Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the Liver Cancer Pooling Project.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women. METHODS: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799,500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248). RESULTS: Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22-5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82-1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility. CONCLUSIONS: The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study.

Investing in prospective cohorts for etiologic study of occupational exposures.

Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures.

Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study.

Although specific pesticides have been associated with wheeze in farmers, little is known about pesticides and asthma. Data from 19,704 male farmers in the Agricultural Health Study were used to evaluate lifetime use of 48 pesticides and prevalent adult-onset asthma, defined as doctor-diagnosed asthma after the age of 20 yrs. Asthma cases were categorised as allergic (n = 127) and nonallergic (n = 314) based on their history of eczema or hay fever. Polytomous logistic regression, controlling for age, state, smoking and body mass, was used to assess pesticide associations. High pesticide exposure events were associated with a doubling of both allergic and nonallergic asthma. For ever-use, 12 individual pesticides were associated with allergic asthma and four with nonallergic asthma. For allergic asthma, coumaphos (OR 2.34; 95% CI 1.49-3.70), heptachlor (OR 2.01; 95% CI 1.30-3.11), parathion (OR 2.05; 95% CI 1.21-3.46), 80/20 mix (carbon tetrachloride/carbon disulfide) (OR 2.15; 95% CI 1.23-3.76) and ethylene dibromide (OR 2.07; 95% CI 1.02-4.20) all showed ORs of >2.0 and significant exposure-response trends. For nonallergic asthma, DDT (dichlorodiphenyltrichloroethane) showed the strongest association (OR 1.41; 95% CI 1.09-1.84), but with little evidence of increasing asthma with increasing use. Current animal handling and farm activities did not confound these results. There was little evidence that allergy alone was driving these associations. In conclusion, pesticides may be an overlooked contributor to asthma risk among farmers.

Rhinitis associated with pesticide exposure among commercial pesticide applicators in the Agricultural Health Study.

OBJECTIVES: Rhinitis is common, but the risk factors are not well described. To investigate the association between current rhinitis and pesticide use, we used data from 2245 Iowa commercial pesticide applicators in the Agricultural Health Study. METHODS: Using logistic regression models adjusted for age, education and growing up on a farm, we evaluated the association between current rhinitis and 34 pesticides used in the past year. RESULTS: 74% of commercial pesticide applicators reported at least one episode of rhinitis in the past year (current rhinitis). Five pesticides used in the past year were significantly positively associated with current rhinitis: the herbicides 2,4-D, glyphosate and petroleum oil, the insecticide diazinon and the fungicide benomyl. The association for 2,4-D and glyphosate was limited to individuals who used both in the past year (OR 1.42, 95% CI 1.14 to 1.77). Both petroleum oil and diazinon showed consistent evidence of an association with rhinitis, based on both current use and exposure-response models. We saw no evidence of confounding by common agricultural rhinitis triggers such as handling grain or hay. CONCLUSIONS: Exposure to pesticides may increase the risk of rhinitis.

Incident diabetes and pesticide exposure among licensed pesticide applicators: Agricultural Health Study, 1993-2003.

Exposure to certain environmental toxicants may be associated with increased risk of developing diabetes. The authors' aim was to investigate the relation between lifetime exposure to specific agricultural pesticides and diabetes incidence among pesticide applicators. The study included 33,457 licensed applicators, predominantly non-Hispanic White males, enrolled in the Agricultural Health Study. Incident diabetes was self-reported in a 5-year follow-up interview (1999-2003), giving 1,176 diabetics and 30,611 nondiabetics for analysis. Lifetime exposure to pesticides and covariate information were reported by participants at enrollment (1993-1997). Using logistic regression, the authors considered two primary measures of pesticide exposure: ever use and cumulative lifetime days of use. They found seven specific pesticides (aldrin, chlordane, heptachlor, dichlorvos, trichlorfon, alachlor, and cyanazine) for which the odds of diabetes incidence increased with both ever use and cumulative days of use. Applicators who had used the organochlorine insecticides aldrin, chlordane, and heptachlor more than 100 lifetime days had 51%, 63%, and 94% increased odds of diabetes, respectively. The observed association of organochlorine and organophosphate insecticides with diabetes is consistent with results from previous human and animal studies. Long-term exposure from handling certain pesticides, in particular, organochlorine and organophosphate insecticides, may be associated with increased risk of diabetes.

Fungicide application practices and personal protective equipment use among orchard farmers in the agricultural health study.

Fungicides are routinely applied to deciduous tree fruits for disease management. Seventy-four private orchard applicators enrolled in the Agricultural Health Study participated in the Orchard Fungicide Exposure Study in 2002-2003. During 144 days of observation, information was obtained on chemicals applied and applicator mixing, application, personal protective, and hygiene practices. At least half of the applicators had orchards with <100 trees. Air blast was the most frequent application method used (55%), followed by hand spray (44%). Rubber gloves were the most frequently worn protective equipment (68% mix; 59% apply), followed by respirators (45% mix; 49% apply), protective outerwear (36% mix; 37% apply), and rubber boots (35% mix; 36% apply). Eye protection was worn while mixing and applying on only 35% and 41% of the days, respectively. Bivariate analyses were performed using repeated logistic or repeated linear regression. Mean duration of mixing, pounds of captan applied, total acres sprayed, and number of tank mixes sprayed were greater for air blast than for hand spray (p < 0.05). Spraying from a tractor/vehicle without an enclosed cab was associated with wearing some type of coverall (p < 0.05). Applicators often did not wash their hands after mixing (77%), a finding not explained by glove use. Glove use during mixing was associated with younger age, while wearing long-sleeve shirts was associated with older age (p < 0.05 each). Self-reported unusually high fungicide exposures were more likely on days applicators performed repairs (p < 0.05). These data will be useful for evaluating fungicide exposure determinants among orchard applicators.

Neurologic symptoms in licensed pesticide applicators in the Agricultural Health Study.

Exposure to high levels of many pesticides has both acute and long-term neurologic consequences, but little is known about the neurotoxicity of chronic exposure to moderate pesticide levels. We analysed cross-sectional data from 18 782 Caucasian, male, licensed pesticide applicators, enrolled in the Agricultural Health Study from 1993 to 1997. Applicators provided information on lifetime pesticide use, and 23 neurologic symptoms typically associated with pesticide intoxication. Increased risk of experiencing >/=10 symptoms during the year before enrollment was associated with cumulative pesticide use, personally mixing or applying pesticides, pesticide-related medical care, diagnosed pesticide poisoning, and events involving high personal pesticide exposure. Greatest risk was associated with use of organophosphate and organochlorine insecticides. Results were similar after stratification by pesticide use during the year before enrollment, or exclusion of applicators with a history of pesticide poisoning, or high-exposure events. Use of pesticide application methods likely to involve high personal exposure was associated with greater risk. Groups of symptoms reflecting several neurologic domains, including affect, cognition, autonomic and motor function, and vision, were also associated with pesticide exposure. These results suggest that neurologic symptoms are associated with cumulative exposure to moderate levels of organophosphate and organochlorine insecticides, regardless of recent exposure or history of poisoning.

High pesticide exposure events among farmers and spouses enrolled in the Agricultural Health Study.

We completed a nested case-control analysis of factors associated with reporting a high pesticide exposure event (HPEE) by pesticide applicators and spouses during the five years since enrollment in the Agricultural Health Study (AHS). Cases and controls were identified from the 16,415 private pesticide applicators and 14,045 spouses with completed five-year follow-up interviews as of October 2000. Among the applicators, 306 cases with at least one HPEE in the five years since enrollment and 612 controls, randomly selected from those without a reported HPEE, were identified for analysis. Among the spouses, 63 cases were identified and 126 controls were selected. Risk for a new HPEE was increased among applicators reporting at enrollment ever having an HPEE with an odds ratio (OR) of 3.8 (95% CI: 2.7, 5.3). Compared to applicators who applied pesticides fewer than 5 days per year, the ORs ranged from 1.4 (95% CI: 0.9, 2.2) for 6 to 10 days per year to 2.2 (95% CI: 1.4, 3.6) for more than 20 application days per year. The incidence of HPEE among Iowa applicators was much greater (8.8/1000 applicators) than among North Carolina applicators (2.0/1000). Spouses reported fewer HPEEs compared to applicators (2/1000 spouses). Overall, the observed risk factors for new HPEEs among applicators are similar to risk factors observed in previous cross-sectional analyses of HPEE history. Further, only 13% of applicators and 22% of spouses with symptoms resulting from HPEE sought medical care, suggesting that pesticide poisoning surveillance data may seriously underreport the frequency of such events.

Animal production and wheeze in the Agricultural Health Study: interactions with atopy, asthma, and smoking.

BACKGROUND: Exposure to animals, their feeds, and by-products contribute to respiratory symptoms among farmers. AIMS: To investigate the role of animal exposures and wheeze, and to assess whether their impact differs among susceptible subgroups, including atopics, asthmatics, and smokers. METHODS: Using the Agricultural Health Study, a cohort of pesticide applicators in Iowa and North Carolina enrolled in 1994-97, wheeze associated with animal production was evaluated and interactions among susceptible subgroups assessed. Logistic regression models were used to examine risk factors for wheeze in the past year among 20 468 farmers. RESULTS: Individuals raising animals requiring direct contact had the highest odds ratios (OR) for wheeze (OR(dairy) = 1.26; OR(eggs) = 1.70). A significant dose response was observed for both the number of poultry and the number of livestock on the farm. Farmers who performed veterinary procedures on a daily basis had an OR of 1.51. The odds of wheeze associated with poultry production was greater among atopic than non-atopic individuals. Milking cows daily increased the odds of wheeze in all individuals, with the largest association observed among atopic asthmatic individuals. The impact of dairy, poultry, and egg production varied among smoking groups. Past smokers had the highest odds ratios, followed by never smokers, and then current smokers. The OR(eggs) was 2.88 among past smokers but only 1.46 for never smokers. The OR(eggs) for current smokers of 0.80 might reflect self selection of exposure among smokers. CONCLUSIONS: Results are consistent with animal production and respiratory symptoms, and suggest that subgroups may respond differently to exposure.

Risk factors for agricultural injury: a case-control analysis of Iowa farmers in the Agricultural Health Study.

The purpose of this case-control study nested in the Agricultural Health Study was to assess risk factors for agricultural injury among a large group of Iowa farmers. A questionnaire sent to 6,999 farmers identified 431 cases who had a farm work-related injury requiring medical advice/treatment in the previous year and 473 controls who had no injury in the previous year. We assessed several potential risk factors for injury. A multiple logistic regression analysis showed significant associations between farm work-related injury and weekly farming work hours (> or = 50 hours/week) (OR = 1.65; 95% CI = 1.23-2.21), the presence of large livestock (OR = 1.77; 95% CI = 1.24-2.51), education beyond high school (OR = 1.61; 95% CI = 1.21-2.12), regular medication use (OR = 1.44; 95% CI = 1.04-1.96), wearing a hearing aid (OR = 2.36; 95% CI = 1.07-5.20), and younger age. These results confirm the importance of risk factors identified in previous analytic studies and suggest directions for future research in preventive intervention strategies to reduce farm work-related injuries.

210Po implanted in glass surfaces by long term exposure to indoor radon.

Recent epidemiologic investigations of the relationship between residential radon gas exposure and lung cancer relied on contemporary radon gas measurements to estimate past radon gas exposures. Significant uncertainties in these exposure estimates can arise from year-to-year variation of indoor radon concentrations and subject mobility. Surface implanted 210Po has shown potential for improving retrospective radon gas exposure estimates. However, in previous studies, the ability of implanted 210Po activity to reconstruct cumulative radon gas exposure was not tested because glass was not available from homes with known radon-gas concentration histories. In this study, we tested the validity of the retrospective radon gas reconstruction using implanted 210Po surface activity by measuring glass surfaces from homes whose annual-average radon gas concentrations had been measured almost every year during two decades. Regression analysis showed a higher correlation between measured surface activity and cumulative radon gas exposure in these homes (R2>0.8) than was observed in homes where only contemporary radon gas measurements were available. The regression slope (0.57 ky m(-1)) was consistent with our earlier retrospective results. Surface activity measurements were as reliable for retrospective radon gas exposure reconstruction as yearlong gas measurements. Both methods produced estimates that were within 25% of the long-term average radon gas concentrations in a home. Surface measurements can be used for home screening tests because they can provide rapid, reliable estimates of past radon gas concentrations. Implanted 210Po measurements are also useful in retrospective epidemiologic studies that include participants who may have been exposed to highly variable radon concentrations in previously occupied or structurally modified homes.

Lung cancer risk and red meat consumption among Iowa women.

OBJECTIVE: Some epidemiologic studies suggest that diets high in total fat, saturated fat, or cholesterol are associated with increased risk of lung cancer. Others suggest that diets high in red meat consumption, particularly well-done red meat, are a lung cancer risk factor. In Iowa, we had the opportunity to investigate concurrently the role of meat intake and macronutrients in lung cancer etiology. METHODS: A population-based case-control study of both non-smoking and smoking women was conducted in Iowa. A 70-item food frequency questionnaire (FFQ) was completed by 360 cases and 574 frequency-matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Multivariate models included age, education, pack-years of smoking, yellow-green vegetable intake, fruit/fruit juice intake, nutrient density calories, previous non-malignant lung disease, alcohol consumption and body mass index (BMI). RESULTS: When comparing the fifth (highest) to the first (lowest) quintile of consumption of total fat, saturated fat and cholesterol, we obtained odds ratios of 2.0 (1.3-3.1), 3.0 (1.9-4.7), and 2.0 (1.3-3.0) respectively. However, when red meat was entered into the model along with total fat, saturated fat or cholesterol, the excess risk for the macronutrients disappeared while an odds ratio of 3.3 (1.7-7.6) was obtained for red meat. The odds ratios for red meat consumption were similar among adenocarcinoma cases, OR=3.0 (1.1-7.9) and non-adenocarcinoma cases, OR=3.2 (1.3-8.3) and among life-time nonsmokers and ex-smokers OR=2.8 (1.4-5.4), and current smokers, OR=4.9 (1.1-22.3). Yellow-green vegetables were protective with an odds ratio of 0.4 (0.2-0.7). CONCLUSIONS: Consumption of red meat, was associated with an increased risk of lung cancer even after controlling for total fat, saturated fat, cholesterol, fruit, yellow-green vegetable consumption and smoking history, while yellow-green vegetables are associated with a decreased risk of lung cancer.

p53 and K-ras mutations in lung cancers from former and never-smoking women.

Somatic p53 mutations are common in lung cancer. Active cigarette smoking is positively correlated with the total frequency of p53 mutations and G:C to T:A transversions on the nontranscribed (DNA coding) strand. Mutational hotspots within the p53 gene, e.g., codon 157, have been identified for tobacco-related lung cancer, whereas these same mutations are found rarely in other cancers. Such data implicate specific p53 mutations as molecular markers of smoking. Because limited data exist concerning the p53 mutation frequency and spectra in ex-smokers and nonsmokers, we have analyzed p53 and K-ras mutations in 126 lung cancers from a population-based case-control study of nonsmoking (n = 117) or ex-smoking (n = 9) women from Missouri with quantitative assessments of exposure to environmental tobacco smoke. Mutations in the p53 gene were found in lung cancers from lifetime nonsmokers (19%) and ex-smokers (67%; odds ratio, 9.08; 95% confidence interval, 2.06-39.98). All deletions were found in tumors from patients who were either ex-smokers or nonsmokers exposed to passive smoking. The G:C to A:T transitions (11 of 28; 39%) were the most frequent p53 mutations found and clustered in tumors from lifetime nonsmokers without passive smoke exposure. The incidence of K-ras codon 12 or 13 mutations was 11% (14 of 115 analyzed) with no difference between long-term ex-smokers and nonsmokers. These and other results indicate that p53 mutations occur more commonly in smokers and ex-smokers than in never-smokers. Such comparisons provide additional evidence of genetic damage caused by tobacco smoke during lung carcinogenesis.

Nested case-control analysis of high pesticide exposure events from the Agricultural Health Study.

BACKGROUND: A nested case-control analysis of high pesticide exposure events (HPEEs) was conducted using the Iowa farmers enrolled in the Agricultural Health Study (AHS). METHODS: In the 12 months of the study, 36 of the 5,970 farmer applicators randomly chosen from the AHS cohort (six per 1,000 farmer applicators per year) met our definition of an HPEE, by reporting "an incident with fertilizers, weed killers, or other pesticides that caused an unusually high personal exposure" resulting in physical symptoms or a visit to a health care provider or hospital. Eligibility criteria were met by 25 HPEE cases and 603 randomly selected controls. RESULTS: Significant risk factors for an HPEE included: poor financial condition of the farm which limited the purchase of rollover protective structures OR = 4.6 (1.5-16.6), and having a high score on a risk acceptance scale OR = 3.8 (1.4-11.2). Other non-significant factors were also identified. CONCLUSIONS: The limited statistical power of this study necessitates replication of these analyses with a larger sample. Nonetheless, the observed elevated odds ratios of an HPEE provide hypotheses for future studies that may lead to preventive action.

Pesticide use by persons who reported a high pesticide exposure event in the agricultural health study.

Almost 16% of the pesticide applicators in the Agricultural Health Study (AHS) cohort (a cohort that includes 52,629 private applicators) reported having a high pesticide exposure event (i.e., an incident or experience while using a pesticide that caused an unusually high personal exposure). Pesticides involved in these events were compared to the frequency with which specific pesticides were ever used by the AHS cohort. Generally, pesticides with greater acute toxicity were more frequently involved with the high pesticide exposure event than were other pesticides. Whereas it is clear that the use of acutely toxic pesticides may be related to more frequent visits to health care facilities, the reason that the spills and immersions of the high pesticide exposure events are associated with the acute toxicity of the pesticide is not intuitively clear. This analysis suggests that current practices directed at minimizing pesticide exposures may not be sufficient for acutely toxic or irritating chemicals.

Previous lung disease and lung cancer risk among women (United States).

OBJECTIVE: The association between previous lung diseases (PLD) and lung cancer risk has not been studied extensively. We conducted a registry-based case-control study to examine the relation between previous lung diseases and lung cancer among women in Missouri. METHODS: Incident cases (n = 676) were identified through the Missouri Cancer Registry for the period 1 January 1993 to 31 January 1994. Controls (n = 700) were selected through drivers' license files and Medicare files. RESULTS: Whether analyzing all respondents or in-person interviews only, elevated effect estimates were noted for several types of PLD. Elevated relative risk estimates were shown for chronic bronchitis (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.2-2.3), emphysema (OR = 2.7; 95% CI = 1.8-4.2), pneumonia (OR = 1.6; 95% CI = 1.2-2.0), and for all PLDs combined (OR = 1.5; 95% CI = 1.2-1.9). Analysis of only direct interviews did not show a substantial or consistent pattern of change in relative risk estimates. Because PLDs identified close to the time of cancer diagnosis could conceivably be misdiagnosed, resulting from early lung cancer symptoms, we evaluated the effects on risk estimates of a "latency exclusion" of up to three years. When these exclusions were taken into account, ORs remained statistically significantly elevated only for emphysema. CONCLUSION: When earlier epidemiologic findings and underlying biological and genetic factors are taken into account, an association between PLD and lung cancer is plausible.

Dietary heterocyclic amines and the risk of lung cancer among Missouri women.

Heterocyclic amines (HCAs) such as 2-amino-3,8-dimethylimidazo[4,5f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx,), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are found in meats cooked at high temperatures. In rodents, MeIQx induces lung tumors. The purpose of this study was to investigate lung cancer risk posed by different HCAs in the diet. A population-based case-control study of 593 cases and 623 frequency-matched controls including both nonsmoking and smoking women was conducted in Missouri. An administered food frequency questionnaire with detailed questions on meat consumption, degrees of internal doneness, surface browning/charring, and cooking technique was linked to a database that provided exposure estimates of three HCAs. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. When comparing the 90th and 10th percentiles, significant excess risks were observed for MeIQx (OR, 1.5; CI, 1.1-2.0), but not for DiMeIQx (OR, 1.2; CI, 0.9-1.6) or PhIP (OR, 0.9; CI, 0.8-1.1). MeIQx consumption was associated with increased risk of lung cancer for nonsmokers (OR, 3.6; CI, 1.3-10.3) and light/moderate smokers (OR, 2.1; CI, 1.3-3.3), but not for heavy smokers (OR, 1.0; CI, 0.7-1.5). There was elevated risk with MeIQx intake for subjects with squamous cell carcinomas (OR, 1.9; CI, 1.2-3.1) and "other histological cell types" (OR, 1.6; CI, 1.1-2.5), but not for subjects with small cell carcinomas and adenocarcinomas. Neither DiMeIQx nor PhIP showed an association with smoking categories or lung cancer histology. In conclusion, MeIQx may be associated with lung cancer risk, but DiMeIQx and PhIP are probably not associated with lung cancer risk.

A model for predicting the frequency of high pesticide exposure events in the Agricultural Health Study.

The frequency of self-reported high pesticide exposure events (HPEE) has been recorded in the NCI/EPA/NIEHS Agricultural Health Study (AHS). Fourteen percent (14%) of the enrolled applicators responding reported "an incident or experience while using any pesticide which caused an unusually high exposure." These data show, as expected, that the probability of a report of an HPEE increases with the cumulative number of days of pesticide application reported by the applicator. We have developed a three-parameter model that predicts the risk odds ratio (OR) of an HPEE as a function of the number of days that pesticides are applied. These events are costly in terms of resulting health-care visits, lost time from work, and potential risk for cancer and other chronic diseases. We propose that failure to carefully follow all the pesticide manufacturer's label requirements, inexperience, and random events (i.e., breaking hose) are the three factors responsible for the events observed. Special precautions for new or infrequent users of pesticides are indicated.