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Shuling Li1, Yi Peng1, Eric D Weinhandl1, Anne H Blaes2, Karynsa Cetin3, Victoria M Chia3, Scott Stryker3, Joseph J Pinzone4, John F Acquavella3, Thomas J Arneson11Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, MN, USA; 2Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA; 3Center for Observational Research, 4Global Development, Amgen, Thousand Oaks, CA, USABackground: The prevalence of metastatic bone disease in the US population is not well understood. We sought to estimate the current number of US adults with metastatic bone disease using two large administrative data sets.Methods: Prevalence was estimated from a commercially insured cohort (ages 18–64 years, MarketScan database) and from a fee-for-service Medicare cohort (ages ≥65 years, Medicare 5% database) with coverage on December 31, 2008, representing approximately two-thirds of the US population in each age group. We searched for claims-based evidence of metastatic bone disease from January 1, 2004, using a combination of relevant diagnosis and treatment codes. The number of cases in the US adult population was extrapolated from age- and sex-specific prevalence estimated in these cohorts. Results are presented for all cancers combined and separately for primary breast, prostate, and lung cancer.Results: In the commercially insured cohort (mean age = 42.3 years [SD = 13.1]), we identified 9505 patients (0.052%) with metastatic bone disease. Breast cancer was the most common primary tumor type (n = 4041). In the Medicare cohort (mean age = 75.6 years [SD = 7.8]), we identified 6427 (0.495%) patients with metastatic bone disease. Breast (n = 1798) and prostate (n = 1862) cancers were the most common primary tumor types. We estimate that 279,679 (95% confidence interval: 274,579–284,780) US adults alive on December 31, 2008, had evidence of metastatic bone disease in the previous 5 years. Breast, prostate, and lung cancers accounted for 68% of these cases.Conclusion: Our findings suggest that approximately 280,000 US adults were living with metastatic bone disease on December 31, 2008. This likely underestimates the true frequency; not all cases of metastatic bone disease are diagnosed, and some diagnosed cases might lack documentation in claims data.Keywords: bone neoplasms, epidemiology, metastasis, prevalence

BACKGROUND: Confounding-by-indication is a bias in nonexperimental studies that occurs when outcomes are compared for treated and untreated patients and the treatment or medication dose is related to predictors of the outcome. Two recent publications reported that greater epoetin alfa (EPO) doses were associated with increased mortality rates. We assessed whether confounding-by-indication might account for these results. STUDY DESIGN: We used a retrospective cohort study design. SETTING & PARTICIPANTS: Hemodialysis patients were randomly selected from a large dialysis organization from July 2000 to June 2002 and were required to have completed a 9-month baseline period. PREDICTOR: EPO dose assessed during months 7 to 9 of the baseline period and monthly throughout the follow-up period. Hemoglobin (Hb) was assessed as average value during months 4 to 6 of the baseline period and monthly throughout the follow-up period. All other covariates were assessed during months 1 to 6 of the baseline period. OUTCOME: All-cause mortality during the 1 year of follow-up. Baseline Cox models were fitted with log EPO and Hb with and without adjustment for baseline patient characteristics. Time-dependent models were fitted with time-varying log EPO and Hb and, separately, lagged log EPO and Hb, with adjustment for baseline patient characteristics. RESULTS: 22,955 patients met our inclusion criteria. In the unadjusted model, we observed increased mortality risk with increasing EPO dose (hazard ratio [HR], 1.31 per log unit increase; 95% confidence interval [CI], 1.26 to 1.36). Adjustment for baseline patient characteristics resulted in an appreciably decreased HR (HR, 1.21; 95% CI, 1.15 to 1.28). In the lagged time-dependent analyses, estimates ranged from HR of 0.93 (95% CI, 0.92 to 0.95) to HR of 1.01 (95% CI, 0.99 to 1.03) for the 1- and 2-month lagged models, respectively. LIMITATIONS: This analysis was limited to prevalent hemodialysis patients, and inhospital EPO dosing information was unavailable. CONCLUSIONS: The observed mortality risk estimates associated with EPO dose in nonexperimental studies in dialysis patients may be highly sensitive to the analytic method used. This highlights the complexity of evaluating the association between EPO dose, Hb level, and mortality in these studies. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Glyphosate is the active ingredient in Roundup agricultural herbicides and other herbicide formulations that are widely used for agricultural, forestry, and residential weed control. As part of the Farm Family Exposure Study, we evaluated urinary glyphosate concentrations for 48 farmers, their spouses, and their 79 children (4-18 years of age). We evaluated 24-hr composite urine samples for each family member the day before, the day of, and for 3 days after a glyphosate application. Sixty percent of farmers had detectable levels of glyphosate in their urine on the day of application. The geometric mean (GM) concentration was 3 ppb, the maximum value was 233 ppb, and the highest estimated systemic dose was 0.004 mg/kg. Farmers who did not use rubber gloves had higher GM urinary concentrations than did other farmers (10 ppb vs. 2.0 ppb). For spouses, 4% had detectable levels in their urine on the day of application. Their maximum value was 3 ppb. For children, 12% had detectable glyphosate in their urine on the day of application, with a maximum concentration of 29 ppb. All but one of the children with detectable concentrations had helped with the application or were present during herbicide mixing, loading, or application. None of the systemic doses estimated in this study approached the U.S. Environmental Protection Agency reference dose for glyphosate of 2 mg/kg/day. Nonetheless, it is advisable to minimize exposure to pesticides, and this study did identify specific practices that could be modified to reduce the potential for exposure. [ABSTRACT FROM AUTHOR]

Purpose: Human health risk assessments of glyphosate have focused on animal toxicology data for determining neurotoxic potential. Human epidemiological studies have not yet been systematically reviewed for glyphosate neurotoxicity hazard identification. The objective of this systematic literature review was to summarize the available epidemiology of glyphosate exposure and neurological outcomes in humans., Methods: As of December 2021, 25 eligible epidemiological studies of glyphosate exposure and neurological endpoints were identified and assessed for five quality dimensions using guidance from the U.S. Environmental Protection Agency. Studies that assessed personal use of glyphosate were prioritized, whereas those assessing indirect exposure (other than personal use) were rated as low quality, since biomonitoring data indicate that indirect metrics of glyphosate exposure almost always equate to non-detectable glyphosate doses., Results: Overall, the scientific evidence on glyphosate and neurotoxicity in humans is sparse and methodologically limited, based on nine included epidemiological studies of neurodegenerative outcomes (two high quality), five studies of neurobehavioral outcomes (two high quality), six studies of neurodevelopmental outcomes (none high quality), and five studies of other and mixed neurological outcomes (one high quality). The five high-quality studies showed no association between glyphosate use and risk of depression, Parkinson disease, or peripheral nerve conduction velocity. Results were mixed among the eight moderate-quality studies, which did not demonstrate consistent associations with any neurological endpoints or categories. Low-quality studies were considered uninformative about possible neurotoxic effects due primarily to questionable assessments of indirect exposure., Conclusions: No association has been demonstrated between glyphosate and any neurological outcomes in humans. To move the state of science forward, epidemiological studies should focus on scenarios involving direct and frequent use of glyphosate while collecting information on validated health outcomes, concomitant agricultural exposures, and relevant personal characteristics., (© 2022. The Author(s).)

Objective: Tenosynovial giant cell tumor (TGCT) is a rare benign proliferative and inflammatory disease arising from synovia of joints, bursae, or tendon sheaths. We aimed to estimate incidence rate and prevalence of TGCT in Denmark, to describe patient characteristics and treatment modalities among patients with TGCT, and to estimate risk of TGCT recurrence., Methods: Using registry data on pathology examinations and inpatient and outpatient hospital diagnoses, we identified adult patients with diagnoses of diffuse TGCT (D-TGCT) or localized TGCT (L-TGCT) between 1997 and 2012, followed through 2012. We described patients' characteristics, treatment modalities, and recurrence., Results: We identified 2087 patients with L-TGCT and 574 patients with D-TGCT. Their incidence rates per million person-years were 30.3 (95% CI 29.1-31.7) and 8.4 (95% CI 7.7-9.1), respectively. At the end of 2012, prevalence per 100,000 persons was 44.3 (95% CI 42.4-46.3) for L-TGCT and 11.5 (95% CI 10.6-12.6) for D-TGCT. Women made up 61% of the patients with L-TGCT and 51% of the patients with D-TGCT. Median age at diagnosis was 47 years. Ten-year risk of recurrence was 9.8% (95% CI 8.4-11.3%) after L-TGCT and 19.1% (95% CI 15.7-22.7%) after D-TGCT., Conclusion: This study contributes evidence about epidemiology of TGCT based on routinely collected population-based data gathered in a setting of universal equal access to healthcare and complete followup.

Purpose: In July 2007, the Centers for Medicare & Medicaid Services released a national coverage determination (NCD) for erythropoiesis-stimulating agent (ESA) use in cancer patients, mandating payment restrictions likely to reduce ESA use and possibly increase red blood cell transfusions. We aimed to quantify ESA and transfusion use pre-NCD and post-NCD., Methods: Medicare 5% sample data, 2005-2007, were used. Patients were 66 years or older, had lung, breast, or colorectal cancer or lymphomas, and initiated chemotherapy in pre-NCD and post-NCD periods (September-November 2006, September-November 2007). ESA use and transfusions were identified from claims. Differences in proportions of patients using ESAs and receiving transfusions pre-NCD and post-NCD were evaluated using logistic regression; differences in transfusion event rates were evaluated using a Poisson model., Results: The pre-NCD cohort included 1897 patients and the post-NCD cohort 1877. In the pre-NCD cohort, 31% of patients had lung cancer, 29% lymphoma, 20% colorectal cancer, and 20% breast cancer; distribution was similar in the post-NCD cohort. Overall, ESA use decreased from 35.0% pre-NCD to 15.2% post-NCD. Transfusion use increased from 9.3% to 10.4%, and transfusion event rates from 19.0 to 21.8 per 100 patient-quarters. Results adjusted for baseline characteristics and comorbid conditions were similar. ESA use reduction achieved statistical significance; transfusion use and rate increases did not., Conclusions: ESA use decreased sharply post-NCD. This was accompanied by an estimated 1.1% (95% confidence interval -0.8% to 3.0%) absolute increase in transfusion use., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: The prevalence of metastatic bone disease in the US population is not well understood. We sought to estimate the current number of US adults with metastatic bone disease using two large administrative data sets., Methods: Prevalence was estimated from a commercially insured cohort (ages 18-64 years, MarketScan database) and from a fee-for-service Medicare cohort (ages ≥65 years, Medicare 5% database) with coverage on December 31, 2008, representing approximately two-thirds of the US population in each age group. We searched for claims-based evidence of metastatic bone disease from January 1, 2004, using a combination of relevant diagnosis and treatment codes. The number of cases in the US adult population was extrapolated from age- and sex-specific prevalence estimated in these cohorts. Results are presented for all cancers combined and separately for primary breast, prostate, and lung cancer., Results: In the commercially insured cohort (mean age = 42.3 years [SD = 13.1]), we identified 9505 patients (0.052%) with metastatic bone disease. Breast cancer was the most common primary tumor type (n = 4041). In the Medicare cohort (mean age = 75.6 years [SD = 7.8]), we identified 6427 (0.495%) patients with metastatic bone disease. Breast (n = 1798) and prostate (n = 1862) cancers were the most common primary tumor types. We estimate that 279,679 (95% confidence interval: 274,579-284,780) US adults alive on December 31, 2008, had evidence of metastatic bone disease in the previous 5 years. Breast, prostate, and lung cancers accounted for 68% of these cases., Conclusion: Our findings suggest that approximately 280,000 US adults were living with metastatic bone disease on December 31, 2008. This likely underestimates the true frequency; not all cases of metastatic bone disease are diagnosed, and some diagnosed cases might lack documentation in claims data.

Background and Objectives: Observational studies relating epoetin alfa (EPO) dose and mortality frequently use analytic methods that do not control time-dependent confounding by indication (CBI). The relationship between EPO dose and 1-year mortality, adjusting for the effects of time-dependent CBI, was examined using a marginal structural model., Design, Setting, Participants, & Measurements: This retrospective cohort study included 27,791 hemodialysis patients between July 2000 and June 2002. Patients were grouped at successive 2-wk intervals into a zero-dose category or four nonzero-dose categories. Ordinal regression was used to calculate inverse probability of treatment weights of patients receiving their own dose level given their covariate and treatment history. Three treatment models with an increasing number of treatment predictors were evaluated to assess the effect of model specification. A small number of excessively large patient weights were truncated. Relative hazards for higher-dose groups compared with the lowest nonzero-dose group varied by treatment model specification and by level of weight truncation., Results: Results differed appreciably between the simplest treatment model, which incorporated only hemoglobin and EPO dosing history with 2% weight truncation (hazard ratio: 1.51; 95% confidence interval: 1.09, 1.89 for highest-dose patients), and the most comprehensive treatment model with 1% weight truncation (hazard ratio: 0.98; 95% confidence interval: 0.76, 1.74)., Conclusions: There is appreciable CBI at higher EPO doses, and EPO dose was not associated with increased mortality in marginal structural model analyses that more completely addressed this confounding.

Findings from randomized controlled trials examining the efficacy of therapy with erythropoiesis-stimulating agents (ESAs) to normalize hemoglobin levels in patients with chronic kidney disease or kidney failure have raised questions regarding the safety of this class of drugs. However, no trial to date has specifically assessed the safety of ESA-dosing algorithms used to achieve the lower hemoglobin targets typically using in clinical practice. Although a wealth of nonexperimental data is available for dialysis patients, analyses based on these data are more susceptible to confounding bias than randomized controlled trials. Conducting valid pharmacoepidemiologic studies of drug effects in hemodialysis patients is complicated by the extent of their comorbidities, frequent hospitalizations, various concomitant medications, and an exceedingly high mortality rate. The need for greater ESA doses for the treatment of anemia in sicker patients potentially and plausibly generates confounding by indication, the control of which is complicated by the presence of time-dependent confounding. Here, we describe sources of bias in nonexperimental studies of ESA therapy in hemodialysis patients and critically appraise analytical methods that may help minimize bias in such studies.

In pesticide biomonitoring studies, researchers typically collect either single voids or daily (24-h) urine samples. Collection of 24-h urine samples is considered the "gold-standard", but this method places a high burden on study volunteers, requires greater resources, and may result in misclassification of exposure or underestimation of dose due to noncompliance with urine collection protocols. To evaluate the potential measurement error introduced by single void samples, we present an analysis of exposure and dose for two commonly used pesticides based on single morning void (MV) and 24-h urine collections in farmers and farm children. The agreement between the MV concentration and its corresponding 24-h concentration was analyzed using simple graphical and statistical techniques and risk assessment methodology. A consistent bias towards overprediction of pesticide concentration was found among the MVs, likely in large part due to the pharmacokinetic time course of the analytes in urine. These results suggest that the use of single voids can either over- or under-estimate daily exposure if recent pesticide applications have occurred. This held true for both farmers as well as farm children, who were not directly exposed to the applications. As a result, single void samples influenced the number of children exposed to chlorpyrifos whose daily dose estimates were above levels of toxicologic significance. In populations where fluctuations in pesticide exposure are expected (e.g., farm families), the pharmacokinetics of the pesticide and the timing of exposure events and urine collection must be understood when relying on single voids as a surrogate for longer time-frames of exposure.

Objective: We estimated 2,4-dichlorophenoxyacetic acid (2,4-D) exposure and systemic dose in farm family members following an application of 2,4-D on their farm., Methods: Farm families were recruited from licensed applicators in Minnesota and South Carolina. Eligible family members collected all urine during five 24-hr intervals, 1 day before through 3 days after an application of 2,4-D. Exposure profiles were characterized with 24-hr urine 2,4-D concentrations, which then were related to potential predictors of exposure. Systemic dose was estimated using the urine collections from the application day through the third day after application., Results: Median urine 2,4-D concentrations at baseline and day after application were 2.1 and 73.1 microg/L for applicators, below the limit of detection, and 1.2 microg/L for spouses, and 1.5 and 2.9 microg/L for children. The younger children (4-11 years of age) had higher median post-application concentrations than the older children (> or = 12 years of age) (6.5 vs. 1.9 microg/L). The geometric mean systemic doses (micrograms per kilogram body weight) were 2.46 (applicators), 0.8 (spouses), 0.22 (all children), 0.32 (children 4-11 years of age), and 0.12 (children > or = 12 years of age). Exposure to the spouses and children was primarily determined by direct contact with the application process and the number of acres treated. Multivariate models identified glove use, repairing equipment, and number of acres treated as predictors of exposure in the applicators., Conclusions: We observed considerable heterogeneity of 2,4-D exposure among farm family members, primarily attributable to level of contact with the application process. Awareness of this variability and the actual magnitude of exposures are important for developing exposure and risk characterizations in 2,4-D-exposed agricultural populations.

We used urinary biological monitoring to characterize chlorpyrifos (O,O-diethyl-O-(3,5,6-trichloro-2-pyridinyl) phosphororthioate) exposure to farm family members from Minnesota and South Carolina who participated in the Farm Family Exposure Study. Five consecutive 24-h urine samples were obtained from 34 families of licensed pesticide applicators 1 day before through 3 days after a chlorpyrifos application. Daily 3,5,6-trichloro-2-pyridinol (TCP) urinary concentrations characterized exposure profiles of the applicator, the spouse, and children aged 4-17 years. Self-reported and observed determinants of exposure were compared to the maximum postapplication TCP concentration. All participants had detectable (> or = 1 microg/l) urinary TCP concentrations at baseline. Applicators' peak TCP levels occurred the day after the application (geometric mean (GM) = 19.0 microg/l). Postapplication TCP change from baseline in the spouses and children was negligible, and the only reliable predictor of exposure was assisting with the application for children aged 12 years and older. The applicators' exposure was primarily influenced by the chemical formulation (GM = 11.3 microg/l for granular and 30.9 microg/l for liquid), and the number of loads applied. Repairing equipment, observed skin contact, and eating during the application were moderately associated TCP levels for those who applied liquid formulations. Estimated absorbed doses (microg chlorpyrifos/kg bodyweight) were calculated based on TCP excretion summed over the 4 postapplication days and corrected for pharmacokinetic recovery. The GM doses were 2.1, 0.7, and 1.0 microg/kg bodyweight for applicators, spouses, and children, respectively. Chlorpyrifos exposure to farm family members from the observed application was largely determined by the extent of contact with the mixing, loading, and application process.

Background: Epidemiologists often assess lifetime pesticide exposure by questioning participants about use of specific pesticides and associated work practices. Recently, Dosemeci and colleagues proposed an algorithm to estimate lifetime average exposure intensity from questionnaire information. We evaluated this algorithm against measured urinary pesticide concentrations for farmers who applied glyphosate (n = 48), 2,4-D (n = 34), or chlorpyrifos (n = 34)., Methods: Algorithm scores were calculated separately based on trained field observers' and farmers' evaluations of application conditions. Statistical analyses included nonparametric correlations, assessment of categorical agreement, and categorical evaluation of exposure distributions., Results: Based on field observers' assessments, there were moderate correlations between algorithm scores and urine concentrations for glyphosate (r = 0.47; 95% confidence interval [CI] = 0.21 to 0.66) and 2,4-D (0.45; 0.13 to 0.68). Correlations were lower when algorithm scores were based on participants' self-reports (for glyphosate, r = 0.23 [CI = -0.07 to 0.48]; for 2,4-D, r = 0.25 [-0.10 to 0.54]). For chlorpyrifos, there were contrasting correlations for liquid (0.42; 0.01 to 0.70) and granular formulations (-0.44; -0.83 to 0.29) based on both observers' and participants' inputs. Percent agreement in categorical analyses for the 3 pesticides ranged from 20% to 44%, and there was appreciable overlap in the exposure distributions across categories., Conclusions: Our results demonstrate the importance of collecting type of pesticide formulation and suggest a generic exposure assessment is likely to result in appreciable exposure misclassification for many pesticides.

Purpose: The Farm Family Exposure Study was initiated to characterize pesticide exposure to farm family members around the time of one pesticide application in a manner that will facilitate exposure assessment in epidemiologic studies of pesticides., Methods: A sample of farm families with children was recruited by randomly selecting farmers from lists of licensed pesticide applicators in Minnesota and South Carolina. Eligible families were selected from among those who planned to apply one of three chemicals, glyphosate, 2,4-D, or chlorpyrifos, as part of their normal operations. The applicator, spouse, and all children in the family ages 4-17 years were included in the study. The applicator and spouse completed self-administered questionnaires addressing demographics, farming practices and potential exposures to them and their children. Field observers documented the application, recorded application practices, equipment, potential exposures, and the presence of children or spouses in the immediate vicinity of pesticide activities. All study participants were asked to collect each urine void for 5 days, 1 day before through 3 days after the application. Pesticides were measured in 24-h composite urine samples with a one part per billion limit of detection., Results: Of 11,164 applicators screened, 994 families met the inclusion criteria. Of these, 95 families were enrolled. Enrollees were similar in most characteristics to their peers who were not participants in the study. In total, there were 106 applications, 10 of which involved more than one chemical. This resulted in urinary data for 48 farmers and spouses and their 79 children for glyphosate, 34 farmers and spouses and their 50 children for chlorpyrifos, and 34 farmers and spouses and their 53 children for 2,4-D. Compliance with the 24-h urine collection was particularly good for the adult participants. There were more missing samples for children than for adults, but overall compliance was high., Conclusion: The Farm Family Exposure Study should provide insights about pesticide exposure under real world conditions and thereby facilitate improved exposure assessment in epidemiologic studies of agricultural populations.

Epidemiologic studies rely on participants' recall to classify their exposure to specific pesticides. As exposure classification evolves, an important issue is whether the recall of pesticide application details can be used to derive measures of exposure intensity or cumulative exposure. A preliminary analysis of biomonitoring data for farmers before, during, and after a pesticide application suggests variation for different pesticides in the proportion with detectable urinary concentrations, urinary levels, and patterns of uptake and elimination. These findings, and the limited predictive modeling done to date, suggest that chemical-specific differences need to be considered in exposure classification schemes. An analysis of biomonitoring data for farm spouses and children found few with appreciable changes in the urinary concentration after a pesticide application. These findings point to the need to validate assumptions about exposures in studies of people who are not directly involved in pesticide application.

Objectives: The Farm Family Exposure Study was conducted to evaluate real-world pesticide exposure for farmers, spouses, and children., Methods: Eligible farm families from Minnesota and South Carolina were randomly selected from a roster of licensed private pesticide applicators. Eligibility required that the family include a farmer, spouse, and at least one child between the ages of 4 and 17 years, that the family live on the farm, that the farmer planned to apply one of the target pesticides [glyphosate, chlorpyrifos, 2,4-dichlorophenoxy acetic acid (2,4-D)] to at least 10 acres (4.1 hectares) of land within 1 mile (1.6 kilometers) of the house. For each family member, geometric means were calculated for 24-hour composite urinary samples, with a 1 ppb (part per billion) limit of detection, the day before, the day of, and for 3 days after the application., Results: For the farmers, the peak geometric mean concentrations were 3 ppb for glyphosate, 64 ppb for 2,4-D, and 19 ppb for the primary chlorpyrifos metabolite. For the spouses and children, the percentage with detectable values varied by chemical, although the average values for each chemical did not vary during the study period. The applicators had the highest urine pesticide concentrations, children had much lower values, and spouses had the lowest values. Exposure to family members was largely, though not exclusively, determined by the degree of direct contact with the application process. The exposure profile varied for the three chemicals for each family member., Conclusions: The data of this study indicate the importance of chemical-specific considerations when exposure assessments are planned in epidemiologic studies.

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.

Glyphosate is among the pesticides most frequently reported to the California EPA Pesticide Illness Surveillance Program. We analyzed glyphosate-related calls to the Pesticide Illness Surveillance Program in order to assess the number of reports involving systemic symptoms and to better understand the nature and severity of reported cases. Data on glyphosate and other pesticides are available for the years 1982-1997 including: type of exposure (agricultural/other); target organ(s) affected (skin/eye/respiratory/systemic); exposure(s); an assessment of causal relationship (possible, probable, or definite); and limited medical text. Of 815 total glyphosate calls, most involved topical irritation of the eye (n = 399), skin (n = 250), upper airway (n = 7), or combinations of these sites (n = 32) without systemic symptoms. Of the 187 systemic cases, only 22 had symptoms recorded as probably or definitely related to glyphosate exposure alone. The reported symptoms were not severe, expected to be limited in duration, and frequently inconsistent with the route of exposure and/or previous experience with glyphosate. We conclude that call volume is not a reliable indicator of the actual incidence or severity of glyphosate-related incidents in California.

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.

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.

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.

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.

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.

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.

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.

The concept of worker notification has evolved over the years to a prevailing view that workers should be notified of all epidemiologic studies that make use of their medical information. To adequately communicate health information to workers, epidemiologists must consider the intended audience along with its need for risk information that is scientifically valid and clearly outlines areas of uncertainty. This goal is facilitated by full disclosure to workers of information pertinent to the planning, conduct, and interpretation of research efforts. Subjectivity in choosing unanticipated research findings for inclusion in worker notifications may permit bias toward a personal viewpoint, but this can be minimized by prestudy agreement on appropriate criteria for selecting which research findings to communicate. Epidemiologic theory and principles of causal inference should guide the development of appropriate criteria. The timeliness of worker communications has received limited attention, and workers have often been the "last to know" about important studies. This may influence workers' receptivity to the risk message. Sponsoring organizations should ensure that an acceptable communications plan is included in research protocols and that the plan accords priority to notifying workers about study results.

A historical cohort study of refinery and chemical plant workers, originally observed from 1970 to 1977, was updated to the end of 1982. This cohort included 25,321 active, retired, and terminated workers at the Exxon refineries and chemical plants in Baton Rouge, Louisiana; Baytown, Texas; and Bayway/Bayonne, New Jersey. An emphasis was placed on the cancers previously reported to be increased in at least one petrochemical worker population. The population included a high proportion of retirees, providing adequate work experience and latency to evaluate risks associated with employment. Vital status was determined for 98.3% of the population and death certificates were obtained for 99.9% of the decedents. Mortality for "all causes of death" (standardised mortality ratio (SMR) = 89, 95% confidence interval (95% CI) 87-91) and for "all cancers" (SMR = 94, 95% CI 89-100) were lower than expected based on state rates. History of cigarette smoking collected from individual medical records and summarised work histories were used for subgroup analyses. There was no indication that cancers of primary interest were increased; however, blue collar workers at one plant had raised rates of kidney cancer (SMR = 246, 95% CI 146-390), which may require further evaluation.

The process of conducting and ensuring the quality of epidemiologic studies has received little attention in the published literature. In concert with the variable nature of observational research, this has created a perceived need for guidelines relating to the conduct and reporting of epidemiologic studies. Amendments to two recent government regulations stipulate that epidemiologic studies should be carried out in accordance with as yet unspecified guidelines. Yet, guidelines alone will not improve the quality of epidemiologic studies. A more comprehensive approach is envisioned with reference to specific quality improvement principles used in industry.

To follow-up on a proportional mortality study that showed significantly elevated proportional mortality ratios for lung cancer and a subgroup of nonmalignant respiratory diseases, we conducted a cohort mortality study (1950-1987) among 4627 employees of a metal components manufacturing facility. The findings of this study showed lower than expected mortality from all causes of death and all cancers. However, lung cancer mortality was significantly elevated (standardized mortality ratio = 131, 95% confidence interval (102-165), owing to elevated mortality among hourly workers (standardized mortality ratio = 153, 95% confidence interval 118-195). Hourly workers also showed a significantly elevated rate for the residual category "other nonmalignant respiratory disease" (standardized mortality ratio = 170, 95% confidence interval 110-251) and a significant deficit of leukemia (standardized mortality ratio = 16, 95% confidence interval 0-87). Analyses by duration of employment did not show significant trends for any cause of death. Smoking information was not available, but several indirect methods were used to estimate the potential confounding effect of smoking.

To assess potential etiologic factors among a population of Texas polypropylene workers previously found to have an excess of colorectal cancer (concentrated among mechanical and process workers), the authors conducted an adenomatous polyp case-control study. Cases (n = 24) were workers found to have adenomatous polyps during a company-sponsored colorectal cancer screening program, while controls (n = 72) were workers found to be free of polyps. Exposure assessment utilized a thorough industrial hygiene and toxicologic review of operations in conjunction with work activity interviews of cases and controls to develop chemical-specific exposure scores weighted by time, exposure level, and frequency of exposure. Stratified analyses and logistic regression found that cases tended to have higher exposure to pre-extrusion polymer plus additives (odds ratio (OR) = 2.6, 90% confidence interval (CI) 1.1-6.3) and higher exposure to certain finishing additives (OR = 4.8, 90% CI 1.5-15.3). Analyses by job category or area of the plant did not indicate additional risk factors. The exposures identified in this study are discussed in light of the available toxicologic data on these and related compounds. The need for confirmatory experimental and epidemiologic studies is noted.

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.

Our recent study reported a colorectal cancer excess among workers involved in the manufacture of polypropylene. To follow up on this finding, we initiated a study of colorectal cancer incidence among polypropylene pilot plant workers within the same company. The purpose of this investigation was to determine whether colorectal cancer incidence was elevated among workers who may have had exposures similar to those experienced on the commercial production unit. The study population included 183 employees who worked at least 6 months on either of two pilot plants. Overall, there were three observed colorectal cases v. 3.3 expected (standardized incidence ratio = 0.9, 90% confidence interval 0.3 to 2.3). Analyses for the process, mechanic, and laboratory subgroup showed rates consistent with expected values (3 observed, 2.8 expected; standardized incidence ratio = 1.1, 90% confidence interval 0.3 to 2.8). Analyses by duration of employment and latency did not show patterns consistent with the colorectal cancer excess previously reported. The likelihood of lower or different exposures on the pilot plant than would be found on commercial production units is discussed along with the need for studies of workers in other polypropylene manufacturing environments.

Little is known about reasons for participation in occupational colorectal cancer screening programs using flexible sigmoidoscopy and barium enema. To assess this issue, telephone interviews were conducted with a sample of participants and nonparticipants in such a program. This study was a follow-up of a previous assessment of factors that affected screening participation among a cohort found to have elevated rates of colorectal cancer. The major finding of this survey was that the absence of symptoms was the major reason for nonparticipation, although both participants and nonparticipants expressed the view that early detection was important and that colorectal cancer could be cured if treated at an early stage. Based on the results of this study and of other surveys, educational messages to workers explaining the asymptomatic development of colorectal cancer should be tried as a way of increasing participation.