Carozza et al. Hodgkin lymphoma (OR = 1.4; 95% CI, 1.1–1.8), and osteosarcoma (OR = 1.4; 95% CI, 1.1–1.9). Several childhood cancers showed increased risk for pairs of crops. There was increased risk of non-Hodgkin lymphoma associated with residence at diagnosis in counties that pro- duced either corn or oats, with the risk esti- mates equivalent for both crops (ORcorn = 1.5; 95% CI, 1.1–1.8; ORoats = 1.5; 95% CI, 1.1–2.1). Thyroid cancer risk also was elevated for both corn- and oat-producing counties, again with the risk estimates roughly equiva- lent (ORcorn = 1.6; 95% CI, 1.1–2.3; ORoats = 2.0; 95% CI, 1.2–3.4). Neuroblastomas and Wilms’ tumors showed increased risk for both corn (ORneuroblastoma = 1.3; 95% CI, 1.1–1.5; ORWilm’s tumor = 1.4; 95% CI, 1.1–1.7) and soybean (ORneuroblastoma = 1.3; 95% CI, 1.1–1.6; ORWilms’ tumor = 1.4; 95% CI, 1.1–1.7) production areas. Again, the risk esti- mates for the individual cancers were equiva- lent for both crops. Last, retinoblastoma risk was increased for both oats (OR = 1.6; 95% CI, 1.1–2.3) and soybean (OR = 1.4; 95% CI, 1.1–1.8) crops. Corn and soybeans were produced in sufﬁ- cient quantities in our study area to allow for an evaluation of risk associated with residence at diagnosis in counties with > 50% of the total county cropland dedicated to growing one or the other compared with counties not growing that crop and having < 20% total cropland. In general, risk estimates increased, and more reached statistical signiﬁcance with this more conservative deﬁnition of exposure (data not shown). Discussion Our study results indicate an increased risk for many types of childhood cancers associ- ated with residence at diagnosis in counties having a moderate to high level of agricultural activity, with a remarkably consistent dose–response effect seen for counties having ≥ 60% of the total county acreage devoted to farming. Further, the ﬁnding that patterns of risk for individual cancers varied by crop type suggests that the development of different childhood cancers is likely to be related to speciﬁc pesticides. A variety of chemical classes are repre- sented by the pesticides applied to the six crops evaluated (Table 6). These data are taken from the NASS Agricultural Chemical Use Database (USDA 2006). Five of the six selected crops had one or more agricultural chemicals applied that have been designated by the U.S. Environmental Protection Agency as a possible carcinogen (U.S. EPA 2004). Very few epidemiologic studies have been able to evaluate cancer risk in general and childhood cancer risk in particular for speciﬁc agricultural chemicals. In two studies based in California, Reynolds et al. (2002, 2005) used information from California’s Department of Pesticide Regulation to examine risk associ- ated with individual pesticides. The authors reported that neither analysis (one ecologic and one case–control) found consistent pat- terns of elevated risk for speciﬁc pesticides nor for classes of pesticides; however, only total cancers, leukemias, and central nervous sys- tem tumors were analyzed. Many of our more striking increased risk estimates were seen for cancers other than these leading types. Epidemiologic studies have linked pesticide exposure to increased risk of several kinds of childhood cancers, generally through measure- ment of parental occupational exposures and/or residential pesticide use. Childhood leukemias and central nervous system tumors have been studied most extensively, perhaps because they are the more common types of what is a rela- tively rare disease, so the bulk of the epidemio- logic evidence for a pesticide risk to children relates to these cancers. As noted in recent reviews, although study results have been mixed, overall this association has been most consistent for leukemias (Nasterlack 2006; Zahm and Ward 1998). Various studies have reported an elevated risk of brain tumors in farmers, with a recent meta-analysis ﬁnding an overall OR of 1.30 (95% CI, 1.09–1.56) for brain cancer and farming (Khuder et al. 1998). Several studies of farm-related exposures among Table 4. Estimated ORs (95% CIs) by age groups for childhood cancers associated with residence at diagnosis in agriculturally intense counties in the U.S. NAACCR, 1995–2001, ICCC major sites and selected subgroups. Age 0 Age 1–4 Age 5–9 Age 10–14 Cancer type Mediuma Highb Mediuma Highb Mediuma Highb Mediuma Highb All cancers 0.9 (0.8–1.0) 1.0 (0.8–1.1) 1.0 (1.0–1.1) 1.1 (1.0–1.2) 1.0 (0.9–1.1) 1.0 (0.9–1.1) 1.0 (0.9–1.0) 1.1 (1.0–1.2) Leukemias 1.0 (0.8–1.3) 0.6 (0.3–1.1) 1.0 (0.9–1.1) 1.3 (1.1–1.5) 1.0 (0.9–1.1) 1.1 (0.9–1.3) 0.9 (0.8–1.1) 1.1 (0.9–1.4) Lymphoid leukemias 1.1 (0.8–1.6) 0.4 (0.1–1.0) 1.0 (0.9–1.1) 1.4 (1.2–1.6) 1.0 (0.8–1.1) 1.1 (0.9–1.4) 1.0 (0.8–1.1) 1.3 (1.1–1.7) Acute myeloid leukemias 1.1 (0.7–1.7) 1.6 (0.7–3.5) 1.1 (0.9–1.5) 2.1 (1.4–3.2) 1.6 (1.1–2.2) 1.7 (0.9–3.0) 1.2 (0.9–1.5) 1.6 (1.0–2.6) Lymphomas 1.2 (0.7–2.3) 1.9 (0.7–4.7) 1.2 (1.0–1.6) 1.1 (0.7–1.9) 1.0 (0.8–1.2) 1.2 (0.8–1.6) 1.1 (0.9–1.2) 1.6 (1.3–2.0) Hodgkin lymphoma 2.6 (0.4–15.7) — 1.7 (0.8–3.5) 0.8 (0.1–6.0) 1.2 (0.8–1.7) 1.7 (0.9–3.2) 1.3 (1.1–1.6) 2.2 (1.7–3.0) Non-Hodgkin lymphoma 1.2 (0.4–3.7) 3.2 (0.7–14.1) 1.4 (0.9–2.0) 1.9 (1.0–3.7) 1.1 (0.8–1.5) 1.7 (1.0–2.8) 1.0 (0.8–1.3) 2.5 (1.7–3.6) Central nervous system 1.1 (0.8–1.4) 1.0 (0.7–1.7) 1.0 (0.9–1.2) 1.4 (1.2–1.7) 1.0 (0.9–1.1) 1.1 (0.9–1.4) 1.2 (1.0–1.3) 1.3 (1.1–1.6) Astrocytomas 0.7 (0.5–1.2) 1.0 (0.5–2.0) 1.1 (0.9–1.3) 1.5 (1.1–2.0) 1.1 (0.9–1.3) 1.4 (1.0–1.8) 1.2 (1.0–1.4) 1.7 (1.4–2.2) PNET 1.6 (1.0–2.7) 2.2 (1.0–5.1) 1.2 (0.9–1.5) 2.3 (1.5–3.4) 1.1 (0.9–1.4) 1.7 (1.2–2.6) 1.3 (0.9–1.7) 1.6 (0.9–2.7) Sympathetic nervous system 1.0 (0.8–1.3) 1.8 (1.3–2.5) 1.2 (1.0–1.4) 1.8 (1.4–2.4) 1.3 (0.9–1.9) 1.2 (0.6–2.3) 1.3 (0.7–2.3) 1.3 (0.5–3.6) Neuroblastomas 1.0 (0.8–1.3) 1.9 (1.4–2.5) 1.2 (1.0–1.4) 1.8 (1.4–2.4) 1.4 (0.9–1.9) 1.3 (0.7–2.6) 1.2 (0.6–2.4) 0.9 (0.2–3.7) Retinoblastoma 1.3 (0.9–1.8) 2.6 (1.6–4.2) 1.2 (0.9–1.6) 2.3 (1.5–3.6) 1.1 (0.4–3.3) 6.7 (2.5–18.1) — — Renal tumors 1.4 (1.0–2.0) 2.7 (1.7–4.5) 1.3 (1.1–1.5) 2.1 (1.6–2.7) 1.3 (1.0–1.8) 1.8 (1.1–3.0) 1.5 (0.9–2.6) 2.3 (1.0–5.3) Wilms’ tumor 1.5 (1.0–2.1) 2.5 (1.4–4.2) 1.3 (1.1–1.6) 2.1 (1.6–2.8) 1.3 (0.9–1.7) 1.9 (1.2–3.1) 1.5 (0.7–3.5) 2.4 (0.7–8.1) Renal carcinoma 0.8 (0.1–6.6) 7.4 (1.5–35.5) 1.9 (0.2–18.1) — 4.6 (1.4–15.2) — 2.2 (1.0–4.8) 3.3 (1.0–11.1) Hepatic tumors 1.7 (1.1–2.8) 2.1 (0.9–5.3) 1.6 (1.0–2.4) 4.6 (2.7–8.0) 2.0 (0.8–4.7) 4.7 (1.4–16.1) 1.3 (0.5–3.2) — Hepatoblastoma 1.7 (1.0–2.8) 2.4 (1.0–6.0) 1.7 (1.1–2.6) 4.7 (2.6–8.5) 2.3 (0.7–7.5) 10.6 (2.9–39.3) 1.0 (0.1–8.7) — Malignant bone tumors — 6.1 (0.6–58.4) 1.7 (0.9–3.2) 0.6 (0.1–4.0) 1.5 (1.1–2.0) 3.0 (2.0–4.5) 1.1 (0.9–1.4) 2.1 (1.6–2.8) Osteosarcoma — — 2.7 (0.9–8.4) — 1.5 (1.0–2.2) 2.1 (1.0–4.2) 1.2 (0.9–1.5) 3.0 (2.1–4.2) Ewing’s sarcoma — 34.6 (2.2–553.3) 2.3 (1.1–4.7) 1.5 (0.2–11.0) 2.3 (1.5–3.6) 7.4 (4.2–13.3) 1.6 (1.1–2.1) 3.3 (2.0–5.5) Soft-tissue sarcomas 1.1 (0.8–1.7) 1.5 (0.8–2.9) 1.2 (0.9–1.5) 1.6 (1.1–2.3) 1.5 (1.2–1.9) 2.1 (1.4–2.9) 1.2 (1.0–1.5) 1.5 (1.0–2.1) Rhabdomyosarcomas 1.3 (0.7–2.4) 2.5 (1.0–6.4) 1.3 (1.0–1.7) 2.6 (1.7–3.9) 1.6 (1.2–2.2) 2.8 (1.7–4.7) 1.7 (1.2–2.3) 2.0 (1.1–3.6) Germ cell, etc.c 1.1 (0.7–1.8) 2.5 (1.3–4.5) 1.7 (1.1–2.6) 0.9 (0.3–2.5) 1.3 (0.8–2.1) 3.3 (1.8–6.0) 1.2 (0.9–1.6) 2.5 (1.7–3.7) Carcinomas and otherd 0.6 (0.3–1.4) 0.8 (0.2–3.1) 1.2 (0.6–2.3) 0.9 (0.2–3.8) 1.2 (0.8–1.8) 1.2 (0.6–2.6) 1.2 (1.0–1.4) 2.8 (2.1–3.6) Thyroid carcinoma 6.1 (0.9–43.6) — 1.0 (0.1–8.4) — 1.8 (0.9–3.6) 1.8 (0.6–6.0) 1.7 (1.2–2.4) 3.5 (2.3–5.4) Malignant melanoma 1.0 (0.2–4.6) — 3.3 (1.3–8.2) 4.6 (1.0–20.1) 1.1 (0.4–2.7) 2.1 (0.5–8.6) 1.6 (1.0–2.4) 5.9 (3.7–9.3) Other and unspeciﬁed 2.4 (0.8–7.3) 24.5 (7.1–85.4) 5.9 (2.7–12.8) — 4.8 (2.0–11.6) 16.6 (3.7–73.5) 0.6 (0.1–2.5) 7.9 (1.9–33.3) Abbreviations: —, no cases; PNET, primitive neuroectodermal tumor. a20% to < 60% of total county acreage in cropland. b ≥ 60% of total county acreage in cropland. cGerm cell, trophoblastic, and other gonadal neoplasms. dCarcinomas and other malignant epithelial neoplasms. 562 VOLUME 116 | NUMBER 4 | April 2008 • Environmental Health Perspectives