Agricultural Pesticide Use and Hypospadias in Eastern Arkansas
Meyer, Kristy J., Reif, John S., Veeramachaneni, D. N. Rao, Luben, Thomas J., Mosley, Bridget S., Nuckols, John R., Environmental Health Perspectives
INTRODUCTION: We assessed the relationship between hypospadias and proximity to agricultural pesticide applications using a GIS-based exposure method.
METHODS: We obtained information for 354 cases of hypospadias born between 1998 and 2002 in eastern Arkansas; 727 controls were selected from birth certificates. We classified exposure on pounds of pesticides (estimated by crop type) applied or persisting within 500 m of each subject's home during gestational weeks 6 to 16. We restricted our analyses to 38 pesticides with some evidence of reproductive, developmental, estrogenic, and/or antiandrogenic effects. We estimated timing of pesticide applications using crop phenology and published records.
RESULTS: Gestational age at birth [odds ratio (OR) = 0.91; 95% confidence interval (CI), 0.83-0.99], parity (OR = 0.79; 95% CI, 0.65-0.95), and delaying prenatal care until the third trimester (OR = 4.04; 95% CI, 1.46-11.23) were significantly associated with hypospadias. Risk of hypospadias increased by 8% for every 0.05-pound increase in estimated exposure to diclofopmethyl use (OR = 1.08; 95% CI, 1.01-1.15). Pesticide applications in aggregate (OR = 0.82; 95% CI, 0.70-0.96) and applications of alachlor (OR = 0.56; 95% CI, 0.35-0.89) and permethrin (OR = 0.37; 95% CI, 0.16-0.86) were negatively associated with hypospadias.
CONCLUSIONS: Except for diclofop-methyl, we did not find evidence that estimated exposure to pesticides known to have reproductive, developmental, or endocrine-disrupting effects increases risk of hypospadias. Further research on the potential effects of exposure to diclofop-methyl is recommended.
KEY WORDS: endocrine disruption, exposure assessment, hypospadias, male urogenital disorders, pesticides. Environ Health Perspect 114:1589-1595 (2006). doi:10.1289/ehp.9146 available via http://dx.doi.org/ [Online 6 July 2006]
Several studies suggest that the incidence of developmental and acquired abnormalities of the male urogenital system, including testicular cancer and cryptorchidism, has increased since 1970 (Giwercman et al. 1993; Paulozzi 1999). A concurrent worldwide increase in the production and use of synthetic chemicals including pesticides suggests that environmental factors may be at least partly responsible (Toppari et al. 1996). The evidence that incidence of specific birth defects such as hypospadias is increasing is less clear; hypospadias incidence was found to be unchanged in California between 1984 and 1997 (Carmichael et al. 2003). Androgen levels are critical in the development of male external genitalia (Baskin 2004). Estrogenic and antiandrogenic substances can disturb normal urogenital development by disrupting hormone dependent pathways (Steinhardt 2004). This can lead to impaired Sertoli and/or Leydig cell function, resulting in manifestations such as hypospadias, cryptorchidism, and testicular cancer, collectively termed testicular dysgenesis syndrome (Skakkebaek et al. 2001).
Hypospadias is a congenital malformation of the urethra with a multifactorial etiology. In children with hypospadias, the urethral opening occurs along the ventral side of the penis or on the scrotum (Baskin 2004). Defects of the male reproductive system, including hypospadias, have been produced experimentally in animal models by prenatal and perinatal administration of pesticides with estrogenic and/or antiandrogenic properties (Gray et al. 2001; Hotchkiss et al. 2004; Ostby et al. 1999a, 1999c; Wolf et al. 1999). A dose-response relationship between perinatal administration of the fungicide procymidone, an androgen receptor antagonist, and hypospadias among male offspring was noted in rats (Ostby et al. 1999b). Perinatal exposure to vinclozolin, another fungicide with antiandrogenic properties, also produced hypospadias in the male offspring of treated rats at relatively low doses (Ostby et al. 1999c). Epidemiologic studies of pesticide exposure and hypospadias have had inconsistent findings but have suffered from weaknesses in study design and exposure assessment (Bianca et al. …