John F. Acquavella

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.

Toxicology and Epidemiology of 1,3-Butadiene

Abstract1,3-Butadiene is a colorless, volatile gas that has high-volume usage in the synthesis of polybutadiene, styrene-butadiene, and other polymers. Due to its volatile nature, uptake of butadiene occurs almost exclusively by inhalation and absorption through the respiratory system. Sources of exposure include production, transport, and end-use processes in industrial settings or environmental exposures through automotive fuel, fossil fuel combustion, and cigarette smoke. Chronic inhalation studies established that butadiene is carcinogenic in B6C3F1 mice and Sprague-Dawley rats, and that mice are considerably more sensitive than rats. For the most part, epidemiologic studies for butadiene have been equivocal, although a recent retrospective follow-up study of styrene-butadiene rubber workers provides the first internally consistent evidence of a relationship between butadiene exposure and leukemia. The mechanism(s) of butadiene-induced carcinogenicity are not entirely understood but are thought to inv...

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.

Biomonitoring of 2,4-Dichlorophenoxyacetic Acid Exposure and Dose in Farm Families

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 μ g/L for applicators, below the limit of detection, and 1.2 μ g/L for spouses, and 1.5 and 2.9 μ g/L for children. The younger children (4–11 years of age) had higher median post-application concentrations than the older children (≥ 12 years of age) (6.5 vs. 1.9 μ g/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 ≥ 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.

Biomonitoring of exposure in farmworker studies.

Although biomonitoring has been used in many occupational and environmental health and exposure studies, we are only beginning to understand the complexities and uncertainties involved with the biomonitoring process—from study design, to sample collection, to chemical analysis—and with interpreting the resulting data. We present an overview of concepts that should be considered when using biomonitoring or biomonitoring data, assess the current status of biomonitoring, and detail potential advancements in the field that may improve our ability to both collect and interpret biomonitoring data. We discuss issues such as the appropriateness of biomonitoring for a given study, the sampling time frame, temporal variability in biological measurements to nonpersistent chemicals, and the complex issues surrounding data interpretation. In addition, we provide recommendations to improve the utility of biomonitoring in farmworker studies.

Agreement of pesticide biomarkers between morning void and 24-h urine samples from farmers and their children.

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.

Epidemiologic Studies of Occupational Pesticide Exposure and Cancer: Regulatory Risk Assessments and Biologic Plausibility

Epidemiologic studies frequently show associations between self-reported use of specific pesticides and human cancers. These findings have engendered debate largely on methodologic grounds. However, biologic plausibility is a more fundamental issue that has received only superficial attention. The purpose of this commentary is to review briefly the toxicology and exposure data that are developed as part of the pesticide regulatory process and to discuss the applicability of this data to epidemiologic research. The authors also provide a generic example of how worker pesticide exposures might be estimated and compared to relevant toxicologic dose levels. This example provides guidance for better characterization of exposure and for consideration of biologic plausibility in epidemiologic studies of pesticides.

Cancer incidence among alachlor manufacturing workers

A historical cohort study was conducted to evaluate cancer incidence among chemical workers with occupational and environmental exposure to alachlor, the active ingredient in a family of pre-emergent acetanilide herbicides. The study followed 943 workers with at least 1 year of cumulative employment at the Monsanto plant in Muscatine, Iowa, from startup of the alachlor manufacturing process in March 1968 through December 1990. Approximately 96% of all workers were successfully traced to determine their last known residence and cancer status. Eighteen workers were diagnosed with cancer during the follow-up period, based on pathology information from the statewide cancer registry maintained by the State Health Registry of Iowa. The standardized incidence ratio for all cancers was 1.5 (95% CI 0.9-2.4) for all workers exposed to alachlor, which was due primarily to elevated rates for colorectal cancer and chronic myeloid leukemia. Workers with 5 or more years in estimated high alachlor exposure jobs had elevated rates of colorectal cancer (3 cases, SIR = 5.2, 95% CI 1.1-15.1). Interpretation of the study results is limited by the small size of the study population, minimal length of follow-up, and current information concerning alachlor metabolism in primates and humans. Nonetheless, the findings suggest the need for continued evaluation of this and other alachlor-exposed cohorts.

Exposure misclassification in studies of agricultural pesticides insights from biomonitoring

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.

Exposure to Butadiene and Lymphatic and Hematopoietic Cancer

Several follow-up studies have assessed lymphatic and hematopoietic cancer (LHC) among workers with potential exposure to 1,3-butadiene. These investigations of the styrene-butadiene rubber and butadiene manufacturing industries include 17,448 subjects with an average of 22 years of follow-up. When the results of the studies are combined, the total number of observed leukemia deaths is 36, compared with 34.2 expected. The standardized mortality ratio is 1.05, with a 95% confidence interval of 0.74–1.46. These null data are compatible with, at most, a weak positive association of butadiene with leukemia. There is little evidence of an association with other forms of LHC among styrene-butadiene rubber workers (55 observed/50.1 expected deaths). Only one study has evaluated directly the relation between estimates of butadiene exposure and leukemia, and this investigation reports a positive association. The result, however, cannot be interpreted as causal, because there is no satisfactory explanation for the marked discrepancy between this case-control study and a null follow-up study based on the same subjects. Overall, the epidemiologic evidence does not provide persuasive evidence that butadiene exposure causes LHC.