The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers.

CARET is a multicenter, two-armed, double-masked randomized chemoprevention trial in Seattle, Portland, San Francisco, Baltimore, Connecticut, and Irvine, to test whether oral administration of beta-carotene (30 mg/day) plus retinyl palmitate (25,000 IU/day) can decrease the incidence of lung cancer in high risk populations, namely, heavy smokers and asbestos-exposed workers. The intervention combines the antioxidant action of beta-carotene and the tumor suppressor mechanism of vitamin A. As of April 30, 1993, CARET had randomized 1,845 participants in the 1985-1988 pilot phase plus 13,260 "efficacy" participants since 1989; of these, 4,000 are asbestos-exposed males and 11,105 are smokers and former smokers (44% female). Accrual is complete everywhere except Irvine, which was the last center added (1991), and the safety profile of the regimen to date has been excellent. With 14,420 smokers, 4,010 asbestos-exposed participants, and 114,100 person-years through February 1998, we expect CARET to be capable of detecting a 23% reduction in lung cancer incidence in the two populations combined and 27, 49, 32, and 35% reductions in the smokers, female smokers, male smokers, and asbestos-exposed subgroups, respectively. CARET is highly complementary to the alpha-tocopherol-beta-carotene study in Finland and the Harvard Physicians Health Study (beta-carotene alone) in the National Cancer Institute portfolio of major cancer chemoprevention trials.

The challenge of teaching occupational and environmental medicine in internal medicine residencies.

Using a mailed survey questionnaire directed toward division chiefs of general internal medicine, we have confirmed that despite increased interest among faculty, few medical residents currently receive required or elective training in occupational medicine. However, recent changes in societal perceptions about environmental risks, corporate health care practices, and medical reimbursement patterns favoring provision by hospitals of contractual outpatient services to healthy workers all portend expanded involvement of residents in certain occupational medicine activities in the future, in response to economic pressures on both consumers and providers. These same forces may, unfortunately, undermine the scientific and ethical quality of such training experiences, compared with emerging, more academically motivated approaches. The implications of these prospects are analyzed in the hope that a proper balance can ultimately be struck between economic and academic imperatives.

Potroom palsy? Neurologic disorder in three aluminum smelter workers.

We studied three patients with a progressive neurologic disorder, all of whom had worked for over 12 years in the same potroom of an aluminum smelting plant. All had incoordination and an intention tremor. Two of the three patients had cognitive deficits, and the most severely affected patient also had spastic paraparesis. None had involvement of the peripheral nervous system. Despite extensive evaluations, the cause of these patients' problems remains obscure. It is tempting to implicate one of the numerous substances to which the patients were exposed in the potroom, but none is known to cause the neurologic problems seen in these patients. Neurotoxic effects of aluminum in animals are directed at the central nervous system, and theoretically long-term low-level exposure to aluminum in the potroom could explain the findings in our patients.

Neurologic syndrome in 25 workers from an aluminum smelting plant.

BACKGROUND: This article expands on an earlier series of three patients with a neurologic syndrome, who had all worked in an aluminum smelting plant. METHODS: Twenty-five symptomatic workers from the same plant were referred for a standardized evaluation, including completion of a health questionnaire, neurologic examination, and neuropsychologic evaluation. An exposure index was calculated for each worker based on level and duration of exposure in the potroom, where exposures were the greatest. This index was correlated with symptoms, signs, and neuropsychologic test scores. RESULTS: Twenty-two (88%) of the patients reported frequent loss of balance, and 21 (84%) reported memory loss. Neurologic examination revealed signs of incoordination in 21 (84%) of the patients. Neuropsychologic test results showed preservation in certain spheres of functioning, such as verbal IQ, with substantial impairment in others, particularly memory functioning. On memory tests, 70% to 75% showed mild or greater impairment. The majority (17 of 19 tested, or 89%) showed depression on the Minnesota Multiphasic Personality Inventory. The exposure index was significantly correlated with signs and symptoms of incoordination. CONCLUSIONS: This study and others in humans and animals support the existence of a syndrome characterized by incoordination, poor memory, impairment in abstract reasoning, and depression. Aluminum exposure in the potroom seems the most likely cause.

The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with asbestos-exposed workers.

Pilot studies are an essential component for major chemoprevention trials. Prior to initiating the multicenter Carotene and Retinol Efficacy Trial to assess the effectiveness of beta-carotene and retinol for preventing lung cancer, we conducted pilot studies in Seattle between 1985 and 1988 in two high risk populations: current and former heavy smokers and asbestos-exposed workers. The Asbestos Workers Pilot Study for the Carotene and Retinol Efficacy Trial demonstrated that recruitment of asbestos-exposed participants with relevant risk factors was feasible from identified sources. We documented negligible toxicity and high adherence with the protocol, schedule, and intervention. Results from the pilot led to extension of the placebo run-in period, changes in the eligibility criteria, improvements in recruitment strategies and scheduling, elimination of stratification by risk factors in randomization, modifications of study vitamin dosage and of side effects monitoring, and refinement of trial design parameters for Carotene and Retinol Efficacy Trial. The Smokers Pilot is reported in the accompanying article (G. E. Goodman et al., Cancer Epidemiol., Biomarkers & Prev., 2: 389-396, 1993).

Contribution of environmental fibers to respiratory cancer.

This article reviews studies of the carcinogenicity of mineral fibers, notably asbestos, and presents seven major recommendations for further research. Mineral fibers represent the greatest cause--after cigarette smoke--of respiratory cancer due to air pollutants. Past asbestos exposure may currently account for 2000 mesothelioma deaths per year and 4000 to 6000 lung cancer deaths per year. All major commercial types of asbestos (crocidolite, amosite, and chrysotile) can cause each of the major asbestos-related respiratory diseases. Lung cancers in asbestos-exposed individuals probably do not have a different distribution of histological types from that of non-asbestos-related lung cancers. Nonoccupational exposures are likely to be associated with malignant disease outcomes qualitatively similar to those associated with occupational exposures. Further investigations of fibers are needed to characterize the relationships among physicochemical properties, patterns of migration and clearance, dose, and adverse health effects. Transmission electron microscopy has been found to be the preferred method of analysis of environmental fibers. Relations among time factors (e.g., age at first exposure), dose, and risk for adverse health effects require analyses of existing and new epidemiologic studies of exposed cohorts. Concomitant exposure, behavioral factors, and host factors affecting susceptibility to asbestos should be identified.

Cadmium chemical pneumonitis.

Metal fume exposures are common to a number of trades and may result in the self-limited acute toxic syndrome of metal fume fever. Acute inhalational cadmium toxicity may mimic metal fume fever on initial presentation, but may have a markedly different clinical course. We report a case of cadmium-induced chemical pneumonitis in a welder who, over four years, has shown persistent pulmonary function abnormalities. The potential for acute cadmium toxicity needs to be considered in any patient suspected of having metal fume fever.

Longitudinal pattern of reported respiratory symptoms and accelerated ventilatory loss in asbestos-exposed workers.

Studies investigating the relation between respiratory symptoms and change in ventilatory function have been limited by use of reported symptoms at a single point in time. To assess the relation between the longitudinal pattern of reported cough, phlegm, wheeze, and dyspnea and ventilatory loss, we prospectively investigated changes in FVC and FEV1 associated with development, resolution, or persistence of these symptoms over a 3- to 5-year period in 446 asbestos-exposed workers. Longitudinally reported symptoms changed frequently, with 52 to 61% of subjects reporting a specific symptom noting resolution or development of that symptom during follow-up. Initially reported symptoms were not predictive of accelerated loss of FVC or FEV1. In contrast, development of any new respiratory symptom, and to a lesser extent persistence of symptoms during follow-up, were associated with significantly greater ventilatory losses compared with asymptomatic individuals, ranging from 28 mL/yr in FEV1 for newly developed dyspnea, to 67 mL/yr in FVC for developed wheeze (p < 0.01). We conclude that development or persistence of respiratory symptoms over time, rather than the presence of symptoms per se, is predictive of future ventilatory loss. Recognition of interval changes in symptom reporting during surveillance of asbestos-exposed workers may effectively identify groups at risk for progressive ventilatory impairment.

Total lung capacity. An insensitive measure of impairment in patients with asbestosis and chronic obstructive pulmonary disease?

The total lung capacity (TLC) is frequently used as a measure of respiratory impairment in patients with asbestosis. Because asbestosis and chronic obstructive pulmonary disease (COPD) exert opposite effects on the TLC, it may be an insensitive measure of impairment in patients with both abnormalities. To assess this, we compared asbestos-exposed patients with functional evidence of COPD and radiographic evidence of interstitial fibrosis (group 1) to those with interstitial fibrosis alone (group 2). Despite the two groups being comparable in degree of radiographic "fibrosis," no case of restrictive impairment (reduced TLC) was identified among those with both interstitial fibrosis and COPD (group 1), compared to 33 percent of those with interstitial fibrosis alone (group 2). In addition, those patients with both interstitial fibrosis and COPD, compared to those with interstitial fibrosis alone, were found to have greater impairment as measured by alveolar-arterial oxygen difference and diffusing capacity. We conclude that the TLC is an insensitive measure of impairment due to asbestosis in patients with the common setting of coexistent asbestosis and COPD.

Carpal tunnel syndrome among ski manufacturing workers.

Carpal tunnel syndrome is a common disorder marked by pain and dysesthesias of the upper extremities. As a test of the hypothesis that carpal tunnel syndrome is associated with occupational risk factors, jobs at a ski assembly plant were classified as repetitive and nonrepetitive. The prevalence of carpal tunnel syndrome among 106 employees with repetitive jobs was compared with that among 67 employees with nonrepetitive jobs. The data collection included a questionnaire, a physical examination, and the measurement of distal sensory latencies of the median and ulnar nerves. Carpal tunnel syndrome was present in either or both hands in 15.4% of those workers with repetitive jobs, but only in 3.1% of those workers with nonrepetitive jobs (crude prevalence ratio 4.92, 95% confidence interval 1.17-20.7). The conclusion was drawn that carpal tunnel syndrome is associated with jobs requiring frequent and sustained hand work.

Work organization research at the National Institute for Occupational Safety and Health.

For 25 years, the National Institute for Occupational Safety and Health (NIOSH) has conducted and sponsored laboratory, field, and epidemiological studies that have helped define the role of work organization factors in occupational safety and health. Research has focused on the health effects of specific job conditions, occupational stressors in specific occupations, occupational difference in the incidence of stressors and stress-related disorders, and intervention strategies. NIOSH and the American Psychological Association have formalized the concept of occupational health psychology and developed a postdoctoral training program. The National Occupational Research Agenda recognizes organization of work as one of 21 national occupational safety and health research priority areas. Future research should focus on industries, occupations, and populations at special risk; the impact of work organization on overall health; the identification of healthy organization characteristics; and the development of intervention strategies.

Research colloquium on occupational respiratory diseases: a conference in Cuba (1984).

At an international conference in Havana, Cuba, March 19-21, 1984, health professionals from the United States, Canada, and Cuba participated in a research colloquium on occupational lung diseases. Participants and speakers discussed the state of the art of knowledge, research, and management of key occupational lung diseases, and suggested directions for future efforts. Differences among the three countries in terms of the medical, economic, and social aspects of defining, treating, and compensating occupational diseases were also considered.