Body Mass Index, Diabetes and Intrahepatic Cholangiocarcinoma Risk: The Liver Cancer Pooling Project and Meta-analysis.

OBJECTIVE: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature. DESIGN: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017. RESULTS: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24-2.12] and an 81% (HR = 1.81, 95% CI: 1.33-2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR) = 1.49, 95% CI: 1.32-1.70; n = 4 studies; I2 = 0%]. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31-1.78; n = 6 studies). While we noted heterogeneity between studies (I2 = 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation. CONCLUSIONS: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

Pesticide exposures and the risk of multiple myeloma in men: An analysis of the North American Pooled Project.

Multiple myeloma (MM) has been consistently linked with agricultural activities, including farming and pesticide exposures. Three case-control studies in the United States and Canada were pooled to create the North American Pooled Project (NAPP) to investigate associations between pesticide use and haematological cancer risk. This analysis used data from 547 MM cases and 2700 controls. Pesticide use was evaluated as follows: ever/never use; duration of use (years); and cumulative lifetime-days (LD) (days/year handled × years of use). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, province/state of residence, use of proxy respondents and selected medical conditions. Increased MM risk was observed for ever use of carbaryl (OR = 2.02, 95% CI = 1.28-3.21), captan (OR = 1.98, 95% CI = 1.04-3.77) and DDT (OR = 1.44, 95% CI = 1.05-1.97). Using the Canadian subset of NAPP data, we observed a more than threefold increase in MM risk (OR = 3.18, 95% CI = 1.40-7.23) for ≤10 cumulative LD of carbaryl use. The association was attenuated but remained significant for >10 LD of carbaryl use (OR = 2.44; 95% CI = 1.05-5.64; ptrend = 0.01). For captan, ≤17.5 LD of exposure was also associated with a more than threefold increase in risk (OR = 3.52, 95% CI = 1.32-9.34), but this association was attenuated in the highest exposure category of >17.5 LD (OR = 2.29, 95% CI = 0.81-6.43; ptrend = 0.01). An increasing trend (ptrend = 0.04) was observed for LD of DDT use (LD > 22; OR = 1.92, 95% CI = 0.95-3.88). In this large North American study of MM and pesticide use, we observed significant increases in MM risk for use of carbaryl, captan and DDT.

Body-mass index and mortality among 1.46 million white adults.

BACKGROUND: A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. METHODS: We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). RESULTS: The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. CONCLUSIONS: In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.

Occupational exposure to formaldehyde and alterations in lymphocyte subsets.

BACKGROUND: Formaldehyde is used in many occupational settings, most notably in manufacturing, health care, and embalming. Formaldehyde has been classified as a human carcinogen, but its mechanism of action remains uncertain. METHODS: We carried out a cross-sectional study of 43 formaldehyde-exposed workers and 51 unexposed age and sex-matched controls in Guangdong, China to study formaldehyde's early biologic effects. To follow up our previous report that the total lymphocyte count was decreased in formaldehyde-exposed workers compared with controls, we evaluated each major lymphocyte subset (i.e., CD4(+) T cells, CD8(+) T cells, natural killer [NK] cells, and B cells) and T cell lymphocyte subset (CD4(+) naïve and memory T cells, CD8(+) naïve and memory T cells, and regulatory T cells). Linear regression of each subset was used to test for differences between exposed workers and controls, adjusting for potential confounders. RESULTS: Total NK cell and T cell counts were about 24% (P = 0.037) and 16% (P = 0.0042) lower, respectively, among exposed workers. Among certain T cell subsets, decreased counts among exposed workers were observed for CD8(+) T cells (P = 0.026), CD8(+) effector memory T cells (P = 0.018), and regulatory T cells (CD4(+) FoxP3(+) : P = 0.04; CD25(+) FoxP3(+) : P = 0.008). CONCLUSIONS: Formaldehyde-exposed workers experienced decreased counts of NK cells, regulatory T cells, and CD8(+) effector memory T cells; however, due to the small sample size; these findings need to be confirmed in larger studies.

Impact of pesticide exposure misclassification on estimates of relative risks in the Agricultural Health Study.

BACKGROUND: The Agricultural Health Study (AHS) is a prospective study of licensed pesticide applicators and their spouses in Iowa and North Carolina. We evaluate the impact of occupational pesticide exposure misclassification on relative risks using data from the cohort and the AHS Pesticide Exposure Study (AHS/PES). METHODS: We assessed the impact of exposure misclassification on relative risks using the range of correlation coefficients observed between measured post-application urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) and a chlorpyrifos metabolite and exposure estimates based on an algorithm from 83 AHS pesticide applications. RESULTS: Correlations between urinary levels of 2,4-D and a chlorpyrifos metabolite and algorithm estimated intensity scores were about 0.4 for 2,4-D (n=64), 0.8 for liquid chlorpyrifos (n=4) and 0.6 for granular chlorpyrifos (n=12). Correlations of urinary levels with kilograms of active ingredient used, duration of application, or number of acres treated were lower and ranged from -0.36 to 0.19. These findings indicate that a priori expert-derived algorithm scores were more closely related to measured urinary levels than individual exposure determinants evaluated here. Estimates of potential bias in relative risks based on the correlations from the AHS/PES indicate that non-differential misclassification of exposure using the algorithm would bias estimates towards the null, but less than that from individual exposure determinants. CONCLUSIONS: Although correlations between algorithm scores and urinary levels were quite good (ie, correlations between 0.4 and 0.8), exposure misclassification would still bias relative risk estimates in the AHS towards the null and diminish study power.

Heterocyclic aromatic amine pesticide use and human cancer risk: results from the U.S. Agricultural Health Study.

Imazethapyr, a heterocyclic aromatic amine, is a widely used crop herbicide first registered for use in the United States in 1989. We evaluated cancer incidence among imazethapyr-exposed pesticide applicators enrolled in the Agricultural Health Study (AHS). The AHS is a prospective cohort of 57,311 licensed pesticide applicators in the U.S., enrolled from 1993-1997. Among the 49,398 licensed pesticide applicators eligible for analysis, 20,646 applicators reported use of imazethapyr and 2,907 incident cancers developed through 2004. Imazethapyr exposure was classified by intensity-weighted lifetime exposure days calculated as [years of use x days per year x intensity level]. Poisson regression analysis was used to evaluate the relationship between imazethapyr exposure and cancer incidence. We found significant trends in risk with increasing lifetime exposure for bladder cancer (p for trend 0.01) and colon cancer (p for trend 0.02). Rate ratios (RRs) were increased by 137% for bladder cancer and 78% for colon cancer when the highest exposed were compared to the nonexposed. The excess risk for colon cancer was limited to proximal cancers, (RR = 2.73, 95% confidence intervals 1.42, 5.25, p for trend 0.001). No association was observed for prostate, lung, rectum, kidney, oral, pancreas, lymphohematopoietic cancers or melanoma. These findings provide new evidence that exposure to aromatic amine pesticides may be an overlooked exposure in the etiology of bladder and colon cancer. The use of imazethapyr and other imidazolinone compounds should continue to be evaluated for potential risk to humans.

Sleep apnea and pesticide exposure in a study of US farmers.

INTRODUCTION: Carbamate and organophosphate pesticides inhibit acetylcholinesterase, and poisoning leads to respiratory depression. Thus, involvement in sleep apnea is plausible, but no data exist at lower levels of exposure. Other pesticides could impact sleep apnea by different mechanisms but have not been studied. Our study examines the associations between pesticide exposure and sleep apnea among pesticide applicators from a US farming population. PARTICIPANTS AND METHODS: We analyzed data from 1569 male pesticide applicators, mostly farmers, from an asthma case-control study nested within the prospective Agricultural Health Study. On questionnaires, participants reported use of specific pesticides and physician diagnosis plus prescribed treatments for sleep apnea. We used multivariable logistic regression to estimate associations between ever use of 63 pesticides and sleep apnea (234 cases, 1335 noncases). RESULTS: The most notable association was for carbofuran, a carbamate (100 exposed cases, odds ratio 1.83, 95% confidence interval 1.34-2.51, P=.0002). Carbofuran use began before reported onset of sleep apnea in all cases. DISCUSSION: This study adds to the known adverse health outcomes of exposure to carbofuran, a pesticide canceled in the United States in 2009 for most agricultural purposes but persists in the environment and remains in use in some other countries. CONCLUSIONS: We conducted the first epidemiological study investigating the association of pesticide exposure and sleep apnea. Our results in a male agricultural population suggests that exposure to carbofuran is positively associated with sleep apnea.

Tobacco Use and Cancer Risk in the Agricultural Health Study.

Background: Cigarettes are well known to cause cancer, but less is known about the risks of other tobacco products and use of more than one product.Methods: We examined cancer incidence in relation to exclusive use of six tobacco products [cigarettes, other combustibles (pipe, cigar, cigarillo), and smokeless tobacco (chewing tobacco, snuff)] in the Agricultural Health Study. We also examined the added cancer risks associated with use of cigarettes and other tobacco products.Results: In our study population of 84,015, ever use of smokeless tobacco was higher than the general United States population, whereas cigarette use was lower and other combustible product use was about the same. The strongest associations for exclusive ever use were for lung cancer [cigarettes HR = 15.48; 95% confidence interval (CI), 11.95-20.06; other combustible tobacco HR = 3.44; 95% CI, 1.53-7.71; smokeless tobacco HR = 2.21; 95% CI, 1.11-4.42]. Compared with exclusive cigarette smokers, cigarette smokers who additionally ever-used another combustible product had higher risks of smoking-related cancers (HR = 1.16; 95% CI, 1.04-1.30), especially among those who smoked cigarettes for more than 15 years.Conclusions and Impact: Cigarette smokers who additionally ever used smokeless tobacco had cancer risks similar to exclusive cigarette smokers. Users of cigarettes and other combustible tobacco may have higher risks of certain cancers than exclusive cigarette users. Cancer Epidemiol Biomarkers Prev; 26(5); 769-78. ©2016 AACR.

Neurologic symptoms associated with cattle farming in the agricultural health study.

OBJECTIVE: Infection with Campylobacter jejuni, a bacterium carried by poultry and livestock, is the most frequently identified antecedent to the autoimmune neurologic condition Guillain-Barré Syndrome. We used Agricultural Health Study data to assess whether cattle farming was associated with prevalence of neurologic symptoms. METHODS: Prevalence of self-reported symptoms in cattle farmers (n = 8878) was compared with farmers who did not work with animals (n = 7462), using multivariate regression. RESULTS: Prevalence of numbness and weakness were increased for beef and dairy farmers compared with the reference group (P < 0.0001). Of cattle farmers, 48% did not report raising other animal species, and prevalence of numbness and weakness were also increased in this subgroup compared with the reference group (P < 0.02). CONCLUSIONS: Occupational exposure to cattle was associated with increased prevalence of self-reported symptoms associated with peripheral neuropathy.

Neurologic symptoms associated with raising poultry and swine among participants in the Agricultural Health Study.

OBJECTIVE: Guillain-Barré Syndrome (GBS) is the leading cause of acute peripheral neuropathy worldwide, often associated with recent foodborne infection with Campylobacter jejuni. In this cross-sectional analysis of data from the Agricultural Health Study, we tested whether swine and poultry exposure were associated with increased prevalence of GBS-like neurologic symptoms. METHODS: Using multivariate analysis, we tested the symptoms such as numbness and weakness, relevant to inflammatory peripheral neuropathies, among farmers with self-reported occupational poultry or swine exposure compared with farmers who reported no occupational animal exposure. RESULTS: Among swine farmers/workers, prevalence of weakness and numbness were increased (P < 0.05). Among poultry farmers/workers, prevalence of weakness and numbness were increased, but increased prevalence of weakness was not statistically significant. CONCLUSIONS: Occupational contact with live poultry or swine, potentially related to C. jejuni exposure, was associated with increased reporting of GBS-like symptoms.

Occupational exposure to formaldehyde, hematotoxicity, and leukemia-specific chromosome changes in cultured myeloid progenitor cells.

There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing, and other industries. Epidemiologic studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on the ability of formaldehyde to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures.

Epidemiologic studies in agricultural populations: observations and future directions.

This paper reviews epidemiologic studies of cancer among agricultural populations to identify possible associations and to provide a focus for future investigations. Meta-analyses of mortality surveys of farmers find excesses of several cancers, including connective tissue, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma and cancers of the skin, stomach, and brain, and deficits for total mortality, heart disease, total cancer, and cancers of the esophagus, colon, lung, and bladder. Meta-analyses of studies of individual cancers also support these findings, indicating a need to identify exposures and lifestyle factors that might account for this mortality pattern. Although cancer studies of other occupations that might have pesticide exposures in common with farmers show some similarities with observations among farmers, the overall patterns are quite different. This suggests that pesticides are not likely to fully explain the cancer and other disease patterns observed among farmers. Because exposures vary by type of farm operation, exposures for individual farmers can differ considerably. Studies in the future need to focus on the full range of exposures to fully understand the cancer pattern in farmers.

Exposure to atrazine and selected non-persistent pesticides among corn farmers during a growing season.

The aim was to develop quantitative estimates of farmers' pesticide exposure to atrazine and to provide an overview of background levels of selected non-persistent pesticides among corn farmers in a longitudinal molecular epidemiologic study. The study population consisted of 30 Agricultural Health Study farmers from Iowa and 10 non-farming controls. Farmers completed daily and weekly diaries from March to November in 2002 and 2003 on pesticide use and other exposure determinants. Urine samples were collected at 10 time points relative to atrazine application and other farming activities. Pesticide exposure was assessed using urinary metabolites and diaries. The analytical limit of detection (LOD) ranged between 0.1 and 0.2 microg/l for all pesticide analytes except for isazaphos (1.5 microg/l) and diazinon (0.7 microg/l). Farmers had higher geometric mean urinary atrazine mercapturate (AZM) values than controls during planting (1.1 vs