Lifetime excess absolute risk for lung cancer due to exposure to radon: results of the pooled uranium miners cohort study PUMA.

The Pooled Uranium Miners Analysis (PUMA) study is the largest uranium miners cohort with 119,709 miners, 4.3 million person-years at risk and 7754 lung cancer deaths. Excess relative rate (ERR) estimates for lung cancer mortality per unit of cumulative exposure to radon progeny in working level months (WLM) based on the PUMA study have been reported. The ERR/WLM was modified by attained age, time since exposure or age at exposure, and exposure rate. This pattern was found for the full PUMA cohort and the 1960 + sub-cohort, i.e., miners hired in 1960 or later with chronic low radon exposures and exposure rates. The aim of the present paper is to calculate the lifetime excess absolute risk (LEAR) of lung cancer mortality per WLM using the PUMA risk models, as well as risk models derived in previously published smaller uranium miner studies, some of which are included in PUMA. The same methods were applied for all risk models, i.e., relative risk projection up to <95 years of age, an exposure scenario of 2 WLM per year from age 18-64 years, and baseline mortality rates representing a mixed Euro-American-Asian population. Depending upon the choice of model, the estimated LEAR per WLM are 5.38 × 10-4 or 5.57 × 10-4 in the full PUMA cohort and 7.50 × 10-4 or 7.66 × 10-4 in the PUMA 1960 + sub-cohort, respectively. The LEAR per WLM estimates derived from risk models reported for previously published uranium miners studies range from 2.5 × 10-4 to 9.2 × 10-4. PUMA strengthens knowledge on the radon-related lung cancer LEAR, a useful way to translate models for policy purposes.

Ventilation rates and health: multidisciplinary review of the scientific literature.

UNLABELLED: The scientific literature through 2005 on the effects of ventilation rates on health in indoor environments has been reviewed by a multidisciplinary group. The group judged 27 papers published in peer-reviewed scientific journals as providing sufficient information on both ventilation rates and health effects to inform the relationship. Consistency was found across multiple investigations and different epidemiologic designs for different populations. Multiple health endpoints show similar relationships with ventilation rate. There is biological plausibility for an association of health outcomes with ventilation rates, although the literature does not provide clear evidence on particular agent(s) for the effects. Higher ventilation rates in offices, up to about 25 l/s per person, are associated with reduced prevalence of sick building syndrome (SBS) symptoms. The limited available data suggest that inflammation, respiratory infections, asthma symptoms and short-term sick leave increase with lower ventilation rates. Home ventilation rates above 0.5 air changes per hour (h(-1)) have been associated with a reduced risk of allergic manifestations among children in a Nordic climate. The need remains for more studies of the relationship between ventilation rates and health, especially in diverse climates, in locations with polluted outdoor air and in buildings other than offices. PRACTICAL IMPLICATIONS: Ventilation with outdoor air plays an important role influencing human exposures to indoor pollutants. This review and assessment indicates that increasing ventilation rates above currently adopted standards and guidelines should result in reduced prevalence of negative health outcomes. Building operators and designers should avoid low ventilation rates unless alternative effective measures, such as source control or air cleaning, are employed to limit indoor pollutant levels.

Modelling the health benefits of smoking cessation in Japan.

BACKGROUND: In Japan, tobacco smoking is one of the main avoidable causes of disease and death. Although the benefits of smoking cessation for reducing disease risk and increasing longevity have been extensively documented, a relatively low proportion of Japanese smokers currently express a willingness to quit. This study attempted to quantify future reduction in the burden of smoking-attributable disease that could result from increases in smoking cessation. METHODS: A simulation model was developed to project changes in mortality in Japan associated with increased quit attempts and use of nicotine replacement therapy (NRT) among smokers, incorporating data on smoking prevalence, cause-specific mortality rates, quitting behaviour and NRT use and effectiveness. RESULTS: Approximately 46 000 lung cancer deaths and 56 000 cardiovascular disease deaths could be avoided over 20 years if the proportion of smokers making a quit attempt per year gradually increased to current US levels over 20 years. If each of these quit attempts were aided by NRT, the estimates of avoidable deaths would increase to 64 000 for lung cancer and 78 000 for cardiovascular disease. In this model, negligible deaths were avoided due to decreased smoking initiation over the 20-year simulation. CONCLUSION: Smoking cessation can have measurable short-term impacts on the smoking-related mortality burden in Japan. However, to achieve these gains, tobacco control policies should focus both on increasing smokers' willingness to quit and providing the support and therapies to increase the likelihood that smoking cessation attempts will succeed.

Diabetes mellitus and tuberculosis in Korean adults: impact on tuberculosis incidence, recurrence and mortality.

The prevalence of diabetes mellitus (DM) worldwide is increasing markedly, and many countries with rising rates also have a high incidence rate of tuberculosis (TB). To investigate the relationships of fasting serum glucose (FSG) and DM with TB incidence, recurrence and mortality risk in a prospective cohort study in South Korea. Our study comprised 1 267 564 Koreans who received health insurance from the National Health Insurance System, had an initial medical evaluation between 1997 and 2000 and were prospectively followed biennially. Participants with DM had a higher risk for incident TB (hazard ratio [HR] 1.81, 95%CI 1.71-1.91 in males, HR 1.33; 95%CI 1.20-1.47 in females) than those without DM. There was a strong positive trend for TB risk with rising FSG among males. The risk for recurrent TB among those with previous TB was significantly higher in males (HR 1.58, 95%CI 1.43-1.75) and in females with DM (HR 1.38, 95%CI 1.08-1.76). The increased risk of death from TB during follow-up was also significant in men (HR 1.91, 95%CI 1.87-1.95) and in women (HR 1.71, 95%CI 1.65-1.77). A diagnosis of DM is a risk factor for TB, TB recurrence and death from TB. Screening for TB should be considered among people living with DM in Korea, particularly those with severe DM. .

Regulation of arachidonic acid, eicosanoid, and phospholipase A2 levels in murine mast cells by recombinant stem cell factor.

The current study evaluates the capacity of recombinant rat stem cell factor (rrSCF) to regulate enzymes that control AA release and eicosanoid generation in mouse bone marrow-derived mast cells (BMMCs). Initial studies indicated that rrSCF provided for 24 h inhibited the release of AA into supernatant fluids of antigen- and ionophore A23187-stimulated BMMCs. Agonist-induced increases in cellular levels of AA were also inhibited, albeit to a lesser degree by rrSCF. To determine the inhibitory mechanism, several steps (e.g., mobilization of cytosolic calcium, release of BMMC granules, and regulation of phospholipase A2 [PLA2] activity) that could influence AA release were measured in rrSCF-treated cells. rrSCF did not alter the capacity of BMMCs to mobilize cytosolic calcium or release histamine in response to antigen and ionophore. BMMCs released large amounts of PLA2 with characteristics of the group II family in response to antigen and ionophore A23187. rrSCF treatment of BMMCs reduced the secretion of this PLA2 activity by BMMCs. Partial purification of acid-extractable PLA2 from rrSCF-treated and untreated BMMCs suggested that rrSCF decreased the quantity of acid-stable PLA2 within the cells. In contrast to group II PLA2, the quantity of cPLA2 (as determined by Western blot analysis) increased in response to rrSCF. To assess the ramifications of rrSCF-induced reductions in AA and group II PLA2, eicosanoid formation was measured in antigen- and ionophore-stimulated BMMCs, rrSCF-inhibited (100 ng/ml, 24 h) prostaglandin D2 (PGD2), thromboxane B2, and leukotriene B4 by 48.4 +/- 7.7%, 61.1 +/- 10.0% AND 38.1 +/- 3.6%, respectively, in antigen-stimulated cells. Similar patterns of inhibition were observed in ionophore-stimulated BMMCs. The addition of a group I PLA2 or exogenous AA to BMMCs reversed the inhibition of eicosanoid generation induced by rrSCF. Together, these data indicate that rrSCF differentially regulates group II and cytosolic PLA2 activities in BMMCs. The resultant reductions in eicosanoid generation suggest that group II PLA2 provides a portion of AA that is used for eicosanoid biosynthesis by BMMCs.

Radon and lung cancer.

Radon, an inert gas released during the decay of uranium-238, is ubiquitous in indoor and outdoor air and contaminates many underground mines. Extensive epidemiologic evidence from studies of underground miners and complementary animal data have documented that radon causes lung cancer in smokers and nonsmokers. Radon must also be considered a potentially important cause of lung cancer for the general population, which is exposed through contamination of indoor air by radon from soil, water, and building materials. This review describes radon's sources, levels in U.S. homes, dosimetry, the epidemiologic evidence from studies of miners and the general population, and the principal, recent risk assessments.

Lung cancer and occupation in New Mexico.

The association between occupation and lung cancer risk was examined in a population-based, case-control study of 506 patients (333 males and 173 females) and 771 control (499 males and 272 females) subjects in New Mexico. A personal interview was used to obtain lifetime occupational and smoking histories and self-reported history of exposures to specific agents. High-risk jobs were identified in advance of data analysis and linked with industrial and occupational codes for hypothesis testing. For females, lung cancer risk was not associated with employment history, but power was limited. For males, elevated risks were found for the uranium mining industry [odds ratio (OR) = 1.9; 95% confidence internal (CI) = 0.8-4.9], underground miners (OR = 2.1; 95% CI = 1.1-3.7), painters (OR = 2.7; 95% CI = 0.8-8.9), and welders (OR = 3.2; 95% CI = 1.4-7.4). For self-reported exposure to any of 18 agents, only the OR for exposure to "other metals" was elevated. The population attributable risk in males was estimated as 14% for employment in any high-risk industry or occupation with an OR above 1 in this study.

Determinants of survival in older cancer patients.

BACKGROUND: We and others have previously described a number of characteristics that are associated with delays in diagnosis and increased risk for inadequate treatment of older women and men with cancer. These characteristics include poor social support, limited access to transportation, and impaired cognition. However, there is little information on how these factors influence survival of older cancer patients. PURPOSE: The purpose of the study was to determine which patient characteristics predicted survival up to 10 years after the diagnosis of cancer. METHODS: In 1984, we initiated a population-based study of men and women who were 65 years of age or older, living in a six-county area of New Mexico, and newly diagnosed with cancer. For 646 individuals with cancer of the breast (n = 188), prostate (n = 247), or colon or rectum (n = 211), we assessed patient baseline characteristics, disease stage at diagnosis, and adequacy of treatment (definitive or nondefinitive) as determinants of survival for up to 10 years following diagnosis. Multivariate survival models were used to analyze the data; all P values were two-sided. RESULTS: In multivariate analyses, we first included all patient characteristics, except the stage at diagnosis and the adequacy of treatment. In this initial analysis, the following were among variables that were significantly associated with patient survival: age, education, cancer knowledge, ethnic group, and cognitive status. When stage at diagnosis and adequacy of treatment were added to the model, both advanced stage at diagnosis (hazard ratio = 1.7 [95% confidence interval ¿CI¿ = 1.3-2.1] for diagnosis at regional stage versus local stage; hazard ratio = 3.0 [95% CI = 2.0-4.7] for distant stage versus local stage) and inadequate treatment (hazard ratio = 1.6 [95% CI = 1.1-2.3]) were associated with poor survival. However, adding stage at diagnosis and adequacy of treatment to the analysis had little influence on the magnitude of the effect of patient characteristics on survival. In separate analyses of patient data by cancer site, receipt of nondefinitive therapy was associated with increased mortality among patients with colon/rectal cancer (hazard ratio = 7.8 [95% CI = 2.8-21.4]) and breast cancer (hazard ratio = 2.2 [95% CI = 1.1-4.3]) but not among patients with prostate cancer (hazard ratio = 1.0 [95% CI = 0.6-1.9]). CONCLUSIONS: Advanced stage at diagnosis and inadequate treatment of older cancer patients are associated with poor survival. Impaired cognition and inadequate education in elderly patients are also associated with poor survival. This decreased survival does not appear to be a consequence of known barriers to health care that are responsible for delays in diagnosis and for inadequate treatment. IMPLICATIONS: Efforts to facilitate early diagnosis and receipt of definitive treatment for cancer in older individuals may improve their survival.

Survival of American Indian and Hispanic cancer patients in New Mexico and Arizona, 1969-82.

Survival was examined by ethnic group for 31,465 incident cancer cases diagnosed from 1969 through 1982 in Hispanic and non-Hispanic whites residing in New Mexico and in American Indians residing in New Mexico and Arizona. In comparison with the 1- and 5-year survival rates following the diagnosis of cancer for non-Hispanic whites, those for American Indians were generally poorer and, to a lesser extent, those for Hispanics were also poorer. The American Indian and Hispanic patients tended to have more advanced disease at the time of diagnosis, although this pattern was not consistent across all sites. For many primary cancer sites, American Indian patients were less likely to receive treatment for their cancer than were non-Hispanic whites. Hispanics were also less likely to be treated for cancers of some sites, although the differences were not as large as for American Indians. However, after adjustment for stage and treatment, American Indians demonstrated significantly poorer survival than non-Hispanic whites for cancers of many sites. After adjustment for stage and treatment, survival in Hispanics was generally comparable to that in non-Hispanic whites.

Delay in seeking care for cancer symptoms: a population-based study of elderly New Mexicans.

To characterize the delay by the elderly in seeking care for cancer symptoms, we interviewed 800 New Mexicans, greater than or equal to 65 years of age, with newly diagnosed cancer. Overall, 29.4% of the subjects were asymptomatic when cancer was detected, and 48.0% presented within 2 months of symptom onset. However, 19.2% of the subjects delayed seeking care for at least 12 weeks and 7.4% delayed at least 1 year. Site of cancer was the strongest determinant of delay. Hispanics tended to report longer delay than non-Hispanics, and age was not associated with delay. Of the numerous other factors considered, only having a regular checkup was significantly associated with delay interval.

Childhood cancer epidemiology in New Mexico's American Indians, Hispanic whites, and non-Hispanic whites, 1970-82.

The statewide population-based New Mexico Tumor Registry identified 473 malignant tumors among children of ages 0-14 years, during the period 1970-82. There were 235 non-Hispanic whites (50%), 189 Hispanic whites (40%), 38 American Indians (8%), and 11 other nonwhites (2%). The average annual age-adjusted incidence rates per million for non-Hispanic whites were 138.6 for males and 108.3 for females; for Hispanic whites, the rates were 108.5 for males and 80.9 for females; for American Indians, the rates were 75.5 for males and 78.0 for females. The incidence rates for all sites of cancer combined were lower for Hispanics and American Indians than for New Mexico's non-Hispanic whites and U.S. whites. Leukemia was the most common cancer in all racial-ethnic groups. In comparison with U.S. whites, American Indians were at low risk for leukemias, lymphomas, central nervous system (CNS), sympathetic nervous system (SNS), and kidney tumors and were at high risk for retinoblastoma, bone, and sex organ tumors. Hispanics were at low risk for CNS, SNS, kidney, sex organ, and liver tumors. Hispanic and non-Hispanic white males both were at increased risk for melanoma.

Determinants of lung cancer risk in cigarette smokers in New Mexico.

Although cigarette smoking is the strongest known risk factor for lung cancer, the effects of specific smoking practices have not been completely characterized. The present study examines determinants of lung cancer risk in a population-based, case-control study conducted in New Mexico, 1980-82. The study included 521 cases and 769 controls matched for age, sex, and ethnicity. Either the index subjects or their next-of-kin were interviewed in person to obtain a detailed history of cigarette smoking and information concerning other risk factors. With the use of multiple logistic regression, a model was constructed of the effects of amount smoked, duration of smoking, cigarette type, and smoking cessation on lung cancer risk. Among current smokers, risk increased with each additional cigarette smoked per day (P less than .001). For duration of smoking, the risk per year smoked in individuals 65 years and older was only one-third that in persons under age 65 years. With regard to cigarette type, a somewhat higher risk was found associated with smoking nonfilter cigarettes, but there was no evidence of decreasing risk as the extent of filter smoking increased. Lifelong filter cigarette smokers and smokers of both filter and nonfilter cigarettes were at lower risk than lifelong smokers of nonfilter cigarettes only. In ex-smokers, the pattern of variation of relative risk with amount and duration was similar to that in the current smokers. Excluding those who had stopped for 1 year or less, the relative risk declined exponentially with duration of smoking cessation (P less than .01). These analyses confirm the strong benefits of smoking cessation and indicate possible reduction of risk from smoking filter cigarettes.

Histopathology of lung cancer in New Mexico, 1970-72 and 1980-81.

In conjunction with a population-based case-control study of lung cancer in New Mexico, the histopathology of cases diagnosed during 1980 and 1981 and during 1970-72 was reviewed. Adequate histologic or cytologic material was obtained for 725 cases, with 308 during 1970-72 and 417 during 1980-81. The light microscopic histologic type was classified on the basis of review by 2 pathologists. No significant differences were found in the histologic-type distributions in Hispanics and non-Hispanic whites. In males, the distributions of histologic types were similar in the two time periods, but in non-Hispanic white women the proportion of adenocarcinoma declined during 1980-81 as the proportion of small cell carcinoma increased. The panel classification was compared with that recorded by the New Mexico Tumor Registry. Overall agreement was 52.1% for 1970-72 and increased to 65.2% for 1980-81. The discrepancies between the two classifications were largest for the categories of large cell undifferentiated carcinoma and "other malignancy."

Cancer mortality among New Mexico's Hispanics, American Indians, and non-Hispanic Whites, 1958-1987.

BACKGROUND: Racial and ethnic differences in cancer incidence and mortality are well documented. New Mexico's ethnically and racially diverse population provides an opportunity to further examine ethnic and racial differences in cancer occurrence. PURPOSE: To address differences in cancer mortality among the state's Hispanics, American Indians, and non-Hispanic Whites, we examined mortality data collected from 1958 through 1987. METHODS: Sex and age-specific and age-adjusted cancer mortality rates were calculated for all sites and specific sites for American Indians, Hispanics, and non-Hispanic Whites. From 1958 through 1987, deaths due to malignant neoplasms were coded according to the International Classification of Diseases. The categories of malignant neoplasms investigated were chosen, in part, to minimize bias due to changes in disease classification. Ethnicity was assigned by the Bureau of Vital Statistics on the basis of information on death certificates. Denominators were derived from the censuses of 1960, 1970, 1980, and 1990. Age-standardized mortality rates were calculated for 5-year periods (1958-1962, 1963-1967, 1968-1972, 1973-1977, 1978-1982, and 1983-1987), with the 1970 U.S. population as the standard. We also examined age-specific rates by time period. RESULTS: Within each of New Mexico's ethnic groups, overall cancer mortality increased over the 30-year time span, and the cancer mortality rates were greater for males than for females. For most major cancer sites, mortality rates for New Mexico's non-Hispanic Whites were comparable with data for U.S. Whites. American Indians had the lowest rates for most sites, whereas cancer mortality rates for most sites among Hispanics were intermediate between the two other groups. However, Hispanics and American Indians had higher mortality rates for cancers of the gallbladder, cervix, and stomach compared with non-Hispanic Whites throughout most of the study period. Several other cancer sites showed major mortality rate differences among these racial and ethnic groups, including cancers of the colon, rectum, breast, bladder, lung, ovary, and uterus. We also observed strong temporal trends of increasing or decreasing mortality rates for several cancer sites. CONCLUSIONS: Race and ethnicity have been strong determinants of cancer mortality in New Mexico. Within the span of one generation, cancer mortality has changed substantially for some cancer sites in each of the population groups studied. IMPLICATIONS: These mortality data underscore the need for appropriately designed etiologic studies of cancer in diverse racial and ethnic groups. Such etiologic studies could provide new insights concerning risk factors for cancer and useful data for developing race- and ethnic-specific cancer control strategies.

Molecular damage in the bronchial epithelium of current and former smokers.

BACKGROUND: Most lung cancers are attributed to smoking. These cancers have been associated with multiple genetic alterations and with the presence of preneoplastic bronchial lesions. In view of such associations, we evaluated the status of specific chromosomal loci in histologically normal and abnormal bronchial biopsy specimens from current and former smokers and specimens from nonsmokers. METHODS: Multiple biopsy specimens were obtained from 18 current smokers, 24 former smokers, and 21 nonsmokers. Polymerase chain reaction-based assays involving 15 polymorphic microsatellite DNA markers were used to examine eight chromosomal regions for genetic changes (loss of heterozygosity [LOH] and microsatellite alterations). RESULTS: LOH and microsatellite alterations were observed in biopsy specimens from both current and former smokers, but no statistically significant differences were observed between the two groups. Among individuals with a history of smoking, 86% demonstrated LOH in one or more biopsy specimens, and 24% showed LOH in all biopsy specimens. About half of the histologically normal specimens from smokers showed LOH, but the frequency of LOH and the severity of histologic change did not correspond until the carcinoma in situ stage. A subset of biopsy specimens from smokers that exhibited either normal or preneoplastic histology showed LOH at multiple chromosomal sites, a phenomenon frequently observed in carcinoma in situ and invasive cancer. LOH on chromosomes 3p and 9p was more frequent than LOH on chromosomes 5q, 17p (17p13; TP53 gene), and 13q (13q14; retinoblastoma gene). Microsatellite alterations were detected in 64% of the smokers. No genetic alterations were detected in nonsmokers. CONCLUSIONS: Genetic changes similar to those found in lung cancers can be detected in the nonmalignant bronchial epithelium of current and former smokers and may persist for many years after smoking cessation.

Lung cancer in radon-exposed miners and estimation of risk from indoor exposure.

BACKGROUND: Radioactive radon is an inert gas that can migrate from soils and rocks and accumulate in enclosed areas, such as homes and underground mines. Studies of miners show that exposure to radon decay products causes lung cancer. Consequently, it is of public health interest to estimate accurately the consequences of daily, low-level exposure in homes to this known carcinogen. Epidemiologic studies of residential radon exposure are burdened by an inability to estimate exposure accurately, low total exposure, and subsequent small excess risks. As a result, the studies have been inconclusive to date. Estimates of the hazard posed by residential radon have been based on analyses of data on miners, with recent estimates based on a pooling of four occupational cohort studies of miners, including 360 lung cancer deaths. PURPOSE: To more fully describe the lung cancer risk in radon-exposed miners, we pooled original data from 11 studies of radon-exposed underground miners, conducted a comprehensive analysis, and developed models for estimating radon-associated lung cancer risk. METHODS: We pooled original data from 11 cohort studies of radon-exposed underground miners, including 65,000 men and more than 2700 lung cancer deaths, and fit various relative risk (RR) regression models. RESULTS: The RR relationship for cumulative radon progeny exposure was consistently linear in the range of miner exposures, suggesting that exposures at lower levels, such as in homes, would carry some risk. The exposure-response trend for never-smokers was threefold the trend for smokers, indicating a greater RR for exposure in never-smokers. The RR from exposure diminished with time since the exposure occurred. For equal total exposure, exposures of long duration (and low rate) were more harmful than exposures of short duration (and high rate). CONCLUSIONS: In the miners, about 40% of all lung cancer deaths may be due to radon progeny exposure, 70% of lung cancer deaths in never-smokers, and 39% of lung cancer deaths in smokers. In the United States, 10% of all lung cancer deaths might be due to indoor radon exposure, 11% of lung cancer deaths in smokers, and 30% of lung cancer deaths in never-smokers. This risk model estimates that reducing radon in all homes exceeding the U. S. Environmental Protection Agency's recommended action level may reduce lung cancer deaths about 2%-4%. These estimates should be interpreted with caution, because concomitant exposures of miners to agents such as arsenic or diesel exhaust may modify the radon effect and, when considered together with other differences between homes and mines, might reduce the generalizability of findings in miners.

Stomach cancer among New Mexico's American Indians, Hispanic whites, and non-Hispanic whites.

Stomach cancer incidence rates vary by ethnic group in New Mexico, with American Indians and Hispanic Whites at higher risk than the state's non-Hispanic White population. To further characterize the descriptive epidemiology of this disease in New Mexico, we investigated temporal trends in stomach cancer mortality and incidence rates. Stomach cancer mortality rates declined over a 25-year period (1958-1982) among New Mexico's Hispanic and non-Hispanic Whites. Birth cohort analysis suggests that much of the decline was achieved prior to 1968. Stomach cancer mortality rates did not drop among American Indians during the same period. Stomach cancer incidence rates remained constant for Hispanic Whites, non-Hispanic Whites, and American Indian males over a 13-year period (1969-1982), but more than doubled among American Indian females. Although environmental factors have been implicated in the etiology of stomach cancer, little is currently known about the distribution of such risk factors among the ethnic groups described in this report. The environmental and biological correlates of sex, ethnicity, and socioeconomic status that determine stomach cancer risk merit further investigation in New Mexico.

p53 protein accumulates frequently in early bronchial neoplasia.

p53 mutations are common in human lung cancer and frequently generate levels of p53 protein that are detectable by immunohistochemistry. For this reason, p53 protein accumulation is a candidate biomarker, but little is known about its timing or frequency in multistage bronchial carcinogenesis. We studied human lung tissues containing preinvasive squamous neoplasms from 34 donors with and without lung cancer. Nuclear p53 protein was present in 0% of normal mucosas, 6.7% of squamous metaplasias, 29.5% of mild dysplasias, 26.9% of moderate dysplasias, 59.7% of severe dysplasias, 58.5% of carcinomas in situ, 67.5% of microinvasive carcinomas, and 79.5% of invasive tumors. These data indicate that (a) p53 protein accumulates in about 30% of the earliest recognized neoplastic lesions (i.e., mild dysplasia), (b) there is an increasing frequency of p53 protein accumulation starting with mild dysplasia, and (c) p53 protein accumulates infrequently in normal or metaplastic mucosa. In a subset of six patients whose most advanced lesion was carcinoma in situ without evidence of invasive cancer, p53 protein was detected in 0% of normal mucosas, 8.3% of squamous metaplasias, 37.5% of mild dysplasias, 12.5% of moderate dysplasias, 93.8% of severe dysplasias, and 55% of carcinoma in situ lesions. These data show clearly that p53 alterations can occur before invasion and suggest that the frequency is similar to that observed in the full series. Since two-thirds or more of lung cancers have p53 alterations, the timing and frequency of p53 protein accumulation make the p53 tumor suppressor gene an attractive marker for early diagnosis and evaluation of chemoprevention agents.

Mechanisms that account for the selective release of arachidonic acid from intact cells by secretory phospholipase A2.

The current study examined mechanisms that account for the selective release of arachidonic acid (AA) from cells by secretory phospholipase A2 (sPLA2). Initial studies demonstrated that low concentrations of group I and group III PLA2 isotypes and an sPLA2-enriched extract from bone marrow-derived mast cells (BMMC) selectively released AA from mast cells. Much higher concentrations of group II PLA2 were required to release comparable quantities of AA. Group I PLA2 also selectively released AA from another mast cell line (CFTL-15) and a monocytic cell line (THP-1). In contrast, high concentrations of group I PLA2 were required to release fatty acids from a promyelocytic cell line (HL-60) and this release was not selective for AA. Binding studies revealed that cell types (BMMC, CFTL-15 and THP-1) which selectively released AA also had the capacity to specifically bind group I PLA2. However, group II PLA2, which did not selectively release AA from cells, also did not specifically bind to these same cell types. Additional studies revealed that sPLA2 binding to the mast cell receptor was attenuated after stimulation with antigen or ionophore A23187. Reverse transcriptase-polymerase chain reaction analyses indicated the presence of mRNA for the sPLA2 receptor in BMMC, CFTL-15 and THP-1 and the absence of this mRNA in HL-60. Final studies demonstrated that p-aminophenyl-alpha-D-mannopyranoside BSA, a known ligand of the sPLA2 receptor, also selectively released AA from mast cells but not from HL-60 cells. These experiments indicated that receptor occupancy alone (without PLA2 activity) is sufficient to induce the release of AA from mast cells. Together, these data reveal that specific isotypes of sPLA2 have the capacity to selectively release AA from certain cells by their capacity to bind to sPLA2 receptors on the cell surface.

A measurement error model for time-series studies of air pollution and mortality.

One barrier to interpreting the observational evidence concerning the adverse health effects of air pollution for public policy purposes is the measurement error inherent in estimates of exposure based on ambient pollutant monitors. Exposure assessment studies have shown that data from monitors at central sites may not adequately represent personal exposure. Thus, the exposure error resulting from using centrally measured data as a surrogate for personal exposure can potentially lead to a bias in estimates of the health effects of air pollution. This paper develops a multi-stage Poisson regression model for evaluating the effects of exposure measurement error on estimates of effects of particulate air pollution on mortality in time-series studies. To implement the model, we have used five validation data sets on personal exposure to PM10. Our goal is to combine data on the associations between ambient concentrations of particulate matter and mortality for a specific location, with the validation data on the association between ambient and personal concentrations of particulate matter at the locations where data have been collected. We use these data in a model to estimate the relative risk of mortality associated with estimated personal-exposure concentrations and make a comparison with the risk of mortality estimated with measurements of ambient concentration alone. We apply this method to data comprising daily mortality counts, ambient concentrations of PM10measured at a central site, and temperature for Baltimore, Maryland from 1987 to 1994. We have selected our home city of Baltimore to illustrate the method; the measurement error correction model is general and can be applied to other appropriate locations.Our approach uses a combination of: (1) a generalized additive model with log link and Poisson error for the mortality-personal-exposure association; (2) a multi-stage linear model to estimate the variability across the five validation data sets in the personal-ambient-exposure association; (3) data augmentation methods to address the uncertainty resulting from the missing personal exposure time series in Baltimore. In the Poisson regression model, we account for smooth seasonal and annual trends in mortality using smoothing splines. Taking into account the heterogeneity across locations in the personal-ambient-exposure relationship, we quantify the degree to which the exposure measurement error biases the results toward the null hypothesis of no effect, and estimate the loss of precision in the estimated health effects due to indirectly estimating personal exposures from ambient measurements.