Children’s Health | Pierik et al. parents of controls, differential reporting between cases and controls may have occurred. However, several reasons argue against infor- mation bias explaining the observed associa- tions. First, the increased cryptorchidism risk for self-reported pesticide exposure (OR = 2.8) was conﬁrmed by the independent JEM-based pesticide exposure (OR = 4.5). Unfortunately, no JEM judgment was available to validate self-reported solvent exposure. Second, parents were not informed about potential risk factors or the JEM classiﬁcation. Third, the agreement between self-reported and JEM exposures was not different between cases and controls. The JEM was developed for a study on occupational risk factors for hypospadias, with a focus on EDs (Van Tongeren et al. 2002; Vrijheid et al. 2003). The interexpert agree- ment among the industrial hygienists develop- ing the JEM was good for pesticides (κ = 0.77) (Van Tongeren et al. 2002). Although the JEM may misclassify occupational exposures, nondifferential misclassiﬁcation leads to atten- uation of the ORs when both the outcome and the determinant are dichotomous variables (Chen 1989; Greenland 1980), and cannot explain the observed association between cryp- torchidism and JEM-based pesticide exposure. Some studies have reported on the associa- tion between occupational exposure and birth defects. Paternal solvent exposure has been asso- ciated with cleft palate, neural tube defects, and preterm birth (Kristensen et al. 1993; Olshan et al. 1991). A study among gardener and farmer families applying pesticides reported an increased risk of cryptorchidism and hypo- spadias in their offspring (Kristensen et al. 1997) but could not distinguish paternal from maternal exposure. Another study observed an increased risk of cryptorchidism in sons of female gardeners and farmers but not in sons of men working in farming or gardening (Weidner et al. 1998). Neither paternal nor maternal occupation was associated with hypospadias. Because exposure assessment was limited to job title, limited information was available on the role of speciﬁc occupational exposures, such as pesticide use (Weidner et al. 1998). It remains to be established whether the associations between external agents and cryp- torchidism and hypospadias are causal or based on confounding (e.g., by unknown but related occupational risk factors). Several plausible biologic mechanisms that could mediate the observed effects of paternal smoking and occupational exposure on the offspring have, however, been described. There is growing human evidence that pater- nal environmental factors around the time of fertilization play a role after fertilization. More than 100 chemicals, including pesti- cides and solvents, have been related to male- mediated adverse reproductive outcomes (Davis et al. 1992). Animal studies provide 1574 extensive evidence for male-mediated develop- mental effects (i.e., spontaneous abortions, growth retardation, malformations, and behavioral abnormalities) of environmental agents (Robaire and Hales 2003). Several modes of action of chemicals have been shown, the most likely being genetic (e.g., germline DNA modification) or epigenetic (e.g., DNA repair, chromatin structure, apop- tosis) effects on germ cells, whereas exposure of the oocyte or embryo to contaminated sem- inal fluid could also play a role (Davis et al. 1992; Robaire and Hales 2003). A study in mice demonstrated that environmental pollu- tion resulted in DNA mutations that were inherited by the offspring, primarily through the paternal germline (Somers et al. 2002). On the basis of the xenoestrogen hypothe- sis (Sharpe 2003), we anticipated that maternal exposure to EDs during fetal life could be a causal pathway leading to cryptorchidism and hypospadias. As of yet, few human data are available to conﬁrm or refute this hypothesis. We did not ﬁnd an association between mater- nal occupational exposure and either abnor- mality, perhaps due to the small proportion of exposed mothers. A previous study reported a maternal vegetarian diet as a risk factor for hypospadias and suggested a higher phyto- estrogen intake as explanation (North and Golding 2000). We speciﬁcally assessed dietary phytoestrogen intake, which was not a sig- nificant risk factor for hypospadias or cryp- torchidism. However, the nutrition data may suffer from inaccuracies because nutrition was assessed only once, whereas considerable intrain- dividual variation has been described with food- frequency questionnaires (Goldbohm et al. Table 2. Univariate analysis of the association between paternal risk factors and the occurrence of cryptorchidism and hypospadias in a case–control study among 326 father–child pairs. Controls Cryptorchidism (n = 50) Cases OR (95% CI) Hypospadias (n = 41) Cases OR (95% CI) Variable Age (years) < 25 25–30 30–35 > 35 Height (cm) < 175 175–180 180–185 > 185 Educational level Low Intermediate High Country of origin Netherlands Morocco Turkey Surinam Other Good general health Yes No Current smoker Yes No Paid employment Yes No Probable exposure to potential EDs (JEM) Yes No Probable exposure to pesticides (JEM) Yes No Self-reported exposure to pesticides Yes No Self-reported exposure to solvents Yes No *p < 0.05. 19 43 64 109 59 42 48 82 59 89 85 127 16 16 31 46 205 30 98 138 209 27 38 198 7 229 9 227 45 191 10 6 19 15 14 9 12 15 19 13 18 26 6 11 2 5 39 10 22 27 41 8 13 37 6 44 5 45 16 34 1.0 0.3* (0.1–0.8) 0.6 (0.2–1.4) 0.3* (0.1–0.7) 1.0 0.9 (0.4–2.3) 1.1 (0.5–2.5) 0.8 (0.4–1.7) 1.0 0.5* (0.2–1.0) 0.7 (0.3–1.4) 1.0 1.8 (0.6–4.9) 3.4* (1.4–8.1) 0.3 (0.1–1.1) 0.5 (0.2–1.4) 1.0 1.8 (0.8–3.9) 1.2 (0.6–2.1) 1.0 0.7 (0.3–1.6) 1.0 1.8 (0.9–3.8) 1.0 4.5* (1.4–13.9) 1.0 2.8 (0.8–8.5) 1.0 2.0* (1.0–3.9) 1.0 5 12 8 16 12 5 11 14 12 25 5 25 2 7 3 5 34 7 29 12 37 5 10 32 1 41 1 41 15 27 1.0 1.1 (0.3–3.4) 0.5 (0.1–1.6) 0.6 (0.2–1.7) 1.0 0.6 (0.1–1.8) 1.1 (0.5–2.8) 0.8 (0.4–2.0) 1.0 1.4 (0.6–4.0) 0.3* (0.1–0.9) 1.0 0.6 (0.1–2.4) 2.2 (0.8–5.8) 0.5 (0.1–1.5) 0.6 (0.2–1.4) 1.0 1.4 (0.6–3.5) 3.4* (1.7–7.0) 1.0 1.0 (0.3–3.6) 1.0 1.6 (0.7–3.6) 1.0 0.8 (0.3–3.6) 1.0 0.6 (0.0–3.4) 1.0 2.4* (1.2–4.8) 1.0 VOLUME 112 | NUMBER 15 | November 2004 • Environmental Health Perspectives