Dale P. Sandler

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.

Pesticide use and colorectal cancer risk in the agricultural health study

We investigated the relationship between agricultural pesticides and colorectal cancer incidence in the Agricultural Health Study. A total of 56,813 pesticide applicators with no prior history of colorectal cancer were included in this analysis. Detailed pesticide exposure and other information were obtained from self‐administered questionnaires completed at the time of enrollment (1993–1997). Cancer incidence was determined through population‐based cancer registries from enrollment through December 31, 2002. A total of 305 incident colorectal cancers (212 colon, 93 rectum) were diagnosed during the study period, 1993–2002. Although most of the 50 pesticides studied were not associated with colorectal cancer risk, chlorpyrifos use showed significant exposure response trend (p for trend = 0.008) for rectal cancer, rising to a 2.7‐fold (95% confidence interval: 1.2–6.4) increased risk in the highest exposure category. Aldicarb was associated with a significantly increased risk of colon cancer (p for trend = 0.001), based on a small number of exposed cases, with the highest exposure category resulting in a 4.1‐fold increased risk (95% confidence interval: 1.3–12.8). In contrast, dichlorophenoxyacetic acid showed a significant inverse association with colon cancer but the association was not monotonic. Our findings should be interpreted cautiously since the literature suggesting that pesticides are related to colorectal cancer is limited. Nonetheless the possibility of an association between exposure to certain pesticides and incidence of colorectal cancer among pesticide applicators deserves further evaluation.

Non-hodgkin lymphoma risk and insecticide, fungicide and fumigant use in the agricultural health study.

Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993–97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999–2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.

Protective glove use and hygiene habits modify the associations of specific pesticides with Parkinson's disease

Pesticides have been associated with Parkinsons disease (PD), and protective gloves and workplace hygiene can reduce pesticide exposure. We assessed whether use of gloves and workplace hygiene modified associations between pesticides and PD. The Farming and Movement Evaluation (FAME) study is a nested case-control study within the Agricultural Health Study. Use of protective gloves, other PPE, and hygiene practices were determined by questionnaire (69 cases and 237 controls were included). We considered interactions of gloves and hygiene with ever-use of pesticides for all pesticides with ≥5 exposed and unexposed cases and controls in each glove-use stratum (paraquat, permethrin, rotenone, and trifluralin). 61% of respondents consistently used protective gloves and 87% consistently used ≥2 hygiene practices. Protective glove use modified the associations of paraquat and permethrin with PD: neither pesticide was associated with PD among protective glove users, while both pesticides were associated with PD among non-users (paraquat OR 3.9 [95% CI 1.3, 11.7], interaction p=0.15; permethrin OR 4.3 [95% CI 1.2, 15.6] interaction p=0.05). Rotenone was associated with PD regardless of glove use. Trifluralin was associated with PD among participants who used <2 hygiene practices (OR 5.5 [95% CI 1.1, 27.1]) but was not associated with PD among participants who used 2 or more practices (interaction p=0.02). Although sample size was limited in the FAME study, protective glove use and hygiene practices appeared to be important modifiers of the association between pesticides and PD and may reduce risk of PD associated with certain pesticides.

Neurobehavioral function and organophosphate insecticide use among pesticide applicators in the Agricultural Health Study

Although persistent decrements in cognitive function have been observed among persons who have recovered from clinically overt organophosphate (OP) pesticide poisoning, little is known about the cognitive effects of chronic OP exposures that do not result in acute poisoning. To examine associations between long-term pesticide use and neurobehavioral (NB) function, NB tests were administered to licensed pesticide applicators enrolled in the Agricultural Health Study (AHS) in Iowa and North Carolina. Between 2006 and 2008, 701 male participants completed nine NB tests to assess memory, motor speed and coordination, sustained attention, verbal learning and visual scanning and processing. Data on ever-use and lifetime days of use of 16 OP pesticides were obtained from AHS interviews conducted before testing between 1993 and 2007 and during the NB visit. The mean age of participants was 61 years (SD=12). Associations between pesticide use and NB test performance were estimated with linear regression controlling for age and outcome-specific covariates. NB test performance was associated with lifetime days of use of some pesticides. Ethoprop was significantly associated with reduced performance on a test of motor speed and visual scanning. Malathion was significantly associated with poor performance on a test of visual scanning and processing. Conversely, we observed significantly better test performance for five OP pesticides. Specifically, chlorpyrifos, coumaphos, parathion, phorate, and tetrachlorvinphos were associated with better verbal learning and memory; coumaphos was associated with better performance on a test of motor speed and visual scanning; and parathion was associated with better performance on a test of sustained attention. Several associations varied by state. Overall, we found no consistent evidence of an association between OP pesticide use and adverse NB test performance among this older sample of pesticide applicators. Potential reasons for these mostly null results include a true absence of effect as well as possible selective participation by healthier applicators.

Pesticides are Associated with Allergic and Non-Allergic Wheeze among Male Farmers

Background: Growing evidence suggests that pesticide use may contribute to respiratory symptoms. Objective: We evaluated the association of currently used pesticides with allergic and non-allergic wheeze among male farmers. Methods: Using the 2005–2010 interview data of the Agricultural Health Study, a prospective study of farmers in North Carolina and Iowa, we evaluated the association between allergic and non-allergic wheeze and self-reported use of 78 specific pesticides, reported by ≥ 1% of the 22,134 men interviewed. We used polytomous regression models adjusted for age, BMI, state, smoking, and current asthma, as well as for days applying pesticides and days driving diesel tractors. We defined allergic wheeze as reporting both wheeze and doctor-diagnosed hay fever (n = 1,310, 6%) and non-allergic wheeze as reporting wheeze but not hay fever (n = 3,939, 18%); men without wheeze were the referent. Results: In models evaluating current use of specific pesticides, 19 pesticides were significantly associated (p < 0.05) with allergic wheeze (18 positive, 1 negative) and 21 pesticides with non-allergic wheeze (19 positive, 2 negative); 11 pesticides were associated with both. Seven pesticides (herbicides: 2,4-D and simazine; insecticides: carbaryl, dimethoate, disulfoton, and zeta-cypermethrin; and fungicide pyraclostrobin) had significantly different associations for allergic and non-allergic wheeze. In exposure–response models with up to five exposure categories, we saw evidence of an exposure–response relationship for several pesticides including the commonly used herbicides 2,4-D and glyphosate, the insecticides permethrin and carbaryl, and the rodenticide warfarin. Conclusions: These results for farmers implicate several pesticides that are commonly used in agricultural and residential settings with adverse respiratory effects. Citation: Hoppin JA, Umbach DM, Long S, London SJ, Henneberger PK, Blair A, Alavanja M, Beane Freeman LE, Sandler DP. 2017. Pesticides are associated with allergic and non-allergic wheeze among male farmers. Environ Health Perspect 125:535–543;u2002http://dx.doi.org/10.1289/EHP315

Asymmetry in Family History Implicates Nonstandard Genetic Mechanisms: Application to the Genetics of Breast Cancer

Genome-wide association studies typically target inherited autosomal variants, but less studied genetic mechanisms can play a role in complex disease. Sex-linked variants aside, three genetic phenomena can induce differential risk in maternal versus paternal lineages of affected individuals: 1. maternal effects, reflecting the maternal genomes influence on prenatal development; 2. mitochondrial variants, which are inherited maternally; 3. autosomal genes, whose effects depend on parent of origin. We algebraically show that small asymmetries in family histories of affected individuals may reflect much larger genetic risks acting via those mechanisms. We apply these ideas to a study of sisters of women with breast cancer. Among 5,091 distinct families of women reporting that exactly one grandmother had breast cancer, risk was skewed toward maternal grandmothers (p<0.0001), especially if the granddaughter was diagnosed between age 45 and 54. Maternal genetic effects, mitochondrial variants, or variant genes with parent-of-origin effects may influence risk of perimenopausal breast cancer.

Nasopharyngeal radium irradiation: The Washington County, Maryland, study☆☆☆★

Although there have been many studies of cancer risk associated with a variety of x-ray treatments for benign conditions of the head and neck, little is known about the possible long-term health consequences of nasopharyngeal radium irradiation. This treatment results in minimal radiation exposure to the thyroid gland, which is the focus of much of the research regarding other head and neck irradiation. With nasopharyngeal radiation, on the other hand, exposure to the pituitary gland and the nasopharynx in the area immediately adjacent to the application site may have been substantial. In 1975 a follow-up study was undertaken in Washington County, Maryland, of 2925 persons who were treated at the Health Departments Clinic for the Prevention of Deafness in Children between 1943 and 1960. Of these, 904 persons had been treated with nasopharyngeal radium. After an average of 24 years of follow-up, an excess risk from brain cancer was suggested on the basis of three cases of cancer occurring in the treated group and none occurring in those who were not treated. This finding could have resulted by chance. Other results were consistent with a potential pituitary effect of radiation, but interpretation is limited by the absence of clinical and laboratory data. The history of the study is reported along with an overview of study methods and results.

High use of complementary and alternative medicine among a large cohort of women with a family history of breast cancer: the Sister Study

Use of complementary and alternative medicine (CAM) is high among U.S. women, yet information is limited on use among women at increased breast cancer risk. We analyzed CAM use among women with a family history of breast cancer. CAM use was analyzed among women enrolled 2003–2009 in the Sister Study cohort. Eligible women were aged 35–74, U.S. or Puerto Rican residents, no personal history of breast cancer, and had ≥1 sister with breast cancer. Baseline data on CAM use in the past year were available for 49,734 women. Logistic regression models examined the association between CAM use and Gail Model breast cancer risk score. Results were compared to female participants in the 2007 National Health Interview Survey (nxa0=xa07965). Among Sister Study participants, there was high use of vitamin/mineral supplements (79xa0%), mind-body practices (41xa0%), manipulative/body-based practices (32xa0%), and botanicals (23xa0%). Overall use was higher than the U.S. female population. No association was observed between familial breast cancer risk and CAM use. Black women were more likely to use spirituality/meditation-based CAM modalities, while non-Hispanic white and Asian women were high users of dietary supplements. In a cohort of women with increased breast cancer risk due to family history, CAM use is higher than women in the general U.S. population and is associated with race/ethnicity. Use was not associated with breast cancer risk. Given the high prevalence of CAM use among women at risk for breast caner, research on the effectiveness of CAM use for disease prevention is needed.

Reproductive history and blood cell telomere length

Telomeres are repetitive nucleotide sequences that protect against chromosomal shortening. They are replenished by telomerase, an enzyme that may be activated by estrogen. Women have longer telomeres than men; this difference might be due to estrogen exposure. We hypothesized that reproductive histories reflecting greater estrogen exposure will be associated with longer blood cell telomeres. Among women in the Sister Study (n= 1,048), we examined telomere length in relation to self-reported data on reproductive history. The difference between age at menarche and last menstrual period was used to approximate the reproductive period. Relative telomere length (rTL) was measured using qPCR. After adjustment, rTL decreased with longer reproductive period (β= -0.019, 95% CI: -0.04, -0.00, p= 0.03). Premenopausal women had shorter rTL than postmenopausal women (β= -0.051, 95% CI: -0.12, 0.01, p= 0.13). Longer breastfeeding duration was associated with longer rTL (β= 0.027, 95% CI: 0.01, 0.05, p=0.01); increasing parity was associated with shorter rTL (β = -0.016, 95% CI: -0.03, 0.00, p=0.07). Duration of exogenous hormone use was not associated with rTL. Reproductive histories reflecting greater endogenous estrogen exposure were associated with shorter rTL. Our findings suggest that longer telomeres in women are unlikely to be explained by greater estrogen exposure.