Hospitalisation for venous thromboembolism in cancer patients and the general population: a population-based cohort study in Denmark, 1997-2006.

BACKGROUND: Venous thromboembolism (VTE) frequently complicates cancer. Data on tumour-specific VTE predictors are limited, but may inform strategies to prevent thrombosis. METHODS: We computed incidence rates (IRs) with 95% confidence intervals (CIs) for VTE hospitalisation in a cohort of cancer patients (n=57,591) and in a comparison general-population cohort (n=287,476) in Denmark. The subjects entered the study in 1997-2005, and the follow-up continued through 2006. Using Cox proportional-hazards regression, we estimated relative risks (RRs) for VTE predictors, while adjusting for comorbidity. RESULTS: Throughout the follow-up, VTE IR was higher among the cancer patients (IR=8.0, 95% CI=7.6-8.5) than the general population (IR=4.7, 95% CI=4.3-5.1), particularly in the first year after cancer diagnosis (IR=15.0, 95% CI=13.8-16.2, vs IR=8.6, 95% CI=7.6-9.9). Incidence rates of VTE were highest in patients with pancreas (IR=40.9, 95% CI=29.5-56.7), brain (IR=17.7, 95% CI=11.3-27.8) or liver (IR=20.4, 95% CI=9.2-45.3) tumours, multiple myeloma (IR=22.6, 95% CI=15.4-33.2) and among patients with advanced-stage cancers (IR=27.7, 95% CI=24.0-32.0) or those who received chemotherapy or no/symptomatic treatment. The adjusted RR (aRR) for VTE was highest among patients with pancreas (aRR=16.3, 95% CI=8.1-32.6) or brain cancer (aRR=19.8 95% CI=7.1-55.2), multiple myeloma (aRR=46.1, 95% CI=13.1-162.0) and among patients receiving chemotherapy, either alone (aRR=18.5, 95% CI=11.9-28.7) or in combination treatments (aRR=16.2, 95% CI=12.0-21.7). CONCLUSIONS: Risk of VTE is higher among cancer patients than in the general population. Predictors of VTE include recency of cancer diagnosis, cancer site, stage and the type of cancer-directed treatment.

The politics of identity in epidemiology.

The predilection to doubt the objectivity of scientists based on their affiliation--particularly, but not exclusively, focused on scientists affiliated with industry-is a malignant influence in modern epidemiology. Manifestations of this "politics of identity" are widespread and include ad hominem attacks, publication restrictions, and exclusions of scientists from expert panels and advisory boards. These actions are likely to be detrimental to progress in epidemiology and are questionable from an ethical standpoint. The purpose of this commentary is to draw critical attention to the politics of identity in epidemiology and the effects it can have on individual scientists and scientific debate.

Cancer among farmers: a meta-analysis.

PURPOSE: We conducted a meta-analysis of 37 studies to assess whether farmers had elevated rates for several cancers, as was concluded in a previous meta-analysis of 21 studies. METHODS: We identified studies from the reference list of the previous meta-analysis and from a MEDLINE search through December 31, 1994. The primary purpose of our analysis was to identify and, if possible, understand the sources of heterogeneity in the literature. Stratified analyses of studies and linear modeling with inverse variance weights were used to assess the impact of study characteristics on results. We calculated summary relative risks as a weighted average of the log relative risks across studies using inverse variance weights. Fixed and random effects models were used as appropriate. RESULTS: The results for most cancers were markedly heterogeneous by study design and, for fewer cancers, by geographic location, and whether the studies focused on crop and livestock farmers. There was some indication of publication bias due to underreporting of near null or sub null findings. Lip cancer was the only cancer that was clearly elevated among farmers. CONCLUSIONS: The results do not suggest that farmers have elevated rates of several cancers. However, the known heterogeneity of exposures by type of farming, geographic area, time period, and other factors limits the informativeness of meta-analyses of these studies for assessing potential carcinogenic exposures in agriculture.

Future directions in epidemiologic studies of 1,3-butadiene-exposed workers.

To date, epidemiologic research on 1,3-butadiene has consisted of cohort mortality studies of workers in the styrene-butadiene rubber (SBR) and butadiene monomer industries. These studies have been extremely useful both in defining the focus on human health effects to the lymphopoietic cancers and in providing a perspective on which to evaluate the available animal models for human risk assessment. The next step for epidemiologic research will involve a lymphopoietic cancer case control approach to enable a more precise assessment of whether there is a relationship between 1,3-butadiene exposure and lymphopoietic cancer. In addition, periodic mortality updates of the 1,3-butadiene-exposed worker cohorts will be important to monitor trends in lymphopoietic cancer rates and to ensure that other cancers with long latency do not begin to show elevated rates. This paper describes an industry-sponsored program of case-control and cohort mortality update studies along with the critical elements in research design and analysis for each study. Epidemiological studies will play an important role in testing hypotheses developed from toxicological studies about potential biological mechanisms of 1,3-butadiene carcinogenesis in humans.

A critique of the World Resources Institute's report "Pesticides and the immune system: the public health risks".

A recent World Resources Institute (WRI) report concluded that pesticides are a likely cause of immune suppression for millions of people throughout the world. The gravity of this conclusion motivated us to review the scientific evidence cited in the report. The predominant human evidence came from cross-sectional studies conducted in the former Soviet Union. These studies were difficult to evaluate due to incomplete reporting and had obvious limitations in terms of subject selection, exposure assessment,lack of quality control, statistical analysis, adequacy of the comparison group, and confounding. The toxicologic evidence was comprised mainly of acute high-dose studies in which the exposure conditions resulted in systemic toxicity. The relevance of these studies to effects at typical human exposure levels is questionable. We did not find consistent, credible evidence to support the conclusion of widespread pesticide-related immune suppression. Nonetheless, the WRI report is an important document because it focuses attention on a potentially important issue for future research and brings a substantial literature of foreign language studies to the attention of Western scientists.

Evaluation of mortality and cancer incidence among alachlor manufacturing workers.

Alachlor is the active ingredient in a family of preemergence herbicides. We assessed mortality rates from 1968 to 1993 and cancer incidence rates from 1969 to 1993 for manufacturing workers with potential alachlor exposure. For workers judged to have high alachlor exposure, mortality from all causes combined was lower than expected [23 observed, standardized mortality ratio (SMR) = 0.7, 95% CI, 0.4-1.0], cancer mortality was similar to expected (6 observed, SMR = 0.7, 95% CI, 0.3-1.6), and there were no cancer deaths among workers with 5 or more years high exposure and 15 or more years since first exposure (2.3 expected, SMR = 0, 95% CI, 0-1.6). Cancer incidence for workers with high exposure potential was similar to the state rate [18 observed, standardized incidence ratio (SIR) = 1.2, 95% CI, 0.7-2.0], especially for workers exposed for 5 or more years and with at least 15 years since first exposure (4 observed, SIR = 1.0, 95% CI, 0.3-2.7). The most common cancer for these latter workers was colorectal cancer (2 observed, SIR 3.9, 95% CI, 0.5-14.2 among workers). Despite the limitations of this study with respect to small size and exposure estimating, the findings are useful for evaluating potential alachlor-related health risks because past manufacturing exposures greatly exceeded those characteristic of agricultural operations. These findings suggest no appreciable effect of alachlor exposure on worker mortality or cancer incidence rates during the study period.

Butadiene epidemiology: a summary of results and outstanding issues.

Published epidemiologic studies of butadiene workers, individually and in aggregate, find rates similar to expected for essentially all forms of cancer, with the possible exception of lymphohematopoietic cancers. Reviewers of the literature have disagreed about whether butadiene is a cause of human lymphohematopoietic cancers. This article reviews the available butadiene epidemiologic studies and focuses on the bases for disagreement among reviewers. The disagreement seems to be due to different conventions in applying, explicitly or implicitly, Hill's causal criteria, fostered, in part, by deficiencies in the available epidemiologic studies. Many of these deficiencies will be remedied by updated studies presented at this Symposium or are remediable by other analyses of the existing data.

A review of the epidemiology of 1,3-butadiene and chloroprene.

Butadiene epidemiologic research has focused primarily on one cohort of workers in the North American styrene-butadiene rubber (SBR) industry and on the largest cohort of workers in the United States butadiene monomer industry. The most recent studies of these populations are characterized by carefully enumerated study populations, extremely long and high quality mortality follow-up, accurate job categorizations, detailed exposure assessments, and comprehensive statistical analyses. Leukemia was clearly associated with increasing estimated butadiene exposure in the SBR study, but not in the monomer industry study. This has lead to hypotheses about exposure differences between these two industries and the presence of co-factors or confounders in the SBR industry. Research presented at this symposium should shed some light on these hypotheses. The chloroprene epidemiologic literature, on the other hand, is in an early stage of development. The existing studies are limited by poor exposure characterization, lack of control of potential confounding factors, incompleteness in cohort enumeration, short follow-up periods, and small numbers of cancer cases. The state of the science for chloroprene would be advanced by arranging more comprehensive studies than those that have been conducted to date.

Mortality and cancer incidence among alachlor manufacturing workers 1968-99.

BACKGROUND: Alachlor is the active ingredient in pre-emergent herbicide formulations that have been used widely on corn, soybeans, and other crops. It has been found to cause nasal, stomach, and thyroid tumours in rodent feeding studies at levels that are much higher than likely human exposures. AIMS: To evaluate mortality rates from 1968 to 1999 and cancer incidence rates from 1969 to 1999 for alachlor manufacturing workers at a plant in Muscatine, Iowa. METHODS: Worker mortality and cancer incidence rates were compared to corresponding rates for the Iowa state general population. Analyses addressed potential intensity and duration of exposure. RESULTS: For workers with any period of high alachlor exposure, mortality from all causes combined was lower than expected (42 observed deaths, SMR 64, 95% CI 46 to 86) and cancer mortality was slightly lower than expected (13 observed deaths, SMR 79, 95% CI 42 to 136). Cancer incidence for workers with potential high exposure was similar to that for Iowa residents, both overall (29 observed cases, SIR 123, 95% CI 82 to 177) and for workers exposed for five or more years and with at least 15 years since first exposure (eight observed cases, SIR 113, 95% CI 49 to 224). There were no cases of nasal, stomach, or thyroid cancer. CONCLUSIONS: There were no cancers of the types found in toxicology studies and no discernible relation between cancer incidence for any site and years of alachlor exposure or time since first exposure. Despite the small size of this population, the findings are important because these workers had chronic exposure potential during extended manufacturing campaigns, while use in agriculture is typically limited to a few days or weeks each year.

An updated meta-analysis of formaldehyde exposure and upper respiratory tract cancers.

In this study, we summarize 47 epidemiologic studies related to formaldehyde exposure and use meta-analytic techniques to assess findings for cancers of the lung, nose/nasal sinuses, and nasopharynx. Our analyses indicate that workers with formaldehyde exposure have essentially null findings for lung cancer and a slight deficit of sinonasal cancer. Nasopharyngeal cancer rates were elevated moderately in a minority of studies. Most studies, however, did not find any nasopharyngeal cancers, and many failed to report their findings. After correcting for underreporting, we found a meta relative risk of 1.0 for cohort studies. Case-control studies had a meta relative risk of 1.3. Our review of the exposure literature indicated that the nasopharyngeal cancer case-control studies represented much lower and less certain exposures than the cohort studies. We conclude that the available studies do not support a causal relation between formaldehyde exposure and nasopharyngeal cancer. This conclusion conflicts with conclusions from two previous meta-analyses, primarily because of our consideration of unreported data.

Review and meta-analysis of studies of acrylonitrile workers.

Twenty-five epidemiologic studies of acrylonitrile workers were reviewed and subjected to meta-analytic techniques in this study to assess the findings for 10 cancer sites. The analyses indicate that workers with acrylonitrile exposure have essentially null findings for most cancers, including lung [meta-relative risk (mRR) 0.9, 95% confidence interval (95% CI) 0.9-1.1], brain (mRR 1.2, 95% CI 0.8-1.7), and prostate (mRR 1.0, 95% CI 0.7-1.4) cancers. Bladder cancer rates were elevated (mRR 1.8, 95% CI 1.0-3.4), but the excess was not dose-related and was limited to plants with aromatic amines. Therefore, the bladder cancer excess is unlikely to be related to acrylonitrile exposure. Some evidence of publication bias was found in the examined literature, but the bias did not have a significant impact on risk estimates for individual cancers. It was concluded that the available studies do not support a causal relation between acrylonitrile exposure and cancer.

An analysis of death ascertainment and follow-up through statistics Canada's Mortality Data Base system.

The Canadian Mortality Data Base (MDB) was utilized in mortality follow-up of 17,446 refinery and petrochemical workers throughout Canada. The performance of the system in detecting 757 previously known deaths was evaluated. Of the deaths submitted, 93.1% (90% confidence interval (CI) 91.5-94.5) were detected, including 97.6% (90% CI 96.5-98.4) of deaths which occurred in Canada. Detection was generally unaffected by age, year of death (1964-1973), and the presence of middle initial or the remainder of first name. Slightly lower ascertainment was found for deaths occurring in Quebec (94.5%) and Newfoundland (93.3%). This could be due to several factors, including fewer MDB records with complete identifier information for these provinces, or lower accuracy of linking fields for records supplied to the Agency. Few links were made to employees presumed to be alive, indicating 99.8% specificity for these records.

Human ocular effects from self-reported exposures to Roundup herbicides.

We evaluated ocular effects from reported human exposures to Roundup herbicides based on 1513 calls to an American Association of Poison Control Centers (AAPCC) certified regional poison center during the years 1993 through 1997. The preponderance of reported exposures were judged by poison center specialists to result in either no injury (21%) or transient minor symptoms (70%). There was some temporary injury in 2% of cases; one injury took more than 2 weeks to resolve. In no instance did exposure result in permanent change to the structure or function of the eye. Since the representativeness of calls to poison control centers is unknown, several interpretations of these findings are possible. The most conservative interpretation is that there were no serious ocular effects from exposure to Roundup herbicides during a 5 year period among callers to a single regional poison center. A less conservative interpretation would be that severe ocular effects from Roundup exposures are rare among users of these products.

Mortality among workers at the Pantex weapons facility.

We compared total and cause-specific mortality for workers at the Pantex nuclear weapons assembly facility employed between 1951 and 31 December 1978 with expected mortality based on U.S. death rates. We observed significantly fewer deaths than expected from all causes of death, all cancers, digestive cancers, lung cancer, arteriosclerotic heart disease, and digestive diseases. There were no causes of death which occurred significantly more frequently than expected. Analyses of worker mortality by duration of employment, time since first employment, and radiation exposure greater than 1.00 rem produced similar results. We found no evidence that mortality from any cause of death was increased as a result of employment at Pantex.

A melanoma case-control study at the Los Alamos National Laboratory.

We conducted a melanoma case-control study at the Los Alamos National Laboratory to investigate whether related occupational exposures or personal characteristics of employees could be identified. This study was prompted by a recent report from the Lawrence Livermore National Laboratory that melanoma was much more frequent than expected among employees and that persons suffering from melanoma more often worked as chemists. Our investigation did not uncover an association with plutonium body burden, cumulative external radiation exposure, or employment as a chemist or a physicist. The major finding was that cases were more educated than controls. Melanoma risk was 2.11 among college-educated employees and increased to 3.17 among those with graduate degrees (Mantel-extension linear trend probability = 0.038). This finding is consistent with the often reported increased melanoma incidence among persons of higher social class. It points to personal characteristics, particular to persons of higher educational attainment, as risk factors for melanoma at the Los Alamos National Laboratory.

An update of epidemiologic studies of plutonium workers.

Retrospective and prospective epidemiologic studies are being conducted as part of a national survey of plutonium workers at four Department of Energy facilities (Los Alamos, NM; Rocky Flats, CO; Mound Laboratory, OH; and Savannah River, SC). A preliminary analysis of mortality was done for all white males who have worked at the Rocky Flats Plant during the period 1952-79. The 452 observed deaths were significantly fewer than the 831 expected for all causes. The 107 deaths due to all malignant neoplasms were also significantly fewer than the 167 expected from these diseases. Expected deaths were derived from age and calendar-specific death rates for U.S. white males. Deaths reported for benign and unspecified neoplasms numbered eight versus an expected two, a significant elevation. These tumors, all intracranial, are the subject of a case-control study to be reported later. Subdividing the cohort on the basis of plutonium exposures and external radiation exposures results in similar overall findings. The benign and unspecified neoplasms, however, were not significantly high in the plutonium-exposed group.

Mortality and incidence of new primary cancers in men with prostate cancer: a Danish population-based cohort study.

BACKGROUND: Prostate cancer (PC) survivors may have an increased risk of new primary cancers (NPCs) due to shared risk factors or PC-directed treatments. METHODS: Using Danish registries, we conducted a cohort study of men with (n=30,220) and without PC (n=151,100) (comparators), matched 1:5 on age and PC diagnosis/index date. We computed incidence rates of NPCs per 10,000 person years (PY) and associated 95% confidence intervals (CI), and used Cox proportional hazards regression to compute hazard ratios (HRs) and 95%CI, adjusting for comorbidities. In order to obviate any impact of shorter survival among prostate cancer patients, we censored comparator patients when the matched prostate cancer patient died or was censored. RESULTS: Follow-up spanned 113,487PY and 462,982PY in the PC and comparison cohorts, respectively. 65% of the cohorts were aged >70 years at diagnosis. Among PC patients, 51% had distant/unspecified stage, and 63% had surgery as primary treatment. The PC cohort had lower incidence of NPCs than their comparators. The adjusted HR of NPC among men with PC versus the comparators was 0.84 (95%CI=0.80, 0.88). Lowest HRs were among older men, those with distant stage, and were particularly evident for cancers of the brain, liver, pancreas, respiratory, upper gastrointestinal, and urinary systems. CONCLUSIONS: We find no evidence of an increased risk of NPCs among men with PC. The deficit of NPCs among men with PC may be a true effect but is more likely due to lower levels of risk factors (e.g., smoking) in PC patients versus comparators, clinical consideration of cancers at new organs as metastases rather than new primaries, or under-recording/under-reporting of NPCs among PC patients.