Changes in plasma lipid and lipoprotein cholesterol and weight prior to the diagnosis of cancer.

Changes in lipoprotein cholesterol, total plasma cholesterol, and weight prior to the diagnosis of cancer were examined in 103 men who developed cancer in a cohort of 3805 type IIa hyperlipidemic men aged 35-59 enrolled in the Lipid Research Clinics Coronary Primary Prevention Trial. Study measurements were made bimonthly. After adjusting for the effects of the trial intervention and other determinants of lipid levels, the cholesterol levels of the cases diagnosed with nonlocalized cancer dropped below the expected level approaching diagnosis when compared to the entire study population. The decrease averaged 9.3 mg/dl and began about 2 years prior to diagnosis. Weight levels dropped an average of 1.2 kg over the same period. Weight and cholesterol were significantly lower than expected within 8 months of diagnosis (P less than 0.05). No decrease was seen for those diagnosed with localized malignancies. Patterns for low-density lipoprotein cholesterol reflected those of total cholesterol. There was no clear relationship between cancer diagnosis and patterns of change for triglycerides and high-density lipoprotein cholesterol. In the future, investigations of any relationship between a host physiological state and cancer occurrence should account for the metabolic effects of preclinical disease demonstrated here. To protect against spurious conclusions, incident cases occurring within 2 years of measurement should be analyzed separately. In studies of cancer mortality, deaths occurring within 3.5 years of the base-line measurement should be analyzed separately.

Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults.

To estimate the fraction of United States (U.S.) adults who are eligible for treatment to reduce elevated low-density lipoprotein (LDL) cholesterol levels based on Adult Treatment Panel II (ATP II) guidelines and the percent reduction in LDL cholesterol required by those who qualify for treatment, we analyzed data on 7,423 respondents to Phase 2 of the third National Health and Nutrition Examination Survey (NHANES III) administered between 1991 and 1994. Approximately 28% of the U.S. adult population aged > or = 20 years is eligible for treatment based on ATP II guidelines. Eighty-two percent of adults with coronary heart disease are not at their target LDL cholesterol level of 100 mg/dl. Of those eligible for treatment, 65% report that they receive no treatment. Overall, 40% of people who qualify for drug therapy require an LDL cholesterol reduction of > 30% to meet their ATP II treatment goal. Approximately 75% of those with coronary heart disease who qualify for drug therapy require an LDL cholesterol reduction of >30%. Although elevated LDL cholesterol levels can be treated, prevalence rates in the U.S. adult population remain high. Several recent studies indicate that a considerable percentage of people treated with drug therapy do not reach their treatment goals. The findings in this study provide at least a partial explanation for why many patients receiving therapy do not reach their treatment goals: they require a larger reduction in LDL cholesterol than many therapies can provide.

Biological markers of intermediate outcomes in studies of indoor air and other complex mixtures.

Biological markers of intermediate health outcomes sometimes provide a superior alternative to traditional measures of pollutant-related disease. Some opportunities and methodologic issues associated with using markers are discussed in the context of exposures to four complex mixtures: environmental tobacco smoke and nitrogen dioxide, acid aerosols and oxidant outdoor pollution, environmental tobacco smoke and radon, and volatile organic compounds. For markers of intermediate health outcomes, the most important property is the positive predictive value for clinical outcomes of interest. Unless the marker has a known relationship with disease, a marker response conveys no information about disease risk. Most markers are nonspecific in that various exposures cause the same marker response. Although nonspecificity can be an asset in studies of complex mixtures, it leads to problems with confounding and dilution of exposure-response associations in the presence of other exposures. The timing of a marker's measurement in relation to the occurrence of exposure influences the ability to detect a response; measurements made too early or too late may underestimate the response's magnitude. Noninvasive markers, such as those measured in urine, blood, or nasal lavage fluid, are generally more useful for field studies than are invasive markers. However, invasive markers, such as those measured in bronchoalveolar lavage fluid or lung specimens from autopsies, provide the most direct evidence of pulmonary damage from exposure to air pollutants. Unfortunately, the lack of basic information about marker properties (e.g., sensitivity, variability, statistical link with disease) currently precludes the effective use of most markers in studies of complex mixtures.

Comparison of DNA adducts from exposure to complex mixtures in various human tissues and experimental systems.

DNA adducts derived from complex mixtures of polycyclic aromatic compounds emitted from tobacco smoke are compared to industrial pollution sources (e.g., coke ovens and aluminum smelters), smoky coal burning, and urban air pollution. Exposures to coke oven emissions and smoky coal, both potent rodent skin tumor initiators and lung carcinogens in humans, result in high levels of DNA adducts compared to tobacco smoke in the in vitro calf thymus DNA model system, in cultured lymphocytes, and in the mouse skin assay. Using tobacco smoke as a model in human studies, we have compared relative DNA adduct levels detected in blood lymphocytes, placental tissue, bronchoalveolar lung lavage cells, sperm, and autopsy tissues of smokers and nonsmokers. Adduct levels in DNA isolated from smokers were highest in human heart and lung tissue with smaller but detectable differences in placental tissue and lung lavage cells. Comparison of the DNA adduct levels resulting from human exposure to different complex mixtures shows that emissions from coke ovens, aluminum smelters, and smoky coal result in higher DNA adduct levels than tobacco smoke exposure. These studies suggest that humans exposed to complex combustion mixtures will have higher DNA adduct levels in target cells (e.g., lung) as compared to nontarget cells (e.g., lymphocytes) and that the adduct levels will be dependent on the genotoxic and DNA adduct-forming potency of the mixture.

Obesity and mortality in the Lipid Research Clinics Program Follow-up Study.

Using data from the Lipid Research Clinics Program for 1972-1983, the study presented here examined weight history and two indices of obesity: the body mass index (BMI) and the triceps skinfold (TSF) thickness. Cox regression analyses with and without adjustment for cardiovascular disease risk factors revealed a significant (p less than 0.05) quadratic association between BMI and all-causes mortality among men, but not women, after an average 8.4 years of follow-up; mortality was relatively high at both extremes of the BMI distribution. The association was stronger among smokers compared with nonsmokers, and it was apparent among male normotensives, but not hypertensives. All TSF-mortality associations and BMI associations with cancer and coronary heart disease mortality were weak and nonsignificant. Among men, per cent weight change in adulthood showed a significant inverse association with all-causes and cancer mortality. Because BMI and weight history were significantly associated with mortality after adjustment for other risk factors, they appear to be independent predictors of mortality among men.

A sensitive color ELISA for detecting polycyclic aromatic hydrocarbon-DNA adducts in human tissues.

Human exposure to polycyclic aromatic hydrocarbons (PAHs) has been determined by measurement of DNA adducts in human tissues. Competitive enzyme-linked immunosorbent assays (ELISAs) using antisera recognizing benzo[a]pyrenediol-epoxide-modified DNA (BPDE-I-DNA) and color of fluorescence endpoint detection have been used extensively for quantifying PAH-DNA adducts. The fluorescence ELISA (limit of detection 1 adduct/10(8) nucleotides) was previously reported to be more sensitive than the color ELISA (1/10(7)) for measuring PAH adducts (Santella et al. (1988) Carcinogenesis, 9, 1265-1269). However, the fluorescence assay has the disadvantages of greater variation among the replicates and higher background levels than the color assay. Using a newly developed antiserum against BPDE-I-DNA, we have modified the color of ELISA so that it has the same sensitivity as the fluorescence ELISA and requires only 33% of the sample quantity needed for the fluorescence ELISA. The modifications included preincubation of the antiserum with the samples, using microtiter plates with half-size, flat bottom wells, and optimizing the assay conditions. The improved color ELISA was used to analyze DNA samples from human autopsy tissues, including heart, lung, liver, kidney, spleen, pancreas and stomach from smokers and nonsmokers. With the exception of spleen and stomach, all tissues from smokers showed higher PAH-DNA adducts (ranging from 0.3 to 19.0 adducts/10(7) nucleotides) than the tissues from the nonsmokers (0.3 to 3.7 adducts/10(7) nucleotides) in two separate experiments. Among the tissues from smokers, heart showed the highest level of DNA adducts. This study demonstrates that a stable color ELISA with high sensitivity can be useful in assessing human exposure to PAH.

Population-based exposure measurements in EPA region 5: a phase I field study in support of the National Human Exposure Assessment Survey.

The National Human Exposure Assessment Survey (NHEXAS) Phase I study is designed to be part of the total NHEXAS framework developed from a series of scientific discussions and workshops conducted by the U.S. Environmental Protection Agency (EPA) during 1992 and 1993. NHEXAS examines total human exposure and is structured to include: Phase I, scoping studies; Phase II, a full national exposure survey; and Phase III, a series of highly focused characterization modules. Our research program examines the scientific issues important to Phase II, including statistical sampling, methods evaluation, media concentration measurements, formulating quality assurance goals, and identification of important pathways leading to exposure. To determine the feasibility of NHEXAS in characterizing human exposure for a representative population, a hypothesis-driven design is used to answer important questions about human exposure to specific environmental contaminants. This paper describes: (1) hypotheses to be tested; (2) contaminants selected for study; (3) strategies for measuring exposure; (4) study area and population; (5) population sampling design; (6) media sampling and analysis procedures; and (7) data analysis. The contaminants of concern in this Phase I study include selected metals and volatile organic compounds. From these classes the first-tier contaminants to be measured are lead, arsenic, benzene, chloroform, perchloroethylene, and trichloroethylene. Contaminants selected for examination may potentially be found in many media (personal-nonoccupational, personal-occupational, indoor, and outdoor residential air; dust; potable water; food/beverages; soil; blood; hair; and urine) and exposures may occur by multiple routes (inhalation, ingestion, dermal). The central hypothesis of our field study is to discover whether individual and population exposures determined by modeled or extant data are/are not significantly different from those determined directly from multipathway and multimedia measurements. In addition, there are a series of subhypotheses ranging from pollutant-specific exposure measurement and body burden hypotheses to the optimization of exposure models. In keeping with the NHEXAS framework, a probability-based population sample for total exposure and the field study will be conducted in counties located throughout EPA Region 5 (Minnesota, Wisconsin, Illinois, Indiana, Ohio, and Michigan). Sampling units will be households and an individual residing within each household. Environmental, exposure, and biological media sample collection will be performed by this consortium. Analyses of the external media and biological media samples will be completed by this consortium or Federal laboratories of the Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), or EPA. The protocols and analytical techniques selected for use represent the best available for total exposure assessment at this time.

The healthy worker effect. Selection of workers and work forces.

The favorable health status of employed populations in comparison to that of the general population is often called the "healthy worker effect," and most researchers feel that it results from the selection of healthy individuals during the hiring process. However, other mechanisms may also contribute to the healthy worker effect. In particular, the healthy worker effect may reflect the selection, for epidemiologic study, of relatively advantaged workforces in terms of socioeconomic status and health. Evidence of differential health by socioeconomic status within the workforce is reviewed, and its possible role in the healthy worker effect is discussed.

Biological markers in epidemiologic research.

This paper identifies some of the issues relevant to the use of biological markers in epidemiologic research. Foremost among these are clarity of definitions and marker classification. Illustrations of markers in the categories of internal dose, biological effective dose, biological response, disease, and susceptibility are presented with a theoretical model for the interrelationship among these. Issues faced by epidemiologists in selecting markers for specific studies concern exposure complexity, marker specificity, marker persistence, time to appearance, and the use of target vs. surrogate biological media. Feasibility issues concern sample collection, transport, storage, and characteristics of the laboratory assay. The rationale for biological markers in epidemiologic research is strong in that markers have the potential for (1.) improving the accuracy of our "exposure variables," (2.) permitting the identification of preclinical disease and providing opportunities for prevention, (3.) allowing for more homogeneous and etiologically relevant classifications of disease, and (4.) enhancing our understanding of the biological processes leading to disease occurrence, thereby strengthening the interpretation of epidemiologic data and the theoretical framework from which we formulate research questions.

Mortality from heart disease among workers exposed to solvents.

Several rubber industry jobs that are associated with cardiovascular disease (CVD) mortality involve the use of solvents and, since the only known occupational cause of atherosclerosis is a solvent (carbon disulfide), solvent exposures may contribute to the CVD excess observed among rubber industry workers. Detailed exposure estimates for 25 solvents were available for a cohort of 1,282 white male production workers in a large rubber- and tire-manufacturing plant, and a survivorship analysis compared the CVD mortality experience of exposed and nonexposed workers during a 15-year follow-up period. The known association between carbon disulfide exposure and ischemic heart disease (IHD) was apparent among these workers, and two other solvents, ethanol and phenol, were also found to be significant predictors of IHD. These exploratory findings suggest that solvents other than carbon disulfide may cause atherosclerotic disease.

The prevalence and correlates of Rose Questionnaire angina among women and men in the Lipid Research Clinics Program Prevalence Study population.

The prevalence and correlates of Rose Questionnaire angina were investigated in a sample of 4,661 white woman and men aged 30 years and above who participated in the Lipid Research Clinics Program Prevalence Study 1972-1976. Among men, the prevalence of Rose angina increased with age from about 1% to 12%, while the prevalence among women ranged from about 3% to 6%. Young women compared with men also had a relatively high prevalence of dyspnea, which was strongly correlated with Rose angina in both sexes. For women and men younger than 50 years, the dyspnea-Rose angina odds ratio was about 6 (p less than 0.001), while older women and men had somewhat lower sand higher odds ratios, respectively. Major and minor resting electrocardiographic abnormalities and self-reported history of a heart attack were not significantly associated with Rose angina among young participants of either sex, but they did show positive associations among older participants with the exception of minor electrocardiographic abnormalities in men. A logistic regression analysis revealed a strong inverse association between high density lipoprotein cholesterol and Rose angina in both sexes. Because mortality studies consistently show an excess of coronary heart disease death among young men compared with women, the female excess of Rose angina at young ages suggests that the grouping of angina and myocardial infarction into a single endpoint in cardiovascular disease studies may be more appropriate for young men than for young women.

A comparison of direct adjustment and regression adjustment of epidemiologic measures.

Although regression adjustment can provide a useful alternative to direct adjustment, especially when data are sparse, many researchers are unaware that adjusted summary measures can be easily derived from regression coefficients. In a non-technical discussion with examples, the direct adjustment procedure is compared with three methods of regression adjustment based on analysis of covariance models: the conditional prediction method, the stratified prediction method, and the marginal prediction method. Both the stratified prediction and direct adjustment methods yield summary measures that are weighted averages of stratum-specific measures, while adjusted measures from the conditional prediction method are similar to stratum-specific estimates. In contrast to the other adjustment procedures, which can use internal or external weights, the marginal prediction method always gives an internally adjusted measure. Under certain conditions, the three regression adjustment procedures produce identical results. Major advantages of direct adjustment include computational simplicity and relatively few statistical assumptions. Regression adjustment, however, is more convenient for statistical tests for interactions and group differences, and often precludes the need to categorize continuous variables, so that problems with empty strata are avoided.

Solvent exposure and cardiovascular disease.

A review of cardiovascular disease (CVD) resulting from environmental exposures pointed out the lack of studies concerned with the cardiovascular effects of hazardous environmental exposures. A later Working Group report on CVD in the workplace recommended further occupational studies of CVD, and it identified carbon monoxide, nitrates, and organic solvents as exposures especially deserving of study. The literature lacks a detailed, critical epidemiologic overview of work on this last topic. Therefore, the following review focuses on the cardiovascular effects of solvent exposures. Some major difficulties inherent in studies of CVD and environmental exposures are brought out, and some suggested areas for future epidemiologic research are discussed.

An evaluation of the associations of leukemia and rubber industry solvent exposures.

Excessive leukemia mortality has appeared consistently in epidemiological studies of British and U.S. rubber industry workers. Attempts to identify causative factors have focused on exposure to benzene and other solvents. Interpretations of findings from these studies have often been influenced by expectations of a benzene/nonlymphocytic leukemia association, seen from previous work in other settings. However, data from the rubber industry studies have not been consistent with this expectation, as lymphocytic and nonlymphocytic leukemia have shown similar mortality excesses. Data from a small case-control study of lymphocytic leukemia are presented to illustrate an approach that considers multiple solvent exposures. The associations with lymphocytic leukemia risk observed for a number of solvents, most notably carbon tetrachloride and carbon disulfide, were stronger than those detected for benzene.

Resting and exercise electrocardiographic abnormalities associated with sex hormone use in women. The Lipid Research Clinics Program Prevalence Study.

Prevalence rates for resting and exercise electrocardiographic abnormalities were determined according to the use or nonuse of oral contraceptives and exogenous estrogens in 1,919 women participants from 10 defined North American study populations of the Lipid Research Clinics Program. Among women 30-49 years of age, no significant differences in the prevalence of resting electrocardiographic abnormalities between oral contraceptive users and nonusers were seen after adjustment for age, blood pressure, cigarette smoking, alcohol, and obesity. Abnormal graded exercise electrocardiograms, however, were more prevalent among the oral contraceptive users (odds ratio = 2.7, p less than 0.05). Among women 50 years and older, a significant deficit of abnormal Q waves on resting electrocardiogram and nonsignificant excess of abnormal S-T segment responses to exercise were noted in estrogen users compared with nonusers. Possible sources of bias and the pathophysiologic implications of these findings are discussed.

Cancer mortality and solvent exposures in the rubber industry.

Some evidence suggests that solvent exposures to rubber industry workers may be associated with excess cancer mortality, but most studies of rubber workers lack information about specific chemical exposures. In one large rubber and tire-manufacturing plant, however, historical documents allowed a classification of jobs based on potential exposures to all solvents that were authorized for use in the plant. A case-control analysis of a 6678 member cohort compared the solvent exposure histories of a 20% age-stratified random sample of the cohort with those of cohort members who died during 1964-1973 from stomach cancer, respiratory system cancer, prostate cancer, lymphosarcoma, or lymphatic leukemia. Of these cancers, only lymphosarcoma and lymphatic leukemia showed significant positive associations with any of the potential solvent exposures. Lymphatic leukemia was especially strongly related to carbon tetrachloride (OR = 15.3, p less than .0001) and carbon disulfide (OR = 8.9, p = .0003). Lymphosarcoma showed similar, but weaker, associations with these two solvents. Benzene, a suspected carcinogen, was not significantly associated with any of the cancers.

Ultrasonographic correlates of carotid atherosclerosis in transient ischemic attack and stroke.

BACKGROUND AND PURPOSE: Atherosclerotic plaques in extracranial carotid arteries, particularly in the bifurcation of the common carotid and internal carotid arteries, may cause transient cerebral ischemia and stroke by lumen stenosis or plaque-related thromboembolism. B-mode ultrasound imaging has the capability of providing information on plaque thickness, characteristics, and location in carotid arteries. METHODS: A retrospective analysis of 242 stroke and 336 transient ischemic attack (TIA) patients, recruited for the B-Scan Ultrasound Imaging Assessment Program, was performed to determine the ultrasonographic correlates of carotid atherosclerosis and acute cerebral ischemia. A matched case-control study design was used to compare brain hemispheres with ischemic lesions ("cases") to unaffected contralateral hemispheres ("controls") with regard to the presence and characteristics of carotid artery plaques. RESULTS: The first set of analyses examined the association between the presence of carotid plaques ipsilateral to the brain lesion and the occurrence of stroke or TIA and showed an association with recent episodes of TIA and stroke (odds ratio [OR], 1.6; P = .03) but not with past episodes. In a subset (n = 232) of patients with plaques in both carotid arteries and recent cerebral ischemic events, stroke was associated with ipsilateral carotid artery occlusion (P = .02). Lumen measurements at the site of the minimum residual lumen (MRL) diameter showed a significant association between a narrower lumen diameter in the carotid artery ipsilateral to case hemisphere and stroke (difference, 1.0 mm; P = .0003). TIA patients showed an association between both hypoechoic carotid plaques (OR, 3.0; P = .005) and the presence of longitudinal lesion motion (OR, 3.0; P = .02) with ipsilateral brain involvement. Plaque thickness at the MRL was positively correlated with both ipsilateral TIA (ipsilateral side, 4.4 +/- 0.15 mm; contralateral side, 3.9 +/- 0.16 mm; P = .007) and stroke (ipsilateral side, 4.2 +/- 0.23 mm; contralateral side, 3.3 +/- 0.21 mm; P = .0006). CONCLUSIONS: These data demonstrate significant relationships between carotid artery ultrasound plaque characteristics and ischemic cerebrovascular events. These findings encourage further prospective studies in asymptomatic subjects focused on echographic carotid plaque characteristics as predictors of subsequent TIA or stroke.

Isoniazid-related fatal hepatitis.

To describe the clinical and demographic characteristics of fatal hepatitis due to single-drug isoniazid preventive therapy for tuberculosis, we did a survey of cases from state health departments, published case reports, and reports to the Centers for Disease Control and Prevention from 1970 to 1992. Of 108 reported cases, some clinical information was available for 76. A medical review panel judged 39 of these deaths as probably due to isoniazid hepatitis and 23 deaths as possibly due to isoniazid hepatitis. Of the 62 probable and possible cases combined, 50 (81%) were female, 49 (79%) were non-Hispanic black or Hispanic, and 19 (31%) were younger than 35 years. The median duration of isoniazid preventive therapy before symptom onset was 16 weeks. Of the 60 cases with symptom information, 54 (90%) presented with jaundice. Of the 62 cases, 26 (42%) were monitored monthly in accordance with current recommendations, and 6 of the patients were younger than 35 years. We estimate that the rate of fatal isoniazid hepatitis among patients in the public sector was no greater than 4.2 per 100,000 persons beginning therapy and no greater than 7 per 100,000 persons completing therapy. Adherence to isoniazid preventive therapy guidelines apparently reduces, but does not eliminate, the risk of fatal hepatitis. Careful patient selection, education, and monitoring are critical for minimizing that risk.

Demographic, behavioral, biochemical, and dietary correlates of plasma triglycerides. Lipid Research Clinics Program Prevalence Study.

Few studies have simultaneously examined the relationship of triglyceride levels with a wide variety of potential covariates. Thus, the present study was designed to assess in a large, free-living population the association of fasting plasma triglyceride values with selected demographic, behavioral, biochemical, and dietary measures. These analyses were done using data obtained from 5189 white men and women aged 20 to 69 years who participated in the Lipid Research Clinics Program Prevalence Study. Of the eight nondietary factors examined, age, Quetelet Index, fasting plasma glucose, and cigarette smoking were strongly, positively associated (p less than 0.0001) with triglycerides in men and in women not using gonadal hormones. Among women using oral contraceptives or estrogens, only Quetelet Index (p less than 0.01) and cigarette smoking (p = 0.01) were significantly related to triglyceride values. Physical activity was inversely associated (p less than 0.0001) and use of diuretic medications was positively related (p less than 0.01) to triglycerides only in men. Results of analyses of triglycerides and six selected dietary measures varied by age, sex, and hormone-use subgroups. Although none of the dietary variables showed consistent associations with triglycerides across all of the subgroups, triglycerides tended to be inversely associated with total calories per kilogram of body weight and the percentage of calories as dietary fat.

Cancer incidence among an HIV-infected cohort. Pulmonary Complications of HIV Infection Study Group.

Malignancies, particularly Kaposi's sarcoma and non-Hodgkin's lymphoma (NHL), are associated with human immunodeficiency virus (HIV) infection. Cancer incidence among 1,073 asymptomatic HIV-infected individuals from the Pulmonary Complications of HIV Infection Study cohort, persons from six states followed from 1988 to 1994, was examined. Total cancer incidence was 3.99/100 person-years; for Kaposi's sarcoma, incidence was 2.64 cases/100 person-years, and for NHL, it was 1.18 cases/100 person-years. Total cancer (n = 156 cases) was higher among nonblacks than among blacks (rate ratio = 2.8, 95% confidence interval 1.3-6.1), with similar results for Kaposi's sarcoma and NHL. The rate of lung cancer (n = 5) among white, homosexual/bisexual males was 0.18 per 100 person-years, suggesting a high risk of lung cancer.