Exposure-response relationship between lung cancer and polycyclic aromatic hydrocarbons (PAHs).

OBJECTIVES: To estimate the exposure-response function associating polycyclic aromatic hydrocarbon (PAH) exposure and lung cancer, with consideration of smoking. METHODS: Mortality, occupational exposure and smoking histories were ascertained for a cohort of 16,431 persons (15,703 men and 728 women) who had worked in one of four aluminium smelters in Quebec from 1950 to 1999. A variety of exposure-response functions were fitted to the cohort data using generalised relative risk models. RESULTS: In 677 lung cancer cases there was a clear trend of increasing risk with increasing cumulative exposure to PAH measured as benzo(a)pyrene (BaP). A linear model predicted a relative risk of 1.35 (95% CI 1.22 to 1.51) at 100 microg/m(-3) BaP years, but there was a significant departure from linearity in the direction of decreasing slope with increasing exposures. Among the models tried, the best fitting were a two-knot cubic spline and a power curve (RR = (1+bx)(p)), the latter predicting a relative risk of 2.68 at 100 microg/m(-3) BaP years. Additive models and multiplicative models for combining risks from occupational PAH and smoking fitted almost equally well, with a slight advantage to the additive. CONCLUSION: Despite the large cohort with long follow-up, the shape of the exposure-response function and the mode of combination of risks due to occupational PAH and smoking remains uncertain. If a linear exposure-response function is assumed, the estimated slope is broadly in line with the estimate from a previous follow-up of the same cohort, and somewhat higher than the average found in a recent meta-analysis of lung cancer studies.

Estimating reduction in occupational disease burden following reduction in exposure.

BACKGROUND/OBJECTIVE: Many occupational exposures causing disease cannot feasibly be eliminated entirely, but policies that reduce the exposures may be under consideration. This paper sets out to clarify how to estimate the reduction in occupational disease following a reduction in exposure, and shows a real-data illustration for doing this. METHODS: Modest extensions of standard expressions for attributable fractions permit estimation of fractions by which cases would be reduced by policies that do not eliminate exposure but change exposure distributions. However, this requires information on the exposure-response relation and on distribution of exposures. RESULTS: From hypothetical scenarios and a real example this paper explores how attributable cases are distributed by exposure level and, in particular, the proportion by which attributable cancers are reduced by eliminating exposures above a limit (the classic occupational limit regulation). It shows how this depends on the shape of the exposure-response relation and to some extent the shape of the exposure distribution, as well as on the proportion exposed above the limit. For linear no-threshold relations and left-skewed exposure distributions, the majority of the burden may be in a large number of people experiencing small relative risks, and thus may not be tackled by a strategy to reduce exposures above a certain limit. CONCLUSION: With appropriate data, estimating the disease burden in terms of the distribution of exposure is straightforward and can help to clarify the likely outcome of an intervention.

Comparing standardized mortality ratios.

It is well known that the ratio of two standardized mortality ratios (SMRs) is not in general an unbiased estimate of the underlying within-stratum ratio of rates of one subcohort relative to another. It is also established, although less well known, that a sufficient condition for unbiasedness is that the underlying stratum-specific rates in each of the two subcohorts be proportional to the reference population. Further, the ratio of SMRs is more precise than the wholly internal (Poisson regression) estimate of rate ratio. In data that are compatible with the proportionality assumption, use of the ratio of SMRs thus buys precision at the cost of increased vulnerability to bias. To further elucidate choice between methods, we derive expressions for the asymptotic precision of each. These show that improved precision of ratio of SMRs depends on the extent to which the distribution of expected deaths over strata is different in the two cohorts, or equivalently, on the variance over strata of the proportion of expected deaths falling in the first cohort. The results are illustrated by hypothetic examples.

Renal function in relation to low levels of cadmium exposure in a group of smelter workers.

Blood and urine samples were obtained from 274 smelter workers and urine samples from 48 controls. Cadmium, beta 2-microglobulin, and creatinine were estimated in blood and urine, and total protein in urine. Concentrations of cadmium in urine (mean 2.0 nmole/mmole creatinine) and blood (mean 21.8 nmole/L) observed in the smelter workers confirmed that this group had absorbed more cadmium than the general population, but less than most other occupationally exposed groups studied. Mean beta 2-microglobulin in urine was not significantly different in the smelter workers and the controls. The mean total protein in urine was 20% higher in the smelter workers, a difference which was significant (p congruent to 0.01). There was no consistent picture within the smelter workers of a relationship between history of cadmium exposure and the effect measures of beta 2-microglobulin in urine and blood, total protein in urine, creatinine clearance and relative beta 2-microglobulin clearance. Small but significant positive correlation coefficients were observed between cadmium in urine and beta 2-microglobulin in urine (r = 0.13), total protein in urine (r = 0.23) and beta 2-microglobulin clearance (r = 0.15), although these may be artifactual.

Comparison of French and English versions of the American Thoracic Society respiratory questionnaire in a bilingual working population.

Standardized French and English versions of the American Thoracic Society (ATS) respiratory disease questionnaire were administered to 204 English-speaking and 406 French-speaking male blue-collar aviation workers unexposed to occupational respiratory hazards. After adjusting for smoking status, age, years of education, foreign birth and maternal language other than French or English, no significant differences between the two questionnaires were found for response rates to usual cough, usual phlegm, mild or moderate dyspnoea, and chronic bronchitis. French-speaking workers reported significantly less wheeze with colds (OR = 0.60, p less than 0.02) and wheeze apart from colds (OR = 0.55, p less than 0.05) than the English-speaking group, but, the occurrence of wheeze on most days or nights was similar for both groups (OR = 1.02, NS). For 66 bilingual workers who completed both French and English questionnaires at a time interval of approximately two months, highly consistent results were found for sociodemographic data, smoking habits, cough, phlegm, breathlessness and chronic bronchitis, but not for wheeze with or apart from colds (agreement less than 90%; Kappa less than 0.50). These results reflect the difficulties in translating the concept of 'wheeze' from English to French. We conclude that most symptoms elicited by the French questionnaire may be generalized to English-speaking populations, but that questions pertaining to wheeze on most days or nights may be preferable to other questions concerning wheeze.

Common origin of inferior mesenteric and accessory renal artery.

Arteriography performed in the preoperative evaluation of a patient with horseshoe kidney and renal calculi revealed a common origin of the inferior mesenteric artery and an anomalous left lower polar renal artery. The origin of the anomaly and its clinical significance are reviewed.

Mortality and temperature in Sofia and London.

STUDY OBJECTIVE: Heat and cold have been associated with increased mortality, independently of seasonal trends, but details are little known. This study explores associations between mortality and temperature in two European capitals-Sofia and London-using four years of daily deaths, air pollution, and weather data. DESIGN: Generalised additive models were used to permit non-linear modelling of confounders such as season and humidity, and to show the shape of mortality-temperature relations-using both two day and two week average temperatures separately. Models with linear terms for heat and cold were used to estimate lags of effect, linear effects, and attributable fractions. PARTICIPANTS: 44701 all age all cause deaths in Sofia (1996-1999) and 256464 in London (1993-1996). MAIN RESULTS: In London, for each degree of extreme cold (below the 10th centile of the two week mean temperature), mortality increased by 4.2% (95% CI 3.4 to 5.1), and in Sofia by 1.8% (0.6 to 3.9). For each degree rise above the 95th centile of the two day mean, mortality increased by 1.9% (1.4 to 2.4) in London, and 3.5% (2.2 to 4.8) in Sofia. Cold effects appeared after lags of around three days and lasted-particularly in London-at least two weeks. Main heat effects occurred more promptly. There were inverse associations at later lags for heat and cold in Sofia. CONCLUSIONS: Average temperatures over short periods do not adequately model cold, and may be inadequate for heat if they ignore harvesting effects. Cold temperatures in London, particularly, seem to harm the general population and the effects are not concentrated among persons close to death.

Methodological approaches to the analysis of hierarchical studies of air pollution and respiratory health--examples from the CESAR study. Central European Study on Air pollution and Respiratory Health.

OBJECTIVES: Many studies of air pollution and health are carried out over several geographical areas, and sometimes over several countries. This paper explores three approaches to analysis in such studies: a non hierarchical model, a two-stage analysis, and multilevel modelling. Illustrations are given using a preliminary subset of data from the CESAR study. DESIGN: The Central European Study on Air pollution and Respiratory Health (CESAR) was conducted in 25 areas within six Central European countries, enrolling 20,271 schoolchildren. Pollution averages were calculated for each area. Associations between pollution and health outcomes were estimated under different models. MAIN RESULTS: A regression analysis of log FVC (forced vital capacity) on PM10, ignoring the geographical hierarchy, estimated a significant mean drop in FVC (adjusted for confounders) of 2.2% (95% CI 0.5% to 1.3%), p=0.007, from the area with the lowest PM10 to that with the highest. A multilevel model (mlm), using data for all children, but with random effects at area and country level, estimated a drop of 2.8% (-0.6% to 6.1%), p=0.110. A two-stage analysis (mean log FVC, adjusted for confounders, was estimated for each area using regression, and these means then regressed on PM10) estimated a drop of 2.6% (-0.5% to 5.5%), p=0.101. Simulation exercises showed the non hierarchical method to be very inadequate in the context of the CESAR study, with only half of all 95% confidence intervals for the estimated PM10 slope containing the true value (i.e., that used to create the simulated data). The two-stage and multilevel modelling methods gave results which were substantially better, though both underperformed slightly. All three methods appeared to give unbiased slope estimates. CONCLUSIONS: Acknowledgement of hierarchical structures is essential in statistical inference--standard errors can be substantially incorrect when they are ignored. Multilevel, random-effects models correctly address hierarchical structures, though having few units at higher levels can cause problems in convergence, especially where complex modelling is required. Two-stage analyses, acknowledging hierarchy, provide simple alternatives to random-effects models.

Effects of approximation in exposure assessments on estimates of exposure- response relationships.

Information on exposure in cohort studies of occupational groups is often very incomplete. If assessments of exposure level are attempted, they are inevitably subject to random error. Even when unbiased, such measurement error can give rise to bias in an estimate of an exposure-response relationship. Since practical techniques exist to account for this effect only in certain situations where response may be measured on a continuous scale, a technique suitable for mortality studies needs developing. In the present report a procedure is described for reducing the bias due to random error in the estimated exposure-response relationship from a cohort mortality study. This procedure is based on a mechanism for adjusting exposure assessments, taking into account the distribution of exposures, and the independently estimated distribution of measurement errors. The initial bias and its reduction through analysis is shown for some simulated data sets. The results of applying this technique to a cohort mortality study of asbestos workers are presented.

Exposure to 60-Hz magnetic and electric fields at a Canadian electric utility.

OBJECTIVES: The purpose of this study was to estimate exposure to extremely low frequency (ELF) magnetic and electric fields in the Québec electrical utility Hydro-Quebec. METHODS: Personal exposures to ELF magnetic and electric fields were measured for workers randomly selected from 32 job categories at Hydro-Québec. Weekly arithmetic and geometric means, and other indices of exposure were estimated from 465 worker-weeks of data. RESULTS: By job category, the arithmetic means of the ELF magnetic field ranged from 0.09 to 2.36 microT. Those of the ELF electric field exposures ranged from 2.5 to 400 V.m-1. Within each field, correlations of either the arithmetic or geometric means with alternative indices, including an index of the time rate of change, were generally high (r > or = 0.8). Exceptions were the 20th percentile of the electric means and the proportion of time above 12.4 and 100 microT. The day-to-day variation of exposure was greater than the variation between workers. The median between-day and between-worker components of variance (as geometric standard deviations) by job category were 2.13 and 1.71 for magnetic fields (2.24 and 1.81 for electric fields). CONCLUSIONS: Substation workers, hydroelectric generating station operators, and cable splicers showed the highest arithmetic means for 60-Hz magnetic fields above 1 microT. For 60-Hz electric fields, forestry workers, equipment electricians in 735 kV substations, and distribution linemen (contact method) had arithmetic mean exposures greater than 100 W.m-1. Of the total variance in the logarithms of the weekly magnetic and electric field means, job category explained 49.6% and 59.5%, respectively.

Estimating the relationship between exposure to tar volatiles and the incidence of bladder cancer in aluminum smelter workers.

A previously reported case-referent study of 85 incident cases of bladder cancer among aluminum smelter workers and 255 matched referents revealed an excess risk among workers exposed to coal-tar pitch volatiles. For the study reported in the present investigation these data have been augmented by estimates of past workplace exposure to total tar (benzene-soluble matter) and to benzo-a-pyrene (BaP). From these new data, exposure-response relationships have been estimated by maximum likelihood. A linear relationship between cumulative exposure and relative risk and a minimum latency period of ten years were assumed on a priori grounds and found compatible with the data. Under these assumptions, relative risk increased for each year of exposure to benzene-soluble matter at a concentration of 1 mg/m3 by 13%, the 95% confidence interval being 5-31. The corresponding figure for BaP (as micrograms/m3 X year) was 2.3%. On the basis of these estimates, 40 years of exposure to benzene-soluble matter at the current exposure limit of 0.2 mg/m3 would lead to a relative risk of 2.4. There was suggestive but not conclusive evidence that relative risks due to exposure to tar volatiles and to cigarette smoke combined multiplicatively.

Task-based estimation of past exposures to 60-hertz magnetic and electric fields at an electrical utility.

OBJECTIVES: Past exposures of electric utility workers to extremely low-frequency (ELF) magnetic (B) and electric fields (E) in Quebec were estimated. METHODS: The current intensities were measured and durations of exposures determined for tasks or work locations in 14 job categories. Past task or location intensities were extrapolated from the present on the basis of interviews with long-term workers and utility personnel. Past task or location durations were estimated for the long-term workers. Time-weighted average (TWA) exposures for past periods were reconstructed for jobs from the intensity and duration estimates. RESULTS: Magnetic fields were estimated to have increased the most over time for substation and distribution-line jobs. Magnetic field exposures for jobs in the generation and transmission of electricity were estimated to have increased very little. For substation jobs, the ratios of magnetic fields in 1945 to those in 1990 ranged from 0.42 to 0.69; the corresponding figures for distribution-line jobs ranged from 0.36 to 0.94. For electric fields in substations, the estimated increase over time was less than for magnetic fields, the 1945:1990 ratios ranging from 0.59 to 0.88. For the distribution line jobs, the 1945:1990 ratios for electric fields were less than 1.0 in 4 cases (0.6 to 0.89), more than 1.0 in 3 others (1.13 to 2.01) and unchanged in 1. CONCLUSIONS: Reconstruction of TWA exposures allowed changes in the intensity and the duration of exposures to be considered separately. Documentation of the intensity and duration of exposures for different tasks allows exposure reconstruction for jobs that have ceased to exist. The method is applicable elsewhere if exposure-monitoring records allow the level and duration of exposures for tasks or locations to be calculated and if estimates of past durations and intensities of exposures can be reliably obtained.

Exposures of children in Canada to 60-Hz magnetic and electric fields.

OBJECTIVES: This study sought to characterize personal exposures of Canadian children to 60-Hz magnetic and electric fields and explain the variability. METHODS: Altogether 382 Canadian children up to 15 years of age wore meters recording 60-Hz electric and magnetic fields over 2 days. Meter location was noted. Thereafter, meters measured fields in the center of the children's bedrooms for 24 hours. Personal exposures were calculated for home, school or day care, outside the home, bedroom at night, and all categories combined (total). RESULTS: The arithmetic mean (AM) was 0.121 microT [geometric mean (GM): 0.085 microT), range 0.01-0.8 microT] for total magnetic fields. Fifteen percent of the total exposures exceeded 0.2 microT. The AM of the total electric fields was 14.4 (GM 12.3, range 0.82-64.7) V/m. By location category, the highest and lowest magnetic fields occurred at home during the day (0.142 microT) and during the night (0.112 microT), respectively. Measurements during sleep provided the highest correlation with total magnetic field exposure. Province of measurement explained 14.7% of the variation in the logarithms of total magnetic fields, and season accounted for an additional 1.5%. CONCLUSIONS: This study has identified differences in children's magnetic field exposures between provinces. Measurements at night provided the best surrogate for predicting total magnetic field exposure, followed by at-home exposure and 24-hour bedroom measurements. Electrical heating and air conditioning, wiring type, and type of housing appear to be promising indicators of magnetic field levels.

Geographical variation in anophthalmia and microphthalmia in England, 1988-94.

OBJECTIVE: To investigate the geographical variation and clustering of congenital anophthalmia and microphthalmia in England, in response to media reports of clusters. DESIGN: Comparison of pattern of residence at birth of cases of anophthalmia and microphthalmia in England in 1988-94, notified to a special register, with pattern of residence of all births. Three groups studied included all cases, all severe cases, and all severe cases of unknown aetiology. OUTCOME MEASURES: Prevalence rates of anophthalmia and microphthalmia by region and district, and by ward population density and socioeconomic deprivation index of enumeration district grouped into fifths. Clustering expressed as the tendency for the three nearest neighbours of a case to be more likely to be cases than expected by chance, or for there to be more cases within circles of fixed radius of a case than expected by chance. RESULTS: The overall prevalence of anophthalmia and microphthalmia was 1.0 per 10 000 births. Regional and district variation in prevalence did not reach statistical significance. Prevalence was higher in rural than urban areas: the relative risk in the group of wards of lowest population density compared with the most densely populated group was 1.79 (95% confidence interval 1.15 to 2.81) for all cases and 2.37 (1.38 to 4. 08) for severe cases. There was no evidence of a trend in risk with socioeconomic deprivation. There was very little evidence of localised clustering. CONCLUSIONS: There is very little evidence to support the presence of strongly localised environmental exposures causing clusters of children to be born with anophthalmia or microphthalmia. The excess risk in rural areas requires further investigation.

Association of mortality with high temperatures in a temperate climate: England and Wales.

BACKGROUND: It is well known that high ambient temperatures are associated with increased mortality, even in temperate climates, but some important details are unclear. In particular, how heat-mortality associations (for example, slopes and thresholds) vary by climate has previously been considered only qualitatively. METHODS: An ecological time-series regression analysis of daily counts of all-cause mortality and ambient temperature in summers between 1993 and 2006 in the 10 government regions was carried out, focusing on all-cause mortality and 2-day mean temperature (lags 0 and 1). RESULTS: All regions showed evidence of increased risk on the hottest days, but the specifics, in particular the threshold temperature at which adverse effects started, varied. Thresholds were at about the same centile temperatures (the 93rd, year-round) in all regions-hotter climates had higher threshold temperatures. Mean supra-threshold slope was 2.1%/°C (95% CI 1.6 to 2.6), but regions with higher summer temperatures showed greater slopes, a pattern well characterised by a linear model with mean summer temperature. These climate-based linear-threshold models capture most, but not all, the association; there was evidence for some non-linearity above thresholds, with slope increasing at highest temperatures. CONCLUSION: Effects of high daily summer temperatures on mortality in English regions are quite well approximated by threshold-linear models that can be predicted from the region's climate (93rd centile and mean summer temperature). It remains to be seen whether similar relationships fit other countries and climates or change over time, such as with climate change.

Effect of measurement error on epidemiological studies of environmental and occupational exposures.

Random error (misclassification) in exposure measurements usually biases a relative risk, regression coefficient, or other effect measure towards the null value (no association). The most important exception is Berkson type error, which causes little or no bias. Berkson type error arises, in particular, due to use of group average exposure in place of individual values. Random error in exposure measurements, Berkson or otherwise, reduces the power of a study, making it more likely that real associations are not detected. Random error in confounding variables compromises the control of their effect, leaving residual confounding. Random error in a variable that modifies the effect of exposure on health--for example, an indicator of susceptibility--tends to diminish the observed modification of effect, but error in the exposure can create a supurious appearance of modification. Methods are available to correct for bias (but not generally power loss) due to measurement error, if information on the magnitude and type of error is available. These methods can be complicated to use, however, and should be used cautiously as "correction" can magnify confounding if it is present.

Optimizing power in allocating resources to exposure assessment in an epidemiologic study.

We consider an epidemiologic study with a fixed budget, in which resources may be put into increasing sample size or into improving accuracy of exposure assessments. To maximize study power (efficiency), improving accuracy is preferable if and only if the proportional increase in the square of the validity coefficient is more than the proportional increase in total study costs per subject that is required to achieve it. (The validity coefficient is the correlation between the true exposure and the approximate assessment in the study base.) This is most likely to be so if the cost of exposure measurement remains a small proportion of the overall costs per subject. The design with maximum power will not generally have minimum bias in measure of effect, so that alternative optimality criteria are required if this bias is important.

The effects of measurement errors on relative risk regressions.

This paper concerns the effects of random error in numerical measurements of risk factors (covariates) in relative risk regressions. When not dependent on outcome (nondifferential), such error usually attenuates relative risk estimates (shifts them toward one) and leads to spuriously narrow confidence intervals. The presence of measurement error also reduces precision of estimates and power of significance tests. However, significance levels obtained by using the approximate measurements are usually valid and as powerful as possible given the measurement error. The attenuation in risk estimate depends not only on the size (variance) of the measurement error, but also on its distributional form, on whether it is dependent on the true level of the risk factor (whether it is of "Berkson" type), on the variance and distributional form of true levels of the risk factor, on the functional form of the regression (exponential or linear), and on the confounding variables included in the model. Error in measuring confounding variables leads to loss of control of confounding, leaving residual bias. Uncomplicated techniques of correcting the effects of measurement error in simple models in which distributions are assumed normal are available in the statistical literature. For these corrections, information on measurement error variance is required. Some approaches appropriate for more general models have been proposed, but these appear to be insufficiently developed for routine application.

Exposure to magnetic fields estimated from last job held in an electrical utility in Québec, Canada: a validation study.

OBJECTIVES: To investigate how closely the variables of exposures to magnetic fields based on the last job held in an electrical utility in Québec, Canada, compared with those based on the workers' entire employment history with the company. METHODS: In large cohort studies, the last job held is often used to assign exposure to the study subjects. Exposure was assigned in this way for a mortality study of a cohort of electrical utility workers in Québec. For the present study, a sample of the cohort was used to compare the exposure estimates obtained from the last job with those obtained from full work histories. RESULTS: The correlations between indices based on the last job and on all jobs varied between 0.75 and 0.78. The mean was slightly lower when only the last job was used. The last job was particularly good in identifying the most highly exposed people (for the exposure cut off point of 90th percentile for the last job and for all jobs, sensitivity = 0.69, specificity = 0.97, kappa = 0.66). The results suggest that although not all workers starting in highly exposed jobs stayed in them, it seemed that the workers who ended their working life in highly exposed jobs had stayed in these jobs throughout their working life. CONCLUSION: The results indicated some (but not catastrophic) loss of information when estimates of exposure were based on the last job only.