We observed an increased risk of childhood ALL associated with moderate lifetime exposure to several categories of agricultural pesticides, including the target-pest classes of insecticides or fumigants and the toxicological classes of probable or possible carcinogens, developmental or reproductive toxins, genotoxins, suspected endocrine disruptors and anti-cholinesterases. Increased risks were not observed in the highest categories of exposure. A similar exposure-response pattern was observed in single-class models of chlorinated phenols, organophosphates, and triazines. Mutual adjustment for all physicochemical classes led to an overall decrease in precision, but effect estimates tended to remain elevated in the moderate exposure categories. In this model, only azoles suggested an increased risk at the highest level of exposure.
Previous studies of ambient agricultural pesticide exposure and childhood leukemia have observed few elevated risks associated with exposure. An ecologic study in California that used pesticide-use reporting data to estimate pesticide use for census block groups at the time of diagnosis found only an increased incidence of childhood leukemia in areas with the highest use of the herbicide propargite (Reynolds et al., 2002
). In a subsequent case-control study in California that used pesticide-use reporting data to characterize exposure at the birth residence, an increased risk of childhood leukemia was observed in the highest categories of exposure to the thiocarbamate fungicide metam sodium and the organochlorine insecticide dicofol. Effect estimates for exposures to pesticides listed as probable or possible carcinogens also suggested an elevated risk (Reynolds et al., 2005b
). A recent US ecological study of childhood cancer in 25 states (excluding California) found an increased risk of childhood leukemia in counties with greater than 60% of acreage devoted to farming compared with counties with less than 20% acreage devoted to farming (Carozza et al., 2008
). However, this study relied only on crop acreage and was unable to differentiate risks for specific pesticides.
The toxic effects of certain pesticides include oxidative stress, genotoxicity, endocrine disruption, and cholinesterase inhibition, but little is known about what role these effects may play in inducing ALL. There is limited toxicological evidence of a leukemogenic effect from exposure to specific types of agricultural pesticides such as organophosphates (Perry and Soreq, 2004
; Williams et al., 2004
). Previous toxicological studies observed a leukemogenic effect from exposure to isofenphos, an organophosphate insecticide (Boros and Williams, 2001
; Williams et al., 2004
). By design, organophosphates and other anti-cholinesterase compounds inhibit the ability of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) to regulate acetylcholine, leading to an over-accumulation of this neurotransmitter (Krieger, 2001
). Emerging evidence suggests that change in AChE and BuChE activity is associated with tumor development and may play a role in cell proliferation and differentiation, although it is not clear whether this is a cause or consequence of neoplastic processes (Vidal, 2005
). Futhermore, cholinesterase inhibitors may induce amplification of the ACHE and BuChE genes in developing blood cells, a phenomenon associated with the development of leukemia (Lapidot-Lifson et al., 1989
). However, it is unlikely that the organophosphate exposures in this study occurred at levels sufficiently high to induce cholinesterase inhibition, especially when applications of these pesticides in agricultural settings are designed to minimize potential exposure.
The non-monotonic exposure-response pattern observed for some pesticide groups in this study may be due to biological effects related to endocrine disruption and/or competing risks. For endocrine-disrupting chemicals, moderate exposure increases the receptor-mediated response, but the response decreases with high exposure as receptors become saturated (Phillips et al., 2008
; Welshons et al., 2003
). Within the context of competing risks, ALL is only one outcome affected by exposure along a continuum ranging from subfertility to congenital malformations to fetal loss. In this framework, an elevated risk of ALL would be observed at a moderate level of exposure, but at higher levels of exposure, the observed risk would decrease as the risks of more severe outcomes such as malformation or fetal death increase (Selevan and Lemasters, 1987
). However, the lack of an observed association with high exposure may be due to artifacts of the study design such as misclassification in the high exposure category or the use of overly broad categories for grouping pesticides, especially by toxicological class. The classification of pesticides as suspected genotoxins or endocrine disruptors is based on less evidence than in the classification of probable carcinogens, developmental or reproductive toxins, and cholinesterase inhibitors. Consequently, this lower specificity may bias effect estimates for these categories of pesticides toward the null.
Among the unique features of this study was the use of detailed residential histories and existing agricultural pesticide application data to improve the spatial and temporal resolution of exposure assessment, focus on specific exposure time windows, and distinguish exposures between specific pesticide compounds or categories. By integrating these data, we were able to minimize potential exposure misclassification arising from using only a single address (e.g., at birth or diagnosis) to characterize exposure during the time period of interest. The average number of residences between birth and the date of diagnosis or reference among subjects was 2.0 (range: 1-10) and did not appear to differ between cases (mean = 2.1) and controls (mean = 1.9). To minimize the potential for error when assigning locations to residential addresses, we used multiple street geocoding databases. However, residential histories were self-reported by mothers and maybe subject to recall error, especially among residentially mobile older children whose earliest addresses would have preceded the interview by several years. Although we were able to characterize residential mobility during children’s lifetimes, we did not have sufficient prenatal address data available to assess agricultural pesticide exposures during gestation which may be the most critical time period for exposure (Birnbaum and Fenton, 2003
). While we were able to estimate the effects of potential exposure to pesticides grouped into categories of target pests, toxicity, and physicochemical properties, we lacked sufficient power to do so for rarer exposures to specific pesticides.
Our exposure metric assumes that only pesticides applied in sections located within ½-mi of the residence of interest have the potential to drift to the residence and that all pesticides applied in sections within ½-mi resulted in exposure at the residence. We did not include factors that affect the fate and drift potential of pesticides in the environment, such as wind speed and direction at the time of application, the mixing of solvents and adjuvants that may affect the persistence and volatility of the active ingredient, and the application method. We also did not utilize available crop maps that could have improved the spatial resolution of pesticide applications beyond the one square-mile section. Future studies utilizing GIS and existing environmental databases to estimate exposure to agricultural pesticides should incorporate land use and meteorological data in the models (Nuckols et al., 2007
; Rull and Ritz, 2003
; Rull et al., 2006
; Ward et al., 2006
; Ritz and Rull, 2008
Proximity to treated crops has been associated with higher pesticide concentrations in ambient air and house dust (Whitmore et al., 1994
; Baker et al., 1996
; Woodrow et al., 1997
; Teske et al., 2002
; Harnly, 2005
; Weppner et al., 2006
). Whether residential proximity is related to an increased body burden of specific agricultural pesticides is not as clear. Urinary metabolite levels were higher for people living in farm compared to non-farm residences for atrazine and chlorpyrifos, but not glyphosate or metolachlor (Curwin, 2007
). Among children living near treated farmland, one study observed higher urinary concentrations of organophosphate metabolites (Lu, 2000
), but this was not observed in other studies (Fenske et al., 2002
; Koch et al., 2002
; Royster, 2002
). An analysis of urine collected from children of farm workers found that organophosphate metabolites were moderately correlated with house dust levels of the insecticide diazinon but not chlorpyrifos (Bradman et al., 2007
). In other studies, children’s urinary organophosphate metabolite levels were observed to be more strongly correlated with hand wipe samples than house dust (Shalat et al., 2003
; Weppner et al., 2006
). A recent study observed that urinary organophosphate metabolites levels from pregnant women in an agricultural community were significantly higher than those from the general U.S. population. Although diet was found to be the dominant source of organophosphate exposure, the authors attributed this increase to non-dietary exposures from local agricultural pesticide use (McKone, 2007
In summary, our study detected a modest increase in ALL risk with residential proximity to moderate levels of agricultural use of several types of pesticides, but not at higher levels of use. The observed consistency of this association across toxicological and physicochemical classes warrants further exploration in future studies. These studies should have a larger pool of cases and controls to allow for the evaluation of the effects of specific pesticides on ALL, AML, and other leukemia subtypes. Pesticide exposure assessment should account for crop locations and be further refined by including factors that influence the drift potential of agricultural pesticides in the environment, and integrating pesticide exposure from other sources such as diet and home use. In addition, prenatal residential histories should be collected and geocoded in order to characterize exposure during the critical gestational period.