Mahajan et al. exposed applicators with a family history of prostate cancer prevented us from conducting the same analysis among those whose ﬁrst expo- sure was after 1980. The results were consistent with those presented above. For comparison with the previously pub- lished prostate cancer analysis (Alavanja et al. 2003), we repeated the analysis using method- ology comparable to that used in the previ- ously published prostate cancer study. That is, we used logistic regression to calculate odds ratios (OR) among all enrolled male applica- tors without prior history of prostate cancer, categorizing phorate exposure as ever/never. We used the cross product of ever/never phor- ated exposure and family history of prostate cancer to assess effect modification (not shown). We found that the age-adjusted prostate cancer risk was signiﬁcantly elevated in those with a family history of prostate cancer (OR = 1.53; 95% CI, 1.09–2.14; 249 exposed cases), but not in those without (OR = 1.11; 95% CI, 0.95–1.31; 73 exposed cases). The interaction OR was 1.40 (95% CI, 0.96–2.04), adjusted for age and family his- tory of prostate cancer. The corresponding interaction OR from the previous paper was 1.64 (95% CI, 1.02–2.63). Discussion Phorate use was not related to the occurrence of all cancers combined in this study. Although previous studies have observed suggestive increases in the risk of NHL and leukemia asso- ciated with the use of organophosphate pesti- cides (Brown et al. 1990; Cantor et al. 1992; Clavel et al. 1996; Zahm et al. 1993), the risk of lymphohematopoietic cancers overall was not associated with phorate use in this cohort. Too few exposed cases of NHL, leukemia, Hodgkin lymphoma, and multiple myeloma prevented evaluations of these cancers individu- ally. As the lymphohematopoietic grouping may not be etiologically homogeneous, it would be prudent for follow-up studies to examine each cancer separately as more cancer cases develop in the cohort. Prostate cancer risk was not significantly associated with phorate use. However, among applicators reporting a family history of prostate cancer, the risk associated with phor- ate exposure was elevated, whereas there was no corresponding increase among those with- out a family history. An elevated interaction term of similar magnitude was observed in an examination of prostate cancer in an article by Alavanja et al. (2003). The study conducted here is a chemical-speciﬁc analysis carried out on 135 phorate-exposed prostate cancer cases using information on lifetime exposure-days and intensity-weighted lifetime-exposure days to examine dose–response relationships. In contrast, the previously published prostate cancer study was a tumor-speciﬁc analysis and in quantifying phorate use as ever/never use could not examine dose–response trends. In addition, this study was carried out over a longer average follow-up period of 7.5 years, compared with 4.3 years. Despite the analytic differences, the results are generally consistent with the previous paper. Family history of prostate cancer is strongly and consistently linked to prostate cancer in the scientiﬁc literature (Bostwick et al. 2004). For example, monozygotic twins have higher prostate cancer concordance than dizygotic twins (Gronberg et al. 1994). Risk is elevated several-fold in individuals with an affected father or brother (Glover et al. 1998; Spitz et al. 1991; Steinberg et al. 1990; Whittemore et al. 1995) and may increase if a greater num- ber of first-degree relatives are affected (Steinberg et al. 1990). Finally, cancers in indi- viduals with affected family members occur at younger ages compared with individuals with- out affected family members (Bratt et al. 1999; Gronberg et al. 1999). Farming occupa- tion has also been modestly but signiﬁcantly associated with prostate cancer (Blair et al. 1985; Checkoway et al. 1987; Sharma-Wagner Table 3. Incidence RRsa (95% CIs) for prostate cancer by phorate lifetime exposure-days after stratiﬁca- tion by family history of prostate cancer among male AHS (1993–1997) applicators. Lifetime exposure-daysb Cases (n) Nonexposed reference Lowest exposed reference No family history 0 > 0–8.75 > 8.75–24.5 > 24.5 p-Trend Family history 0 > 0–8.75 > 8.75–24.5 > 24.5 p-Trend Interactionc 1208 270 49 35 35 56 10 11 17 1.00 1.01 (0.74–1.39) 1.05 (0.73–1.51) 0.91 (0.64–1.30) 0.66 1.00 0.69 (0.35–1.39) 1.27 (0.65–2.49) 1.48 (0.85–2.58) 0.11 1.18 (0.96–1.44) 1.00 1.03 (0.67–1.60) 0.92 (0.59–1.43) 0.69 1.00 1.90 (0.80–4.50) 1.91 (0.86–4.24) 0.16 1.53 (0.99–2.37) p-Trend, p-value for trend test. aRRs adjusted for age and state of residence. bLifetime exposure-days = years of use × days of use per year. cRR and 95% CI for the cross product of family history of prostate cancer and lifetime exposure-days category, adjusted for age, state of residence, and family history of prostate cancer. et al. 2000; van der Gulden and Vogelzang 1996; Van Maele-Fabry and Willems 2004). In particular, the results of several studies suggest that this association may be caused by exposure to pesticides (Potti et al. 2003). Signiﬁcant asso- ciations were found specifically among those individuals who were ever employed in the mixing and application of pesticides (Fleming et al. 1999; Settimi et al. 2001), and cancer risk increased with both the number of days of pes- ticides applied per year (van der Gulden et al. 1995) and the number of acres sprayed with herbicides in 1 year (Morrison et al. 1993). Although a number of exposures shared in common between study subjects and their ﬁrst- degree relatives could lead to a statistical inter- action between phorate use and family history of prostate cancer, the presence of family his- tory of prostate cancer may serve as a surrogate for an inherited genetic trait, such as a polymor- phism in a metabolism enzyme. The active form of most organophosphates, including phorate and chlorpyrifos, is the corresponding oxon (Pope 1999; Sultatos 1994), and both of these insecticides are metabolized using many of the same enzymes (Tang et al. 2001; Usmani et al. 2004). Polymorphic variants of several cytochrome P450 isoforms vary considerably in their ratio of bioactivation to detoxiﬁcation of chlorpyrifos (Dai et al. 2001; Tang et al. 2001). Thus, it is possible that the observation of an interaction of family history and phorate expo- sure reﬂects the presence of an inherited poly- morphism that alters the balance between bioactivation and detoxiﬁcation in the body. There are some limitations of this study. At this time, investigation of certain cancers is hindered by small numbers of exposed cases, making it difficult to analyze some cancers. However, as the cohort ages, more cancer cases will accrue and allow for more statistically powerful investigations. Additionally, some exposure misclassification is likely, although there is no reason to believe that it occurred differentially between cancer cases and cancer- free subjects, because exposure information was gathered prior to disease onset. Another general limitation of studies of pes- ticide applicators is that few applicators are exposed to one agent. To attempt to control for potential confounding from other pesticides, the risk estimates were adjusted for use of the five pesticides most correlated with phorate. However, the use of other pesticides did not likely confound the observed relationships because the correlation coefficients, which ranged between 0.36 for butylate and 0.39 for aldicarb, were not very high. Moreover, risk estimates were similar when they were adjusted for cumulative lifetime exposure-days to all pes- ticides. An examination of pesticide usage and speciﬁc farming activities found that these activ- ities likely resulted in minimal confounding (Coble et al. 2002). VOLUME 114 | NUMBER 8 | August 2006 • Environmental Health Perspectives