The development of a new method to estimate total daily dose of pesticides in professional turf applicators following multiple and varied exposures in occupational settings.

The evaluation of absorbed dose of pesticides in humans requires a knowledge of the kinetics and dynamics of the compound. In some circumstances, data that allow for the estimation of dose may be available from human volunteer studies, although often, it will be based on results from animal studies. If human metabolism data are available, estimates of dose may be more accurate, but it should be recognized that pesticide exposure in an occupational setting may differ from that in a controlled laboratory study. In this study, data from previously published studies are used to evaluate the urinary excretion of 2,4-dichlorophenoxyacetic acid (2,4-D), following single dermal applications to human volunteers. These studies are evaluated with the objective of determining the best method of predicting total absorbed dose following multiple and varied exposures in occupational settings. Further, an alternative to laboratory-controlled human volunteer studies is presented. Data from a third previously published biological monitoring study on six professional pesticide applicators over a 2-week period were used to generate estimates of the urinary excretion of the pesticide 2,4-D that would result from a single dose. The method used to estimate the urinary excretion parameters is a variation of an overlay technique used in pharmacology, and may provide information on the kinetics of other pesticides when it is not possible to conduct human studies. The generated estimates of 24-h urinary excretion of 2,4-D over a 6-day period were remarkably similar to those obtained in controlled studies. Finally, a method was developed to use the generated estimates to determine total absorbed dose of pesticides for an independent group of 95 professional pesticide applicators. This method requires information on the amount of pesticide used for 6 days prior to the collection of two, 24-h urine samples.

An evaluation of 24-hour urinary creatinine excretion for use in identification of incomplete urine collections and adjustment of absorbed dose of pesticides.

The accurate quantification of the absorbed dose of pesticides following occupational exposures generally requires complete 24-hour urine collections, often over extended periods of time. Difficulty in obtaining volunteer cooperation may result in incomplete urine collections. Traditionally, 24-hour urinary creatinine has been used to identify incomplete urine samples and has been used to standardize pesticide and other chemical dose estimates. More recently, the use of creatinine to standardize dose estimates has been questioned, as has its utility in the identification of incomplete urine collections. This research evaluates the use of personal observation, statistical methods, and published models to predict creatinine excretion to identify and adjust for incomplete urine collections. Based on the use of published creatinine prediction models, an evaluation of the day-to-day creatinine excretion within subjects, and personal observation, a small number of suspected urine samples were identified. Although it is likely that these samples were incomplete, correction of these urine volumes based on the published models did little to improve pesticide dose prediction. Further, results indicate that subjects who report missed urine samples may be able to estimate the missing volumes with some accuracy. In future pesticide exposure studies, the use of self-reported missed volumes may help to increase the accuracy of dose prediction when there is strong cooperation with collection procedures. A statistical model to predict creatinine excretion in professional turf applicators was developed to provide a preliminary screening for urinary completeness for future studies in which compliance with urinary collection is thought to be insufficient.

Leukemia in electric utility workers: the evaluation of alternative indices of exposure to 60 Hz electric and magnetic fields.

BACKGROUND: Epidemiological studies have inconsistently demonstrated a positive relationship between magnetic and/or electric fields and leukemia. Although exposure to both 60 Hz electric and magnetic fields can be characterized in many ways, to date, risk assessment has been performed by using only a limited number of exposure indices. METHODS: The associations between adult leukemia and indices of electric and magnetic fields were explored within a nested case-control study of 31,453 Ontario electric utility workers. RESULTS: The percentage of time spent above electric field thresholds of 20 and 39 V/m was predictive of leukemia risk after adjusting for duration of employment and the arithmetic mean exposure to both electric and magnetic fields (P<0.05). Duration of employment was strongly associated with an increased risk of leukemia. Those who had worked for at least 20 years, and were in the highest tertiles of percentage of time spent above 10 and 20 V/m had odds ratios of 10.17 (95% CI = 1.58-65.30) and 8.23 (95% CI = 1. 24-54.43), respectively, when compared to those in the lowest tertile. Nonsignificant elevations in risk were observed between indices of magnetic fields and leukemia. CONCLUSIONS: Our results support the hypothesis that electric fields act as a promoting agent in the etiology of adult leukemia. Exposure assessment based on alternate indices of electric and magnetic fields should be incorporated into future occupational studies of cancer.

Non-Hodgkin's lymphoma among electric utility workers in Ontario: the evaluation of alternate indices of exposure to 60 Hz electric and magnetic fields.

OBJECTIVES: To examine associations between non-Hodgkin's lymphoma (NHL) and exposures to 60 Hz magnetic and electric fields in electric utility workers with a series of indices that capture a variety of aspects of field strength. METHODS: The study population consisted of 51 cases of NHL and 203 individually matched controls identified from within a cohort of male electric utility workers in Ontario. Odds ratios were calculated for several exposure indices with conditional logistic regression models. Aspects of exposure to electric and magnetic fields that were modelled included: the percentage of time spent above selected threshold field intensities, mean transitions in field strength, SD, and the arithmetic and geometric mean field intensities. RESULTS: For the most part, there was a lack of an association between exposure indices of magnetic fields and the incidence of NHL. Subjects in the upper tertile of percentage of time spent above electric field intensities of 10 and 40 V/m had odds ratios of 3.05 (95% confidence interval (95% CI) 1. 07 to 8.80) and 3.57 (1.30 to 9.80), respectively, when compared with those in the lowest tertile. Moreover, the percentages of time spent above these electric field thresholds were significant predictors of case status over and above the association explained by duration of employment and the arithmetic or geometric mean exposure. CONCLUSIONS: These data suggest that exposures above electric field threshold intensities of 10 and 40 V/m are important predictors of NHL. Consequently, the findings support the hypothesis that electric fields may play a promoting part in the aetiology of this cancer. Further occupational studies that include assessment of exposure to electric fields and measures of field strength above similar threshold cut off points are needed to confirm these findings.

A study of the reliability of the Canada Fitness Survey questionnaire.

PURPOSE: The purposes of this study are to assess the reliability of the physical activity components of the Canada Fitness Survey (CFS) questionnaire (N = 64 males, N = 63 females) and the Canadian Aerobic Fitness Test (N = 44 males, N = 52 females) in a sample of subjects between 15 and 80 yr. RESULTS: The intraclass correlation (rI) for the fitness scores was 0.98. The activity variables showed low to moderate correlations (rI = 0.48-0.53). Correlations were higher for males (rI = 0.38-0.65) than females (rI = 0.28-0.60) for most of the activity variables reported. Males generally report leisure activity more reliably than nonleisure activity, whereas the opposite was true for females. Males reported strenuous activity with higher reliability (rI = 0.86) than females (rI = 0.31). There was considerable variation in the reliability of specific activities. Of the components of physical activity (time, intensity, duration) that comprise the energy expenditure (EE) variable, the least reliably reported is intensity for both males (rI = 0.43) and females (rI = 0.55). CONCLUSIONS: The CFS questionnaire is moderately reliable for most measures of physical activity. Estimates of reliability vary considerably among the various activities and components of these activities and between males and females.

Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.

OBJECTIVE: To estimate the incidence of serious and fatal adverse drug reactions (ADR) in hospital patients. DATA SOURCES: Four electronic databases were searched from 1966 to 1996. STUDY SELECTION: Of 153, we selected 39 prospective studies from US hospitals. DATA EXTRACTION: Data extracted independently by 2 investigators were analyzed by a random-effects model. To obtain the overall incidence of ADRs in hospitalized patients, we combined the incidence of ADRs occurring while in the hospital plus the incidence of ADRs causing admission to hospital. We excluded errors in drug administration, noncompliance, overdose, drug abuse, therapeutic failures, and possible ADRs. Serious ADRs were defined as those that required hospitalization, were permanently disabling, or resulted in death. DATA SYNTHESIS: The overall incidence of serious ADRs was 6.7% (95% confidence interval [CI], 5.2%-8.2%) and of fatal ADRs was 0.32% (95% CI, 0.23%-0.41%) of hospitalized patients. We estimated that in 1994 overall 2216000 (1721000-2711000) hospitalized patients had serious ADRs and 106000 (76000-137000) had fatal ADRs, making these reactions between the fourth and sixth leading cause of death. CONCLUSIONS: The incidence of serious and fatal ADRs in US hospitals was found to be extremely high. While our results must be viewed with circumspection because of heterogeneity among studies and small biases in the samples, these data nevertheless suggest that ADRs represent an important clinical issue.

Alternate indices of electric and magnetic field exposures among Ontario electrical utility workers.

Epidemiologic studies examining the risk of cancer among occupational groups exposed to electric fields (EF) and or magnetic fields (MF) have relied on traditional summaries of exposure such as the time weighted arithmetic or geometric mean exposure. Findings from animal and cellular studies support the consideration of alternative measures of exposure capable of capturing threshold and intermittent measures of field strength. The main objective of this study was to identify a series of suitable exposure metrics for an ongoing cancer incidence study in a cohort of Ontario electric utility workers. Principal components analysis (PCA) and correlational analysis were used to explore the relationships within and between series of EF and MF exposure indices. Exposure data were collected using personal monitors worn by a sample of 820 workers which yielded 4247 worker days of measurement data. For both EF and MF, the first axis of the PCA identified a series of intercorrelated indices that included the geometric mean, median and arithmetic mean. A considerable portion of the variability in EF and MF exposures were accounted for by two other principal component axes. The second axes for EF and MF exposures were representative of the standard deviation (standard deviation) and thresholds of field measures. To a lesser extent, the variability in the exposure variable was explained by time dependent indices which consisted of autocorrelations at 5 min lags and average transitions in field strength. Our results suggest that the variability in exposure data can only be accounted for by using several exposure indices, and consequently, a series of metrics should be used when exploring the risk of cancer owing to MF and EF exposure in this cohort. Furthermore, the poor correlations observed between indices of MF and EF reinforce the need to be take both fields into account when assessing the risk of cancer in this occupational group.

Effect of breast self-examination techniques on the risk of death from breast cancer.

OBJECTIVE: To measure the effect of breast self-examination (BSE) technique and frequency on the risk of death from breast cancer. DESIGN: Case-control study nested within the Canadian National Breast Screening Study (NBSS). SETTING: The Canadian NBSS, a multicentre randomized controlled trial of screening for breast cancer in Canadian women. SUBJECTS: The case subjects were 163 women who had died from breast cancer and 57 women with distant metastases. Ten control subjects matched by 5-year age group, screening centre, year of enrolment and random allocation group were randomly selected for each case subject. EXPOSURE MEASURES: Self-reported BSE frequency before enrolment in the NBSS, annual self-reports of BSE frequency during the program and annual objective assessments of BSE technique. OUTCOME MEASURES: Odds ratios (ORs) associated with BSE practice were estimated by conditional multiple logistic regression modelling, which permitted control of covariates. RESULTS: Relative to women who, when assessed 2 years before diagnosis, examined their breasts visually, used their finger pads for palpation and examined with their 3 middle fingers, the OR for death from breast cancer or distant metastatic disease for women who omitted 1, 2 or 3 of these components was 2.20 (95% confidence interval [CI] 1.30 to 3.71, p = 0.003). The OR for women who omitted 1 of the 3 components was 1.82 (95% CI 1.00 to 3.29, p = 0.05), for those who omitted 2 of the 3 components, 2.84 (95% CI 1.44 to 5.59, p = 0.003), and for those who omitted all 3 components, 2.95 (95% CI 1.19 to 7.30, p = 0.02). The results remained unchanged after adjustment for potential confounders. CONCLUSION: The results, obtained with the use of prospectively collected data, suggest that the performance of specific BSE components may reduce the risk of death from breast cancer.

Effect of psyllium in hypercholesterolemia at two monounsaturated fatty acid intakes.

We performed two studies to determine whether the lipid-lowering effect of viscous soluble fiber was modified by monounsaturated fatty acid (MUFA). First, psyllium (1.4 g/MJ) was compared with wheat bran (control) in 1-mo metabolic diets by using a randomized crossover design (n = 32 hyperlipidemic subjects). The background diet contained approximately 6% of energy as MUFA (20% of total fat). The second study (n = 27 hyperlipidemic subjects) was similar to the first but the background diet contained approximately 12% MUFA (29% of total fat) because of the addition of canola oil. At both fat intakes, psyllium resulted in significant reductions in total, low-density-lipoprotein (LDL), and high-density-lipoprotein (HDL) cholesterol compared with the wheat bran control. For the psyllium diet at 6% compared with 12% MUFA, the decreases in LDL cholesterol were 12.3 +/- 1.5% (P < 0.001) and 15.3 +/- 2.4% (P < 0.001), respectively. With the higher-MUFA diet triacylglycerol fell significantly over the control phase (16.6 +/- 5.5%, P = 0.006) and the ratio of LDL to HDL cholesterol fell significantly over the psyllium phase (7.3 +/- 2.8%, P = 0.015). Psyllium and MUFA intakes were negatively related to the percentage change in the ratio of LDL to HDL cholesterol (r = -0.34, P = 0.019 and r = -0.44, P = 0.002, respectively). Chenodeoxycholate synthesis rate increased (30 +/- 13%, P = 0.038) with the psyllium diet in the 12 subjects in whom this was assessed. We conclude that psyllium lowered LDL- and HDL-cholesterol concentrations similarly at both MUFA intakes. However, there may be some advantage in combining soluble fiber and MUFA to reduce the ratio of LDL to HDL cholesterol.

An investigation of the association between exposure to styrene and hearing loss.

The importance of the association between advancing age and hearing loss is well recognized. Further, prolonged significant noise exposures are also known to result in permanent hearing loss. However, little is known of the contribution of industrial chemical exposures to hearing loss. Information available, from both animal and human studies, raises the possibility that certain aromatic hydrocarbons are ototoxic. The purpose of this study was to assess whether occupational styrene exposure causes hearing loss in a group of workers in the fiber-reinforced plastics manufacturing industry. The hearing acuity of 299 subjects was determined, using pure-tone screening audiometry, at the beginning of a single workshift and again at the end of the shift. On the same day, the personal, time-weighted average exposures of each subject to both styrene and noise were measured. In addition, information on the following factors was obtained from each participant: previous work history, including exposures to noise and chemicals; use of personal protective equipment for noise or solvents; personal and family history of hearing problems; and smoking history. Current exposures together with work histories were used to construct lifetime noise and styrene exposure indices. No conclusive evidence was found for a chronic styrene-induced effect on hearing acuity, when both noise and styrene lifetime exposures were taken into account. As expected, age and noise exposures were highly important variables, both positively associated with hearing loss. In addition, the detrimental effect of noise exposure on hearing acuity was found to be strengthened with increased age. Noise and styrene exposures were highly correlated, clearly illustrating the importance of considering all associated variables in analysis of such data. No evidence was found for a relationship between smoking, recreational noise, solvent exposures, and hearing loss.

Prediction of maximal oxygen uptake from a modified Canadian aerobic fitness test.

The purpose of the present study was to increase the accuracy of prediction of VO2max from the Canadian Aerobic Fitness Test (CAFT) by modifying the protocol and developing a new equation. Males and females between the ages of 15 and 69 years (n = 129) were tested on four occasions. Each subject performed four submaximal step tests (modified CAFT protocol) and a maximal treadmill test. The modification of the protocol consisted of allowing each subject to complete the number of stages needed to reach a target heart rate of 85% of age-predicted maximum. This required adding a new Stage 8 for men and Stages 7 and 8 for women. The prediction equation resulting from regression analysis was, VO2max (ml.kg-1 x min-1) = 32.0 + 16.0 VO2 - 0.24 Age - 0.17 Wt (R2 - 0.77; delta 2 - 26.6), where VO2 = oxygen cost of stepping at the final level (L.min-1), Age = age (yrs), and Wt = body mass (kg).

An efficacy trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine in infants born to mothers positive for HBsAg, in Shanghai, China.

We conducted a randomized, double-blind clinical trial of an experimental mammalian cell-derived DNA hepatitis B vaccine (Betagen, Connaught Laboratories Ltd, Toronto, Canada) to determine its efficacy in infants born to mothers who were carriers of hepatitis B surface antigen (HBsAg). Four groups of 55 infants received injections as follows: (1) a licensed plasma-derived vaccine (Lanzhou, Lanzhou Institute for Biological Products, Lanzhou, People's Republic of China), 20 micrograms; (2) Betagen, 20 micrograms; (3) Betagen, 20 micrograms+hepatitis B immune globulin (HBIG); and (4) Betagen, 10 micrograms+HBIG. Vaccine injections were given at birth and at 1 and 6 months and HBIG was given at birth. The vaccines were compared to a historical placebo control group. The efficacy of Betagen alone was 82.6% compared to 51.0% for the Lanzhou. Efficacy of Betagen increased with the concomitant use of HBIG. No infants who were HBsAg negative at birth and/or were born to hepatitis B e antigen (HBeAg) negative mothers became carriers. The rate of HBsAg in infants receiving Betagen alone, and born to mothers who were HBeAg positive, decreased from 60% at birth to 20% by the ninth month, compared to 62.5% and 50% (respectively) for Lanzhou. The percentage of infants with protective levels of antiHBs was significantly higher for Betagen alone than for Lanzhou, but the geometric mean titre of antiHBs for responders was not significantly different. We have shown that Betagen alone is highly efficacious in preventing the development of hepatitis B in infants born to mothers who are carriers of HBsAg and is also highly effective in reducing the carriage of HBsAg in infants who are HBsAg positive at birth and/or born to HBeAg positive mothers.

PIP: Researchers assigned 220 infants born at 5 participating hospitals in Shanghai, China to receive either a 20mcg of an experimental recombinant DNA hepatitis B vaccine (Betagen), a licensed plasma derived hepatitis B vaccine (Lanzhou), 20 mcg of Betagen and hepatitis B immune globulin (HBIG), or 10mcg of Betagen and HBIG to determine the efficacy of Betagen in infants born to mothers with hepatitis B surface antigen (HBsAg) positive. Since China is a hyperendemic hepatitis B carrier area (in Shanghai, for example, prevalence rate is 57%), China hopes to reduce the carrier state via a low cost, safe, immunogenic, and efficacious recombinant vaccine. 20mcg of Betagen resulted in 82.6% efficacy which was significantly higher than that of Lanzhou (51%). The efficacy increased when HBIG was administered with the 20mcg of Betagen (92%). None of the infants born HBsAg negative and/or born to hepatitis B e antigen (HBeAg) mothers later became carriers. Further the HBsAg positive fell from 60-2-% in 9 months whereas these corresponding figures for those who received only Lanzhou were 62.5% and 50%. Even though the percentage of infants with protective levels of antiHBs stood much higher in those who received only Betagen than for those who received Lanzhou in all the months of follow up, except the 1st, their geometric mean titre of antiHBs was not statistically significant. Since Betagen prompted a quick antibody response which probably helped decrease HBsAg in the serum of those infants already positive for HBsAg at birth, it had an advantage over Lanzhou. In conclusion, Betagen given alone proved to be very efficacious in preventing hepatitis B in infants born to carriers of HBsAg. Further it was effective in reducing carriage of HBsAg in infants born HBsAg positive and/or born to HBeAg positive mothers.

Selection of a maximal test protocol to validate the Canadian Aerobic Fitness Test.

The purpose of this study was to select a maximal aerobic power test protocol with which to validate a submaximal step test prediction equation. Subjects (N = 129), males and females 15 to 69 years of age, performed one maximal step test and one maximal treadmill test. The maximal treadmill protocol yielded higher peak VO2, ventilation, heart rate, and RER values. An age-predicted maximum heart rate was achieved by 35% of subjects on the step test and 55% on the treadmill. An RER of 1.15 was attained by 22% of the subjects on the step test and 53% on the treadmill. Regression analysis indicated that the submaximal test was more predictive of VO2max when the maximum was attained using the treadmill rather than the maximal step protocol. Peak VO2 values obtained from subjects tested on the treadmill will be used to develop a new prediction equation for the Canadian Aerobic Fitness Test.

A study to validate the Canadian Aerobic Fitness Test.

Our purpose was to assess the validity of VO2 max values predicted from The Canadian Aerobic Fitness Test (CAFT) by comparing them with peak VO2 values measured during a maximal treadmill protocol. Male and female subjects, 15-69 yr (n = 129), performed two submaximal exercise tests (CAFT protocol), and one maximal treadmill test. There was no significant heart rate habituation between the first two CAFT protocols. Peak VO2 values measured during the treadmill test (TM) were significantly higher than those predicted from the CAFT whether the sample was analyzed overall or categorized by sex. When the sample was categorized by age group, all but groups 1 (15-19) and 6 (60-69) had treadmill peak VO2 values significantly higher than those predicted using Jetté's equation. Using treadmill measured peak VO2 scores as the gold standard, VO2 max predictions using the CAFT protocol and Jetté equation placed individuals of lower fitness levels more accurately than highly fit individuals, into one of five fitness categories.

Effect of exposure of miners to aluminium powder.

'McIntyre Powder' (finely ground aluminium and aluminium oxide) was used as a prophylactic agent against silicotic lung disease between 1944 and 1979 in mines in northern Ontario. To find out whether the practice produced neurotoxic effects a morbidity prevalence study was conducted between 1988 and 1989. There were no significant differences between exposed and non-exposed miners in reported diagnoses of neurological disorder; however, exposed miners performed less well than did unexposed workers on cognitive state examinations; also, the proportion of men with scores in the impaired range was greater in the exposed than non-exposed group. Likelihood of scores in the impaired range increased with duration of exposure. The findings are consistent with putative neurotoxicity of chronic aluminium exposure.

A randomized double-blind clinical trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine compared with a plasma-derived vaccine.

Eight hundred volunteers from heath care and emergency fields participated in a randomized double-blind clinical trial of a new experimental mammalian cell-derived recombinant DNA hepatitis B vaccine (Betagen) compared with a licensed plasma-derived vaccine (Heptavax-B). Vaccine injections (20 micrograms) were administered intramuscularly at 0, 1, and 6 months, and sera were tested at 0, 1, 2, 3, 6, 7, and 12 months for hepatitis B surface antigen, antibody to hepatitis B surface antigen, and antibody to hepatitis B core antigen. Data from 745 vaccinees (93.1%), analyzed at the 7th month of follow-up, showed no significant difference in the seroconversion rates for Betagen (94.4%) vs Heptavax-B (97.3%), but the geometric mean titer of antibody was significantly higher for Heptavax-B (11 833 mIU/L) than for Betagen (4628 mIU/mL). The antibody response of Betagen was significantly and independently related to age and sex, while that of Heptavax-B was related to age only. Reported side effects from both vaccines were minor and mild, with approximately one fourth of all vaccinees reporting at least one side effect. Vaccinees, who had a protective level of antibody at the 7th month, were tested for antibodies at the 12th month. Of those in the Betagen-vaccinated group and those in the Heptavax-B-vaccinated group, 99.0% and 100%, respectively, were still protected. There was a proportionately larger decline in the geometric mean titers of antibody to hepatitis B surface antigen for Heptavax-B than for Betagen.

Adjusting for clustering in survey research.

The current widespread application of cluster sampling in survey design presents concerns to the researcher regarding the chosen unit of study. The statistical power of a study could be spuriously increased or decreased, sample size could be altered dramatically, and the uniqueness of the individual unit under study (e.g., a patient) could be lost and substituted by average values of characteristics depending on which unit of study is selected. The 1985 National Ambulatory Medical Care Survey of the U.S. National Center for Health Statistics was used to illustrate research methodologies that would deflate spuriously high results due to clustered sampling. Using the individual patient as the study unit, correction factors ranging from 1.99 to 35.40 were calculated in order to deflate exaggerated t-tests, chi-square, and F values of predictor variables. The effect of clustering was more marked on (1) continuous rather than binary outcome variables, as the former provide a richer environment to form clusters; and (2) on outcome variables relating to the practice-related or personal style of physicians. Using the physician (who represented a cluster of patients) as the unit of study, it was realized that correction factors were relevant to physician-specific predictors but not patient-specific predictors. Using design effect correction factors developed from a simple univariate analysis of variance, pharmacoepidemiologists can analyze accurately the currently available large survey databases of clustered samples.

Conceptual and methodological issues regarding the epidemiology of iron deficiency and their implications for studies of the functional consequences of iron deficiency.

This paper reviews the measures of iron status (hemoglobin, hematocrit, mean corpuscular hemoglobin concentration, mean cell volume, free erythrocyte protoporphyrin, serum iron, transferrin saturation, and serum ferritin) that are potentially available for inclusion in field studies of the relationship between iron and mental performance. The characteristics of these measures (sensitivity to iron status, specificity to iron, and diurnal and day-to-day variability) are reviewed and the implications of choice of variable for the design, analysis, and interpretation of studies are discussed. Brief consideration is given to the question of confounding variables and to sources of both false-positive and false-negative conclusions. The explicit message of the paper is that there is no perfect choice of measure of iron status but, given explicit definition of the research question, there are preferred choices that can most effectively combine the choice of variable and the design of the study.

Six-month double-blind, controlled trial of high dose, concentrated beclomethasone dipropionate in the treatment of severe chronic asthma.

A six-month double-blind controlled trial compared a 2,000 microgram per day dose of beclomethasone dipropionate aerosol (BDP), with current upper level doses of 800 micrograms per day of the standard BDP, in asthmatics requiring oral corticosteroids in addition to BDP and bronchodilators. Both groups showed a significant reduction in their oral steroid requirements during the study, with a 34 percent reduction in the lower dose group and a 57 percent reduction in the high dose BDP group while maintaining good symptomatic control of asthma; there was an associated improvement in baseline serum cortisol levels. Over the same period, the pulmonary function of the lower dose group showed significant worsening relative to that of the group receiving the high dose BDP which improved. There was no increase in dysphonia or oropharyngeal candidiasis among those using the concentrated BDP. We conclude that high dose concentrated BDP appears to be a safe medication in long-term steroid-dependent asthma, and is effective in reducing dependence on the use of oral corticosteroid with associated improvement both in pulmonary and adrenal function.

The hazards of using active clinic patients as a source of subjects for clinical studies.

The authors describe and empirically demonstrate a form of bias that results from deriving subjects for clinical studies from available patients currently being followed in specific disease clinics instead of inception cohorts (patients enrolled at a uniform and early point in their disease). They label this effect "clinic patient bias." It is a variation of prevalence-incidence (Neyman) bias in that it also results from the time gap between the onset of a specific characteristic (a risk factor, exposure or disease) and enrollment in the study, causing selective exclusion of fatal or short episodes, or mild or silent cases. Clinic patient bias may distort an estimate of relative risk in either direction. The empirical example is derived from a study of risk factors for developing complications such as peritonitis among end-stage renal disease patients treated with continuous ambulatory peritoneal dialysis (CAPD). The use of available clinic patients rather than an inception cohort (patients newly beginning CAPD) resulted in the demonstration of false apparent risk relationships for two variables: the calendar date when patients began CAPD (with those enrolled at an earlier time appearing to be at lower risk), and serum albumin level at the start of CAPD (with those having lower albumin levels appearing to be at higher risk). This example demonstrates one of the potential hazards of using active or available clinic patients as a source of subjects for clinical studies.