Cancer incidence among pesticide applicators exposed to dicamba in the Agricultural Health Study.BACKGROUND: Dicamba is an herbicide herbicide (hr`bəsīd'), chemical compound that kills plants or inhibits their normal growth. A herbicide in a particular formulation and application can be described as selective or nonselective. commonly applied to crops in the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. and abroad. We evaluated cancer incidence among pesticide pesticide, biological, physical, or chemical agent used to kill plants or animals that are harmful to people; in practice, the term pesticide is often applied only to chemical agents. applicators exposed to dicamba in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in North Carolina North Carolina, state in the SE United States. It is bordered by the Atlantic Ocean (E), South Carolina and Georgia (S), Tennessee (W), and Virginia (N). Facts and Figures Area, 52,586 sq mi (136,198 sq km). Pop. and Iowa. METHODS: Detailed pesticide exposure information was obtained through a self-administered questionnaire completed from 1993 to 1997. Cancer incidence was followed through 31 December 2002 by linkage to state cancer registries A cancer registry is a systematic collection of data about cancer and tumor diseases. The data is collected by Cancer Registrars. Cancer Registrars capture a complete summary of patient history, diagnosis, treatment, and status for every cancer patient in the United States, and . We used Poisson regression In statistics, the Poisson regression model attributes to a response variable Y a Poisson distribution whose expected value depends on a predictor variable x, typically in the following way: n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. for cancer subtypes by tertiles of dicamba exposure. Two dicamba exposure metrics metrics Managed care A popular term for standards by which the quality of a product, service, or outcome of a particular form of Pt management is evaluated. See TQM. were used: lifetime exposure days and intensity-weighted lifetime exposure days (lifetime days x intensity score). RESULTS: A total of 41,969 applicators were included in the analysis, and 22,036 (52.5%) reported ever using dicamba. Exposure was not associated with overall cancer incidence nor were there strong associations with any specific type of cancer. When the reference group comprised low-exposed applicators, we observed a positive trend in risk between lifetime exposure days and lung cancer lung cancer, cancer that originates in the tissues of the lungs. Lung cancer is the leading cause of cancer death in the United States in both men and women. Like other cancers, lung cancer occurs after repeated insults to the genetic material of the cell. (p = 0.02), but none of the individual point estimates was significantly elevated. We also observed significant trends of increasing risk for colon cancer colon cancer, cancer of any part of the colon (often called the large intestine). Colon cancer is the second most common cancer diagnosed in the United States. for both lifetime exposure days and intensity-weighted lifetime days, although these results are largely due to elevated risk at the highest exposure level. There was no apparent risk for non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL) describes a group of cancers arising from lymphocytes, a type of white blood cell. It is distinct from Hodgkin lymphoma in its pathologic features, epidemiology, common sites of involvement, clinical behavior, and treatment. . CONCLUSIONS: Although associations between exposure and lung and colon cancer were observed, we did not find clear evidence for an association between dicamba exposure and cancer risk. KEY WORDS: cancer incidence, farming, neoplasms, pesticides, United States. Environ Health Perspect 114:1521-1526 (2006). doi:10.1289/ehp.9204 available via http://dx.doi.org/ [Online 13 July 2006] Background Dicamba (3,6-dichloro-2-methoxybenzoic acid) is a benzoic acid benzoic acid (bĕnzō`ĭk), C6H5CO2H, crystalline solid organic acid that melts at 122°C; and boils at 249°C;. It is the simplest aromatic carboxylic acid (see aryl group and carboxyl group). herbicide used to control annual and perennial broadleaf broad·leaf adj. Broad-leaved. Adj. 1. broadleaf - having relatively broad rather than needlelike or scalelike leaves broad-leafed, broad-leaved weeds in grain crops, grasslands, and non-crop areas such as fence rows and roadways. Dicamba may be used in combination with other herbicides, such as 2,4-dichlorophenoxyacetic acid (2,4-D) or atrazine atrazine a triazine herbicide; it is not poisonous at levels of intake likely to be encountered in agriculture. atrazine Toxicology A nonphytoestrogenic herbicide. See Phytoestrogen. . In 2001 Dicamba ranked 24th of the 25 most commonly used agricultural pesticides with 7-10 million pounds applied, and 7th of the 10 most commonly used home and garden pesticides (Kiely et al. 2004). Dicamba was first registered for use in 1967 (National Pesticide Information Center 2005). The U.S. Environmental Protection Agency Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and (EPA EPA eicosapentaenoic acid. EPA abbr. eicosapentaenoic acid EPA, n.pr See acid, eicosapentaenoic. EPA, n. ) has classified this general use pesticide as toxicity class Toxicity Class refers to a classification system for pesticides created by a national or international government-related or -sponsored organization. It addresses the acute toxicity of agents such as soil fumigants, fungicides, herbicides, insecticides, miticides, molluscicides, III--slightly toxic (Extension Toxicology toxicology, study of poisons, or toxins, from the standpoint of detection, isolation, identification, and determination of their effects on the human body. Toxicology may be considered the branch of pharmacology devoted to the study of the poisonous effects of drugs. Network 1996), and as a Group D carcinogen carcinogen: see cancer. carcinogen Agent that can cause cancer. Exposure to one or more carcinogens, including certain chemicals, radiation, and certain viruses, can initiate cancer under conditions not completely understood. : "not classifiable as to human carcinogenicity carcinogenicity /car·ci·no·ge·nic·i·ty/ (kahr?si-no-je-nis´i-te) the ability or tendency to produce cancer. carcinogenicity the ability or tendency to produce cancer. " (U.S. EPA 2004). There is no experimental evidence that dicamba is mutagenic mutagenic inducing genetic mutation. or carcinogenic carcinogenic having a capacity for carcinogenesis. (Extension Toxicology Network 1996; U.S. EPA 2005), although rats fed dicamba at high levels over long periods experienced liver changes and decreased body weight (Edson and Sanderson 1965). Limited animal evidence suggests that dicamba could induce tumors through epigenetic epigenetic /epi·ge·net·ic/ (-je-net´ik) 1. pertaining to epigenesis. 2. altering the activity of genes without changing their structure. mechanisms (Espandiari et al. 1998, 1999). In epidemiologic studies epidemiologic study A study that compares 2 groups of people who are alike except for one factor, such as exposure to a chemical or the presence of a health effect; the investigators try to determine if any factor is associated with the health effect , occupational use of dicamba has been associated with non-Hodgkin lymphoma (NHL NHL Non-Hodgkin's lymphoma, see there ; McDuffie et al. 2001) and multiple myeloma multiple myeloma A malignant proliferation of abnormal plasma cells that populate the marrow-containing bones of the body. The affected plasma cells produce myeloma protein, a monoclonal antibody that replaces normal antibodies in the blood, thereby increasing susceptibility (Burmeister 1990). More recently, in the Agricultural Health Study (AHS AHS Assistant House Surgeon. ) cohort, dicamba was associated with an increased risk of lung cancer in a nested case-control analysis (Alavanja et al. 2004). Dicamba has been found in carpet dust samples, with higher levels from states with higher prevalence of lawn and garden use (Colt COLT. An animal of the horse species, whether male or female, not more than four years old. Russ. & Ry. 416. et al. 2005), and in 1.4% of urine samples collected between 1976 and 1980 from 6,990 participants in the Second National Health and Nutrition Examination Survey (Kutz et al. 1992). Despite its common use and some epidemiologic ep·i·de·mi·ol·o·gy n. The branch of medicine that deals with the study of the causes, distribution, and control of disease in populations. [Medieval Latin epid evidence that suggests increased cancer risk, existing evaluations of dicamba-related health effects are inadequate. In an effort to add to existing knowledge, as well as follow-up on the suggested association with lung cancer previously observed in this cohort, we investigated site-specific cancer incidence and risk among pesticide applicators exposed to dicamba in the AHS cohort. Materials and Methods Cohort enrollment and follow-up. The AHS is a prospective cohort study A cohort study is a form of longitudinal study used in medicine and social science. It is one type of study design. In medicine, it is usually undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease; failure to refute of 57,311 private and commercial pesticide applicators in Iowa and North Carolina recruited between 1993 and 1997 (AHS 2006b). Cohort members were matched to cancer registry files in Iowa and North Carolina for case identification and to state death registries and the National Death Index (Centers for Disease Conrol and Prevention 2006) to ascertain vital status. We included incident cancers diagnosed between date of enrollment and 31 December 2002. Cancers were coded according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. the International Classification of Diseases for Oncology The International Classification of Diseases for Oncology (ICD-O) is a domain specific extension of the International Statistical Classification of Diseases and Related Health Problems for tumor diseases. This classification is widely used by cancer registries. (ICD-O-2; New South Wales Department of Health The New South Wales Department of Health is an agency of the Government of New South Wales with responsibility for the provision of healthcare, particularly through public hospitals. The Minister for Health is Reba Meagher. 2000). Surviving cohort members no longer residing in Iowa or North Carolina were identified through current address records of the Internal Revenue Service, state motor vehicle registration offices, and pesticide license registries of state agricultural departments. These individuals were censored cen·sor n. 1. A person authorized to examine books, films, or other material and to remove or suppress what is considered morally, politically, or otherwise objectionable. 2. from cancer incidence follow-up on the dates they departed Iowa or North Carolina. The average period of follow-up time was 7.3 years. This study was approved by all appropriate Institutional Review Boards. Verbal informed consent was obtained from all participants. Exposure assessment. A self-administered enrollment questionnaire sought comprehensive information on use of 22 specific pesticides, ever/never use information for 28 additional pesticides, pesticide mixing and application methods, repair of application equipment, use of personal protective equipment (PPE PPE (Brit) n abbr (Univ) (= philosophy, politics, and economics) → Studiengang bestehend aus Philosophie, Politologie und Volkswirtschaft PPE n abbr (BRIT ) (SCOL ), and demographic and lifestyle characteristics such as smoking status, alcohol consumption, and personal and family medical histories. This questionnaire may be accessed at the AHS website (AHS 2006a). We used two exposure metrics for this analysis: lifetime exposure days and intensity-weighted lifetime exposure days. We estimated the number of lifetime exposure days to dicamba on the basis of the number of years applied and the frequency of application, using the midpoints of the questionnaire categories for total years of use and days per year of use. Lifetime exposure days were grouped into tertiles on the basis of the distribution among all cancer cases combined. To more finely explore potential dose-response curves dose-response curve A graphic representation of the effects that varous doses of an agent–eg, ionizing radiation or a chemotherapeutic agent, have on a given parameter–eg, cell viability, mutation frequency, DNA damage, tumor growth or metastasis or , we divided the highest tertile at the median, producing the following categories for lifetime exposure days: No exposure, 1 to < 20 days, 20 to < 56 days, 56 to < 116 days, and [greater than or equal to] 116 days. To account for factors that may increase or decrease exposure, we incorporated the AHS exposure-intensity algorithm that is based on the following formula: Intensity level = [(mixing status + application method + equipment repair status) x personal protective equipment (PPE) score] (Dosemeci et al. 2002). Scores were assigned to each of the four factors that the formula comprises, which served to weight each factor according to each possible outcome defined by what was reported on the enrollment questionnaire. For example, mixing status was a three-level variable based on never mixing, personally mixing < 50% of the time, and personally mixing > 50% of the time (Mix score = 0, 3, 9, respectively). Pesticides are typically purchased in concentrated form and must be diluted di·lute tr.v. di·lut·ed, di·lut·ing, di·lutes 1. To make thinner or less concentrated by adding a liquid such as water. 2. To lessen the force, strength, purity, or brilliance of, especially by admixture. prior to application, and the diluted material is then transferred to application containers. This mixing and loading process provides opportunities for greater pesticide exposure due to contact with contaminated contaminated, v 1. made radioactive by the addition of small quantities of radioactive material. 2. made contaminated by adding infective or radiographic materials. 3. an infective surface or object. surfaces, splashes, and spills. Application method was a six-level variable which, for herbicides, was based on never applying, aerial application Aerial application, commonly called crop dusting, involves spraying crops with fertilizers, pesticides, and fungicides from an agricultural aircraft. The specific spreading of fertiliser is also known as aerial topdressing. or distribution of tablets, application in furrow furrow /fur·row/ (fur´o) a groove or sulcus. atrioventricular furrow the transverse groove marking off the atria of the heart from the ventricles. , use of tractor-mounted boom sprayer, use of backpack, and use of hand spray (application score = 0, 1, 2, 3, 8, 9, respectively). The use of backpack sprayers or hand sprayers to apply pesticides may result in higher dermal dermal /der·mal/ (der´mal) pertaining to the dermis or to the skin. der·mal or der·mic adj. Of or relating to the skin or dermis. exposures than use of a tractor-mounted boom sprayer because the backpack and hand spray wands are in direct contact with the applicator's hands or body. Equipment repair status was a two-level variable based on not repairing or repairing (repair score = 0, 2, respectively). PPE was an eight-level variable based on four groups of PPE combinations (PPE = 0 if never used PPE; PPE = 1 if wore face shield/goggles or fabric/leather gloves or other protective clothing; PPE = 2 if wore cartridge respirator/gas mask or disposable outer clothing; and PPE = 3 if wore chemical resistant rubber gloves rubber gloves rubber npl → gants mpl en caoutchouc ). Intensity-weighted lifetime exposure days is the product of lifetime exposure days and intensity level, and was categorized cat·e·go·rize tr.v. cat·e·go·rized, cat·e·go·riz·ing, cat·e·go·riz·es To put into a category or categories; classify. cat into tertiles with the upper tertile further divided at the median. Categories included no exposure, 1 to < 86.6 intensity-weighted days, 86.6 to < 344.3 intensity-weighted days, 344.3 to < 739.2 intensity-weighted days, and [greater than or equal to] 739.2 intensity-weighted days. Data analysis. Rate ratios (RRs) and 95% confidence intervals (CIs) were calculated to estimate risk of various cancers associated with dicamba exposure. All models were based on the Poisson distribution A statistical method developed by the 18th century French mathematician S. D. Poisson, which is used for predicting the probable distribution of a series of events. For example, when the average transaction volume in a communications system can be estimated, Poisson distribution is used and included first primary incident cancer cases. Individuals with cancer prevalent at the time of enrollment (n = 1,075) were excluded from the analysis. Of the remaining participants, 6,362 were missing information about dicamba use and were also excluded. Because there were only four exposed cancer cases, we were unable to adequately examine risk among the 1,297 female applicators. A total of 41,969 male applicators remained in the analysis after losing 6,608 additional participants who were missing one or more covariates. We examined risk for all cancer sites classified under ICD-O-2 (New South Wales Department of Health 2000). In the tables we present only cancers for which there were at least five cases in each exposure category. All models were adjusted for baseline variables: age at enrollment (< 40, 40-49, 50-59, [greater than or equal to] 60 years), race (white, nonwhite non·white n. A person who is not white. non  white adj. ), alcohol consumption during the year of
enrollment (ever, never), smoking status at enrollment (never, low, and
high based on the median value Noun 1. median value - the value below which 50% of the cases fallmedian statistics - a branch of applied mathematics concerned with the collection and interpretation of quantitative data and the use of probability theory to estimate population of pack-years among smokers), family history of cancer in first degree relatives (yes, no), applicator ap·pli·ca·tor n. An instrument for applying something, such as a medication. applicator, n a device for applying medication; usually a slender rod of glass or wood, used with a pledget of cotton on the end. status (private, commercial), and state of residence (Iowa, North Carolina). Because of potential concurrent exposure to other pesticides, we examined the impact of adjusting for pesticides highly correlated with use of dicamba, as well as adjusting all RRs for total lifetime days of pesticide use as a continuous variable (Alavanja et al. 2004). In addition to tertiles of lifetime exposure days and intensity-weighted lifetime exposure days, we examined the association between cancer risk and tertiles of each exposure component: days per year of dicamba use, total years of dicamba use, and the dicamba intensity score. We analyzed exposure-response trends by including the midpoint mid·point n. 1. Mathematics The point of a line segment or curvilinear arc that divides it into two parts of the same length. 2. A position midway between two extremes. of each tertile as a continuous variable in the model and testing for the statistical significance of the slope. To evaluate the most appropriate reference group, we examined a number of characteristics that may be related to intensity of lifetime days of dicamba exposure, which was divided into three categories: those who never applied dicamba, applicators in the lowest tertile of lifetime exposure days (low-exposed), and applicators in the top two tertiles of lifetime exposure days (high-exposed). Differences with respect to these and other baseline characteristics baseline characteristic Medical practice An initial finding or value in a Pt, before any formal intervention may introduce residual confounding confounding when the effects of two, or more, processes on results cannot be separated, the results are said to be confounded, a cause of bias in disease studies. confounding factor from a variety of unidentified sources. To avoid this, we assumed that applicators with baseline characteristics more similar to those of the applicators in the higher exposure group would be most appropriate as a reference group for the Poisson regression analyses (Rusiecki et al. 2004). Results Selected characteristics of the dicamba-exposed and non-dicamba-exposed applicators are presented in Table 1. Among 41,969 participants with complete exposure information, 22,036 (52.5%) reported ever having personally applied or mixed dicamba and had complete data on lifetime days of exposure. The study population comprised primarily white, male private applicators. In both the exposed and nonexposed groups, about half of the participants reported that they had never smoked. High-exposed applicators tended to be more similar to low-exposed applicators than never-exposed applicators with respect to baseline characteristics of age, race, state of residence, smoking status, education, alcohol consumption during year of enrollment, family history of cancer, applicator type, living or working on a farm at enrollment, and corn and soybean soybean, soya bean, or soy pea, leguminous plant (Glycine max, G. soja, or Soja max) of the family Leguminosae (pulse family), native to tropical and warm temperate regions of Asia, where it has been production. Despite differences between the never-exposed and low-exposed groups, results differed only slightly when either was used as the reference group, and we provide results for both analyses. We found no strong associations between any cancer site and dicamba exposure for either lifetime exposure days or intensity-weighted lifetime exposure days (Tables 2 and 3). We did observe a trend of increasing lung cancer risk with increasing lifetime exposure days when the referent ref·er·ent n. A person or thing to which a linguistic expression refers. Noun 1. referent - something referred to; the object of a reference group was low-exposed participants (p-value for trend = 0.02), with a RR of 2.16 (95% CI, 0.97-4.82) for the upper half of the highest tertile. The number of nonsmoking non·smok·ing adj. 1. Not engaging in the smoking of tobacco: nonsmoking passengers. 2. Designated or reserved for nonsmokers: the nonsmoking section of a restaurant. , dicamba-exposed lung cancer cases (n = 5) was too small to assess risk among nonsmokers. In an analysis based on intensity-weighted exposure days, those with exposure in the top two tertiles had nearly twice the risk as those with low exposure, but no dose response was evident. There was no evidence of increased lung cancer risk with either lifetime exposure days or intensity-weighted lifetime days when applicators unexposed to dicamba served as the referent. We also observed significant trends of increasing risk for colon cancer for both lifetime exposure days and intensity-weighted lifetime days when the referent group comprised low-exposed applicators. However, only RRs for the highest exposure category were significant (lifetime days RR = 3.29; 95% CI, 1.40-7.73; p-trend = 0.02; intensity-weighted lifetime days RR = 2.57; 95% CI, 1.28-5.17; p-trend = 0.002). This trend was not observed when the referent group comprised applicators who never used dicamba. There were no differences in risk for lung or colon cancer when we restricted the analysis to applicators who first applied dicamba prior to 1990 (data not shown). NHL was not associated with dicamba exposure, and there were too few cases of multiple myeloma to analyze. We attempted to stratify strat·i·fy v. strat·i·fied, strat·i·fy·ing, strat·i·fies v.tr. 1. To form, arrange, or deposit in layers. 2. risk for all cancers by state of residence (Iowa vs. North Carolina) and applicator type (private vs. commercial) but were unable to provide stable estimates for most cancers in North Carolina because of small numbers. For example, there were only 6 dicamba-exposed colon cancer cases in North Carolina, and 12 dicamba-exposed lung cancer cases. Given that a large proportion of participants with no dicamba exposure came from North Carolina (50%) and the majority of our highly exposed participants came from Iowa (92%), state of residence is clearly associated with dicamba exposure. The trends in risk for lung and colon cancer did not significantly change after restricting the analyses to the state of Iowa. We also examined risk for each cancer site for each of the three components of the exposure algorithm grouped into tertiles: days per year of dicamba use, total years of dicamba use, and the dicamba intensity score. We observed no association between any of these components and risk for any cancer site, except for lung cancer, where the RR was 2.07 (95% CI, 1.05-4.08) for participants in the top tertile (> 15.5 years of dicamba exposure; n = 13 exposed cases) relative to that for unexposed participants (data not shown). Because dicamba is often used in combination with the herbicides 2,4-D, atrazine, or glyphosate glyphosate herbicide and desiccant for grains. Heavy doses to birds cause soft shells on their eggs. , we attempted to examine dicamba-associated risk of lung and colon cancers stratified stratified /strat·i·fied/ (strat´i-fid) formed or arranged in layers. strat·i·fied adj. Arranged in the form of layers or strata. by never/ever use of these three herbicides. However, a large proportion of applicators reported ever using 2,4-D, atrazine, and glyphosate (78, 72, and 77%, respectively), so the numbers of dicamba-exposed cases in the never-used strata were too small to provide a meaningful comparison of risk between strata. Last, we attempted to adjust for confounding due to concurrent exposure to other pesticide in multiple ways. We examined the effect of adjusting for ever/never use of nine other pesticides most highly correlated with dicamba use. None of the individual pesticides substantially altered the trends in risk. When all nine pesticide variables were entered into the models simultaneously, the magnitude of adjustment was similar to when we used total lifetime days of any pesticide use in continuous form. For the sake of efficiency we selected total lifetime days of any pesticide use as the main adjustment variable. We also subtracted the number of dicamba lifetime exposure days from the total lifetime days of any pesticide use. This did not substantially alter the trends in risk for any of the cancer sites we examined; almost all point estimates remained the same. Discussion Our study is the largest study to date of cancer risk associated with exposure to the herbicide dicamba. We observed a suggestion of increased risk for lung and colon cancer when the referent group comprised low-exposed applicators but not when the referent group comprised unexposed applicators. With further follow-up and accumulation of exposed cases, we believe we will better understand this phenomenon. The association with lung cancer we observed in our study is similar to that reported in an earlier nested case-control study A nested case-control study is a type of study design where new case controls are applied into cohorts which were defined before the study begins. Compared with case-control study, nested case-control study can reduce 'recall bias' and temporal ambiguity, and compared with in the AHS cohort. Alavanja et al. (2004) observed a positive trend in risk for lung cancer with lifetime exposure days of dicamba, for the highest exposure tertile (highest tertile divided at the median) relative to the lowest exposure tertile [odds ratio (OR) = 1.0, 1.3, 1.7, 3.1; p-value for trend = 0.04). A significant trend was not observed when the investigators used unexposed participants as the referent group (OR = 1.0, 0.7, 0.9, 1.1, 1.6; p-value for trend = 0.15). When we modeled risk of lung cancer associated with lifetime dicamba exposure days using the low exposed as the referent group and the same tertile cut points used in the analysis conducted by Alavanja et al. (2004), not surprisingly, our results were very similar (OR = 1.0, 1.1, 1.6, 2.1; p-value for trend = 0.02). There is no prior evidence that suggests an association between dicamba exposure and colon cancer. Exposure to dicamba has been associated with increased risk for NHL in a few previous case-control studies case-control study, n an investigation employing an epidemiologic approach in which previously existing incidents of a medical condition are used in lieu of gathering new information from a randomized population. . In a case-control study of NHL and pesticide exposure conducted in Canada, information on pesticide exposure was collected through a combination of mailed questionnaires and telephone interviews (McDuffie et al. 2001). After adjusting for demographic characteristics, family history of cancer in a first-degree relative, and history of selected medical conditions See carpal tunnel syndrome, computer vision syndrome, dry eyes and deep vein thrombosis. , increasing days per year of dicamba application was associated with an increased risk of NHL (OR = 1.7; 95% CI, 1.0-2.8). When exposure to dicamba as a general class was evaluated, which included dicamba-only products as well as mixtures of dicamba and glyphosate and mixtures of dicamba, 2,4-D and mecoprop, NHL risk increased slightly with increasing days per year of application (OR = 1.9; 95 %CI, 1.3-2.7). Conversely con·verse 1 intr.v. con·versed, con·vers·ing, con·vers·es 1. To engage in a spoken exchange of thoughts, ideas, or feelings; talk. See Synonyms at speak. 2. , results from a case-control study of NHL and farming in the United States suggested no association between risk of NHL and ever handling either benzoic acids as a class (OR = 1.3; 95% CI, 0.9-1.9) or dicamba in particular (OR = 1.2; 95% CI, 0.7-2.0) (Cantor et al. 1992). After restricting the analyses to pesticides handled prior to 1965, risk for NHL was elevated among dicamba users (OR = 2.8; 95% CI, 0.96-8.1). Our prospective data do not provide evidence of an association between dicamba and NHL. Our findings, however, may be influenced by the small number of cases and relatively short follow-up time. Results from other studies provide no evidence for an association between dicamba and risk of leukemia leukemia (l  kē`mēə), cancerous disorder of the blood-forming tissues (bone marrow, lymphatics, liver, spleen) characterized by excessive production of immature or mature (OR = 0.7; 95% CI, 0.4-1.4) (Brown
et al. 1990) or multiple myeloma (OR = 1.3; 95% CI, 0.6-2.8) (Brown et
al. 1993). However, Burmeister (1990) reported a nonsignificant non·sig·nif·i·cant adj. 1. Not significant. 2. Having, producing, or being a value obtained from a statistical test that lies within the limits for being of random occurrence. , marginal association between exposure to benzoic acids as a class and risk of multiple myeloma (OR = 1.22; confidence interval/p-value not reported). In our study, exposure to dicamba is likely to be a combination of exposure to dicamba-only products as well as to dicamba mixtures, making it difficult to disentangle the effect of dicamba from other pesticides included in dicamba mixtures. After stratifying dicamba models for lung and colon cancers by never/ever use of 2,4-D, atrazine, and glyphosate (three herbicides commonly mixed with dicamba), there was no evidence for either increased risk among dicamba-only users, or for increased risk among participants who also used 2,4-D, atrazine, or glyphosate. Because this analysis is based on information pertaining per·tain intr.v. per·tained, per·tain·ing, per·tains 1. To have reference; relate: evidence that pertains to the accident. 2. to ever/never use of individual pesticide active ingredients An active ingredient, also active pharmaceutical ingredient (or API), is the substance in a drug that is pharmaceutically active. Some medications may contain more than one active ingredient. , however, we were unable to unambiguously differentiate between use of dicamba-only products and dicamba mixtures at this time. There is little experimental evidence to suggest that dicamba is carcinogenic or mutagenic (U.S. EPA 1999). Feeding studies in rats, mice, dogs, and rabbits have shown no increased incidence of tumors (Extension Toxicology Network 1999). There is evidence that dicamba acts as a peroxisome Peroxisome An intracellular organelle found in all eukaryotes except the archezoa (original lifeforms). In electron micrographs, peroxisomes appear round with a diameter of 0.1–1. proliferator (PP) by increasing fatty acyl-coenzyme A oxidase oxidase /ox·i·dase/ (ok´si-das) any enzyme of the class of oxidoreductases in which molecular oxygen is the hydrogen acceptor. ox·i·dase n. activity in the livers of rats and activating the peroxisome proliferator receptor in a dose-dependent fashion (Espandiari et al. 1998, 1999). It is thought that PPs may induce liver tumors Hepatic tumors are tumors or growths on or in the liver (medical terms pertaining to the liver often start in hepato- or hepatic from the Greek word for liver, hepar). These growths can be benign or malignant (cancerous). in rats through mechanisms related to oxidative stress oxidative stress, n an imbalance of the prooxidant antioxidant ratio in which too few antioxidants are produced or ingested or too many oxidizing agents are produced. , inducing replicative DNA synthesis DNA synthesis commonly refers to:
DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. damage in one study of rats (Perocco et al. 1990). In another study of mice, dicamba caused mortality in two of four mice injected in·ject·ed adj. 1. Of or relating to a substance introduced into the body. 2. Of or relating to a blood vessel that is visibly distended with blood. injected 1. introduced by injection. 2. congested. with dicamba but did not increase xenobiotic-metabolizing activities in the two surviving mice (Moody et al. 1991). Few epidemiologic studies on the effect of PPs on humans have been conducted (Nakajima et al. 2002), but there are marked species differences in response to PPs (Lai 2004). Humans seem to exhibit a weak response to PP chemicals (including certain pesticides, industrial solvents, and hypolipidemic drugs), which may be due to low levels of peroxisome proliferator-activated receptor In cell biology, peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor isoforms that exist across biology. They are intimately connected to cellular metabolism (carbohydrate, lipid and protein) and cell differentiation. alpha in human liver (Lai 2004; Maloney and Waxman 1999). The Agricultural Health Study is the largest study to date of pesticide applicators exposed to dicamba. The potential for recall bias is minimal, as exposure information was collected prior to cancer diagnosis. AHS applicators have been shown to provide reliable information about their histories of pesticide use (Blair et al. 2002; Hoppin et al. 2002), although misclassification can occur. Misclassification in a prospective study is likely to be nondifferential with regard to cancer occurrence and, although it could diminish estimates of relative risk, it is unlikely to create false positives (Checkoway et. al. 2004). Our results may be affected by simultaneous exposure to other pesticides of varying intensity that has changed over time, although we attempted to account for this by adjusting for total lifetime days of any pesticide use. In addition, we could not differentiate use of dicamba-only products from dicamba mixtures. This is one of the biggest challenges in conducting epidemiologic research on pesticides, as many pesticides are most often used in combination with others in complex mixtures and not as individual pesticides. The existing toxicologic data, however, pertain to pertain to verb relate to, concern, refer to, regard, be part of, belong to, apply to, bear on, befit, be relevant to, be appropriate to, appertain to dicamba as an individual chemical. Our findings may also be limited because of a relatively short period of follow-up and small numbers of cases for some cancer sites. Because of the lack of consistency among results from the four evaluations of exposure metric and referent type for lung and colon cancer, these findings should be interpreted with caution. Despite these limitations, our prospective study of cancer incidence among dicamba-exposed pesticide applicators provided an opportunity afforded in few other studies to evaluate cancer risks associated with exposure to dicamba while adjusting for lifetime use of other pesticides and lifestyle factors. We did not detect much evidence for an association between dicamba exposure and any of the cancer sites investigated, but the patterns of associations observed for lung and colon cancers warrant further attention. We will re-examine re·ex·am·ine also re-ex·am·ine tr.v. re·ex·am·ined, re·ex·am·in·ing, re·ex·am·ines 1. To examine again or anew; review. 2. Law To question (a witness) again after cross-examination. dicamba in the future when larger numbers will allow for a more comprehensive evaluation of lung and colon cancer, as well as additional cancer sites. REFERENCES AHS (Agricultural Health Study). 2006a. Full Text of Questionnaires. Available: http://www.aghealth.org/questionnaires. html [accessed 25 August 2006]. AHS (Agricultural Health Study). 2006b. Home Page. Available: http://www.aghealth.org/ [accessed 25 August 2006]. Alavanja MC, Dosemeci M, Samanic C, Lubin JH, Lynch CF, Knott C, et al. 2004. Pesticides and lung cancer risk in the agricultural health study cohort. Am J Epidemiol 160:876-885. Blair A, Tarone R, Sandler D, Lynch CF, Rowland A, Wintersteen W, et al. 2002. Reliability of reporting on lifestyle and agricultural factors by a sample of participants in the Agricultural Health Study from Iowa. 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It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of :Oxford University Press, 83-121. Colt JS, Severson RK, Lubin J, Rothman N, Camann D, Davis S, et al. 2005. Organochlorines organochlorines see chlorinated hydrocarbons. organochlorines poisoning cause excitement and irritability, tremor, ataxia, weakness, paralysis, convulsions. and carpet dust in non-Hodgkin lymphoma. Epidemiology 16:516-525. Dosemeci M, Alavanja MC, Rowland AS, Mage D, Zahm SH, Rothman N, et al. 2002. A quantitative approach for estimating exposure to pesticides in the Agricultural Health Study. Ann Occup Hyg 46:245-260. Edson EF, Sanderson DM. 1965. Toxicity of the herbicides 2-methoxy-3,6-dichlorobenzoic acid (dicamba) and 2-methoxy-3,5,6-trichlorobenzoic acid (tricamba). Food Cosmet Toxicol 3:299-304. Espandiari P, Glauert HP, Lee EY, Robertson LW. 1999. Promoting activity of the herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) in two stage hepatocarcinogenesis. Int J Oncol 14:79-84. Espandiari P, Ludewig G, Glauert HP, Robertson LW. 1998. Activation of hepatic hepatic /he·pat·ic/ (he-pat´ik) pertaining to the liver. he·pat·ic adj. 1. Of, relating to, or resembling the liver. 2. Acting on or occurring in the liver. n. NF-kB by the herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) in female and male rats. J Biochem Mol Toxicol 12:339-344. Extension Toxicology Network. 1996. Dicamba. Pesticide Information Profiles. Available: http://extoxnet.orst. edu/pips/dicamba.htm [accessed 23 March 2006]. Hoppin JA, Yucel F, Dosemeci M, Sandler DP. 2002. Accuracy of self-reported pesticide use duration information from licensed pesticide applicators in the Agricultural Health Study. J Expo Anal anal (a´n'l) relating to the anus. a·nal adj. 1. Of, relating to, or near the anus. 2. Environ Epidemiol 12:313-318. Kiely T, Donaldson D, Grube A. 2004. Pesticide Industry Sales and Usage: 2000 and 2001 Market Estimates. EPA-733-R-04-001. Washington, DC:U.S. Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic Substances. Kutz FW, Cook BT, Carter-Pokras OD, Brody D, Murphy RS. 1992. Selected pesticide residues Pesticide residue refers to the pesticides that may remain on or in food after they are applied to food crops.[1] Regulation of pesticide residue in the US and metabolites Metabolites Substances produced by metabolism or by a metabolic process. Mentioned in: Interactions in urine from a survey of the U.S. general population. J Toxicol Environ Health 37:277-291. Lai DY. 2004. Rodent rodent, member of the mammalian order Rodentia, characterized by front teeth adapted for gnawing and cheek teeth adapted for chewing. The Rodentia is by far the largest mammalian order; nearly half of all mammal species are rodents. carcinogenicity of peroxisome proliferators and issues on human relevance. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 22:37-55. Maloney EK, Waxman DJ. 1999. trans-Activation of PPAR PPAR Peroxisome Proliferator Activated Receptor PPAR Physical Partitions [alpha] and PPAR[gamma] by structurally diverse environmental chemicals. Toxicol Appl Pharmacol 161:209-218. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. 2001. Non-Hodgkin's lymphoma and specific pesticide exposures in men: cross-Canada study of pesticides and health. Cancer Epidemiol Biomarkers Prev 10:1155-1163. Moody DE, Narloch BA, Shull LR, Hammock hammock, suspended bed, usually of netting, canvas, or leather. The hammock and its name were introduced to Europeans by Christopher Columbus, who learned of them from Native Americans. BD. 1991. The effect of structurally divergent di·ver·gent adj. 1. Drawing apart from a common point; diverging. 2. Departing from convention. 3. Differing from another: a divergent opinion. 4. herbicides on mouse liver xenobiotic-metabolizing enzymes (P-450-dependent mono-oxygenases, epoxide hydrolases Epoxide hydrolase (also known as Epoxide hydratase) functions in detoxication during drug metabolism. It converts epoxides from the degradation of aromatic compounds to trans-dihydrodiols which can be conjugated and excreted from the body. and glutathione S-transferases The glutathione S-transferase (GST) family of enzymes comprises a long list of cytosolic, mitochondrial, and microsomal proteins which are capable of multiple reactions with a multitude of substrates, both endogenous and xenobiotic. ) and carnitine carnitine /car·ni·tine/ (kahr´ni-ten) a betaine derivative involved in the transport of fatty acids into mitochondria, where they are metabolized. car·ni·tine n. acetyltransferase. Toxicol Lett 59:175-185. Nakjima T, Ichihara G, Kamijima M, Itohara S, Aoyama T. 2002. Functional activation of peroxisome proliferator-activated receptor alpha (PPAR[alpha]) by environmental chemicals in relation to their toxicities. Nagoya J Med Sci 65:85-94. National Pesticide Information Center. 2005. Dicamba (General Fact Sheet). Available: http://npic.orst.edu/factsheets/dicamba_gen.pdf [accessed 26 June 2006]. New South Wales Department of Health. 2000. ICD ICD International Classification of Diseases (of the World Health Organization); intrauterine contraceptive device. ICD abbr. Codes for Diseases and Procedures. Sydney:Population Health Division, NSW NSW New South Wales Noun 1. NSW - the agency that provides units to conduct unconventional and counter-guerilla warfare Naval Special Warfare Department of Health. Available: http://www.health.nsw.gov.au/public-health/chorep/toc/app_icd9icd10map.htm [accessed 25 August 2006]. Perocco P, Ancora G, Rani ra·ni also ra·nee n. pl. ra·nis also ra·nees 1. The wife of a rajah. 2. A princess or queen in India or the East Indies. P, Valenti AM, Mazzullo M, Colacci A, et al. 1990. Evaluation of genotoxic genotoxic /ge·no·tox·ic/ (je´no-tok?sik) damaging to DNA: pertaining to agents known to damage DNA, thereby causing mutations, which can result in cancer. ge·no·tox·ic adj. effects of the herbicide dicamba using in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body. in vi·vo adj. Within a living organism. in vivo adv. and in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment. in vi·tro adj. In an artificial environment outside a living organism. test systems. Environ Mol Mutagen mutagen: see mutation. mutagen Any agent capable of altering a cell's genetic makeup by changing the structure of the hereditary material, DNA. Many forms of electromagnetic radiation (e.g. 15:131-135. Rusiecki J, De Roos A, Lee WJ, Dosemeci M, Lubin JH, Hoppin JA, et al. 2004. Cancer incidence among pesticide applicators exposed to atrazine in the Agricultural Health Study. J Natl Cancer Inst 96:1375-1382. U.S. EPA (U.S. Environmental Protection Agency). 1999. Dicamba (3,6-dichloro-o-anisic acid): pesticide tolerance; final rule. Fed Reg FED REG Federal Register 64:759-769. U.S. EPA. 2004. Chemicals Evaluated for Carcinogenic Potential. Washington, DC:U.S. Environmental Protection Agency, Office of Pesticide Programs, Health Effects Division, Science Information Management Branch. U.S. EPA (U.S. Environmental Protection Agency). 2005. Integrated Risk Information System. Available: http://www. epa.gov/iris/subst/0223.htm [accessed 23 March 2006). Claudine Samanic, (1) Jennifer Rusiecki, (2) Mustafa Dosemeci, (1) Lifang Hou, (1) Jane A. Hoppin, (3) Dale P. Sandler, (3) Jay Lubin, (1) Aaron Blair, (1) and Michael C.R. Alavanja (1) (1) Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services Noun 1. Department of Health and Human Services - the United States federal department that administers all federal programs dealing with health and welfare; created in 1979 Health and Human Services, HHS , Bethesda, Maryland Bethesda is an urbanized, but unincorporated, area in southern Montgomery County, Maryland, just Northwest of Washington, D.C. It takes its name from a church located there, the Bethesda Presbyterian Church, built in 1820 and rebuilt in 1850, which in turn took its name from , USA; (2) Uniformed Services University of the Health Sciences The university currently has two mottos: "Learning to Care For Those In Harm's Way" and "Providing Good Medicine In Bad Places." USU School of Medicine With an enrollment of approximately 167 students per class, USU School of Medicine is located in Bethesda, Maryland on the , Department of Preventive Medicine preventive medicine, branch of medicine dealing with the prevention of disease and the maintenance of good health practices. Until recently preventive medicine was largely the domain of the U.S. and Biometrics, Bethesda, Maryland, USA; (3) Epidemiology Branch, National Institute of Environmental Health Sciences The National Institute of Environmental Health Sciences (NIEHS) is one of 27 Institutes and Centers of the National Institutes of Health (NIH),which is a component of the Department of Health and Human Services (DHHS). The Director of the NIEHS is Dr. David A. Schwartz. , National Institutes of Health, Department of Health and Human Services, Research Triangle Park Research Triangle Park, research, business, medical, and educational complex situated in central North Carolina. It has an area of 6,900 acres (2,795 hectares) and is 8 × 2 mi (13 × 3 km) in size. Named for the triangle formed by Duke Univ. , North Carolina, USA Address correspondence to M.C.R. Alavanja, NCI See Liberate. , 6120 Executive Blvd., Room 8000, Rockville, MD 20852 USA. Telephone: (301) 435-4720. Fax: (301) 402-1819. E-mail: alavanjm@mail.nih.gov The authors acknowledge the Iowa (C. Lynch, N. Logsden-Sackett, P. Gillette, and E. Heywood) and North Carolina (C. Knott, M. Pennybacker, and J. Herrington) field stations for conducting the Agricultural Health Study. This research was supported by the Intramural intramural /in·tra·mu·ral/ (-mu´r'l) within the wall of an organ. in·tra·mu·ral adj. Occurring or situated within the walls of a cavity or organ. Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics, and the NIEHS NIEHS National Institute of Environmental Health Sciences (NIH, DHHS) . The authors declare they have no competing financial interests. Received 27 March 2006; accepted 13 July 2006.
Table 1. Selected characteristics of male applicators enrolled in the
Agricultural Health Study categorized by dicamba exposure, 1993-2001
[no. (%)].
Unexposed
Characteristic (n = 19,933)
Age (years)
< 40 7,325 (36.7)
40-49 5,234 (26.3)
50-59 3,855 (19.3)
[greater than or equal to] 60 3,519 (17.7)
Race
White 19,362 (97.1)
Nonwhite 571 (2.9)
State
Iowa 9,911 (49.7)
North Carolina 10,022 (50.3)
Smoking
Never 10,359 (52.0)
Former 4,710 (23.6)
Current 4,864 (24.4)
Education
[less than or equal to] High School 11,005 (55.2)
> High School 8,490 (46.2)
Missing 438 (2.2)
Alcohol consumption (c)
No 7,518 (37.7)
Yes 12,415 (62.3)
Family history, cancer
No 12,332 (61.9)
Yes 7,601 (38.1)
Applicator type
Private 11,822 (59.3)
Commercial 8,111 (40.7)
Own or work on farm (c)
Never 2251 (11.3)
Ever 17,568 (88.1)
Missing 114 (0.6)
Field corn production
No 8,111 (40.7)
Yes 11,822 (59.3)
Soybean production
No 8,403 (42.2)
Yes 11,530 (57.8)
Person-years (total) 148,314.7
Follow-up (years) (d) 7.4 [+ or -] 1.5
Total lifetime days of 345.0 [+ or -] 617.2
pesticide application (d)
Low-exposed (a)
Characteristic (n = 6,116)
Age (years)
< 40 2,059 (33.7)
40-49 1,838 (30.0)
50-59 1,235 (20.2)
[greater than or equal to] 60 984 (16.1)
Race
White 6,094 (99.6)
Nonwhite 22 (0.4)
State
Iowa 5,350 (87.5)
North Carolina 766 (12.5)
Smoking
Never 3,736 (61.2)
Former 1,378 (22.5)
Current 1,002 (16.4)
Education
[less than or equal to] High School 3,042 (49.7)
> High School 2,983 (48.8)
Missing 91 (1.5)
Alcohol consumption (c)
No 1,521 (24.9)
Yes 4,595 (75.1)
Family history, cancer
No 3,510 (57.4)
Yes 2,606 (42.6)
Applicator type
Private 5,277 (86.3)
Commercial 839 (13.7)
Own or work on farm (c)
Never 275 (4.5)
Ever 5834 (95.4)
Missing 7 (0.1)
Field corn production
No 839 (13.7)
Yes 5,277 (86.3)
Soybean production
No 1,324 (21.6)
Yes 4,792 (78.4)
Person-years (total) 44,557.4
Follow-up (years) (d) 7.3 [+ or -] 1.4
Total lifetime days of 278.0 [+ or -] 434.9
pesticide application (d)
High-exposed (b)
Characteristic (n = 15,920)
Age (years)
< 40 5,190 (32.6)
40-49 5,269 (33.1)
50-59 3,349 (21.0)
[greater than or equal to] 60 2,112 (13.3)
Race
White 15,850 (99.6)
Nonwhite 70 (0.4)
State
Iowa 14,693 (92.3)
North Carolina 1,227 (7.7)
Smoking
Never 9,153 (57.5)
Former 3,716 (23.3)
Current 3,051 (19.2)
Education
[less than or equal to] High School 8,175 (51.3)
> High School 7,541 (47.4)
Missing 204 (1.3)
Alcohol consumption (c)
No 3,093 (19.4)
Yes 12,827 (80.6)
Family history, cancer
No 9,201 (57.8)
Yes 6,719 (42.2)
Applicator type
Private 13,679 (85.9)
Commercial 2,241 (14.1)
Own or work on farm (c)
Never 1,281 (8.0)
Ever 1,4615 (91.8)
Missing 24 (0.2)
Field corn production
No 2,241 (14.1)
Yes 13,679 (85.9)
Soybean production
No 3,155 (19.8)
Yes 12,765 (80.2)
Person-years (total) 115,806.4
Follow-up (years) (d) 7.3 [+ or -] 1.4
Total lifetime days of 472.9 [+ or -] 615.6
pesticide application (d)
(a) First tertile of lifetime exposure-days (years of use [+ or -] days
per year). (b) Second and third tertiles of lifetime exposure days.
(c) During enrollment year. (d) Mean [+ or -] SD.
Table 2. Rate ratios and 95% CI for selected cancers by tertiles of
total dicamba lifetime exposure days among male pesticide applicators in
the Agricultural Health Study. (a)
Dicamba exposure
No exposure--referent
Cancer site Cases (n) RR 95% CI
All cancers
No exposure 887 1.00
1 to < 20 227 0.90 0.77-1.05
20 to < 56 254 1.00 0.82-1.11
56 to < 116 169 0.90 0.73-1.03
[greater than or equal to] 116 157 1.02 0.85-1.23
p = 0.69
Colon
No exposure 76 1.00
1 to < 20 9 0.42 0.20-0.85
20 to < 56 20 0.88 0.52-1.50
56 to < 116 13 0.81 0.43-1.51
[greater than or equal to] 116 17 1.42 0.78-2.58
p = 0.10
Lung
No exposure 95 1.00
1 to < 20 14 0.84 0.45-1.54
20 to < 56 11 0.64 0.33-1.26
56 to < 116 12 0.96 0.50-1.85
[greater than or equal to] 116 15 1.47 0.79-2.72
p = 0.13
Prostate
No exposure 343 1.00
1 to < 20 106 1.00 0.80-1.27
20 to < 56 102 0.94 0.74-1.20
56 to < 116 76 0.96 0.73-1.25
[greater than or equal to] 116 67 1.08 0.81-1.46
p = 0.45
Bladder
No exposure 43 1.00
1 to < 20 6 0.51 0.21-1.25
20 to < 56 9 0.66 0.31-1.43
56 to < 116 6 0.59 0.24-1.45
[greater than or equal to] 116 8 0.82 0.36-1.88
p = 0.66
Melanoma
No exposure 32 1.00
1 to < 20 10 0.97 0.46-2.06
20 to < 56 18 1.59 0.84-3.00
56 to < 116 6 0.72 0.29-1.81
[greater than or equal to] 116 6 0.83 0.33-2.13
p = 0.51
Non-Hodgkin lymphoma
No exposure 39 1.00
1 to < 20 18 1.75 0.96-3.21
20 to < 56 14 1.29 0.66-2.53
56 to < 116 7 0.92 0.39-2.16
[greater than or equal to] 116 7 1.19 0.50-2.85
p = 0.92
All hematopoietic (b)
No exposure 82 1.00
1 to < 20 31 1.38 0.89-2.15
20 to < 56 32 1.37 0.87-2.14
56 to < 116 16 0.96 0.54-1.70
[greater than or equal to] 116 17 1.31 0.74-2.31
p = 0.66
Dicamba exposure
Low exposed--referent
Cancer site RR 95% CI
All cancers
No exposure
1 to < 20 1.00
20 to < 56 1.07 0.89-1.28
56 to < 116 0.97 0.79-1.19
[greater than or equal to] 116 1.18 0.94-1.46
p = 0.18
Colon
No exposure
1 to < 20 1.00
20 to < 56 2.07 0.94-4.57
56 to < 116 1.85 0.79-4.37
[greater than or equal to] 116 3.29 1.40-7.73
p = 0.02
Lung
No exposure
1 to < 20 1.00
20 to < 56 0.82 0.36-1.85
56 to < 116 1.29 0.58-2.89
[greater than or equal to] 116 2.16 0.97-4.82
p = 0.02
Prostate
No exposure
1 to < 20 1.00
20 to < 56 0.94 0.72-1.24
56 to < 116 0.95 0.71-1.29
[greater than or equal to] 116 1.10 0.79-1.53
p = 0.45
Bladder
No exposure
1 to < 20 1.00
20 to < 56 1.26 0.44-3.55
56 to < 116 1.11 0.36-3.47
[greater than or equal to] 116 1.39 0.44-4.42
p = 0.66
Melanoma
No exposure
1 to < 20 1.00
20 to < 56 1.65 0.76-3.60
56 to < 116 0.75 0.27-2.07
[greater than or equal to] 116 0.93 0.32-2.71
p = 0.48
Non-Hodgkin lymphoma
No exposure
1 to < 20 1.00
20 to < 56 0.73 0.36-1.48
56 to < 116 0.54 0.22-1.31
[greater than or equal to] 116 0.76 0.30-1.97
p = 0.71
All hematopoietic (b)
No exposure
1 to < 20 1.00
20 to < 56 0.97 0.59-1.59
56 to < 116 0.69 0.37-1.26
[greater than or equal to] 116 0.99 0.53-1.87
p = 0.99
(a) Adjusted for age, state of residence, smoking (pack-years),
education, family history of cancer, and total lifetime days of
pesticide application; upper tertile divided at the median.
(b) Includes leukemia, multiple myeloma, Hodgkin lymphoma, and
non-Hodgkin lymphoma.
Table 3. Rate ratios and 95% CI for selected cancers by tertiles of
dicamba intensity-weighted lifetime exposure days among male pesticide
applicators in the Agricultural Health Study. (a)
Dicamba exposure
No exposure--referent
Cancer site Cases (n) RR 95% CI
All cancers
No exposure 888 1.00
1 to < 86.6 251 0.90 0.80-1.00
86.6 to < 344.25 278 1.00 0.84-1.13
344.25 to < 739.2 131 0.90 0.73-1.08
[greater than or equal to] 739.2 144 1.00 0.82-1.20
p = 0.91
Colon
No exposure 76 1.00
1 to < 86.6 16 0.64 0.36-1.14
86.6 to < 344.25 17 0.70 0.40-1.22
344.25 to < 739.2 6 0.50 0.21-1.17
[greater than or equal to] 739.2 20 1.76 1.00-3.07
p = 0.02
Lung
No exposure 95 1.00
1 to < 86.6 11 0.61 0.31-1.21
86.6 to < 344.25 20 1.07 0.62-1.84
344.25 to < 739.2 10 1.03 0.51-2.08
[greater than or equal to] 739.2 11 1.10 0.56-2.18
p = 0.58
Prostate
No exposure 343 1.00
1 to < 86.6 115 0.97 0.77-1.21
86.6 to < 344.25 110 0.95 0.75-1.20
344.25 to < 739.2 59 1.03 0.77-1.37
[greater than or equal to] 739.2 61 1.11 0.83-1.50
p = 0.38
Bladder
No exposure 43 1.00
1 to < 86.6 6 0.46 0.19-1.11
86.6 to < 344.25 13 0.89 0.45-1.74
344.25 to < 739.2 6 0.77 0.31-1.90
[greater than or equal to] 739.2 4 0.43 0.15-1.25
p = 0.20
Melanoma
No exposure 32 1.00
1 to < 86.6 10 0.84 0.40-1.80
86.6 to < 344.25 18 1.51 0.80-2.84
344.25 to < 739.2 7 1.06 0.45-2.53
[greater than or equal to] 739.2 5 0.77 0.28-2.07
p = 0.60
Non-Hodgkin lymphoma
No exposure 39 1.00
1 to < 86.6 17 1.43 0.77-2.67
86.6 to < 344.25 18 1.55 0.83-2.87
344.25 to < 739.2 4 0.67 0.23-1.91
[greater than or equal to] 739.2 6 1.07 0.43-2.67
p = 0.68
All hematopoietic (b)
No exposure 82 1.00
1 to < 86.6 31 1.22 0.78-1.90
86.6 to < 344.25 35 1.41 0.91-2.18
344.25 to < 739.2 16 1.23 0.69-2.17
[greater than or equal to] 739.2 12 1.00 0.51-1.86
p = 0.81
Dicamba exposure
Low exposed--referent
Cancer site RR 95% CI
All cancers
No exposure
1 to < 86.6 1.00
86.6 to < 344.25 1.11 0.93-1.32
344.25 to < 739.2 1.02 0.82-1.26
[greater than or equal to] 739.2 1.15 0.93-1.43
p = 0.35
Colon
No exposure
1 to < 86.6 1.00
86.6 to < 344.25 1.04 0.52-2.06
344.25 to < 739.2 0.74 0.29-1.91
[greater than or equal to] 739.2 2.57 1.28-5.17
p = 0.002
Lung
No exposure
1 to < 86.6 1.00
86.6 to < 344.25 1.92 0.89-4.11
344.25 to < 739.2 1.90 0.78-4.60
[greater than or equal to] 739.2 2.20 0.90-5.38
p = 0.21
Prostate
No exposure
1 to < 86.6 1.00
86.6 to < 344.25 1.00 0.75-1.27
344.25 to < 739.2 1.07 0.78-1.46
[greater than or equal to] 739.2 1.17 0.84-1.62
p = 0.27
Bladder
No exposure
1 to < 86.6 1.00
86.6 to < 344.25 1.95 0.74-5.13
344.25 to < 739.2 1.70 1.54-5.27
[greater than or equal to] 739.2 0.94 0.26-3.41
p = 0.34
Melanoma
No exposure
1 to < 86.6 1.00
86.6 to < 344.25 1.80 0.83-3.91
344.25 to < 739.2 1.27 0.48-3.35
[greater than or equal to] 739.2 1.00 0.32-2.90
p = 0.54
Non-Hodgkin lymphoma
No exposure
1 to < 86.6 1.00
86.6 to < 344.25 1.08 0.56-2.10
344.25 to < 739.2 0.46 0.15-1.37
[greater than or equal to] 739.2 0.74 0.29-1.93
p = 0.51
All hematopoietic (b)
No exposure
1 to < 86.6 1.00
86.6 to < 344.25 1.13 0.70-1.84
344.25 to < 739.2 1.00 0.54-1.82
[greater than or equal to] 739.2 0.83 0.41-1.66
p = 0.46
(a) Adjusted for age, state of residence, smoking (pack-years),
education, family history of cancer, and total lifetime days of
pesticide application; upper tertile divided at the median.
(b) Includes leukemia, multiple myeloma, Hodgkin lymphoma, and
non-Hodgkin lymphoma.
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