung cancer, however, there was little convincing evidence of gradients over four classes of exposure, divided at 30, 100, and 300 mpcf.y. Over seven narrower categories of exposure up to 300 mpcf.y the SMR for lung cancer fluctuated around 1.27 with no indication of trend, but increased steeply above that level. Mortality form pneumoconiosis was strongly related to exposure, and the trend for mesothelioma was not dissimilar. Mortality generally was related systematically to cigarette smoking habit, recorded in life from 99% of survivors into 1976; smokers of 20 or more cigarettes a day had the highest SMRs not only for lung cancer but also for all causes, cancer of the stomach, pancreas, and larynx, and ischaemic heart disease. For lung cancer SMRs increased fivefold with smoking, but the increase with dust exposure was comparatively slight for non-smokers, lower again for ex-smokers, and negligible for smokers of at least 20 cigarettes a day; thus the asbestos-smoking interaction was less than multiplicative. Of the 33 deaths from mesothelioma in the cohort to date, 28 were in miners and millers and five were in employees of a small asbestos products factory where commercial amphiboles had also been used. Preliminary analysis also suggest that the risk of mesothelioma was higher in the mines and mills at Thetford Mines than in those at Asbestos. More detailed studies of these differences and of exposure-response relations for lung cancer are under way.

Aged↗
PubMed1992

Ferruginous body counts in sputum as an index of past exposure to mineral fibres.

Previous work by our group among vermiculite miners exposed to fibrous tremolite demonstrated that asbestos body counts in sputum closely reflected intensity and duration of past exposure. In the present project sputum samples from nearly 600 volunteers from 11 cohorts of workers exposed to asbestos and other mineral fibres were found to contain much lower numbers of asbestos bodies than had been observed in vermiculite workers and these counts did not reliably reflect past levels of exposure. No evidence was found that occupational exposure to man-made mineral fibres led to any ferruginous body formation. Asbestos body counts appeared to differentiate between mesothelioma cases and controls and between levels of radiological asbestosis, but in both comparisons, based on small numbers, the power of discrimination was low. Substantial variation was found both in asbestos body and in macrophage counts in daily sampling of vermiculite workers but it was not sufficient to invalidate comparison between groups for epidemiological study. In individual subjects, however, little reliance can be put on results from a single sputum sample, particularly if negative.

Adult↗