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We evaluated as functions of age and gender participation and adherence rates in older adults recruited to pilot studies for CARET, a multicenter chemoprevention trial. Eligible were men and women aged 50-69 who were current or recent former smokers, and men aged 45-74 with occupational exposure to asbestos. We found negligible differences by age in response to recruitment mailings, drop out during the enrollment process and after randomization, and adherence to taking the study capsules. Men had numerically lower drop-out and higher adherence rates than women, but differences were not statistically significant. These results should encourage researchers to recruit older men and women (at least up to age 69) to clinical trials.

There are many productive directions for future research in cancer ecogenetics. Genetic variation in susceptibility to chemicals and other carcinogenic agents has been neglected in most epidemiologic and rodent investigations of cancer etiology. Genetic variation is important to characterization of risks for population subgroups. Genetic investigations also may enhance inquiries into the underlying mechanisms of carcinogenesis and of cancer prevention. Polymorphisms of cytochrome P450 mono-oxygenases, epoxide hydrolase, glutathione-S-transferases, and N-acetyltransferase offer important windows on biotransformation of pro-carcinogens. Assays in peripheral blood cells need to be related closely to variation in activity in target organs. Tumor suppressor genes, signal transduction pathways, and cell surface receptors are additional sites where genetic variation would be highly important to cancer risks.

CARET is a two-armed, double-blind, randomized chemo-prevention trial to test the hypothesis that oral administration of beta-carotene 30 mg/day plus retinyl palmitate 25,000 IU/day will decrease the incidence of lung cancer in high-risk populations: heavy smokers and asbestos-exposed workers who have smoked. The agents combine anti-oxidant and nuclear tumor suppressor mechanisms. Fastidious monitoring for possible side effects is facilitated by inclusion of a Vanguard population. As of 31 December 1990, 6,105 participants of the 18,000 needed have been randomized in the trial. Efficacy results are expected in 1999.

Background: CARET is a multi-center collaboration, with participants recruited in Seattle, Portland, San Francisco, Irvine, Baltimore and New Haven., Methods: CARET is a two-armed double-blind randomized chemoprevention trial to test the hypothesis that oral administration of beta-carotene 30 mg/day plus retinyl palmitate 25,000 IU/day will decrease the incidence of lung cancer in high-risk populations: heavy smokers and asbestos-exposed workers who have smoked. The agents combine anti-oxidant and nuclear tumor suppressor mechanisms. Fastidious monitoring for possible side effects is facilitated by inclusion of a Vanguard population (continued from pilot studies)., Results: As of 31 July 1991, 8129 participants had been randomized into the Trial, of the 18,000 needed. Efficacy results are expected in 1998., Conclusion: The Trial demonstrates the movement of environmental epidemiology into interventionist research to prevent adverse health effects.

We investigated the excess mortality risks of former smokers according to the number of years since they quit smoking in a cohort of 21,112 men and women evaluated with coronary angiography and included in the Coronary Artery Surgery Study registry. There is a prompt decline in mortality risk within the first year of quitting. Thereafter, former smokers have a sustained, modestly elevated mortality risk for at least 20 years compared with people who never smoked. The pattern is similar in men and women, in 35-54, 55-64, and greater than or equal to 65 age groups, and in subcohorts of those with coronary artery disease and those without coronary artery disease.

Considerable controversy surrounds the question of whether cigarette smoking has the potential to increase the prevalence of small opacities on chest roentgenographs among asbestos-exposed workers. To compare the relative contribution of smoking with other predictors of the presence of roentgenographic small opacities, we examined 661 men enrolled in a double-blind, randomized trial designed to assess the efficacy of vitamin A and beta-carotene in the prevention of lung cancer among workers with heavy occupational asbestos exposure. Subjects in the study population had a mean latency of 35 yr from first asbestos exposure and a mean of 28 yr in their trade. The prevalence of roentgenographic abnormalities consistent with asbestos exposure was 26% for pleural abnormalities alone, 10% for parenchymal abnormalities alone, and 20% for pleural and parenchymal abnormalities together. We investigated occupation, age, latency from first asbestos exposure, and smoking status as predictors of roentgenographic small opacities. Smoking history, independent of latency, contributed to the prevalence and extent of small opacities, but its effect was less than that of latency. We conclude, that in the setting of heavy occupational exposure to asbestos, cigarette smoking confers added risk for the development of roentgenographic small opacities.

Paraoxon and chlorpyrifos-oxon, the active metabolites of the organophosphorus insecticides parathion and chlorpyrifos, respectively, are hydrolyzed by an "A"-esterase, paraoxonase, which is present in the sera of several mammalian species. In this study, we investigated whether levels of serum paraoxonase activity in laboratory animals can influence the in vivo toxicity of paraoxon and chlorpyrifos-oxon. Paraoxonase was found to be 7-fold higher in rabbit serum than in rat serum. The dose of paraoxon required to produce similar signs of toxicity and similar degrees of cholinesterase inhibition in rats and rabbits (0.5 and 2.0 mg/kg, respectively) differed by 4-fold. Paraoxonase was then purified from rabbit serum and 8.35 units was injected in the tail veins of rats, increasing the peak hydrolytic activity of rat serum by 9-fold toward paraoxon and by 50-fold toward chlorpyrifos-oxon. The increase in serum paraoxonase/chlorpyrifos-oxonase activity was long-lasting, with a 2- and 10-fold increase, respectively, still present after 24 hr. Thirty minutes following enzyme injection, rats were challenged with an acute dose of paraoxon or chlorpyrifos-oxon given by the intravenous, intraperitoneal, dermal, or oral route. Cholinesterase activities were measured in plasma, red blood cells, brain, and diaphragm after 4 hr. Rats pretreated with paraoxonase exhibited less inhibition of cholinesterase than vehicle-treated controls following identical doses of paraoxon, particularly when the organophosphate was given iv or dermally. A very high degree of protection, particularly toward brain and diaphragm cholinesterase, was provided by paraoxonase pretreatment in animals challenged with chlorpyrifos-oxon by all routes. These results indicate that levels of serum paraoxonase activity can affect the toxicity of paraoxon and chlorpyrifos-oxon.

Choosing a cost-effective strategy for classifying chemicals as human carcinogens and non-carcinogens depends upon the costs of false positives (carcinogens erroneously treated as non-carcinogenic) and false negatives (non-carcinogens erroneously treated as carcinogenic); upon the accuracy (sensitivity and specificity) of the classification strategy; and upon the underlying proportion of carcinogens in the population of chemicals to be classified. If these values are known, value-of-information analyses can indicate the most cost-effective among three strategies: classify as carcinogenic without testing, classify as non-carcinogenic without testing, or choose the most cost-effective test and classify on the basis of the test result. When some or all of the values are uncertain, the analysis becomes more complex, but still helps to guide decisions among the three classification strategies.

Carter Administration actions to enhance basic research and stimulate industrial innovation have focused attention on the importance of formal university-industry cooperative relationships in science and engineering. We have examined the status of, and potential for, university-industry research consortia and research partnerships and the current and prospective roles of the federal government in stimulating such relationships.

Because of the tremendous impact of recent findings of association between genes in the major histocompatibility system and certain rheumatic diseases, the genetics of this system and the methods of analyzing disease association are discussed in detail. These associations represent an important step forward in the search for basic causes and mechanisms of these diseases. Further analyses may permit better classification of diseases and increased understanding of the relationships between genetic and environmental factors in the susceptibility to specific disease.

Four groups of rats received by intratracheal instillation (1) a lead chromate paint particulate suspension, (2) lead tetraoxide suspension, (3) lead acetate solution, or (4) saline. Lead-dosed animals received an equivalent dose of 1 mg lead/kg body weight. Distribution of lead was monitored through assays of urine, feces, and tissues (lung, bone, muscle kidney, liver) obtained at post-mortem 5 weeks after exposure. Delta-aminolevulinic acid dehydratase (ALA-D) activity was measured to determine the effect of lead on heme biosynthesis. The vast majority of the dosed lead in the paint matrix remained in the lung. In contrast, in the lead acetate-dosed animals, little remained in the lung, but significant elevations were found in bone and kidney. Blood ADA-D was significantly depressed in the lead acetate-treated animals, but was not significantly different from control animals in the animals dosed with lead paint or lead tetraoxide. These findings suggest that lead chromate in an alkyd resin paint matrix is poorly absorbed from the lung compared with lead acetate and lead tetraoxide.

The continuing discoveries of hazardous waste sites have stimulated environmental health risk assessment efforts in State and local environmental health agencies. Elements of risk assessment are defined, showing how risk assessment interfaces with risk management. Environmental health risk assessment involves work components (tasks, activities, and technologies), the worker (position, classification, and occupation), and work organization (purpose, outputs, and objectives). Information from six State agencies was used to describe current State government experiences with environmental health risk assessment. Education and risk assessment are described, particularly as they relate to schools of public health and the role of continuing education for the public health work force.

Alcoholism is an extremely common psychosocial behavioral disorder for which genetic factors may play an important role. Statistical analysis of special kinds of family studies that separate inherited factors from the common family environment point strongly to genetic predisposition. This paper presents data and speculations on the genetically determined differences among population subgroups and individuals in the acute effects of ethanol ingestion, the metabolism of ethanol, the process of tolerance, physical dependence and addictability, premorbid personality features and serious complications of alcoholism in the liver and brain of the alcoholic and in the offspring of alcoholic mothers.

A sample of 31 patients with congenital adrenal hyperplasia was matched to a control group by sex, age, height, full-scale IQ score, and urban/rural site of residence. Patients and matched controls were tested on measures of masculinity and femininity and on sex-typed tests of cognitive ability. The two groups did not differ significantly on these measures. The finding is in disagreement with earlier reports of "masculinization" of behavior in female patients with congenital adrenal hyperplasia.

Immunoreactive parathyroid hormone (PTH) in nonparathyroid malignant tumors associated with hypercalcemia and hypophosphatemia in the absence of demonstrable bone metastases was determined by radioimmunoassay and immunofluorescent techniques. Six of seven tumors contained material with immunological cross-reactivity to bovine PTH by radioimmunoassay and immunofluorescence. The intensity of the immunofluorescent stain varied considerably in the different tumors. From 15 to 90% of neoplastic cells were stained specifically with fluorescein-labeled anti-PTH. In contrast, normal parathyroid glands and parathyroid adenomas showed uniform distribution of immunofluorescence in all parenchymal cells. In one malignant tumor, PTH was localized also by immunoautoradiography. In every case PTH was detected only in the cytoplasm of parenchymal cells. One patient lacked detectable PTH in his tumor, yet showed regression of the hypercalcemia to normal values after removal of large masses of neoplastic tissue and recurrence of hypercalcemia when new growth occurred.Dilutional radioimmunoassay curves of nonparathyroid malignant tumors were in most cases different from those obtained with extracts of normal parathyroid glands and parathyroid adenomas. Although both nonparathyroid neoplasmas and parathyroid extracts demonstrated immunoheterogeneity by gel filtration, greater heterogeneity was found in nonparathyroid malignant tumors. In those tumors in which immunological cross-reactivity to PTH was detected, the capability of secreting PTH may be restricted to derepressed cell clones amidst other neoplastic cells, whereas the greater heterogeneity of ectopic PTH may reflect hormone cleavage by proteolytic enzymes in the tumor that is less specific than the Pro-PTH cleaving enzyme in the parathyroids.

To assess the impact of computed tomography (CT) on patient care, a cohort of patients with suspected hydrocephalus admitted before installation of CT was compared to a similar cohort admitted after installation of CT. The after CT cohort used significantly fewer pneumoencephalograms and radionuclide brain scans. The average cost of neurodiagnostic evaluation was 22% less after CT. However, speed of workup, therapy, institution of therapy, discharge plans, and discharge diagnoses were not different for the two cohorts. We conclude that CT has made the diagnostic evaluation of patients who otherwise would have required pneumoencephalography for suspected hydrocephalus less expensive and less hazardous.

This work (in three parts) inquires into whether respirable dusts derived from the machining of six composite-epoxy materials (e.g., aircraft industry) may pose a health risk to the operators. Dust samples representative of a variety of composites and structural components were aerodynamically sized and fractionated. Bulk and fractionated samples were examined by light and electron microscopy and analyzed chemically by thermogravimetry (TGA), gas chromatography (GC) and mass spectrometry (MS). Relative fractions of respirable to total mass of bulk samples were less than 3%; aerodynamic diameters of fractionated particles ranged from 0.8 to 2.0 microns. By microscopy, bulk particles ranged from 7 to 11 microns in diameter, with mean aspect ratios from 4 to 8:1. Mean diameter of fractionated particles was 2.7 microns. By TGA, weight losses were negligible below 250 degrees C and variable but elevated at temperatures up to 860 degrees C. In assays of vapors released at 250 degrees C, GC/MS indicated a variety of compounds in different amounts for each sample. We conclude that under the present machining protocols, dusts at the tool face contained few particles of respirable size with no evidence of splitting of fibers longitudinally and were of a low volatilizable chemical content. Overall, composites were judged to be well cured and thermally stable.

We investigated the effects of cigarette smoking and cessation of smoking in a cohort of 1893 men and women from the Coronary Artery Surgery Study (CASS) registry who were 55 years of age or older and had angiographically documented coronary artery disease. The six-year mortality rate was greater among continuing smokers (n = 1086) than among those who quit smoking during the year before enrollment in the study and abstained throughout the study (n = 807) (relative risk, 1.7 [95 percent confidence limits, 1.4, 2.0]). Continuing smokers were also at higher risk of either myocardial infarction or death (1.5 [1.2, 1.7]). There was no diminution of the beneficial effect with increasing age. The relative risks of death were 1.7 (1.4, 2.1) and 1.6 (1.1, 2.3) for the groups 55 to 64 years old and 65 or older, respectively, and 1.6 (1.4, 1.9) for comparable subgroups among CASS subjects 35 to 54 years of age. When subjects were arrayed according to risk quartile, the benefits of smoking cessation were greatest in those at moderate risk. We conclude that smoking cessation lessens the risk of death or myocardial infarction in older as well as younger persons with coronary artery disease.

Evidence favoring genetic predisposition to each of the major classes of rheumatic diseases is reviewed, including juvenile-onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis and other syndromes associated with spondylitis, adult-onset rheumatoid arthritis, gout and pseudogout, and systemic lupus erythematosus. In addition, simply inherited genetic diseases that may present with arthritis are noted for purposes of differential diagnosis. The importance of heterogeneous causes and mechanisms within each major class of disease is emphasized, both for patient care and for clinical investigation.

We describe four patients with Waardenburg syndrome and Hirschsprung aganglionic megacolon. In view of pathophysiologic relationships and animal studies, we conclude that the association of these two uncommon disorders is pathophysiologically significant.

The purpose of this paper is to alert pediatric ophthalmologists to problems of rendering genetic counseling to adoptees at-risk for genetic disease. All states have statutes that provide for secrecy of adoption records. These records are maintained by adoption agencies, county courts, and state registrar. In most cases, the counseling clinician must file a lawsuit to reach the parents of an at-risk adoptee. An administrative procedure is proposed to allow access to certain adoption information for the purposes of genetic counseling and offer of treatment.

In screening the majority of job applicants, most of this nation's railroads administer a low-back X-ray examination in an attempt to ascertain the likelihood that the applicant will sustain future work-related low-back pain or injury. Many applicants are rejected for employment on the basis of the X-ray findings. The railroads apparently perceive this screening program as a cost-effective means (1) of decreasing the incidence of compensation claims for work-related injuries, brought against the railroads under the Federal Employers' Liability Act (FELA), (2) of reducing the number of lost workdays resulting from low-back pain or injury, and (3) of protecting particularly susceptible workers from job-related hazards. The authors of this Article submit that low-back X-ray examinations are poor predictors of future low-back pain or injury. They assert that the railroads' use of such examinations misclassifies a substantial number of job applicants as being at increased risk for such pain or injury, and, in consequence, unfairly denies them employment. Furthermore, the authors claim, the screening program has other negative consequences. For example, applicants rejected for railroad employment on the basis of X-ray findings may as a result have difficulty finding jobs in other industries. In addition, they state, there is a potential radiation hazard to examinees. Moreover, both the railroads and those applicants accepted for employment may inappropriately be reassured by normal findings. On balance, the authors conclude, the screening program has a negative social value. The authors suggest that the program, in effect, erraneously labels many applicants as handicapped, and then denies them employment. Such persons might have legal recourse under federal and state statutes prohibiting employment discrimination against the handicapped.

Medical histories of the 15,924 male twin pairs in the National Academy of Sciences-National Research Council Twin Registry were examined to determine, within pairs, concordances for alcoholism and its medical end points. Prevalences per 1,000 among individual twin subjects were 29.6 for alcoholism, 4.1 for alcoholic psychosis, 14.2 for liver cirrhosis, and 2.1 for pancreatitis. Prevalences were similar to monozygotic (MZ) and dizygotic (DZ) twins. Prevalences in percent among co-twins of diagnosed subjects, that is case-wise twin concordance rates, were, respectively, by diagnosis: alcoholism: 26.3 (MZ), 11.9 (DZ); alcoholic psychosis: 21.1 (MZ), 6.0 (DZ); and liver cirrhosis: 14.6 (MZ), 5.4 (DZ). No twin pairs concordant for pancreatitis were found. The greater concordance for alcoholic psychosis and for liver cirrhosis among MZ than DZ twins could not be explained by the difference in alcoholism concordance between them. The difference in concordance between MZ and DZ twins persisted when, in addition, it was assumed that only half of the actually occurring cases of alcoholism and of each of the end points have been ascertained. These results provide evidence in favor of genetic predisposition to organ-specific complications of alcoholism and should serve to stimulate searches for the underlying biochemical mechanisms.

One hundred sixty-one highly selected patients with headache were studied to assess the impact of computerized tomography (CT) on diagnostic evaluation and to determine cost-effectiveness of neurodiagnostic evaluation of headache. Fewer nuclide brain scans were performed after availability of CT, but diagnostic charges stayed about the same. A careful history and physical and neurological examinations were adequate screens to detect intracranial mass lesions or systemic disease associated with headache. In patients with normal findings from neurological examination, no clinically important abnormalities were detected by CT, skull roentgenogram, angiography, or nuclide brain scan. The cost of finding a case of brain tumor was estimated to be at least $1,265 for patients with abnormalities on neurological examination and $11,901 for patients with normal findings on neurological examination. Neurodiagnostic evaluation of headache patients with normal findings from neurological examination is expensive and was clinically unrewarding in this series.