The exposure metric: does including time since exposure in the calculation of working lifetime exposure provide a better understanding of disease risk than the cumulative exposure?

BACKGROUND: When exposure measurements are available for occupational epidemiology studies, the cumulative exposure (the sum of the products of duration and exposure intensity at all jobs) is generally selected as the summary metric for chronic diseases. For silica exposures, a metric that weights each exposure by the number of years since it occurred has been suggested as more biologically relevant. Comparative reports of analyses using both metrics have not been found in the literature, however. METHODS: We calculated both metrics for silica exposure, and evaluated exposure-response relations for lung cancer and silicosis in two separate case-control studies. RESULTS: Generally the results were consistent, due to the high correlation between the two metrics and the fact that the rate of time away from work during the employment years was low. CONCLUSION: The significant relation between exposure and silicosis using the weighted metric provides additional point estimates of risk, adding to the understanding of exposure-response.

Impact of differential cyclin D1 expression and localisation in prostate cancer.

Cyclin D1 is a critical regulator of androgen-dependent transcription and cell cycle progression in prostate cancer cells. Despite the influence of D-type cyclins on prostate cancer proliferation, few studies have examined the expression of cyclin D1 in localised tumours or challenged its relevance to disease progression. Cyclin D1 status was characterised using immunohistochemistry in 38 non-neoplastic prostate samples, 138 primary human prostate carcinomas, and three lymph node metastatic specimens. Relevance of cyclin D1 to preoperative prostate-specific antigen (PSA) levels, Ki-67 index, and p21Cip1 status was also examined. Cyclin D1-positive phenotype was increased in primary carcinoma compared to non-neoplastic tissue, and was evident in all lymph node metastases cases. Interestingly, at least three distinct localisation patterns were observed in the cyclin D1-positive cohort, wherein cytoplasmic localisation was identified in a large fraction, and this pattern was predominant in lower grade tumours. Relevance of altered cyclin D1 status was observed, wherein cyclin D1-positive tumours were associated with low preoperative PSA levels, consistent with in vitro reports that cyclin D1 may alter the expression of this tumour marker. Moreover, tumours with predominantly cytoplasmic cyclin D1 showed the lowest Ki-67 index, whereas nuclear cyclin D1 was associated with higher grade, elevated Ki-67, and increased nuclear p21Cip1. These data demonstrate that differential cyclin D1 status may influence clinicopathological parameters, and reveal new insight as to the regulation and potential consequence of cyclin D1 expression in prostate cancer.

Consequences of smoking and caffeine consumption during pregnancy in women with type 1 diabetes.

OBJECTIVE: To test the hypothesis that, in women with type 1 diabetes, prenatal smoking and caffeine consumption during pregnancy are associated with an increased risk of adverse maternal and perinatal outcomes. METHODS: A secondary analysis of data on pregnant women with type 1 diabetes from an interdisciplinary program of Diabetes in Pregnancy. Women were interviewed monthly, by a trained non-medical member of the research team, using a standardized questionnaire, to ascertain daily smoking habits and caffeine consumption. RESULTS: Smoking and caffeine information were available on 191 pregnancies, 168 progressing beyond 20 weeks of gestation. Early pregnancy smoking (OR 3.3, 95% CI 1.2, 8.7) and caffeine consumption (OR 4.5, 95% CI 1.2, 16.8) were associated with increased risk of spontaneous abortion when controlling for age, years since diagnosis of diabetes, previous spontaneous abortion, nephropathy and retinopathy. Smoking throughout pregnancy was significantly associated with decreased birth weight and prolonged neonatal hospital stay. Smoking throughout pregnancy (OR 0.2, 95% 0.1, 1.0) and caffeine consumption after 20 weeks (OR 0.3, 95% CI 0.1, 1.0) were associated with reduced risk of pre-eclampsia. CONCLUSIONS: Caffeine consumption during early pregnancy, regardless of glycemic control, increases the risk of spontaneous abortion. Smoking throughout pregnancy and caffeine consumption are associated with reduced risk of pre-eclampsia.

A prospective 15-year follow up of 154 consecutive patients with trigeminal neuralgia treated by percutaneous stereotactic radiofrequency thermal rhizotomy.

There is a lack of prospective studies for the long-term results of percutaneous stereotactic radiofrequency rhizotomy (PSR) in the treatment of patients with trigeminal neuralgia. The authors present results in 154 consecutive patients with trigeminal neuralgia treated by PSR and prospectively followed for 15 years. Ninety-nine percent of the patients obtained initial pain relief after one PSR. Dysesthesia occurred in 31 patients (23%): in 7% with mild initial hypalgesia; in 15% with dense hypalgesia; and in 36% with analgesia. Dysesthesia was mild and did not require treatment in most patients. The corneal reflex was absent or depressed in 29 patients, and keratitis developed in three patients. In 19 of 22 patients with trigeminal motor weakness, the paresis resolved within 1 year. Of 33 patients who had pain recurrence, 10 patients had pain that was mild or controlled with medications, and 23 patients required additional surgical treatment. The authors estimated using Kaplan-Meier analysis that the 14-year recurrence rate was 25% in the total group: 60% in patients with mild hypalgesia, 25% in those with dense hypalgesia, and 20% in those with analgesia. Timing of pain recurrence varied according to the degree of sensory loss. All pain recurrences in patients with mild hypalgesia occurred within 4 years after surgery; 10% more of the patients with dense hypalgesia had pain recurrences within the first 10 years compared with patients with analgesia. The median pain-free survival rate was 32 months for patients with mild hypalgesia and more than 15 years for patients with either analgesia or dense hypalgesia. Of the 100 patients followed for 15 years after one or two PSR procedures, 95 patients (95%) rated the procedure excellent (77 patients) or good (18 patients). The authors conclude that PSR is an effective, safe treatment for trigeminal neuralgia. Dense hypalgesia in the painful trigger zone, rather than analgesia, should be the target lesion.

Evaluation of a possible association of urban air toxics and asthma.

The prevalence of asthma, measured either as the frequency of hospital admissions or number of deaths attributed to asthma, has increased over the last 15 to 20 years. Rapid increases in disease prevalence are more likely to be attributable to environmental than genetic factors. Inferring from past associations between air pollution and asthma, it is feasible that changes in the ambient environment could contribute to this increase in morbidity and mortality. Scientific evaluation of the links between air pollution and the exacerbation of asthma is incomplete, however. Currently, criteria pollutants [SOx, NOx, O3, CO, Pb, particulate matter (PM10)] and other risk factors (exposure to environmental tobacco smoke, volatile organic compounds, etc.) are constantly being evaluated as to their possible contributions to this situation. Data from these studies suggest that increases in respiratory disease are associated with exposures to ambient concentrations of particulate and gaseous pollutants. Similarly, exposure to environmental tobacco smoke, also a mixture of particulate and gaseous air toxics, has been associated with an increase in asthma among children. In addition, current associations of adverse health effects with existing pollution measurements are often noted at concentrations below those that produce effects in controlled animal and human exposures to each pollutant alone. These findings imply that adverse responses are augmented when persons are exposed to irritant mixtures of particles and gases and that current measurements of air pollution are, in part, indirect in that the concentrations of criteria pollutants are acting as surrogates of our exposure to a complex mixture. Other irritant air pollutants, including certain urban air toxics, are associated with asthma in occupational settings and may interact with criteria pollutants in ambient air to exacerbate asthma. An evaluation of dose-response information for urban air toxics and biological feasibility as possible contributors to asthma is therefore needed. However, this evaluation is compounded by a lack of information on the concentrations of these compounds in the ambient air and their effects on asthma morbidity and mortality. Through an initial review of the current toxicological literature, we propose a tentative list of 30 compounds that could have the highest impact on asthma and respiratory health. These compounds were selected based on their ability to induce or exacerbate asthma in occupational and nonoccupational settings, their allergic potential and ability to react with biological macromolecules, and lastly, their ability to irritate the respiratory passages. We recommend better documentation of exposure to these compounds through routine air sampling and evaluation of total exposure and further evaluation of biological mechanisms through laboratory and epidemiological studies directed specifically at the role these substances play in the induction and exacerbation of asthma.

Exposure-response analysis of mortality among coal miners in the United States.

The quantitative relationship between exposure to respirable coal mine dust and mortality from nonmalignant respiratory diseases was investigated in a study of 8,878 working male coal miners who were medically examined from 1969 to 1971 and followed to 1979. Exposure-related mortality was evaluated using Cox proportional hazards modeling for underlying or contributing causes of death and modified lifetable methods for underlying causes. For pneumoconiosis mortality, the lifetable analyses showed increasing standardized mortality ratios (SMRs) with increasing cumulative exposure category. Significant exposure-response relationships for mortality from pneumoconiosis (p < 0.001) and from chronic bronchitis or emphysema (p < 0.05) were observed in the proportional hazards models after controlling for age and smoking. No exposure-related increases in lung cancer or stomach cancer were observed. Pneumoconiosis mortality was found to vary significantly by the rank of coal dust to which miners were exposed. Miners exposed at or below the current U.S. coal dust standard of 2 mg/m3 over a working lifetime, based on these analyses, have an elevated risk of dying from pneumoconiosis or from chronic bronchitis or emphysema.

Proportional mortality analysis of wastewater treatment system workers by birthplace with comments on amyotrophic lateral sclerosis.

There is concern that wastewater treatment system workers are at risk for cancers and diseases affecting the neurological and digestive systems. However, these diseases have also been linked to early exposures. A proportional mortality study was conducted on a large cohort of wastewater treatment system workers who were divided into two groups, migrants and nonmigrants, by place of birth as reported on their death certificates. The migrant worker group was significantly higher than the US white male population for cancer of the stomach, leukemia, and all lymphopoietic cancers. Migrant workers also had an elevated ratio for all diseases of the nervous system and sense organs. No cases of amyotrophic lateral sclerosis were found. The American-born workers had an elevated rate of death for arteriosclerotic heart disease compared with the US white male population. We suggest that place of birth may present a confounding factor when evaluating exposures in employee groups.

Retrieval of p53 protein in paraffin-embedded head and neck tumor tissues.

OBJECTIVES: To improve the detection of p53 protein in formalin-fixed, paraffin-embedded head and neck tumor tissues. DESIGN: Cohort. SETTING: University and Veterans Administration medical centers. PATIENTS OR OTHER PARTICIPANTS: Retrospective samples. INTERVENTION: Surgery for head and neck carcinoma. MAIN OUTCOME MEASURES: Retrieval of p53 antigen. Hypothesis formulated after data collection. RESULTS: An antigen retrieval method facilitated the unmasking of previously inaccessible p53 antigenic determinants in formalin-fixed, paraffin-embedded tissues. This approach has made possible a much more reliable and sensitive immunohistochemical detection of p53 antigen. The procedure is simple, requiring only microwave heating of tissue sections to 100 degrees C in the presence of a zinc sulfate solution. CONCLUSIONS: Antigen retrieval method in formalin-fixed, paraffin-embedded tissue demonstrated a significant increase in p53 immunostaining.

Latent period for malignant mesothelioma of occupational origin.

To estimate the minimal latent period for malignant mesothelioma of occupational origin, we reviewed 21 articles that documented latent periods for malignant mesothelioma, totaling 1690 cases. Of these, 1105 (65%) cases fulfilled the strict histologic and exposure criteria and were included in this analysis. Of these mesotheliomas, 99% had a latent period more than 15 years; 96% had a latent period of at least 20 years; and the observed probability of an occupational exposure within a decade of the first exposure was zero. The estimated median latent period was at least 32 years after the initial exposure. These epidemiologic conclusions are important in determining the source of a specific case of the disease, understanding the natural history of the disease, determining liability, and in aiding in the diagnosis of malignant mesotheliomas of occupational origin.

Intestinal cadmium permeability in mature and immature rats.

To compare the intrinsic permeability properties of the small intestine in adult (average body wt 300 g) and 25- to 27-day-old (average body wt 50 g) male rats, the uptake rates of cycloleucine and of cadmium were measured in intestinal segments isolated in situ with their blood supply intact. Uptake rates were expressed on the basis of that of ethanol, a solute whose absorption depends primarily on the size, rather than the composition, of the available surface area and on the presence of unstirred layers. These layers may be concluded to affect movement of cycloleucine, cadmium, and ethanol to the same extent. The ratio of uptake rates, therefore, provides in arbitrary units a measure of the intrinsic permeability of the luminal surface area to cadmium and to cycloleucine. On this basis, no developmental change in cycloleucine permeability could be detected. In contrast, the rate of cadmium uptake relative to that for ethanol decreased with age by about 50%. Possible mechanisms are discussed for this significant change in the intrinsic cadmium permeability of the jejunum in post-"closure" animals.

Therapeutic responses of spontaneous canine malignancies to combinations of radiotherapy and hyperthermia.

The goals of this ongoing Phase III study of adjuvant local hyperthermia with radiotherapy were to evaluate how tumor control and normal tissue complications were related to patient and treatment variables. Canine veterinary patients with localized malignancies were stratified by histology and anatomic site and randomized into three groups. All patients received radiotherapy (60CO) in 3.5 Gy fractions given Mon-Wed-Fri to 14 treatments (49 Gy). One group received radiotherapy alone while the others also received microwave-induced hyperthermia (44 degrees C) for 30 minutes once each week. Hyperthermia followed radiotherapy and was given to one group immediately and delayed 4-5 hours in the other. Adjuvant hyperthermia resulted in a significant (p less than .05) increase in complete response rate, reduction in the frequency of non-responders, and increased persistent local control relative to radiotherapy alone. Hyperthermia increased the complete response rate regardless of histology, site, or volume and with the current sample size control was significantly (p less than .05) greater for sarcomas, tumors of the trunk and extremities, and those with volumes less than 10 cc. Quantitative clinical assessment of the acute response of skin and oral mucosa indicated that hyperthermia significantly enhanced these acute reactions, which required roughly twice the healing time observed with radiotherapy alone. Quantitative histologic scoring of changes seen between pre- and post-therapy skin biopsies indicated that a treatment induced decline in the frequency of dermal blood vessels, sebaceous glands, and hair follicles was enhanced by adjuvant hyperthermia, particularly in the late response evaluation interval. The probability of tumor control and adverse normal tissue responses correlated with several measures of thermal dose. Thermal doses in excess of 120 equivalent minutes at 43 degrees C correlated positively with increased skin reactions and negatively with the complete response rate, and these trends were usually evident during the animals' first treatment.

Pulmonary embolism and lung scanning: cost-effectiveness and benefit:risk.

The cost-effectiveness of pulmonary imaging (lung scan) on the management of 2,023 patients was studied. Prior and postscan probabilities of pulmonary embolism (PE) were obtained from referring physicians. After the scan, anticoagulant therapy (ACT) was appropriately changed in 20% of the patients and confirmed in 67%. The incremental cost of scanning was $124 per patient when the prior probability was 0.01-9.99%, dropping to $38 when the probability was 10-25%. Hospitalization and ACT cost was reduced when the prior probability was 25.01-99.99%. The greatest benefit in lives saved was when the prior probability was 25-74.99%; 1.5% of this probability group would survive as a result of the change in management attributable to the scan, at a cost of $117 per life saved. The benefit:risk ratio, as measured by lives saved compared to estimates of lives lost due to radiation exposure, was of the order of 6,000:1.

The National Cancer Institute Cooperative Early Lung Cancer Detection Program. Results of the initial screen (prevalence). Early lung cancer detection: Introduction.

This introduction provides a description of 3 cooperating studies on Screening for Early Lung Cancer conducted under the auspices of the National Cancer Institute. The next 3 reports detail the unique aspects and results of the individual screening studies. The final presentation summarizes the initial ("prevalence") screening for all 3 centers (approximately 30,000 men), and gives our conclusions.

Skin and eye diseases among arc welders those exposed to welding operations.

The prevalence of skin and eye abnormalities was determined in 77 journeymen welders, 75 members of other trades exposed to welding operations and 58 non-exposed comparison workers. Characteristics including possible risk factors for skin cancer were compared among the groups. Localized cutaneous erythema was frequent in welders and occasional in other exposed workers. Small cutaneous scars were frequent in welders. There was no significant difference in the prevalence of actinic elastosis by occupational group; however, the degree of elastosis was significantly associated with type of complexion, original hair color, eye color, childhood freckling poor ability to tan and ease of sunburning. There were no significant difference among the groups in the prevalence of various dermatoses, skin tumors, alterations in visual acuity or clinical ocular abnormalities on slit lamp biomicroscopy and fundoscopy apart from variations in the amount of dust in the lids. The observed prevalences of skin and eye diseases may provide useful comparative data.

Clinically important radiation-associated thyroid disease. A controlled study.

We evaluated 1,266 persons who had received external radiotherapy for benign diseases in childhood. The evaluation used detailed questionnaires completed by trained interviewers and neoplastic disease registry data. The control population included 958 age-, sex-, race-, and disease-matched persons who had not received radiotherapy and 9,865 family members of the two study groups. An excess number of clinically important thyroid neoplasms, both benign and malignant, was noted in the irradiated group.

National Cancer Institute study: evaluation of computed tomography in the diagnosis of intracranial neoplasms. II. Was randomization necessary?

The final results of the National Cancer Institute study were evaluated to determine whether there were any differences in the comparative ability to diagnose intracranial tumors depending upon the order in which computed tomography (CT) and radionuclide scanning (RN), the two basic modalities, were performed. Only those patients who were examined by noncontrast CT and RN (with an interval of one or more days between the tests) were studied for this paper. There were 684 patients who underwent CT before RN, and 959 who underwent RN before CT. It was found that any effects of order, if they exist at all, were sufficiently unimportant that they did not change the results of the study. It is concluded that, for this study, randomization was not necessary.

Enhanced development of mammary tumors in rats following transplacental and neonatal exposure to ethylnitrosourea.

Transplacental and neonatal induction of mammary tumors (MT's) with ethylnitrosourea (ENU) was studied in Sprague-Dawley rats. A low transplacental ENU dose (10 mg/kg) did not increase the number of MT's or shorten their latency period. High ENU doses (30 mg/kg neonatal, 60 mg/kg transplacental, or 120 mg/kg transplacental) when corrected for differences in life span caused a significant shortening of the tumor induction period and an overall increase in the tumor incidence. With high ENU doses, the MT's were frequently multiple in the same animal and were more often malignant. Tumors developed mostly in females; only a few were observed in males. It is concluded that with a sufficient dose of the carcinogen in susceptible animals, transplacental and neonatal ENU mammary carcinogenesis takes place. The experiment was originally designed to evaluate ENU-induced neurogenic tumors; the results on MT's were obtained incidentally.