hypospadias (OR = 3.0), but no interaction with age was identified. When also taking into account the characteristics of the father, current smoking of the father was a strong risk factor (OR = 3.8). The risk for self- reported exposure to solvents among fathers was elevated (OR = 2.0) but of borderline sig- nificance (p = 0.09). This risk factor was included because it influenced the risk esti- mates of time to pregnancy, because of the moderate association between time to preg- nancy and solvent exposure. When manually entered into the multivariate model, the risk estimates for maternal and paternal occupa- tional exposures and dietary phytoestrogens (that were not selected by the stepwise proce- dure) were very similar to their univariate effects, except for a reduced risk associated with self-reported maternal exposure to pesti- cides (OR = 1.1; 95% CI, 0.2–6.2) and an increased risk associated with lignan intake of 4–6 g/day (OR = 1.5; 95% CI, 0.6–3.5) and < 4 g/day (OR = 1.7; 95% CI, 0.7–3.9). Discussion This study reports the novel ﬁndings that pater- nal pesticide exposure is a risk factor for cryptorchidism and that paternal smoking is associated with hypospadias in the offspring. A strength of the study is that the results are based on a case–control study nested within a large birth cohort in the general population of Rotterdam. Because 95% of all consecutive newborn boys in Rotterdam were prospectively subjected to a standardized examination of the external genitalia, bias in case identiﬁcation by exposure is unlikely. The prevalence of 1.1% cryptorchidism and 0.8% hypospadias in our population has been described elsewhere and is within the range reported by comparable studies (Pierik FH et al., unpublished data; Pierik et al. 2002). A good accuracy of the diagnosis of both abnormalities by CHC physicians is expected because of the standardized and sys- tematic examination of a birth cohort. A high accuracy (88% verification) of the hypospa- dias diagnosis by CHC physicians has been Controls Cryptorchidism (n = 78) Cases OR (95% CI) Hypospadias (n = 56) Cases OR (95% CI) *p < 0.05. **Signiﬁcant trends were observed for maternal height with cryptorchidism and hypospadias (OR = 0.67 and 0.52 per 10 cm height increase, respectively) and birth weight and hypospadias (OR = 0.91 per 100 g of body weight increase). Environmental Health Perspectives • VOLUME 112 | NUMBER 15 | November 2004 Table 1. Continued Variable Premature birth Yes No Primiparous Yes No Folic acid supplements in pregnancy Yes No Vegetable-rich diet Yes No Soy protein intake ≥ 20 g/day > 0–20 g/day 0 g/day Lignan intake ≥ 6 g/day 4–6 g/day < 4 g/day Paid employment Yes No Probable exposure to 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 25 288 162 151 179 134 125 186 51 41 221 115 119 79 213 100 24 289 7 306 4 309 32 281 14 64 44 34 35 43 24 54 8 12 58 23 31 24 46 32 6 72 2 76 2 76 6 72 2.5* (1.2–5.1) 1.0 1.2 (0.7–2.0) 1.0 0.6 (0.4–1.0) 1.0 0.7 (0.4–1.1) 1.0 0.6 (0.3–1.3) 1.1 (0.6–2.3) 1.0 0.7 (0.4–1.3) 0.9 (0.5–1.6) 1.0 0.7 (0.4–1.1) 1.0 1.0 (0.4–2.6) 1.0 1.2 (0.2–4.9) 1.0 2.0 (0.3–10.6) 1.0 0.7 (0.3–1.8) 1.0 8 48 25 31 32 24 17 39 9 8 39 22 19 15 31 25 3 53 2 54 1 55 9 47 1.9 (0.8–4.5) 1.0 0.8 (0.4–1.3) 1.0 1.0 (0.6–1.8) 1.0 0.7 (0.4–1.2) 1.0 1.0 (0.5–2.2) 1.1 (0.5–2.5) 1.0 1.0 (0.5–2.1) 0.8 (0.4–1.8) 1.0 0.6 (0.3–1.0) 1.0 0.7 (0.2–2.0) 1.0 1.6 (0.2–6.9) 1.0 1.4 (0.1–9.7) 1.0 1.7 (0.8–3.8) 1.0 Children’s Health | Cryptorchidism and hypospadias study demonstrated previously (Pierik et al. 2002), whereas the accuracy of cryptorchidism diag- nosis was not assessed. Because the case status was assessed prospectively before data on deter- minants were collected, the misclassiﬁcation by CHC physicians is probably nondifferential, which would bias the results toward unity in our analyses. Resources were insufficient to have CHC physicians report the exact location of the urethral opening and the left and right testis for the nearly 9,000 subjects. Another strength of the present study is that both maternal and paternal determinants were included. A weakness of the study is that the paternal determinants were missing for 26% (n = 116) of the subjects, and in the subjects with paternal information, the paternal deter- minants were presented by the fathers them- selves in only 28% (n = 91). Differential misclassiﬁcation between mothers and fathers on self-reported paternal exposure to solvents cannot be ruled out because fathers and moth- ers reported a paternal exposure prevalence of 31 and 20%, respectively. However, the hypospadias risk for paternal solvent exposure reported by the father (OR = 1.9; 95% CI, 0.6–6.2) or mother (OR = 2.5; 95% CI, 1.0–6.2) was comparable in size, although the 95% CI was wider in these smaller subsets. For other paternal occupational exposures and lifestyle factors, such as smoking and alcohol use, no differences were observed between reporting mothers and fathers. The multivariate analyses suggest an important role of paternal smoking and occu- pational exposures. Paternal smoking was significantly associated with hypospadias (OR = 3.8; Table 4). Paternal smoking has previously been associated with the occur- rence of single and multiple birth defects (Zhang et al. 1992), but not speciﬁcally with hypospadias. Paternal smoking could have an effect through passive exposure of the mother, but this is unlikely because active smoking by the mother was not a risk factor. We cannot exclude that mothers have underreported their smoking. When mothers of cases under- report their own smoking more than that of their partner, paternal smoking may partly be a spurious risk factor. After correction for other significant risk factors, paternal pesticide exposure based on the JEM was significantly associated with cryptorchidism (OR = 3.8; Table 3), and self- reported paternal solvent exposure was border- line associated with hypospadias (OR = 2.0; Table 4). The exposure classiﬁcations of sol- vents and pesticides were too broad to allow identiﬁcation of speciﬁc (groups of) chemical agents to be held responsible for the increased risks of either anomaly. Because parents of cryp- torchidism and hypospadias cases may have been more concerned with and knowledgeable about environmental risk factors than were 1573