Alachlor Use and Cancer Incidence in the Agricultural Health Study: An Updated Analysis

Alachlor Use and Cancer Incidence in the Agricultural Health Study: An Updated Analysis Abstract Background The herbicide alachlor has been widely used in US agriculture since its introduction in 1969. Experimental animal studies show that alachlor causes tumors in vivo; however, few epidemiologic studies have examined associations with human cancer risk. We evaluated alachlor use and cancer incidence in the Agricultural Health Study, updating an earlier analysis that suggested associations with lymphohematopoietic cancers with an additional 540 142 person-years of follow-up and 5113 cancer cases. Methods Pesticide applicators in Iowa and North Carolina reported lifetime alachlor use at enrollment (1993–1997) and follow-up (1999–2005). Exposure was characterized by cumulative intensity-weighted days. We estimated relative risks (RRs) and 95% confidence intervals (CIs) using Poisson regression for incident cancers from enrollment through 2012(NC)/2013(IA). Models adjusted for age, tobacco, alcohol, and other pesticides. All statistical tests are two-sided. Results Among 49 685 applicators, 25 640 (51.6%) used alachlor, with 3534 alachlor-exposed cancers. The relative risks of laryngeal cancer (nexposed = 34) increased in the second (RR = 4.68, 95% CI = 1.95 to 11.23), third (RR = 6.04, 95% CI = 2.44 to 14.99), and fourth quartiles (RR = 7.10, 95% CI = 2.58 to 19.53) of intensity-weighted days of use compared with no use (Ptrend = .001). Risk of myeloid leukemia was elevated, though not statistically significantly so, in the fourth quartile of intensity-weighted days of use (RR = 1.82, 95% CI = 0.85 to 3.87, Ptrend = .17). Conclusions We observed a strong positive association with use of alachlor and laryngeal cancer and a weaker association with myeloid leukemia. The strength and robustness of the association with laryngeal cancer suggests that long-term occupational exposure to alachlor may be a risk factor for laryngeal cancer. This first report requires confirmation. Alachlor is a chloroacetanilide herbicide registered for use primarily on corn and soybeans in the United States (1). From its registration in 1969 through the mid-1990s, alachlor was among the most widely used agricultural pesticides (55–60 million pounds per year in the late 1980s). Alachlor and its metabolites are mobile and moderately persistent in the environment, and have been detected in groundwater, streams, and rivers despite declining use, indicating potential for broad population exposures (1–4). Alachlor has acute toxicity (5,6), and in 1986 the US Environmental Protection Agency (EPA) classified alachlor as a probable human carcinogen based primarily on evidence of tumors in laboratory animals (1). This classification combined with further EPA regulatory reviews resulted in new requirements for alachlor use, including usage guidelines designed to prevent groundwater contamination and personal protective equipment requirements stated on the product label to minimize occupational exposure (1,7). Subsequently, alachlor use has declined, and it has been replaced by newer chloroacetanilide chemicals (ie, acetochlor, S-metolachlor) (6). EPA classification of alachlor as a probable carcinogen is based on evidence of thyroid, stomach, and nasal tumors in rats (1). Thyroid tumors were observed at very high doses; however, stomach and nasal tumors occurred at doses more relevant to human exposures (1). In vitro, alachlor metabolites form DNA adducts and induce DNA single-strand breaks (8,9). Despite studies demonstrating carcinogenic and mutagenic effects in vivo and in vitro, the epidemiologic literature examining alachlor and cancer is limited. Two population-based case–control studies in the Midwestern United States found no association with self-reported alachlor use and leukemia or non-Hodgkin lymphoma (NHL) (10,11). Among alachlor manufacturing workers, elevated standardized incidence ratios were observed for myeloid leukemia and melanoma based on two and six cases, respectively (12). No differences in cancer mortality were observed compared with the general population, but with 16 total cancer deaths, statistical power was limited (12). In the Agricultural Health Study (AHS), an earlier analysis with follow-up through 2000 (mean = 5.5 years follow-up) found evidence for an association with all lymphohematopoietic cancers, and noted non–statistically significantly elevated risks for multiple myeloma and leukemia (13). Given the evidence for carcinogenicity in laboratory animals, and suggestive evidence of cancer risk in humans based on studies with few exposed cases, we conducted an updated analysis in the AHS including an additional 5113 cancer cases and 540 142 person-years of follow-up. Methods Study Population The AHS is described elsewhere (14). Briefly, the AHS is a prospective cohort that includes 57 310 licensed private and commercial pesticide applicators enrolled during 1993–1997 in Iowa (IA) and North Carolina (NC). Applicators were recruited when they applied for or renewed their restricted use pesticide license. They completed a self-administered questionnaire providing detailed information about lifetime pesticide use, agricultural practices, demographic characteristics, behavioral factors, and personal and family medical history. We conducted follow-up interviews via computer-assisted telephone interview approximately five years after enrollment during 1999–2005 (n = 36 342, 63%). AHS questionnaires are available at https://aghealth.nih.gov/collaboration/questionnaires.html. The study protocol, including implied consent for completion of questionnaires, was approved by all relevant institutional review boards. Exposure Assessment On the enrollment questionnaire, applicators provided information on duration (years) and frequency (average days/year) of alachlor use in categories. The midpoints of the categories were multiplied to obtain an estimate of cumulative lifetime days of exposure at enrollment. At follow-up, applicators provided updated information regarding alachlor days/year applied in the last year they farmed. If the last year the applicator farmed was after study enrollment, we assumed that he/she applied alachlor for the number of days/year reported at follow-up interview for each year from enrollment through the last year farmed. We used multiple imputation to estimate pesticide exposures for individuals who did not complete follow-up interview; these methods have been described (15). We utilized two exposure metrics for alachlor: cumulative lifetime days and intensity-weighted lifetime days. The cumulative lifetime days is the sum of days of alachlor use reported at enrollment through the year last farmed reported at follow-up. Intensity-weighted days is cumulative lifetime days multiplied by an intensity-weighting factor, which incorporates information on factors that influence pesticide exposure, including repair and cleaning of equipment, application method, whether the applicator mixed pesticides, and personal protective equipment use (16). Lifetime days and intensity-weighted days were categorized as no exposure and quartiles of exposure among all cancer cases. For stratified and sensitivity analyses, lifetime days and intensity-weighted days were categorized as no, low (≤median), and high exposure (>median) among all cancer cases. Case Ascertainment and Classification We obtained incident cancer cases via linkage with Iowa and North Carolina state cancer registries. We analyzed first primary cancers diagnosed from enrollment through date of death, movement out of state, or last study follow-up (December 31, 2013, for IA, December 31, 2012, for NC), whichever was earliest. A detailed description of cancer site classification is provided in the Supplementary Methods (available online) (17–20). Statistical Analysis We excluded applicators with missing or zero follow-up time (n = 343), cancer diagnoses prior to enrollment (n = 1096), and missing days of alachlor use at enrollment and follow-up (n = 6139), leaving 49 732 applicators. Analyses examining intensity-weighted days of alachlor use excluded those missing this information at enrollment and follow-up (n = 47, including eight incident cancers), leaving 49 685 applicators. We report results for all cancer sites with at least 20 alachlor-exposed cases. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Poisson regression for each quartile of alachlor exposure compared with no alachlor use. Subjects contributed person-time from date of enrollment through date of first cancer diagnosis, date moved out of state, date of death, or last follow-up, whichever occurred first. Analyses were restricted based on sex for sex-specific cancers. All models were adjusted for potential confounders including attained age (continuous, time-varying in two-year increments), state (IA, NC), applicator type (private, commercial), cigarette smoking history at enrollment (never, former smoker, current smoker, missing) family history of cancer (yes, no, missing; specific site where available), and use of five pesticides most correlated with alachlor (none, low, high, or missing based on median intensity-weighted days of use): atrazine (Spearman P = .49), cyanazine (P = .38), metolachlor (P = .38), 2,4-D (P = .38), and terbufos (P = .33). We also adjusted specific cancer site models for known risk factors including detailed smoking history (never, tertiles of pack-years among former smokers: <3.75, 3.75–15, ≥15; tertiles of pack-years among current smokers: <11.5, 11.5–28.4, ≥24.5, missing), smokeless tobacco use (ever, never, missing), and alcohol consumption (never, less than one drink/week, one or more drinks/week, missing). Tests for trend used the median of each exposure category as a continuous variable. To address issues related to latency, we lagged alachlor intensity-weighted days of use by 10 years. We performed additional analyses to evaluate the robustness of observations for alachlor and laryngeal cancer. To determine if inherent unmeasured differences between alachlor-exposed and -unexposed applicators were biasing our results, we calculated relative risks with low-exposed applicators as the referent category. We adjusted for exposure to suspected occupational larynx carcinogens including grain dusts, other dusts (wood, cotton, sand, silica), asbestos, solvents, engine exhaust, swine/poultry confinement areas, and metal grinding. We tested potential interactions with smoking, alcohol consumption, and atrazine, an herbicide inversely associated with laryngeal cancer in the AHS (21), by including an interaction term (eg, smoking × alachlor) in each model. Finally, we compared our standard model for melanoma with a model adjusted for known risk factors, which were available for a portion of the cohort (n = 20 238), including skin reaction to sun (no/mild burn, blistering/painful burn), sun protection (any, none), and hours per day spent in the sun during the growing season 10 years before enrollment (<3, 3–5, 6–10, >10 hours). Analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC). All statistical tests were two-sided, with an α of .05. Results Table 1 displays selected characteristics of 49 685 applicators, stratified by alachlor use. The 25 640 applicators reporting alachlor use (51.6%) were generally older and from Iowa, compared with those who reported no use; there was no clear association with intensity-weighted days of alachlor use. Commercial applicators and men were more likely to report greater alachlor use. Current smokers and heavier alcohol drinkers reported the highest alachlor use (fourth quartile of intensity-weighted days). Alachlor users generally reported a family history of cancer and lower smokeless tobacco use. Table 1. Selected characteristics of Agricultural Health Study pesticide applicators (n = 49 685), stratified by lifetime days of alachlor use (none, quartiles of exposure calculated among cancer cases) Characteristic Cumulative intensity-weighted days of alachlor exposure None ≤560 561–1762 1763–5075 >5075 (n = 24 045) (n = 6282) (n = 6602) (n = 6202) (n = 6554) No. (%)* No. (%)* No. (%)* No. (%)* No. (%)* Attained age, y  <50 4701 (19.6) 766 (12.2) 733 (11.1) 711 (11.5) 560 (8.5)  50–59.9 7044 (29.3) 1863 (29.7) 1940 (29.4) 1900 (30.6) 2148 (32.8)  60–69.9 6107 (25.4) 1875 (29.8) 2022 (30.6) 1864 (30.1) 2085 (31.8)  ≥70 6193 (25.8) 1778 (28.3) 1907 (28.9) 1727 (27.8) 1761 (26.9) State  Iowa 15 088 (62.7) 4996 (79.5) 5098 (77.2) 4480 (72.2) 3898 (59.5)  North Carolina 8957 (37.3) 1286 (20.5) 1504 (22.8) 1722 (27.8) 2656 (40.5) Applicator type  Private 21 546 (89.6) 5952 (94.7) 6246 (94.6) 5744 (92.6) 5734 (87.5)  Commercial 2499 (10.4) 330 (5.3) 356 (5.4) 458 (7.4) 820 (12.5) Sex  Male 22 972 (95.5) 6198 (98.7) 6542 (99.1) 6165 (99.4) 6518 (99.5)  Female 1073 (4.5) 84 (1.3) 60 (0.9) 37 (0.6) 36 (0.5) Race  White 23 390 (97.3) 6142 (97.8) 6488 (98.3) 6084 (98.1) 6405 (97.7)  Other 655 (2.7) 140 (2.2) 114 (1.7) 118 (1.9) 149 (2.3) Educational attainment  High school or less 13 245 (55.1) 3267 (52.0) 3537 (53.6) 3324 (53.6) 3661 (55.9)  More than high school 10 208 (42.5) 2863 (45.6) 2936 (44.5) 2757 (44.5) 2754 (42)  Missing 592 (2.5) 152 (2.4) 129 (2.0) 121 (2.0) 139 (2.1) Family history of cancer  No 14 464 (60.2) 3435 (54.7) 3588 (54.3) 3421 (55.2) 3590 (54.8)  Yes 8814 (36.7) 2683 (42.7) 2861 (43.3) 2638 (42.5) 2802 (42.8)  Missing/don't know 767 (3.2) 164 (2.6) 153 (2.3) 143 (2.3) 162 (2.5) Smoking status and pack-years  Never 12 796 (53.2) 3507 (55.8) 3659 (55.4) 3300 (53.2) 3151 (48.1)  Former, <4 pack-years 2237 (9.3) 709 (11.3) 720 (10.9) 608 (9.8) 672 (10.3)  Former, 4–15 pack-years 2064 (8.6) 575 (9.2) 619 (9.4) 565 (9.1) 598 (9.1)  Former, >15 pack-years 1855 (7.7) 477 (7.6) 544 (8.2) 557 (9.0) 644 (9.8)  Current, <11.5 pack-years 1568 (6.5) 295 (4.7) 285 (4.3) 335 (5.4) 365 (5.6)  Current, 11.5–29 pack-years 1293 (5.4) 260 (4.1) 290 (4.4) 332 (5.4) 405 (6.2)  Current, >29 pack-years 1230 (5.1) 255 (4.1) 289 (4.4) 327 (5.3) 498 (7.6)  Missing 1002 (4.2) 204 (3.2) 196 (3.0) 178 (2.9) 221 (3.4) Smokeless tobacco use  Never 19 478 (81.0) 5235 (83.3) 5494 (83.2) 5120 (82.6) 5311 (81.0)  Ever 4567 (19.0) 1047 (16.7) 1108 (16.8) 1082 (17.4) 1243 (19.0) Alcohol use  Never 8001 (33.3) 1729 (27.5) 1813 (27.5) 1686 (27.2) 1983 (30.3)  <1 drink/wk 7501 (31.2) 2185 (34.8) 2261 (34.2) 2083 (33.6) 1989 (30.3)  ≥1 drink/wk 8087 (33.6) 2268 (36.1) 2458 (37.2) 2367 (38.2) 2518 (38.4)  Missing 456 (1.9) 100 (1.6) 70 (1.1) 66 (1.1) 64 (1.0) Use of selected pesticides†  Atrazine use   None 10 690 (44.5) 890 (14.2) 755 (11.4) 582 (9.4) 413 (6.3)   Low (≤2720) 7821 (32.5) 4119 (65.6) 3623 (54.9) 2020 (32.6) 790 (12.1)   High (>2720) 4966 (20.7) 1197 (19.1) 2159 (32.7) 3548 (57.2) 5304 (80.9)   Missing 568 (2.4) 76 (1.2) 65 (1) 52 (0.8) 47 (0.7)  Cyanazine use   None 18 366 (76.4) 2667 (42.5) 2771 (42) 2480 (40.0) 2516 (38.4)   Low (≤1120) 2831 (11.8) 2652 (42.2) 2138 (32.4) 1282 (20.7) 680 (10.4)   High (>1120) 2590 (10.8) 745 (11.9) 1510 (22.9) 2251 (36.3) 3128 (47.7)   Missing 258 (1.1) 218 (3.5) 183 (2.8) 189 (3.0) 230 (3.5)  Metolachlor use   None 16 070 (66.8) 2351 (37.4) 2384 (36.1) 2096 (33.8) 1836 (28.0)   Low (≤1456) 3984 (16.6) 2753 (43.8) 2454 (37.2) 1346 (21.7) 796 (12.1)   High (>1456) 3574 (14.9) 956 (15.2) 1591 (24.1) 2576 (41.5) 3719 (56.7)   Missing 417 (1.7) 222 (3.5) 173 (2.6) 184 (3.0) 203 (3.1)  2,4-D use   None 7737 (32.2) 769 (12.2) 711 (10.8) 655 (10.6) 560 (8.5)   Low (≤3270) 9562 (39.8) 3909 (62.2) 3461 (52.4) 2220 (35.8) 1140 (17.4)   High (>3270) 6082 (25.3) 1507 (24) 2346 (35.5) 3243 (52.3) 4778 (72.9)   Missing 664 (2.8) 97 (1.5) 84 (1.3) 84 (1.4) 76 (1.2)  Terbufos use   None 18 029 (75.0) 3262 (51.9) 3326 (50.4) 2832 (45.7) 2726 (41.6)   Low (≤1322) 3060 (12.7) 2124 (33.8) 1919 (29.1) 1271 (20.5) 744 (11.4)   High (>1322) 2289 (9.5) 629 (10.0) 1132 (17.1) 1892 (30.5) 2832 (43.2)   Missing 667 (2.8) 267 (4.3) 225 (3.4) 207 (3.3) 252 (3.8) Characteristic Cumulative intensity-weighted days of alachlor exposure None ≤560 561–1762 1763–5075 >5075 (n = 24 045) (n = 6282) (n = 6602) (n = 6202) (n = 6554) No. (%)* No. (%)* No. (%)* No. (%)* No. (%)* Attained age, y  <50 4701 (19.6) 766 (12.2) 733 (11.1) 711 (11.5) 560 (8.5)  50–59.9 7044 (29.3) 1863 (29.7) 1940 (29.4) 1900 (30.6) 2148 (32.8)  60–69.9 6107 (25.4) 1875 (29.8) 2022 (30.6) 1864 (30.1) 2085 (31.8)  ≥70 6193 (25.8) 1778 (28.3) 1907 (28.9) 1727 (27.8) 1761 (26.9) State  Iowa 15 088 (62.7) 4996 (79.5) 5098 (77.2) 4480 (72.2) 3898 (59.5)  North Carolina 8957 (37.3) 1286 (20.5) 1504 (22.8) 1722 (27.8) 2656 (40.5) Applicator type  Private 21 546 (89.6) 5952 (94.7) 6246 (94.6) 5744 (92.6) 5734 (87.5)  Commercial 2499 (10.4) 330 (5.3) 356 (5.4) 458 (7.4) 820 (12.5) Sex  Male 22 972 (95.5) 6198 (98.7) 6542 (99.1) 6165 (99.4) 6518 (99.5)  Female 1073 (4.5) 84 (1.3) 60 (0.9) 37 (0.6) 36 (0.5) Race  White 23 390 (97.3) 6142 (97.8) 6488 (98.3) 6084 (98.1) 6405 (97.7)  Other 655 (2.7) 140 (2.2) 114 (1.7) 118 (1.9) 149 (2.3) Educational attainment  High school or less 13 245 (55.1) 3267 (52.0) 3537 (53.6) 3324 (53.6) 3661 (55.9)  More than high school 10 208 (42.5) 2863 (45.6) 2936 (44.5) 2757 (44.5) 2754 (42)  Missing 592 (2.5) 152 (2.4) 129 (2.0) 121 (2.0) 139 (2.1) Family history of cancer  No 14 464 (60.2) 3435 (54.7) 3588 (54.3) 3421 (55.2) 3590 (54.8)  Yes 8814 (36.7) 2683 (42.7) 2861 (43.3) 2638 (42.5) 2802 (42.8)  Missing/don't know 767 (3.2) 164 (2.6) 153 (2.3) 143 (2.3) 162 (2.5) Smoking status and pack-years  Never 12 796 (53.2) 3507 (55.8) 3659 (55.4) 3300 (53.2) 3151 (48.1)  Former, <4 pack-years 2237 (9.3) 709 (11.3) 720 (10.9) 608 (9.8) 672 (10.3)  Former, 4–15 pack-years 2064 (8.6) 575 (9.2) 619 (9.4) 565 (9.1) 598 (9.1)  Former, >15 pack-years 1855 (7.7) 477 (7.6) 544 (8.2) 557 (9.0) 644 (9.8)  Current, <11.5 pack-years 1568 (6.5) 295 (4.7) 285 (4.3) 335 (5.4) 365 (5.6)  Current, 11.5–29 pack-years 1293 (5.4) 260 (4.1) 290 (4.4) 332 (5.4) 405 (6.2)  Current, >29 pack-years 1230 (5.1) 255 (4.1) 289 (4.4) 327 (5.3) 498 (7.6)  Missing 1002 (4.2) 204 (3.2) 196 (3.0) 178 (2.9) 221 (3.4) Smokeless tobacco use  Never 19 478 (81.0) 5235 (83.3) 5494 (83.2) 5120 (82.6) 5311 (81.0)  Ever 4567 (19.0) 1047 (16.7) 1108 (16.8) 1082 (17.4) 1243 (19.0) Alcohol use  Never 8001 (33.3) 1729 (27.5) 1813 (27.5) 1686 (27.2) 1983 (30.3)  <1 drink/wk 7501 (31.2) 2185 (34.8) 2261 (34.2) 2083 (33.6) 1989 (30.3)  ≥1 drink/wk 8087 (33.6) 2268 (36.1) 2458 (37.2) 2367 (38.2) 2518 (38.4)  Missing 456 (1.9) 100 (1.6) 70 (1.1) 66 (1.1) 64 (1.0) Use of selected pesticides†  Atrazine use   None 10 690 (44.5) 890 (14.2) 755 (11.4) 582 (9.4) 413 (6.3)   Low (≤2720) 7821 (32.5) 4119 (65.6) 3623 (54.9) 2020 (32.6) 790 (12.1)   High (>2720) 4966 (20.7) 1197 (19.1) 2159 (32.7) 3548 (57.2) 5304 (80.9)   Missing 568 (2.4) 76 (1.2) 65 (1) 52 (0.8) 47 (0.7)  Cyanazine use   None 18 366 (76.4) 2667 (42.5) 2771 (42) 2480 (40.0) 2516 (38.4)   Low (≤1120) 2831 (11.8) 2652 (42.2) 2138 (32.4) 1282 (20.7) 680 (10.4)   High (>1120) 2590 (10.8) 745 (11.9) 1510 (22.9) 2251 (36.3) 3128 (47.7)   Missing 258 (1.1) 218 (3.5) 183 (2.8) 189 (3.0) 230 (3.5)  Metolachlor use   None 16 070 (66.8) 2351 (37.4) 2384 (36.1) 2096 (33.8) 1836 (28.0)   Low (≤1456) 3984 (16.6) 2753 (43.8) 2454 (37.2) 1346 (21.7) 796 (12.1)   High (>1456) 3574 (14.9) 956 (15.2) 1591 (24.1) 2576 (41.5) 3719 (56.7)   Missing 417 (1.7) 222 (3.5) 173 (2.6) 184 (3.0) 203 (3.1)  2,4-D use   None 7737 (32.2) 769 (12.2) 711 (10.8) 655 (10.6) 560 (8.5)   Low (≤3270) 9562 (39.8) 3909 (62.2) 3461 (52.4) 2220 (35.8) 1140 (17.4)   High (>3270) 6082 (25.3) 1507 (24) 2346 (35.5) 3243 (52.3) 4778 (72.9)   Missing 664 (2.8) 97 (1.5) 84 (1.3) 84 (1.4) 76 (1.2)  Terbufos use   None 18 029 (75.0) 3262 (51.9) 3326 (50.4) 2832 (45.7) 2726 (41.6)   Low (≤1322) 3060 (12.7) 2124 (33.8) 1919 (29.1) 1271 (20.5) 744 (11.4)   High (>1322) 2289 (9.5) 629 (10.0) 1132 (17.1) 1892 (30.5) 2832 (43.2)   Missing 667 (2.8) 267 (4.3) 225 (3.4) 207 (3.3) 252 (3.8) * Percentages may not sum to 100 due to rounding. † Five pesticides most highly correlated with alachlor; classified as no use, low use (≤median), or high use (>median) based on cumulative intensity-weighted lifetime days. Table 1. Selected characteristics of Agricultural Health Study pesticide applicators (n = 49 685), stratified by lifetime days of alachlor use (none, quartiles of exposure calculated among cancer cases) Characteristic Cumulative intensity-weighted days of alachlor exposure None ≤560 561–1762 1763–5075 >5075 (n = 24 045) (n = 6282) (n = 6602) (n = 6202) (n = 6554) No. (%)* No. (%)* No. (%)* No. (%)* No. (%)* Attained age, y  <50 4701 (19.6) 766 (12.2) 733 (11.1) 711 (11.5) 560 (8.5)  50–59.9 7044 (29.3) 1863 (29.7) 1940 (29.4) 1900 (30.6) 2148 (32.8)  60–69.9 6107 (25.4) 1875 (29.8) 2022 (30.6) 1864 (30.1) 2085 (31.8)  ≥70 6193 (25.8) 1778 (28.3) 1907 (28.9) 1727 (27.8) 1761 (26.9) State  Iowa 15 088 (62.7) 4996 (79.5) 5098 (77.2) 4480 (72.2) 3898 (59.5)  North Carolina 8957 (37.3) 1286 (20.5) 1504 (22.8) 1722 (27.8) 2656 (40.5) Applicator type  Private 21 546 (89.6) 5952 (94.7) 6246 (94.6) 5744 (92.6) 5734 (87.5)  Commercial 2499 (10.4) 330 (5.3) 356 (5.4) 458 (7.4) 820 (12.5) Sex  Male 22 972 (95.5) 6198 (98.7) 6542 (99.1) 6165 (99.4) 6518 (99.5)  Female 1073 (4.5) 84 (1.3) 60 (0.9) 37 (0.6) 36 (0.5) Race  White 23 390 (97.3) 6142 (97.8) 6488 (98.3) 6084 (98.1) 6405 (97.7)  Other 655 (2.7) 140 (2.2) 114 (1.7) 118 (1.9) 149 (2.3) Educational attainment  High school or less 13 245 (55.1) 3267 (52.0) 3537 (53.6) 3324 (53.6) 3661 (55.9)  More than high school 10 208 (42.5) 2863 (45.6) 2936 (44.5) 2757 (44.5) 2754 (42)  Missing 592 (2.5) 152 (2.4) 129 (2.0) 121 (2.0) 139 (2.1) Family history of cancer  No 14 464 (60.2) 3435 (54.7) 3588 (54.3) 3421 (55.2) 3590 (54.8)  Yes 8814 (36.7) 2683 (42.7) 2861 (43.3) 2638 (42.5) 2802 (42.8)  Missing/don't know 767 (3.2) 164 (2.6) 153 (2.3) 143 (2.3) 162 (2.5) Smoking status and pack-years  Never 12 796 (53.2) 3507 (55.8) 3659 (55.4) 3300 (53.2) 3151 (48.1)  Former, <4 pack-years 2237 (9.3) 709 (11.3) 720 (10.9) 608 (9.8) 672 (10.3)  Former, 4–15 pack-years 2064 (8.6) 575 (9.2) 619 (9.4) 565 (9.1) 598 (9.1)  Former, >15 pack-years 1855 (7.7) 477 (7.6) 544 (8.2) 557 (9.0) 644 (9.8)  Current, <11.5 pack-years 1568 (6.5) 295 (4.7) 285 (4.3) 335 (5.4) 365 (5.6)  Current, 11.5–29 pack-years 1293 (5.4) 260 (4.1) 290 (4.4) 332 (5.4) 405 (6.2)  Current, >29 pack-years 1230 (5.1) 255 (4.1) 289 (4.4) 327 (5.3) 498 (7.6)  Missing 1002 (4.2) 204 (3.2) 196 (3.0) 178 (2.9) 221 (3.4) Smokeless tobacco use  Never 19 478 (81.0) 5235 (83.3) 5494 (83.2) 5120 (82.6) 5311 (81.0)  Ever 4567 (19.0) 1047 (16.7) 1108 (16.8) 1082 (17.4) 1243 (19.0) Alcohol use  Never 8001 (33.3) 1729 (27.5) 1813 (27.5) 1686 (27.2) 1983 (30.3)  <1 drink/wk 7501 (31.2) 2185 (34.8) 2261 (34.2) 2083 (33.6) 1989 (30.3)  ≥1 drink/wk 8087 (33.6) 2268 (36.1) 2458 (37.2) 2367 (38.2) 2518 (38.4)  Missing 456 (1.9) 100 (1.6) 70 (1.1) 66 (1.1) 64 (1.0) Use of selected pesticides†  Atrazine use   None 10 690 (44.5) 890 (14.2) 755 (11.4) 582 (9.4) 413 (6.3)   Low (≤2720) 7821 (32.5) 4119 (65.6) 3623 (54.9) 2020 (32.6) 790 (12.1)   High (>2720) 4966 (20.7) 1197 (19.1) 2159 (32.7) 3548 (57.2) 5304 (80.9)   Missing 568 (2.4) 76 (1.2) 65 (1) 52 (0.8) 47 (0.7)  Cyanazine use   None 18 366 (76.4) 2667 (42.5) 2771 (42) 2480 (40.0) 2516 (38.4)   Low (≤1120) 2831 (11.8) 2652 (42.2) 2138 (32.4) 1282 (20.7) 680 (10.4)   High (>1120) 2590 (10.8) 745 (11.9) 1510 (22.9) 2251 (36.3) 3128 (47.7)   Missing 258 (1.1) 218 (3.5) 183 (2.8) 189 (3.0) 230 (3.5)  Metolachlor use   None 16 070 (66.8) 2351 (37.4) 2384 (36.1) 2096 (33.8) 1836 (28.0)   Low (≤1456) 3984 (16.6) 2753 (43.8) 2454 (37.2) 1346 (21.7) 796 (12.1)   High (>1456) 3574 (14.9) 956 (15.2) 1591 (24.1) 2576 (41.5) 3719 (56.7)   Missing 417 (1.7) 222 (3.5) 173 (2.6) 184 (3.0) 203 (3.1)  2,4-D use   None 7737 (32.2) 769 (12.2) 711 (10.8) 655 (10.6) 560 (8.5)   Low (≤3270) 9562 (39.8) 3909 (62.2) 3461 (52.4) 2220 (35.8) 1140 (17.4)   High (>3270) 6082 (25.3) 1507 (24) 2346 (35.5) 3243 (52.3) 4778 (72.9)   Missing 664 (2.8) 97 (1.5) 84 (1.3) 84 (1.4) 76 (1.2)  Terbufos use   None 18 029 (75.0) 3262 (51.9) 3326 (50.4) 2832 (45.7) 2726 (41.6)   Low (≤1322) 3060 (12.7) 2124 (33.8) 1919 (29.1) 1271 (20.5) 744 (11.4)   High (>1322) 2289 (9.5) 629 (10.0) 1132 (17.1) 1892 (30.5) 2832 (43.2)   Missing 667 (2.8) 267 (4.3) 225 (3.4) 207 (3.3) 252 (3.8) Characteristic Cumulative intensity-weighted days of alachlor exposure None ≤560 561–1762 1763–5075 >5075 (n = 24 045) (n = 6282) (n = 6602) (n = 6202) (n = 6554) No. (%)* No. (%)* No. (%)* No. (%)* No. (%)* Attained age, y  <50 4701 (19.6) 766 (12.2) 733 (11.1) 711 (11.5) 560 (8.5)  50–59.9 7044 (29.3) 1863 (29.7) 1940 (29.4) 1900 (30.6) 2148 (32.8)  60–69.9 6107 (25.4) 1875 (29.8) 2022 (30.6) 1864 (30.1) 2085 (31.8)  ≥70 6193 (25.8) 1778 (28.3) 1907 (28.9) 1727 (27.8) 1761 (26.9) State  Iowa 15 088 (62.7) 4996 (79.5) 5098 (77.2) 4480 (72.2) 3898 (59.5)  North Carolina 8957 (37.3) 1286 (20.5) 1504 (22.8) 1722 (27.8) 2656 (40.5) Applicator type  Private 21 546 (89.6) 5952 (94.7) 6246 (94.6) 5744 (92.6) 5734 (87.5)  Commercial 2499 (10.4) 330 (5.3) 356 (5.4) 458 (7.4) 820 (12.5) Sex  Male 22 972 (95.5) 6198 (98.7) 6542 (99.1) 6165 (99.4) 6518 (99.5)  Female 1073 (4.5) 84 (1.3) 60 (0.9) 37 (0.6) 36 (0.5) Race  White 23 390 (97.3) 6142 (97.8) 6488 (98.3) 6084 (98.1) 6405 (97.7)  Other 655 (2.7) 140 (2.2) 114 (1.7) 118 (1.9) 149 (2.3) Educational attainment  High school or less 13 245 (55.1) 3267 (52.0) 3537 (53.6) 3324 (53.6) 3661 (55.9)  More than high school 10 208 (42.5) 2863 (45.6) 2936 (44.5) 2757 (44.5) 2754 (42)  Missing 592 (2.5) 152 (2.4) 129 (2.0) 121 (2.0) 139 (2.1) Family history of cancer  No 14 464 (60.2) 3435 (54.7) 3588 (54.3) 3421 (55.2) 3590 (54.8)  Yes 8814 (36.7) 2683 (42.7) 2861 (43.3) 2638 (42.5) 2802 (42.8)  Missing/don't know 767 (3.2) 164 (2.6) 153 (2.3) 143 (2.3) 162 (2.5) Smoking status and pack-years  Never 12 796 (53.2) 3507 (55.8) 3659 (55.4) 3300 (53.2) 3151 (48.1)  Former, <4 pack-years 2237 (9.3) 709 (11.3) 720 (10.9) 608 (9.8) 672 (10.3)  Former, 4–15 pack-years 2064 (8.6) 575 (9.2) 619 (9.4) 565 (9.1) 598 (9.1)  Former, >15 pack-years 1855 (7.7) 477 (7.6) 544 (8.2) 557 (9.0) 644 (9.8)  Current, <11.5 pack-years 1568 (6.5) 295 (4.7) 285 (4.3) 335 (5.4) 365 (5.6)  Current, 11.5–29 pack-years 1293 (5.4) 260 (4.1) 290 (4.4) 332 (5.4) 405 (6.2)  Current, >29 pack-years 1230 (5.1) 255 (4.1) 289 (4.4) 327 (5.3) 498 (7.6)  Missing 1002 (4.2) 204 (3.2) 196 (3.0) 178 (2.9) 221 (3.4) Smokeless tobacco use  Never 19 478 (81.0) 5235 (83.3) 5494 (83.2) 5120 (82.6) 5311 (81.0)  Ever 4567 (19.0) 1047 (16.7) 1108 (16.8) 1082 (17.4) 1243 (19.0) Alcohol use  Never 8001 (33.3) 1729 (27.5) 1813 (27.5) 1686 (27.2) 1983 (30.3)  <1 drink/wk 7501 (31.2) 2185 (34.8) 2261 (34.2) 2083 (33.6) 1989 (30.3)  ≥1 drink/wk 8087 (33.6) 2268 (36.1) 2458 (37.2) 2367 (38.2) 2518 (38.4)  Missing 456 (1.9) 100 (1.6) 70 (1.1) 66 (1.1) 64 (1.0) Use of selected pesticides†  Atrazine use   None 10 690 (44.5) 890 (14.2) 755 (11.4) 582 (9.4) 413 (6.3)   Low (≤2720) 7821 (32.5) 4119 (65.6) 3623 (54.9) 2020 (32.6) 790 (12.1)   High (>2720) 4966 (20.7) 1197 (19.1) 2159 (32.7) 3548 (57.2) 5304 (80.9)   Missing 568 (2.4) 76 (1.2) 65 (1) 52 (0.8) 47 (0.7)  Cyanazine use   None 18 366 (76.4) 2667 (42.5) 2771 (42) 2480 (40.0) 2516 (38.4)   Low (≤1120) 2831 (11.8) 2652 (42.2) 2138 (32.4) 1282 (20.7) 680 (10.4)   High (>1120) 2590 (10.8) 745 (11.9) 1510 (22.9) 2251 (36.3) 3128 (47.7)   Missing 258 (1.1) 218 (3.5) 183 (2.8) 189 (3.0) 230 (3.5)  Metolachlor use   None 16 070 (66.8) 2351 (37.4) 2384 (36.1) 2096 (33.8) 1836 (28.0)   Low (≤1456) 3984 (16.6) 2753 (43.8) 2454 (37.2) 1346 (21.7) 796 (12.1)   High (>1456) 3574 (14.9) 956 (15.2) 1591 (24.1) 2576 (41.5) 3719 (56.7)   Missing 417 (1.7) 222 (3.5) 173 (2.6) 184 (3.0) 203 (3.1)  2,4-D use   None 7737 (32.2) 769 (12.2) 711 (10.8) 655 (10.6) 560 (8.5)   Low (≤3270) 9562 (39.8) 3909 (62.2) 3461 (52.4) 2220 (35.8) 1140 (17.4)   High (>3270) 6082 (25.3) 1507 (24) 2346 (35.5) 3243 (52.3) 4778 (72.9)   Missing 664 (2.8) 97 (1.5) 84 (1.3) 84 (1.4) 76 (1.2)  Terbufos use   None 18 029 (75.0) 3262 (51.9) 3326 (50.4) 2832 (45.7) 2726 (41.6)   Low (≤1322) 3060 (12.7) 2124 (33.8) 1919 (29.1) 1271 (20.5) 744 (11.4)   High (>1322) 2289 (9.5) 629 (10.0) 1132 (17.1) 1892 (30.5) 2832 (43.2)   Missing 667 (2.8) 267 (4.3) 225 (3.4) 207 (3.3) 252 (3.8) * Percentages may not sum to 100 due to rounding. † Five pesticides most highly correlated with alachlor; classified as no use, low use (≤median), or high use (>median) based on cumulative intensity-weighted lifetime days. Four point seven percent of applicators who applied alachlor at enrollment continued to apply alachlor at follow-up; very few (0.9%) applicators first reported alachlor use during follow-up (Figure 1). Applicators who reported greater alachlor use at enrollment were more likely to report use of alachlor and other chloroacetanilides such as acetochlor or metolachlor at follow-up; 13.4% of applicators in the cohort had stopped applying pesticides on the farm at follow-up, while virtually all applicators reported pesticide use at enrollment (not shown). Figure 1. View largeDownload slide Use of alachlor at enrollment (A) and chloroacetanilide herbicides at follow-up interview (B) among Agricultural Health Study applicators who completed follow-up interview (n = 31 822). Figure 1. View largeDownload slide Use of alachlor at enrollment (A) and chloroacetanilide herbicides at follow-up interview (B) among Agricultural Health Study applicators who completed follow-up interview (n = 31 822). Table 2 displays model results for cumulative intensity-weighted days of alachlor use and cancer risk. We saw no association for all cancer sites combined. Laryngeal cancer was associated with alachlor exposure in the second (RR = 4.68, 95% CI = 1.95 to 11.23), third (RR = 6.04, 95% CI = 2.44 to 14.99), and fourth (RR = 7.10, 95% CI = 2.58 to 19.53) quartiles of use compared with unexposed, with a statistically significant exposure-response trend (Ptrend = .001). Alachlor intensity-weighted days of use in the third quartile was associated with cancers of the small intestine (RR = 3.41, 95% CI = 1.26 to 9.25); risk estimates in other quartiles were elevated but not statistically significant, and there was no evidence for exposure-response trend (Ptrend = .48). Alachlor intensity-weighted days of use in the first quartile of exposure was associated with increased risk of melanoma (RR = 1.44, 95% CI = 1.01 to 2.06, Ptrend = .94); risk estimates remained unchanged after further adjustment for sun protection and sensitivity (not shown). We also noted a non–statistically significant inverse association with stomach cancer for alachlor exposure in the fourth quartile (RR = 0.53, 95% CI = 0.23 to 1.23, Ptrend = .14). There was no association for lymphohematopoietic cancers combined (Ptrend = .44). However, myeloid leukemia was elevated among applicators in the fourth quartile of use (RR = 1.82, 95% CI = 0.85 to 3.87, Ptrend = .17) based on 48 exposed cases. Of these, 34 were acute myeloid leukemia (AML), for which similar results were observed in the fourth quartile of alachlor exposure (RR = 1.73, 95% CI = 0.73 to 4.13, Ptrend = .22, not shown). There were not enough chronic myeloid leukemia (CML) cases to evaluate separately. For comparison with Lee et al., we examined total leukemia including chronic lymphocytic leukemia (CLL; now classified as an NHL subtype) (18). We noted a non–statistically significantly elevated relative risk in the fourth quartile of intensity-weighted days of exposure (RR = 1.25, 95% CI = 0.78 to 2.02, Ptrend = .29) compared with unexposed (not shown). Results for models examining alachlor days of exposure were similar (Supplementary Table 1, available online); a statistically significant trend for lifetime days of exposure and laryngeal cancer was apparent (Ptrend = .004). Table 2. Adjusted* relative risks and 95% confidence intervals for cancer incidence associated with cumulative alachlor intensity-weighted days of exposure, compared with no alachlor use, in the Agricultural Health Study Cancer site No use Quartile 1 Quartile 2 Quartile 3 Quartile 4 Ptrend† (ref) ≤560 561–1762 1763–5075 >5075 No. No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Any cancer‡ 3037 884 1.07 (0.98 to 1.16) 883 1.00 (0.92 to 1.08) 884 1.07 (0.98 to 1.16) 883 1.00 (0.91 to 1.09) .77 Oral cavity§ 76 19 0.86 (0.50 to 1.48) 26 1.08 (0.67 to 1.73) 11 0.48 (0.25 to 0.94) 26 1.10 (0.64 to 1.87) .65  Lip 19 8 1.30 (0.53 to 3.21) 11 1.72 (0.77 to 3.84) 3 0.54 (0.15 to 1.90) 7 1.34 (0.49 to 3.65) .76 Esophagus‡,‖ 36 13 1.38 (0.68 to 2.81) 10 0.87 (0.41 to 1.88) 15 1.33 (0.68 to 2.59) 16 1.16 (0.56 to 2.41) .77 Stomach 45 10 0.85 (0.41 to 1.79) 13 0.98 (0.50 to 1.91) 12 0.89 (0.44 to 1.77) 8 0.53 (0.23 to 1.23) .14 Small intestine 14 6 2.25 (0.77 to 6.57) 5 1.87 (0.61 to 5.68) 8 3.41 (1.26 to 9.25) 4 1.93 (0.53 to 7.00) .48 Colon 221 60 1.04 (0.76 to 1.42) 48 0.79 (0.57 to 1.11) 64 1.12 (0.82 to 1.53) 63 1.07 (0.77 to 1.49) .58 Rectum 98 33 1.35 (0.86 to 2.13) 20 0.77 (0.46 to 1.29) 27 1.06 (0.66 to 1.69) 23 0.80 (0.47 to 1.36) .35 Liver‖ 16 4 1.27 (0.40 to 4.09) 6 1.58 (0.57 to 4.36) 9 1.91 (0.75 to 4.89) 9 1.23 (0.42 to 3.62) 1.00 Pancreas‡ 71 15 0.89 (0.48 to 1.65) 20 1.05 (0.61 to 1.81) 17 0.90 (0.50 to 1.64) 15 0.76 (0.39 to 1.48) .42 Lung‡ 293 69 1.14 (0.86 to 1.53) 72 1.06 (0.80 to 1.40) 87 1.28 (0.98 to 1.67) 78 0.94 (0.69 to 1.27) .47  Small cell 86 22 1.24 (0.73 to 2.11) 20 1.01 (0.60 to 1.72) 26 1.36 (0.83 to 2.22) 22 0.92 (0.52 to 1.62) .64  Squamous cell 67 21 1.33 (0.76 to 2.34) 14 0.83 (0.45 to 1.53) 23 1.30 (0.76 to 2.22) 23 0.99 (0.55 to 1.78) .84  Adenocarcinoma 86 18 1.03 (0.59 to 1.80) 24 1.18 (0.72 to 1.94) 27 1.37 (0.84 to 2.22) 22 1.02 (0.59 to 1.78) .96 Larynx‡,‖ 15 4 1.60 (0.49 to 5.24) 11 4.68 (1.95 to 11.23) 10 6.04 (2.44 to 14.99) 9 7.10 (2.58 to 19.53) .001 Melanoma 129 51 1.44 (1.01 to 2.06) 29 0.78 (0.50 to 1.19) 47 1.35 (0.94 to 1.96) 40 1.06 (0.69 to 1.62) .94 Prostate 1138 355 1.04 (0.92 to 1.19) 391 1.07 (0.95 to 1.22) 341 1.02 (0.89 to 1.16) 357 1.03 (0.89 to 1.18) .91  Aggressive prostate 618 198 1.01 (0.94 to 1.08) 198 0.94 (0.88 to 1.01) 173 0.94 (0.88 to 1.01) 188 0.94 (0.87 to 1.01) .14 Testis 24 8 1.15 (0.49 to 2.73) 8 1.18 (0.50 to 2.77) 7 1.10 (0.43 to 2.76) 1 0.17 (0.02 to 1.35) .08 Bladder‡ 150 57 1.31 (0.93 to 1.84) 39 0.86 (0.59 to 1.26) 44 1.04 (0.72 to 1.49) 42 0.91 (0.61 to 1.37) .55 Kidney‡ 110 32 1.04 (0.67 to 1.62) 29 0.91 (0.59 to 1.41) 37 1.17 (0.78 to 1.78) 26 0.79 (0.48 to 1.29) .34 Brain 39 13 1.08 (0.54 to 2.18) 9 0.76 (0.36 to 1.64) 10 0.89 (0.41 to 1.91) 9 0.83 (0.35 to 1.97) .71 Thyroid 35 10 1.31 (0.61 to 2.78) 15 1.69 (0.85 to 3.36) 8 1.09 (0.47 to 2.52) 8 1.14 (0.46 to 2.83) .98 Lymphohematopoietic 307 84 0.92 (0.71 to 1.20) 83 0.85 (0.65 to 1.10) 86 0.98 (0.75 to 1.27) 94 1.07 (0.81 to 1.40) .44  Non-Hodgkin lymphoid  malignancies 251 70 0.86 (0.65 to 1.15) 61 0.70 (0.52 to 0.95) 72 0.93 (0.70 to 1.24) 79 1.02 (0.76 to 1.38) .50    CLL/SLL/PLL/MCL 74 17 0.67 (0.38 to 1.18) 14 0.51 (0.28 to 0.95) 25 1.14 (0.69 to 1.87) 23 1.15 (0.66 to 1.99) .31    Diffuse large B cell    lymphoma 62 13 0.73 (0.39 to 1.39) 18 0.84 (0.47 to 1.51) 12 0.64 (0.33 to 1.24) 17 0.81 (0.43 to 1.54) .68    Follicular lymphoma 28 9 0.94 (0.42 to 2.13) 5 0.52 (0.19 to 1.42) 6 0.57 (0.21 to 1.57) 11 1.22 (0.52 to 2.85) .43    Multiple myeloma 52 17 1.26 (0.68 to 2.32) 13 0.84 (0.44 to 1.61) 15 0.94 (0.50 to 1.78) 14 0.77 (0.39 to 1.55) .43  Myeloid leukemia 40 11 1.28 (0.62 to 2.66) 13 1.42 (0.72 to 2.81) 11 1.46 (0.69 to 3.09) 13 1.82 (0.85 to 3.87) .17 Cancer site No use Quartile 1 Quartile 2 Quartile 3 Quartile 4 Ptrend† (ref) ≤560 561–1762 1763–5075 >5075 No. No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Any cancer‡ 3037 884 1.07 (0.98 to 1.16) 883 1.00 (0.92 to 1.08) 884 1.07 (0.98 to 1.16) 883 1.00 (0.91 to 1.09) .77 Oral cavity§ 76 19 0.86 (0.50 to 1.48) 26 1.08 (0.67 to 1.73) 11 0.48 (0.25 to 0.94) 26 1.10 (0.64 to 1.87) .65  Lip 19 8 1.30 (0.53 to 3.21) 11 1.72 (0.77 to 3.84) 3 0.54 (0.15 to 1.90) 7 1.34 (0.49 to 3.65) .76 Esophagus‡,‖ 36 13 1.38 (0.68 to 2.81) 10 0.87 (0.41 to 1.88) 15 1.33 (0.68 to 2.59) 16 1.16 (0.56 to 2.41) .77 Stomach 45 10 0.85 (0.41 to 1.79) 13 0.98 (0.50 to 1.91) 12 0.89 (0.44 to 1.77) 8 0.53 (0.23 to 1.23) .14 Small intestine 14 6 2.25 (0.77 to 6.57) 5 1.87 (0.61 to 5.68) 8 3.41 (1.26 to 9.25) 4 1.93 (0.53 to 7.00) .48 Colon 221 60 1.04 (0.76 to 1.42) 48 0.79 (0.57 to 1.11) 64 1.12 (0.82 to 1.53) 63 1.07 (0.77 to 1.49) .58 Rectum 98 33 1.35 (0.86 to 2.13) 20 0.77 (0.46 to 1.29) 27 1.06 (0.66 to 1.69) 23 0.80 (0.47 to 1.36) .35 Liver‖ 16 4 1.27 (0.40 to 4.09) 6 1.58 (0.57 to 4.36) 9 1.91 (0.75 to 4.89) 9 1.23 (0.42 to 3.62) 1.00 Pancreas‡ 71 15 0.89 (0.48 to 1.65) 20 1.05 (0.61 to 1.81) 17 0.90 (0.50 to 1.64) 15 0.76 (0.39 to 1.48) .42 Lung‡ 293 69 1.14 (0.86 to 1.53) 72 1.06 (0.80 to 1.40) 87 1.28 (0.98 to 1.67) 78 0.94 (0.69 to 1.27) .47  Small cell 86 22 1.24 (0.73 to 2.11) 20 1.01 (0.60 to 1.72) 26 1.36 (0.83 to 2.22) 22 0.92 (0.52 to 1.62) .64  Squamous cell 67 21 1.33 (0.76 to 2.34) 14 0.83 (0.45 to 1.53) 23 1.30 (0.76 to 2.22) 23 0.99 (0.55 to 1.78) .84  Adenocarcinoma 86 18 1.03 (0.59 to 1.80) 24 1.18 (0.72 to 1.94) 27 1.37 (0.84 to 2.22) 22 1.02 (0.59 to 1.78) .96 Larynx‡,‖ 15 4 1.60 (0.49 to 5.24) 11 4.68 (1.95 to 11.23) 10 6.04 (2.44 to 14.99) 9 7.10 (2.58 to 19.53) .001 Melanoma 129 51 1.44 (1.01 to 2.06) 29 0.78 (0.50 to 1.19) 47 1.35 (0.94 to 1.96) 40 1.06 (0.69 to 1.62) .94 Prostate 1138 355 1.04 (0.92 to 1.19) 391 1.07 (0.95 to 1.22) 341 1.02 (0.89 to 1.16) 357 1.03 (0.89 to 1.18) .91  Aggressive prostate 618 198 1.01 (0.94 to 1.08) 198 0.94 (0.88 to 1.01) 173 0.94 (0.88 to 1.01) 188 0.94 (0.87 to 1.01) .14 Testis 24 8 1.15 (0.49 to 2.73) 8 1.18 (0.50 to 2.77) 7 1.10 (0.43 to 2.76) 1 0.17 (0.02 to 1.35) .08 Bladder‡ 150 57 1.31 (0.93 to 1.84) 39 0.86 (0.59 to 1.26) 44 1.04 (0.72 to 1.49) 42 0.91 (0.61 to 1.37) .55 Kidney‡ 110 32 1.04 (0.67 to 1.62) 29 0.91 (0.59 to 1.41) 37 1.17 (0.78 to 1.78) 26 0.79 (0.48 to 1.29) .34 Brain 39 13 1.08 (0.54 to 2.18) 9 0.76 (0.36 to 1.64) 10 0.89 (0.41 to 1.91) 9 0.83 (0.35 to 1.97) .71 Thyroid 35 10 1.31 (0.61 to 2.78) 15 1.69 (0.85 to 3.36) 8 1.09 (0.47 to 2.52) 8 1.14 (0.46 to 2.83) .98 Lymphohematopoietic 307 84 0.92 (0.71 to 1.20) 83 0.85 (0.65 to 1.10) 86 0.98 (0.75 to 1.27) 94 1.07 (0.81 to 1.40) .44  Non-Hodgkin lymphoid  malignancies 251 70 0.86 (0.65 to 1.15) 61 0.70 (0.52 to 0.95) 72 0.93 (0.70 to 1.24) 79 1.02 (0.76 to 1.38) .50    CLL/SLL/PLL/MCL 74 17 0.67 (0.38 to 1.18) 14 0.51 (0.28 to 0.95) 25 1.14 (0.69 to 1.87) 23 1.15 (0.66 to 1.99) .31    Diffuse large B cell    lymphoma 62 13 0.73 (0.39 to 1.39) 18 0.84 (0.47 to 1.51) 12 0.64 (0.33 to 1.24) 17 0.81 (0.43 to 1.54) .68    Follicular lymphoma 28 9 0.94 (0.42 to 2.13) 5 0.52 (0.19 to 1.42) 6 0.57 (0.21 to 1.57) 11 1.22 (0.52 to 2.85) .43    Multiple myeloma 52 17 1.26 (0.68 to 2.32) 13 0.84 (0.44 to 1.61) 15 0.94 (0.50 to 1.78) 14 0.77 (0.39 to 1.55) .43  Myeloid leukemia 40 11 1.28 (0.62 to 2.66) 13 1.42 (0.72 to 2.81) 11 1.46 (0.69 to 3.09) 13 1.82 (0.85 to 3.87) .17 * Adjusted for attained age, state, applicator type, smoking status, family history of cancer, correlated pesticides (atrazine, cyanazine, metolachlor, 2,4-D, terbufos). CI = confidence interval; CLL = chronic lymphocytic leukemia; MCL = mantle cell lymphoma; PLL = prolymphocytic leukemia; RR = relative risk; SLL = small lymphocytic lymphoma. † Two-sided Wald chi-square test. ‡ Additionally adjusted for pack-years smoked. § Additionally adjusted for smokeless tobacco use. ‖ Additionally adjusted for alcohol use. Table 2. Adjusted* relative risks and 95% confidence intervals for cancer incidence associated with cumulative alachlor intensity-weighted days of exposure, compared with no alachlor use, in the Agricultural Health Study Cancer site No use Quartile 1 Quartile 2 Quartile 3 Quartile 4 Ptrend† (ref) ≤560 561–1762 1763–5075 >5075 No. No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Any cancer‡ 3037 884 1.07 (0.98 to 1.16) 883 1.00 (0.92 to 1.08) 884 1.07 (0.98 to 1.16) 883 1.00 (0.91 to 1.09) .77 Oral cavity§ 76 19 0.86 (0.50 to 1.48) 26 1.08 (0.67 to 1.73) 11 0.48 (0.25 to 0.94) 26 1.10 (0.64 to 1.87) .65  Lip 19 8 1.30 (0.53 to 3.21) 11 1.72 (0.77 to 3.84) 3 0.54 (0.15 to 1.90) 7 1.34 (0.49 to 3.65) .76 Esophagus‡,‖ 36 13 1.38 (0.68 to 2.81) 10 0.87 (0.41 to 1.88) 15 1.33 (0.68 to 2.59) 16 1.16 (0.56 to 2.41) .77 Stomach 45 10 0.85 (0.41 to 1.79) 13 0.98 (0.50 to 1.91) 12 0.89 (0.44 to 1.77) 8 0.53 (0.23 to 1.23) .14 Small intestine 14 6 2.25 (0.77 to 6.57) 5 1.87 (0.61 to 5.68) 8 3.41 (1.26 to 9.25) 4 1.93 (0.53 to 7.00) .48 Colon 221 60 1.04 (0.76 to 1.42) 48 0.79 (0.57 to 1.11) 64 1.12 (0.82 to 1.53) 63 1.07 (0.77 to 1.49) .58 Rectum 98 33 1.35 (0.86 to 2.13) 20 0.77 (0.46 to 1.29) 27 1.06 (0.66 to 1.69) 23 0.80 (0.47 to 1.36) .35 Liver‖ 16 4 1.27 (0.40 to 4.09) 6 1.58 (0.57 to 4.36) 9 1.91 (0.75 to 4.89) 9 1.23 (0.42 to 3.62) 1.00 Pancreas‡ 71 15 0.89 (0.48 to 1.65) 20 1.05 (0.61 to 1.81) 17 0.90 (0.50 to 1.64) 15 0.76 (0.39 to 1.48) .42 Lung‡ 293 69 1.14 (0.86 to 1.53) 72 1.06 (0.80 to 1.40) 87 1.28 (0.98 to 1.67) 78 0.94 (0.69 to 1.27) .47  Small cell 86 22 1.24 (0.73 to 2.11) 20 1.01 (0.60 to 1.72) 26 1.36 (0.83 to 2.22) 22 0.92 (0.52 to 1.62) .64  Squamous cell 67 21 1.33 (0.76 to 2.34) 14 0.83 (0.45 to 1.53) 23 1.30 (0.76 to 2.22) 23 0.99 (0.55 to 1.78) .84  Adenocarcinoma 86 18 1.03 (0.59 to 1.80) 24 1.18 (0.72 to 1.94) 27 1.37 (0.84 to 2.22) 22 1.02 (0.59 to 1.78) .96 Larynx‡,‖ 15 4 1.60 (0.49 to 5.24) 11 4.68 (1.95 to 11.23) 10 6.04 (2.44 to 14.99) 9 7.10 (2.58 to 19.53) .001 Melanoma 129 51 1.44 (1.01 to 2.06) 29 0.78 (0.50 to 1.19) 47 1.35 (0.94 to 1.96) 40 1.06 (0.69 to 1.62) .94 Prostate 1138 355 1.04 (0.92 to 1.19) 391 1.07 (0.95 to 1.22) 341 1.02 (0.89 to 1.16) 357 1.03 (0.89 to 1.18) .91  Aggressive prostate 618 198 1.01 (0.94 to 1.08) 198 0.94 (0.88 to 1.01) 173 0.94 (0.88 to 1.01) 188 0.94 (0.87 to 1.01) .14 Testis 24 8 1.15 (0.49 to 2.73) 8 1.18 (0.50 to 2.77) 7 1.10 (0.43 to 2.76) 1 0.17 (0.02 to 1.35) .08 Bladder‡ 150 57 1.31 (0.93 to 1.84) 39 0.86 (0.59 to 1.26) 44 1.04 (0.72 to 1.49) 42 0.91 (0.61 to 1.37) .55 Kidney‡ 110 32 1.04 (0.67 to 1.62) 29 0.91 (0.59 to 1.41) 37 1.17 (0.78 to 1.78) 26 0.79 (0.48 to 1.29) .34 Brain 39 13 1.08 (0.54 to 2.18) 9 0.76 (0.36 to 1.64) 10 0.89 (0.41 to 1.91) 9 0.83 (0.35 to 1.97) .71 Thyroid 35 10 1.31 (0.61 to 2.78) 15 1.69 (0.85 to 3.36) 8 1.09 (0.47 to 2.52) 8 1.14 (0.46 to 2.83) .98 Lymphohematopoietic 307 84 0.92 (0.71 to 1.20) 83 0.85 (0.65 to 1.10) 86 0.98 (0.75 to 1.27) 94 1.07 (0.81 to 1.40) .44  Non-Hodgkin lymphoid  malignancies 251 70 0.86 (0.65 to 1.15) 61 0.70 (0.52 to 0.95) 72 0.93 (0.70 to 1.24) 79 1.02 (0.76 to 1.38) .50    CLL/SLL/PLL/MCL 74 17 0.67 (0.38 to 1.18) 14 0.51 (0.28 to 0.95) 25 1.14 (0.69 to 1.87) 23 1.15 (0.66 to 1.99) .31    Diffuse large B cell    lymphoma 62 13 0.73 (0.39 to 1.39) 18 0.84 (0.47 to 1.51) 12 0.64 (0.33 to 1.24) 17 0.81 (0.43 to 1.54) .68    Follicular lymphoma 28 9 0.94 (0.42 to 2.13) 5 0.52 (0.19 to 1.42) 6 0.57 (0.21 to 1.57) 11 1.22 (0.52 to 2.85) .43    Multiple myeloma 52 17 1.26 (0.68 to 2.32) 13 0.84 (0.44 to 1.61) 15 0.94 (0.50 to 1.78) 14 0.77 (0.39 to 1.55) .43  Myeloid leukemia 40 11 1.28 (0.62 to 2.66) 13 1.42 (0.72 to 2.81) 11 1.46 (0.69 to 3.09) 13 1.82 (0.85 to 3.87) .17 Cancer site No use Quartile 1 Quartile 2 Quartile 3 Quartile 4 Ptrend† (ref) ≤560 561–1762 1763–5075 >5075 No. No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Any cancer‡ 3037 884 1.07 (0.98 to 1.16) 883 1.00 (0.92 to 1.08) 884 1.07 (0.98 to 1.16) 883 1.00 (0.91 to 1.09) .77 Oral cavity§ 76 19 0.86 (0.50 to 1.48) 26 1.08 (0.67 to 1.73) 11 0.48 (0.25 to 0.94) 26 1.10 (0.64 to 1.87) .65  Lip 19 8 1.30 (0.53 to 3.21) 11 1.72 (0.77 to 3.84) 3 0.54 (0.15 to 1.90) 7 1.34 (0.49 to 3.65) .76 Esophagus‡,‖ 36 13 1.38 (0.68 to 2.81) 10 0.87 (0.41 to 1.88) 15 1.33 (0.68 to 2.59) 16 1.16 (0.56 to 2.41) .77 Stomach 45 10 0.85 (0.41 to 1.79) 13 0.98 (0.50 to 1.91) 12 0.89 (0.44 to 1.77) 8 0.53 (0.23 to 1.23) .14 Small intestine 14 6 2.25 (0.77 to 6.57) 5 1.87 (0.61 to 5.68) 8 3.41 (1.26 to 9.25) 4 1.93 (0.53 to 7.00) .48 Colon 221 60 1.04 (0.76 to 1.42) 48 0.79 (0.57 to 1.11) 64 1.12 (0.82 to 1.53) 63 1.07 (0.77 to 1.49) .58 Rectum 98 33 1.35 (0.86 to 2.13) 20 0.77 (0.46 to 1.29) 27 1.06 (0.66 to 1.69) 23 0.80 (0.47 to 1.36) .35 Liver‖ 16 4 1.27 (0.40 to 4.09) 6 1.58 (0.57 to 4.36) 9 1.91 (0.75 to 4.89) 9 1.23 (0.42 to 3.62) 1.00 Pancreas‡ 71 15 0.89 (0.48 to 1.65) 20 1.05 (0.61 to 1.81) 17 0.90 (0.50 to 1.64) 15 0.76 (0.39 to 1.48) .42 Lung‡ 293 69 1.14 (0.86 to 1.53) 72 1.06 (0.80 to 1.40) 87 1.28 (0.98 to 1.67) 78 0.94 (0.69 to 1.27) .47  Small cell 86 22 1.24 (0.73 to 2.11) 20 1.01 (0.60 to 1.72) 26 1.36 (0.83 to 2.22) 22 0.92 (0.52 to 1.62) .64  Squamous cell 67 21 1.33 (0.76 to 2.34) 14 0.83 (0.45 to 1.53) 23 1.30 (0.76 to 2.22) 23 0.99 (0.55 to 1.78) .84  Adenocarcinoma 86 18 1.03 (0.59 to 1.80) 24 1.18 (0.72 to 1.94) 27 1.37 (0.84 to 2.22) 22 1.02 (0.59 to 1.78) .96 Larynx‡,‖ 15 4 1.60 (0.49 to 5.24) 11 4.68 (1.95 to 11.23) 10 6.04 (2.44 to 14.99) 9 7.10 (2.58 to 19.53) .001 Melanoma 129 51 1.44 (1.01 to 2.06) 29 0.78 (0.50 to 1.19) 47 1.35 (0.94 to 1.96) 40 1.06 (0.69 to 1.62) .94 Prostate 1138 355 1.04 (0.92 to 1.19) 391 1.07 (0.95 to 1.22) 341 1.02 (0.89 to 1.16) 357 1.03 (0.89 to 1.18) .91  Aggressive prostate 618 198 1.01 (0.94 to 1.08) 198 0.94 (0.88 to 1.01) 173 0.94 (0.88 to 1.01) 188 0.94 (0.87 to 1.01) .14 Testis 24 8 1.15 (0.49 to 2.73) 8 1.18 (0.50 to 2.77) 7 1.10 (0.43 to 2.76) 1 0.17 (0.02 to 1.35) .08 Bladder‡ 150 57 1.31 (0.93 to 1.84) 39 0.86 (0.59 to 1.26) 44 1.04 (0.72 to 1.49) 42 0.91 (0.61 to 1.37) .55 Kidney‡ 110 32 1.04 (0.67 to 1.62) 29 0.91 (0.59 to 1.41) 37 1.17 (0.78 to 1.78) 26 0.79 (0.48 to 1.29) .34 Brain 39 13 1.08 (0.54 to 2.18) 9 0.76 (0.36 to 1.64) 10 0.89 (0.41 to 1.91) 9 0.83 (0.35 to 1.97) .71 Thyroid 35 10 1.31 (0.61 to 2.78) 15 1.69 (0.85 to 3.36) 8 1.09 (0.47 to 2.52) 8 1.14 (0.46 to 2.83) .98 Lymphohematopoietic 307 84 0.92 (0.71 to 1.20) 83 0.85 (0.65 to 1.10) 86 0.98 (0.75 to 1.27) 94 1.07 (0.81 to 1.40) .44  Non-Hodgkin lymphoid  malignancies 251 70 0.86 (0.65 to 1.15) 61 0.70 (0.52 to 0.95) 72 0.93 (0.70 to 1.24) 79 1.02 (0.76 to 1.38) .50    CLL/SLL/PLL/MCL 74 17 0.67 (0.38 to 1.18) 14 0.51 (0.28 to 0.95) 25 1.14 (0.69 to 1.87) 23 1.15 (0.66 to 1.99) .31    Diffuse large B cell    lymphoma 62 13 0.73 (0.39 to 1.39) 18 0.84 (0.47 to 1.51) 12 0.64 (0.33 to 1.24) 17 0.81 (0.43 to 1.54) .68    Follicular lymphoma 28 9 0.94 (0.42 to 2.13) 5 0.52 (0.19 to 1.42) 6 0.57 (0.21 to 1.57) 11 1.22 (0.52 to 2.85) .43    Multiple myeloma 52 17 1.26 (0.68 to 2.32) 13 0.84 (0.44 to 1.61) 15 0.94 (0.50 to 1.78) 14 0.77 (0.39 to 1.55) .43  Myeloid leukemia 40 11 1.28 (0.62 to 2.66) 13 1.42 (0.72 to 2.81) 11 1.46 (0.69 to 3.09) 13 1.82 (0.85 to 3.87) .17 * Adjusted for attained age, state, applicator type, smoking status, family history of cancer, correlated pesticides (atrazine, cyanazine, metolachlor, 2,4-D, terbufos). CI = confidence interval; CLL = chronic lymphocytic leukemia; MCL = mantle cell lymphoma; PLL = prolymphocytic leukemia; RR = relative risk; SLL = small lymphocytic lymphoma. † Two-sided Wald chi-square test. ‡ Additionally adjusted for pack-years smoked. § Additionally adjusted for smokeless tobacco use. ‖ Additionally adjusted for alcohol use. We further explored the relationship between intensity-weighted alachlor days and laryngeal cancer (Table 3). Using low exposure as the referent, high alachlor exposure was statistically nonsignificantly associated with laryngeal cancer (RR = 2.03, 95% CI = 0.92 to 4.49). Adjusting for occupational exposures potentially associated with laryngeal cancer generally did not impact the overall associations, though adjustment for exposure to grain dusts did result in slight attenuation of the relative risk. Among never smokers, there was only one laryngeal cancer case who had never applied alachlor, though even with limited power we observed that increasing alachlor use was associated with laryngeal cancer (not shown). To increase precision, we stratified by pack-years of cigarette smoking. Compared with those with fewer than five pack-years of cigarette smoking and no use of alachlor, risk of laryngeal cancer increased with increasing alachlor exposure regardless of smoking status (Pinteraction = .45). High alachlor use was associated with laryngeal cancer among never (RR = 9.87, 95% CI = 2.94 to 33.14) and ever drinkers (RR = 5.72, 95% CI = 1.69 to 19.31), compared with never drinkers who did not apply alachlor. In our study, there was no interaction between smoking and alcohol use, and adjusting for combined smoking and alcohol use did not impact the risk estimates for alachlor exposure and laryngeal cancer (not shown). High alachlor exposure was associated with laryngeal cancer among both atrazine-unexposed (RR = 4.15, 95% CI = 1.02 to 16.93) and -exposed (RR = 3.21, 95% CI = 1.22 to 8.46) individuals, compared with individuals exposed to neither herbicide (Pinteraction = .47). Table 3. Adjusted* relative risks and 95% confidence intervals for low (≤median) and high (>median) intensity-weighted days of alachlor exposure for laryngeal cancer in the Agricultural Health Study Analysis No use Low use High use ≤1762 >1762 No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Ptrend† Overall‡,§,‖ 15 1.00 (ref) 15 3.15 (1.38 to 7.19) 19 6.28 (2.73 to 14.45) <.001 Low exposure as referent‡,§,‖ –¶ –¶ 15 1.00 (ref) 19 2.03 (0.92 to 4.49) Adjusted for occupational exposures‡,§,‖  Dusts (wood, cotton, sand, silica) 15 1.00 (ref) 15 3.19 (1.40 to 7.29) 19 6.33 (2.75 to 14.57) <.001  Dusts (grain) 15 1.00 (ref) 15 2.94 (1.29 to 6.71) 19 5.72 (2.49 to 13.15) <.001  Asbestos 15 1.00 (ref) 15 3.15 (1.38 to 7.18) 19 6.26 (2.72 to 14.41) <.001  Solvents 15 1.00 (ref) 15 3.18 (1.39 to 7.25) 19 6.30 (2.74 to 14.50) <.001  Engine exhaust 15 1.00 (ref) 15 3.18 (1.39 to 7.26) 19 6.33 (2.75 to 14.56) <.001  Work in swine/poultry confinement areas 15 1.00 (ref) 15 3.14 (1.38 to 7.16) 19 6.30 (2.74 to 14.49) <.001  Metal grinding 15 1.00 (ref) 15 3.16 (1.38 to 7.23) 19 6.25 (2.72 to 14.38) <.001 Pinteraction# ≤5 cigarette pack-years§,‖ 5 1.00 (ref) 3 1.57 (0.36 to 6.96) 6 5.58 (1.57 to 19.80) .45  >5 cigarette pack-years 9 0.88 (0.26 to 2.93) 12 3.89 (1.16 to 13.07) 13 6.40 (1.85 to 22.15) Never drinkers‡,‖ 5 1.00 (ref) 5 4.06 (1.10 to 14.93) 8 9.87 (2.94 to 33.14) .69  Ever drinkers 9 1.11 (0.36 to 3.47) 10 3.14 (0.94 to 10.45) 11 5.72 (1.69 to 19.31) Atrazine never use‡,§ 12 1.00 (ref) 3 2.05 (0.56 to 7.57) 3 4.15 (1.02 to 16.93) .47  Ever use 3 0.36 (0.10 to 1.34) 12 2.00 (0.74 to 5.38) 16 3.21 (1.22 to 8.46) Analysis No use Low use High use ≤1762 >1762 No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Ptrend† Overall‡,§,‖ 15 1.00 (ref) 15 3.15 (1.38 to 7.19) 19 6.28 (2.73 to 14.45) <.001 Low exposure as referent‡,§,‖ –¶ –¶ 15 1.00 (ref) 19 2.03 (0.92 to 4.49) Adjusted for occupational exposures‡,§,‖  Dusts (wood, cotton, sand, silica) 15 1.00 (ref) 15 3.19 (1.40 to 7.29) 19 6.33 (2.75 to 14.57) <.001  Dusts (grain) 15 1.00 (ref) 15 2.94 (1.29 to 6.71) 19 5.72 (2.49 to 13.15) <.001  Asbestos 15 1.00 (ref) 15 3.15 (1.38 to 7.18) 19 6.26 (2.72 to 14.41) <.001  Solvents 15 1.00 (ref) 15 3.18 (1.39 to 7.25) 19 6.30 (2.74 to 14.50) <.001  Engine exhaust 15 1.00 (ref) 15 3.18 (1.39 to 7.26) 19 6.33 (2.75 to 14.56) <.001  Work in swine/poultry confinement areas 15 1.00 (ref) 15 3.14 (1.38 to 7.16) 19 6.30 (2.74 to 14.49) <.001  Metal grinding 15 1.00 (ref) 15 3.16 (1.38 to 7.23) 19 6.25 (2.72 to 14.38) <.001 Pinteraction# ≤5 cigarette pack-years§,‖ 5 1.00 (ref) 3 1.57 (0.36 to 6.96) 6 5.58 (1.57 to 19.80) .45  >5 cigarette pack-years 9 0.88 (0.26 to 2.93) 12 3.89 (1.16 to 13.07) 13 6.40 (1.85 to 22.15) Never drinkers‡,‖ 5 1.00 (ref) 5 4.06 (1.10 to 14.93) 8 9.87 (2.94 to 33.14) .69  Ever drinkers 9 1.11 (0.36 to 3.47) 10 3.14 (0.94 to 10.45) 11 5.72 (1.69 to 19.31) Atrazine never use‡,§ 12 1.00 (ref) 3 2.05 (0.56 to 7.57) 3 4.15 (1.02 to 16.93) .47  Ever use 3 0.36 (0.10 to 1.34) 12 2.00 (0.74 to 5.38) 16 3.21 (1.22 to 8.46) * Adjusted for attained age, state, applicator type, smoking status, family history of cancer, correlated pesticides (cyanazine, metolachlor, 2,4-D, terbufos). CI = confidence interval; RR = relative risk. † Two-sided Wald chi-square test. ‡ Additionally adjusted for pack-years smoked. § Additionally adjusted for alcohol use. ‖ Additionally adjusted for atrazine. ¶ Low alachlor-exposed as the referent category; individuals with no use excluded from analysis. # Two-sided likelihood ratio test. Table 3. Adjusted* relative risks and 95% confidence intervals for low (≤median) and high (>median) intensity-weighted days of alachlor exposure for laryngeal cancer in the Agricultural Health Study Analysis No use Low use High use ≤1762 >1762 No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Ptrend† Overall‡,§,‖ 15 1.00 (ref) 15 3.15 (1.38 to 7.19) 19 6.28 (2.73 to 14.45) <.001 Low exposure as referent‡,§,‖ –¶ –¶ 15 1.00 (ref) 19 2.03 (0.92 to 4.49) Adjusted for occupational exposures‡,§,‖  Dusts (wood, cotton, sand, silica) 15 1.00 (ref) 15 3.19 (1.40 to 7.29) 19 6.33 (2.75 to 14.57) <.001  Dusts (grain) 15 1.00 (ref) 15 2.94 (1.29 to 6.71) 19 5.72 (2.49 to 13.15) <.001  Asbestos 15 1.00 (ref) 15 3.15 (1.38 to 7.18) 19 6.26 (2.72 to 14.41) <.001  Solvents 15 1.00 (ref) 15 3.18 (1.39 to 7.25) 19 6.30 (2.74 to 14.50) <.001  Engine exhaust 15 1.00 (ref) 15 3.18 (1.39 to 7.26) 19 6.33 (2.75 to 14.56) <.001  Work in swine/poultry confinement areas 15 1.00 (ref) 15 3.14 (1.38 to 7.16) 19 6.30 (2.74 to 14.49) <.001  Metal grinding 15 1.00 (ref) 15 3.16 (1.38 to 7.23) 19 6.25 (2.72 to 14.38) <.001 Pinteraction# ≤5 cigarette pack-years§,‖ 5 1.00 (ref) 3 1.57 (0.36 to 6.96) 6 5.58 (1.57 to 19.80) .45  >5 cigarette pack-years 9 0.88 (0.26 to 2.93) 12 3.89 (1.16 to 13.07) 13 6.40 (1.85 to 22.15) Never drinkers‡,‖ 5 1.00 (ref) 5 4.06 (1.10 to 14.93) 8 9.87 (2.94 to 33.14) .69  Ever drinkers 9 1.11 (0.36 to 3.47) 10 3.14 (0.94 to 10.45) 11 5.72 (1.69 to 19.31) Atrazine never use‡,§ 12 1.00 (ref) 3 2.05 (0.56 to 7.57) 3 4.15 (1.02 to 16.93) .47  Ever use 3 0.36 (0.10 to 1.34) 12 2.00 (0.74 to 5.38) 16 3.21 (1.22 to 8.46) Analysis No use Low use High use ≤1762 >1762 No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Ptrend† Overall‡,§,‖ 15 1.00 (ref) 15 3.15 (1.38 to 7.19) 19 6.28 (2.73 to 14.45) <.001 Low exposure as referent‡,§,‖ –¶ –¶ 15 1.00 (ref) 19 2.03 (0.92 to 4.49) Adjusted for occupational exposures‡,§,‖  Dusts (wood, cotton, sand, silica) 15 1.00 (ref) 15 3.19 (1.40 to 7.29) 19 6.33 (2.75 to 14.57) <.001  Dusts (grain) 15 1.00 (ref) 15 2.94 (1.29 to 6.71) 19 5.72 (2.49 to 13.15) <.001  Asbestos 15 1.00 (ref) 15 3.15 (1.38 to 7.18) 19 6.26 (2.72 to 14.41) <.001  Solvents 15 1.00 (ref) 15 3.18 (1.39 to 7.25) 19 6.30 (2.74 to 14.50) <.001  Engine exhaust 15 1.00 (ref) 15 3.18 (1.39 to 7.26) 19 6.33 (2.75 to 14.56) <.001  Work in swine/poultry confinement areas 15 1.00 (ref) 15 3.14 (1.38 to 7.16) 19 6.30 (2.74 to 14.49) <.001  Metal grinding 15 1.00 (ref) 15 3.16 (1.38 to 7.23) 19 6.25 (2.72 to 14.38) <.001 Pinteraction# ≤5 cigarette pack-years§,‖ 5 1.00 (ref) 3 1.57 (0.36 to 6.96) 6 5.58 (1.57 to 19.80) .45  >5 cigarette pack-years 9 0.88 (0.26 to 2.93) 12 3.89 (1.16 to 13.07) 13 6.40 (1.85 to 22.15) Never drinkers‡,‖ 5 1.00 (ref) 5 4.06 (1.10 to 14.93) 8 9.87 (2.94 to 33.14) .69  Ever drinkers 9 1.11 (0.36 to 3.47) 10 3.14 (0.94 to 10.45) 11 5.72 (1.69 to 19.31) Atrazine never use‡,§ 12 1.00 (ref) 3 2.05 (0.56 to 7.57) 3 4.15 (1.02 to 16.93) .47  Ever use 3 0.36 (0.10 to 1.34) 12 2.00 (0.74 to 5.38) 16 3.21 (1.22 to 8.46) * Adjusted for attained age, state, applicator type, smoking status, family history of cancer, correlated pesticides (cyanazine, metolachlor, 2,4-D, terbufos). CI = confidence interval; RR = relative risk. † Two-sided Wald chi-square test. ‡ Additionally adjusted for pack-years smoked. § Additionally adjusted for alcohol use. ‖ Additionally adjusted for atrazine. ¶ Low alachlor-exposed as the referent category; individuals with no use excluded from analysis. # Two-sided likelihood ratio test. Results for models examining alachlor exposure with a 10-year exposure lag were similar compared with standard models (Supplementary Table 2, available online). Associations for laryngeal, stomach, small intestine cancer, and myeloid leukemia were consistent with unlagged results. We noted inverse associations with aggressive prostate cancer in the second (RR = 0.91, 95% CI = 0.85 to 0.98) and third (RR = 0.91, 95% CI = 0.85 to 0.98) quartiles of exposure, with no exposure-response trend (Ptrend = .32). Discussion Our study is the largest and most comprehensive analysis of occupational alachlor exposure and cancer risk to date. The most striking finding was a strong positive monotonic association with laryngeal cancer, with a sevenfold risk in the highest quartile of exposure compared with unexposed. This association remained after lagging exposure, stratifying by important potential effect modifiers (eg, tobacco and alcohol use) and adjusting for known and suspected occupational risk factors (22). In these data, atrazine is inversely associated with laryngeal cancer (21) and correlated with alachlor; however, we observed elevated risks for alachlor use and laryngeal cancer among both atrazine-unexposed and -exposed applicators, compared with those reporting use of neither. Lee et al. previously reported a non–statistically significant association between ever use of alachlor and risk of laryngeal cancer based on seven exposed cases (13). The only other epidemiologic study directly assessing alachlor exposure and multiple cancer outcomes did not examine laryngeal cancer (12). Occupation as a farmer or agricultural worker has been associated with laryngeal cancer (23–27); however, there is no clear consensus in the literature regarding this association (22,28–30). Furthermore, with little or no information on participants’ farming activities, it is not possible to attribute the observed associations in these studies to pesticide exposure or alachlor specifically. There is ample evidence for alachlor’s carcinogenicity in vivo and in vitro, including formation of tumors (1), DNA adducts (8), and single-strand DNA breaks (9), as well as epidemiologic evidence for telomere effects in the AHS (31,32). In alachlor chronic feeding studies, another upper respiratory tract cancer, nasal olfactory tumor, occurs consistently (33,34). Rats are obligate nasal breathers; in humans, mouth breathing involves bypassing filtration by the nasal passages and may result in effects on more distant respiratory tract organs such as the larynx (35). Furthermore, it has been posited that elevated expression of cytochrome P450 isoforms that metabolize alachlor to its reactive intermediate, particularly in target tissues (ie, nasal tissue), may play a role in carcinogenesis in animal models (36). Taken together, this literature suggests that the larynx may not only be a point of direct access for inhaled pesticide exposures, but may be more susceptible than other tissue due to increased bioactivation of alachlor. These mechanisms are not well studied in humans; however, there is evidence that CYP2B6, known to metabolize and bioactivate alachlor in vitro (37), is expressed at high levels in human larynx tissue (38). In the previous AHS analysis of alachlor, the authors noted a statistically significant exposure-response trend for alachlor use and all lymphohematopoietic cancers combined, elevated associations for leukemia and multiple myeloma, and no association with NHL (13). We found no association with lymphohematopoietic cancers overall, nor did we see an association for NHL, multiple myeloma, CLL, or other NHL subtypes based on extended follow-up. However, we observed elevated risks for myeloid leukemia in all exposure categories, though associations were not statistically significant, with limited evidence for exposure-response trend. Results for AML (70.8% of alachlor-exposed myeloid leukemias) were similar. For consistency with the previous AHS analysis, we examined total leukemia, combining all subtypes including CLL (grouped with NHL in the primary analyses) (18). Combined, we noted an elevated association in the fourth quartile of exposure, likely driven by the myeloid subtypes. A case–control study examining pesticides and leukemia found no association with alachlor, though leukemia subtypes were not examined (10). Alachlor manufacturing workers with any or high alachlor exposure had elevated incidence of CML (among two exposed cases); there was no association with total leukemia (12). It is possible that the relevant period to capture associations in this cohort has passed, with declining use of alachlor and short latency for certain lymphohematopoietic cancers. In addition, our analysis was underpowered to examine many rare NHL and leukemia subtypes, even with extended follow-up. Additional studies are needed to understand this possible association, examining finer subtypes. Trends in the use of specific herbicides change over time, as more effective chemicals come on the market and/or pesticides of known concern are phased out of use. Alachlor use has declined in the United States since its peak in the 1980s, and it has been replaced by newer chloroacetanilide chemicals (ie, S-metolachlor, acetochlor) with the same mechanism of action and closely related chemical structures. As of 2012, S-metolachlor and acetochlor account for more 10% of the agricultural herbicides sold in the United States by volume; in recent years alachlor is no longer reported among the most highly used chemicals by the US EPA (39). Despite similarity in chemical structure, there is often discordance between observed cancer associations for pesticides in the same chemical class. Previously in the AHS, metolachlor use has been associated with increased risk of liver cancer and acetochlor use has been associated with a suggestive increased risk of lung cancer, particularly when applied as a product mixture with atrazine (40,41). Laryngeal cancer was not evaluated for associations with either pesticide due to few exposed cases. Strengths of our analysis include longitudinal study design with regular follow-up of participants for cancer and mortality outcomes and detailed and validated self-reported pesticide exposure and intensity information (42). Although there is potential for misclassification of self-reported alachlor use, because of the prospective study design, exposure misclassification will be nondifferential with respect to cancer outcome, which would bias relative risks toward the null (43). Participants with missing information on alachlor use were excluded (11%), which is potentially a biased sample that may not be representative of the larger cohort. Although overall very similar to the general cohort, individuals who were missing alachlor use information were more likely to be older, from North Carolina, private applicators, and to report a race/ethnicity other than white. To date, this is the largest study to examine alachlor exposure and cancer risk, with a total of 3534 exposed cases (2729 additional accrued cases since the previous analysis within the cohort). Because of the high prevalence of alachlor use, we could examine many rarer cancer sites and subtypes. However, due to few exposed female applicators, we were unable to evaluate cancer sites such as breast (n = 8) and endometrial cancer (n = 1). We were able to control for potential confounders including tobacco use (smoking and smokeless tobacco), alcohol consumption, family history of cancer, ultraviolet radiation, and other farming and agricultural exposures. Laryngeal cancer shares risk factors with other respiratory tract cancers, such as tobacco use, and head and neck cancers, such as alcohol use. We saw no associations with alachlor exposure and cancers of the lung, oral cavity, or esophagus, or any other respiratory tract cancers, indicating that unmeasured confounding by these shared risk factors is unlikely responsible for the laryngeal cancer finding. We controlled for use of other pesticides that were most highly correlated with alachlor to minimize confounding. Because of its inverse association with laryngeal cancer, we also examined alachlor use among applicators never exposed to atrazine, with these stratified analyses indicating that confounding by atrazine is unlikely to explain this association. In conclusion, we observed increased risk of laryngeal cancer with increasing alachlor exposure. We also noted a suggestive association for myeloid leukemia, consistent with excess CML in a study of alachlor manufacturing workers and prior findings in AHS for total leukemia. This is the first epidemiologic study to evaluate the association with alachlor and laryngeal cancer. However, the relatively large risk estimates, coupled with the consistent associations after extensive adjustment for potential confounders, examination of lagged exposure, and stratification by potential effect modifiers, indicate that occupational alachlor exposure may play a role in larynx carcinogenesis. Replication in other studies with detailed pesticide exposure assessment is needed. Funding This work was supported by the intramural research program of the National Institutes of Health, the National Cancer Institute at the National Institutes of Health (Z01-CP010119), and the National Institute of Environmental Health Sciences at the National Institutes of Health (Z01-ES049030). Notes Affiliations of authors: Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (CCL, GA, SK, JNH, AB, LEBF); Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea (WJL); National Institute of Environmental Health Sciences, Research Triangle Park, NC (DPS, CGP); Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (JHL). 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J Expo Sci Environ Epidemiol. 2010 ; 20 6 : 559 – 569 . http://dx.doi.org/10.1038/jes.2009.54 Google Scholar Crossref Search ADS PubMed 43 Blair A , Thomas K , Coble J , et al. . Impact of pesticide exposure misclassification on estimates of relative risks in the Agricultural Health Study . Occup Environ Med. 2011 ; 68 7 : 537 – 541 . http://dx.doi.org/10.1136/oem.2010.059469 Google Scholar Crossref Search ADS PubMed Published by Oxford University Press 2018. This work is written by US Government employees and is in the public domain in the US. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

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Oxford University Press
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Published by Oxford University Press 2018. This work is written by US Government employees and is in the public domain in the US.
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0027-8874
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Abstract

Abstract Background The herbicide alachlor has been widely used in US agriculture since its introduction in 1969. Experimental animal studies show that alachlor causes tumors in vivo; however, few epidemiologic studies have examined associations with human cancer risk. We evaluated alachlor use and cancer incidence in the Agricultural Health Study, updating an earlier analysis that suggested associations with lymphohematopoietic cancers with an additional 540 142 person-years of follow-up and 5113 cancer cases. Methods Pesticide applicators in Iowa and North Carolina reported lifetime alachlor use at enrollment (1993–1997) and follow-up (1999–2005). Exposure was characterized by cumulative intensity-weighted days. We estimated relative risks (RRs) and 95% confidence intervals (CIs) using Poisson regression for incident cancers from enrollment through 2012(NC)/2013(IA). Models adjusted for age, tobacco, alcohol, and other pesticides. All statistical tests are two-sided. Results Among 49 685 applicators, 25 640 (51.6%) used alachlor, with 3534 alachlor-exposed cancers. The relative risks of laryngeal cancer (nexposed = 34) increased in the second (RR = 4.68, 95% CI = 1.95 to 11.23), third (RR = 6.04, 95% CI = 2.44 to 14.99), and fourth quartiles (RR = 7.10, 95% CI = 2.58 to 19.53) of intensity-weighted days of use compared with no use (Ptrend = .001). Risk of myeloid leukemia was elevated, though not statistically significantly so, in the fourth quartile of intensity-weighted days of use (RR = 1.82, 95% CI = 0.85 to 3.87, Ptrend = .17). Conclusions We observed a strong positive association with use of alachlor and laryngeal cancer and a weaker association with myeloid leukemia. The strength and robustness of the association with laryngeal cancer suggests that long-term occupational exposure to alachlor may be a risk factor for laryngeal cancer. This first report requires confirmation. Alachlor is a chloroacetanilide herbicide registered for use primarily on corn and soybeans in the United States (1). From its registration in 1969 through the mid-1990s, alachlor was among the most widely used agricultural pesticides (55–60 million pounds per year in the late 1980s). Alachlor and its metabolites are mobile and moderately persistent in the environment, and have been detected in groundwater, streams, and rivers despite declining use, indicating potential for broad population exposures (1–4). Alachlor has acute toxicity (5,6), and in 1986 the US Environmental Protection Agency (EPA) classified alachlor as a probable human carcinogen based primarily on evidence of tumors in laboratory animals (1). This classification combined with further EPA regulatory reviews resulted in new requirements for alachlor use, including usage guidelines designed to prevent groundwater contamination and personal protective equipment requirements stated on the product label to minimize occupational exposure (1,7). Subsequently, alachlor use has declined, and it has been replaced by newer chloroacetanilide chemicals (ie, acetochlor, S-metolachlor) (6). EPA classification of alachlor as a probable carcinogen is based on evidence of thyroid, stomach, and nasal tumors in rats (1). Thyroid tumors were observed at very high doses; however, stomach and nasal tumors occurred at doses more relevant to human exposures (1). In vitro, alachlor metabolites form DNA adducts and induce DNA single-strand breaks (8,9). Despite studies demonstrating carcinogenic and mutagenic effects in vivo and in vitro, the epidemiologic literature examining alachlor and cancer is limited. Two population-based case–control studies in the Midwestern United States found no association with self-reported alachlor use and leukemia or non-Hodgkin lymphoma (NHL) (10,11). Among alachlor manufacturing workers, elevated standardized incidence ratios were observed for myeloid leukemia and melanoma based on two and six cases, respectively (12). No differences in cancer mortality were observed compared with the general population, but with 16 total cancer deaths, statistical power was limited (12). In the Agricultural Health Study (AHS), an earlier analysis with follow-up through 2000 (mean = 5.5 years follow-up) found evidence for an association with all lymphohematopoietic cancers, and noted non–statistically significantly elevated risks for multiple myeloma and leukemia (13). Given the evidence for carcinogenicity in laboratory animals, and suggestive evidence of cancer risk in humans based on studies with few exposed cases, we conducted an updated analysis in the AHS including an additional 5113 cancer cases and 540 142 person-years of follow-up. Methods Study Population The AHS is described elsewhere (14). Briefly, the AHS is a prospective cohort that includes 57 310 licensed private and commercial pesticide applicators enrolled during 1993–1997 in Iowa (IA) and North Carolina (NC). Applicators were recruited when they applied for or renewed their restricted use pesticide license. They completed a self-administered questionnaire providing detailed information about lifetime pesticide use, agricultural practices, demographic characteristics, behavioral factors, and personal and family medical history. We conducted follow-up interviews via computer-assisted telephone interview approximately five years after enrollment during 1999–2005 (n = 36 342, 63%). AHS questionnaires are available at https://aghealth.nih.gov/collaboration/questionnaires.html. The study protocol, including implied consent for completion of questionnaires, was approved by all relevant institutional review boards. Exposure Assessment On the enrollment questionnaire, applicators provided information on duration (years) and frequency (average days/year) of alachlor use in categories. The midpoints of the categories were multiplied to obtain an estimate of cumulative lifetime days of exposure at enrollment. At follow-up, applicators provided updated information regarding alachlor days/year applied in the last year they farmed. If the last year the applicator farmed was after study enrollment, we assumed that he/she applied alachlor for the number of days/year reported at follow-up interview for each year from enrollment through the last year farmed. We used multiple imputation to estimate pesticide exposures for individuals who did not complete follow-up interview; these methods have been described (15). We utilized two exposure metrics for alachlor: cumulative lifetime days and intensity-weighted lifetime days. The cumulative lifetime days is the sum of days of alachlor use reported at enrollment through the year last farmed reported at follow-up. Intensity-weighted days is cumulative lifetime days multiplied by an intensity-weighting factor, which incorporates information on factors that influence pesticide exposure, including repair and cleaning of equipment, application method, whether the applicator mixed pesticides, and personal protective equipment use (16). Lifetime days and intensity-weighted days were categorized as no exposure and quartiles of exposure among all cancer cases. For stratified and sensitivity analyses, lifetime days and intensity-weighted days were categorized as no, low (≤median), and high exposure (>median) among all cancer cases. Case Ascertainment and Classification We obtained incident cancer cases via linkage with Iowa and North Carolina state cancer registries. We analyzed first primary cancers diagnosed from enrollment through date of death, movement out of state, or last study follow-up (December 31, 2013, for IA, December 31, 2012, for NC), whichever was earliest. A detailed description of cancer site classification is provided in the Supplementary Methods (available online) (17–20). Statistical Analysis We excluded applicators with missing or zero follow-up time (n = 343), cancer diagnoses prior to enrollment (n = 1096), and missing days of alachlor use at enrollment and follow-up (n = 6139), leaving 49 732 applicators. Analyses examining intensity-weighted days of alachlor use excluded those missing this information at enrollment and follow-up (n = 47, including eight incident cancers), leaving 49 685 applicators. We report results for all cancer sites with at least 20 alachlor-exposed cases. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Poisson regression for each quartile of alachlor exposure compared with no alachlor use. Subjects contributed person-time from date of enrollment through date of first cancer diagnosis, date moved out of state, date of death, or last follow-up, whichever occurred first. Analyses were restricted based on sex for sex-specific cancers. All models were adjusted for potential confounders including attained age (continuous, time-varying in two-year increments), state (IA, NC), applicator type (private, commercial), cigarette smoking history at enrollment (never, former smoker, current smoker, missing) family history of cancer (yes, no, missing; specific site where available), and use of five pesticides most correlated with alachlor (none, low, high, or missing based on median intensity-weighted days of use): atrazine (Spearman P = .49), cyanazine (P = .38), metolachlor (P = .38), 2,4-D (P = .38), and terbufos (P = .33). We also adjusted specific cancer site models for known risk factors including detailed smoking history (never, tertiles of pack-years among former smokers: <3.75, 3.75–15, ≥15; tertiles of pack-years among current smokers: <11.5, 11.5–28.4, ≥24.5, missing), smokeless tobacco use (ever, never, missing), and alcohol consumption (never, less than one drink/week, one or more drinks/week, missing). Tests for trend used the median of each exposure category as a continuous variable. To address issues related to latency, we lagged alachlor intensity-weighted days of use by 10 years. We performed additional analyses to evaluate the robustness of observations for alachlor and laryngeal cancer. To determine if inherent unmeasured differences between alachlor-exposed and -unexposed applicators were biasing our results, we calculated relative risks with low-exposed applicators as the referent category. We adjusted for exposure to suspected occupational larynx carcinogens including grain dusts, other dusts (wood, cotton, sand, silica), asbestos, solvents, engine exhaust, swine/poultry confinement areas, and metal grinding. We tested potential interactions with smoking, alcohol consumption, and atrazine, an herbicide inversely associated with laryngeal cancer in the AHS (21), by including an interaction term (eg, smoking × alachlor) in each model. Finally, we compared our standard model for melanoma with a model adjusted for known risk factors, which were available for a portion of the cohort (n = 20 238), including skin reaction to sun (no/mild burn, blistering/painful burn), sun protection (any, none), and hours per day spent in the sun during the growing season 10 years before enrollment (<3, 3–5, 6–10, >10 hours). Analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC). All statistical tests were two-sided, with an α of .05. Results Table 1 displays selected characteristics of 49 685 applicators, stratified by alachlor use. The 25 640 applicators reporting alachlor use (51.6%) were generally older and from Iowa, compared with those who reported no use; there was no clear association with intensity-weighted days of alachlor use. Commercial applicators and men were more likely to report greater alachlor use. Current smokers and heavier alcohol drinkers reported the highest alachlor use (fourth quartile of intensity-weighted days). Alachlor users generally reported a family history of cancer and lower smokeless tobacco use. Table 1. Selected characteristics of Agricultural Health Study pesticide applicators (n = 49 685), stratified by lifetime days of alachlor use (none, quartiles of exposure calculated among cancer cases) Characteristic Cumulative intensity-weighted days of alachlor exposure None ≤560 561–1762 1763–5075 >5075 (n = 24 045) (n = 6282) (n = 6602) (n = 6202) (n = 6554) No. (%)* No. (%)* No. (%)* No. (%)* No. (%)* Attained age, y  <50 4701 (19.6) 766 (12.2) 733 (11.1) 711 (11.5) 560 (8.5)  50–59.9 7044 (29.3) 1863 (29.7) 1940 (29.4) 1900 (30.6) 2148 (32.8)  60–69.9 6107 (25.4) 1875 (29.8) 2022 (30.6) 1864 (30.1) 2085 (31.8)  ≥70 6193 (25.8) 1778 (28.3) 1907 (28.9) 1727 (27.8) 1761 (26.9) State  Iowa 15 088 (62.7) 4996 (79.5) 5098 (77.2) 4480 (72.2) 3898 (59.5)  North Carolina 8957 (37.3) 1286 (20.5) 1504 (22.8) 1722 (27.8) 2656 (40.5) Applicator type  Private 21 546 (89.6) 5952 (94.7) 6246 (94.6) 5744 (92.6) 5734 (87.5)  Commercial 2499 (10.4) 330 (5.3) 356 (5.4) 458 (7.4) 820 (12.5) Sex  Male 22 972 (95.5) 6198 (98.7) 6542 (99.1) 6165 (99.4) 6518 (99.5)  Female 1073 (4.5) 84 (1.3) 60 (0.9) 37 (0.6) 36 (0.5) Race  White 23 390 (97.3) 6142 (97.8) 6488 (98.3) 6084 (98.1) 6405 (97.7)  Other 655 (2.7) 140 (2.2) 114 (1.7) 118 (1.9) 149 (2.3) Educational attainment  High school or less 13 245 (55.1) 3267 (52.0) 3537 (53.6) 3324 (53.6) 3661 (55.9)  More than high school 10 208 (42.5) 2863 (45.6) 2936 (44.5) 2757 (44.5) 2754 (42)  Missing 592 (2.5) 152 (2.4) 129 (2.0) 121 (2.0) 139 (2.1) Family history of cancer  No 14 464 (60.2) 3435 (54.7) 3588 (54.3) 3421 (55.2) 3590 (54.8)  Yes 8814 (36.7) 2683 (42.7) 2861 (43.3) 2638 (42.5) 2802 (42.8)  Missing/don't know 767 (3.2) 164 (2.6) 153 (2.3) 143 (2.3) 162 (2.5) Smoking status and pack-years  Never 12 796 (53.2) 3507 (55.8) 3659 (55.4) 3300 (53.2) 3151 (48.1)  Former, <4 pack-years 2237 (9.3) 709 (11.3) 720 (10.9) 608 (9.8) 672 (10.3)  Former, 4–15 pack-years 2064 (8.6) 575 (9.2) 619 (9.4) 565 (9.1) 598 (9.1)  Former, >15 pack-years 1855 (7.7) 477 (7.6) 544 (8.2) 557 (9.0) 644 (9.8)  Current, <11.5 pack-years 1568 (6.5) 295 (4.7) 285 (4.3) 335 (5.4) 365 (5.6)  Current, 11.5–29 pack-years 1293 (5.4) 260 (4.1) 290 (4.4) 332 (5.4) 405 (6.2)  Current, >29 pack-years 1230 (5.1) 255 (4.1) 289 (4.4) 327 (5.3) 498 (7.6)  Missing 1002 (4.2) 204 (3.2) 196 (3.0) 178 (2.9) 221 (3.4) Smokeless tobacco use  Never 19 478 (81.0) 5235 (83.3) 5494 (83.2) 5120 (82.6) 5311 (81.0)  Ever 4567 (19.0) 1047 (16.7) 1108 (16.8) 1082 (17.4) 1243 (19.0) Alcohol use  Never 8001 (33.3) 1729 (27.5) 1813 (27.5) 1686 (27.2) 1983 (30.3)  <1 drink/wk 7501 (31.2) 2185 (34.8) 2261 (34.2) 2083 (33.6) 1989 (30.3)  ≥1 drink/wk 8087 (33.6) 2268 (36.1) 2458 (37.2) 2367 (38.2) 2518 (38.4)  Missing 456 (1.9) 100 (1.6) 70 (1.1) 66 (1.1) 64 (1.0) Use of selected pesticides†  Atrazine use   None 10 690 (44.5) 890 (14.2) 755 (11.4) 582 (9.4) 413 (6.3)   Low (≤2720) 7821 (32.5) 4119 (65.6) 3623 (54.9) 2020 (32.6) 790 (12.1)   High (>2720) 4966 (20.7) 1197 (19.1) 2159 (32.7) 3548 (57.2) 5304 (80.9)   Missing 568 (2.4) 76 (1.2) 65 (1) 52 (0.8) 47 (0.7)  Cyanazine use   None 18 366 (76.4) 2667 (42.5) 2771 (42) 2480 (40.0) 2516 (38.4)   Low (≤1120) 2831 (11.8) 2652 (42.2) 2138 (32.4) 1282 (20.7) 680 (10.4)   High (>1120) 2590 (10.8) 745 (11.9) 1510 (22.9) 2251 (36.3) 3128 (47.7)   Missing 258 (1.1) 218 (3.5) 183 (2.8) 189 (3.0) 230 (3.5)  Metolachlor use   None 16 070 (66.8) 2351 (37.4) 2384 (36.1) 2096 (33.8) 1836 (28.0)   Low (≤1456) 3984 (16.6) 2753 (43.8) 2454 (37.2) 1346 (21.7) 796 (12.1)   High (>1456) 3574 (14.9) 956 (15.2) 1591 (24.1) 2576 (41.5) 3719 (56.7)   Missing 417 (1.7) 222 (3.5) 173 (2.6) 184 (3.0) 203 (3.1)  2,4-D use   None 7737 (32.2) 769 (12.2) 711 (10.8) 655 (10.6) 560 (8.5)   Low (≤3270) 9562 (39.8) 3909 (62.2) 3461 (52.4) 2220 (35.8) 1140 (17.4)   High (>3270) 6082 (25.3) 1507 (24) 2346 (35.5) 3243 (52.3) 4778 (72.9)   Missing 664 (2.8) 97 (1.5) 84 (1.3) 84 (1.4) 76 (1.2)  Terbufos use   None 18 029 (75.0) 3262 (51.9) 3326 (50.4) 2832 (45.7) 2726 (41.6)   Low (≤1322) 3060 (12.7) 2124 (33.8) 1919 (29.1) 1271 (20.5) 744 (11.4)   High (>1322) 2289 (9.5) 629 (10.0) 1132 (17.1) 1892 (30.5) 2832 (43.2)   Missing 667 (2.8) 267 (4.3) 225 (3.4) 207 (3.3) 252 (3.8) Characteristic Cumulative intensity-weighted days of alachlor exposure None ≤560 561–1762 1763–5075 >5075 (n = 24 045) (n = 6282) (n = 6602) (n = 6202) (n = 6554) No. (%)* No. (%)* No. (%)* No. (%)* No. (%)* Attained age, y  <50 4701 (19.6) 766 (12.2) 733 (11.1) 711 (11.5) 560 (8.5)  50–59.9 7044 (29.3) 1863 (29.7) 1940 (29.4) 1900 (30.6) 2148 (32.8)  60–69.9 6107 (25.4) 1875 (29.8) 2022 (30.6) 1864 (30.1) 2085 (31.8)  ≥70 6193 (25.8) 1778 (28.3) 1907 (28.9) 1727 (27.8) 1761 (26.9) State  Iowa 15 088 (62.7) 4996 (79.5) 5098 (77.2) 4480 (72.2) 3898 (59.5)  North Carolina 8957 (37.3) 1286 (20.5) 1504 (22.8) 1722 (27.8) 2656 (40.5) Applicator type  Private 21 546 (89.6) 5952 (94.7) 6246 (94.6) 5744 (92.6) 5734 (87.5)  Commercial 2499 (10.4) 330 (5.3) 356 (5.4) 458 (7.4) 820 (12.5) Sex  Male 22 972 (95.5) 6198 (98.7) 6542 (99.1) 6165 (99.4) 6518 (99.5)  Female 1073 (4.5) 84 (1.3) 60 (0.9) 37 (0.6) 36 (0.5) Race  White 23 390 (97.3) 6142 (97.8) 6488 (98.3) 6084 (98.1) 6405 (97.7)  Other 655 (2.7) 140 (2.2) 114 (1.7) 118 (1.9) 149 (2.3) Educational attainment  High school or less 13 245 (55.1) 3267 (52.0) 3537 (53.6) 3324 (53.6) 3661 (55.9)  More than high school 10 208 (42.5) 2863 (45.6) 2936 (44.5) 2757 (44.5) 2754 (42)  Missing 592 (2.5) 152 (2.4) 129 (2.0) 121 (2.0) 139 (2.1) Family history of cancer  No 14 464 (60.2) 3435 (54.7) 3588 (54.3) 3421 (55.2) 3590 (54.8)  Yes 8814 (36.7) 2683 (42.7) 2861 (43.3) 2638 (42.5) 2802 (42.8)  Missing/don't know 767 (3.2) 164 (2.6) 153 (2.3) 143 (2.3) 162 (2.5) Smoking status and pack-years  Never 12 796 (53.2) 3507 (55.8) 3659 (55.4) 3300 (53.2) 3151 (48.1)  Former, <4 pack-years 2237 (9.3) 709 (11.3) 720 (10.9) 608 (9.8) 672 (10.3)  Former, 4–15 pack-years 2064 (8.6) 575 (9.2) 619 (9.4) 565 (9.1) 598 (9.1)  Former, >15 pack-years 1855 (7.7) 477 (7.6) 544 (8.2) 557 (9.0) 644 (9.8)  Current, <11.5 pack-years 1568 (6.5) 295 (4.7) 285 (4.3) 335 (5.4) 365 (5.6)  Current, 11.5–29 pack-years 1293 (5.4) 260 (4.1) 290 (4.4) 332 (5.4) 405 (6.2)  Current, >29 pack-years 1230 (5.1) 255 (4.1) 289 (4.4) 327 (5.3) 498 (7.6)  Missing 1002 (4.2) 204 (3.2) 196 (3.0) 178 (2.9) 221 (3.4) Smokeless tobacco use  Never 19 478 (81.0) 5235 (83.3) 5494 (83.2) 5120 (82.6) 5311 (81.0)  Ever 4567 (19.0) 1047 (16.7) 1108 (16.8) 1082 (17.4) 1243 (19.0) Alcohol use  Never 8001 (33.3) 1729 (27.5) 1813 (27.5) 1686 (27.2) 1983 (30.3)  <1 drink/wk 7501 (31.2) 2185 (34.8) 2261 (34.2) 2083 (33.6) 1989 (30.3)  ≥1 drink/wk 8087 (33.6) 2268 (36.1) 2458 (37.2) 2367 (38.2) 2518 (38.4)  Missing 456 (1.9) 100 (1.6) 70 (1.1) 66 (1.1) 64 (1.0) Use of selected pesticides†  Atrazine use   None 10 690 (44.5) 890 (14.2) 755 (11.4) 582 (9.4) 413 (6.3)   Low (≤2720) 7821 (32.5) 4119 (65.6) 3623 (54.9) 2020 (32.6) 790 (12.1)   High (>2720) 4966 (20.7) 1197 (19.1) 2159 (32.7) 3548 (57.2) 5304 (80.9)   Missing 568 (2.4) 76 (1.2) 65 (1) 52 (0.8) 47 (0.7)  Cyanazine use   None 18 366 (76.4) 2667 (42.5) 2771 (42) 2480 (40.0) 2516 (38.4)   Low (≤1120) 2831 (11.8) 2652 (42.2) 2138 (32.4) 1282 (20.7) 680 (10.4)   High (>1120) 2590 (10.8) 745 (11.9) 1510 (22.9) 2251 (36.3) 3128 (47.7)   Missing 258 (1.1) 218 (3.5) 183 (2.8) 189 (3.0) 230 (3.5)  Metolachlor use   None 16 070 (66.8) 2351 (37.4) 2384 (36.1) 2096 (33.8) 1836 (28.0)   Low (≤1456) 3984 (16.6) 2753 (43.8) 2454 (37.2) 1346 (21.7) 796 (12.1)   High (>1456) 3574 (14.9) 956 (15.2) 1591 (24.1) 2576 (41.5) 3719 (56.7)   Missing 417 (1.7) 222 (3.5) 173 (2.6) 184 (3.0) 203 (3.1)  2,4-D use   None 7737 (32.2) 769 (12.2) 711 (10.8) 655 (10.6) 560 (8.5)   Low (≤3270) 9562 (39.8) 3909 (62.2) 3461 (52.4) 2220 (35.8) 1140 (17.4)   High (>3270) 6082 (25.3) 1507 (24) 2346 (35.5) 3243 (52.3) 4778 (72.9)   Missing 664 (2.8) 97 (1.5) 84 (1.3) 84 (1.4) 76 (1.2)  Terbufos use   None 18 029 (75.0) 3262 (51.9) 3326 (50.4) 2832 (45.7) 2726 (41.6)   Low (≤1322) 3060 (12.7) 2124 (33.8) 1919 (29.1) 1271 (20.5) 744 (11.4)   High (>1322) 2289 (9.5) 629 (10.0) 1132 (17.1) 1892 (30.5) 2832 (43.2)   Missing 667 (2.8) 267 (4.3) 225 (3.4) 207 (3.3) 252 (3.8) * Percentages may not sum to 100 due to rounding. † Five pesticides most highly correlated with alachlor; classified as no use, low use (≤median), or high use (>median) based on cumulative intensity-weighted lifetime days. Table 1. Selected characteristics of Agricultural Health Study pesticide applicators (n = 49 685), stratified by lifetime days of alachlor use (none, quartiles of exposure calculated among cancer cases) Characteristic Cumulative intensity-weighted days of alachlor exposure None ≤560 561–1762 1763–5075 >5075 (n = 24 045) (n = 6282) (n = 6602) (n = 6202) (n = 6554) No. (%)* No. (%)* No. (%)* No. (%)* No. (%)* Attained age, y  <50 4701 (19.6) 766 (12.2) 733 (11.1) 711 (11.5) 560 (8.5)  50–59.9 7044 (29.3) 1863 (29.7) 1940 (29.4) 1900 (30.6) 2148 (32.8)  60–69.9 6107 (25.4) 1875 (29.8) 2022 (30.6) 1864 (30.1) 2085 (31.8)  ≥70 6193 (25.8) 1778 (28.3) 1907 (28.9) 1727 (27.8) 1761 (26.9) State  Iowa 15 088 (62.7) 4996 (79.5) 5098 (77.2) 4480 (72.2) 3898 (59.5)  North Carolina 8957 (37.3) 1286 (20.5) 1504 (22.8) 1722 (27.8) 2656 (40.5) Applicator type  Private 21 546 (89.6) 5952 (94.7) 6246 (94.6) 5744 (92.6) 5734 (87.5)  Commercial 2499 (10.4) 330 (5.3) 356 (5.4) 458 (7.4) 820 (12.5) Sex  Male 22 972 (95.5) 6198 (98.7) 6542 (99.1) 6165 (99.4) 6518 (99.5)  Female 1073 (4.5) 84 (1.3) 60 (0.9) 37 (0.6) 36 (0.5) Race  White 23 390 (97.3) 6142 (97.8) 6488 (98.3) 6084 (98.1) 6405 (97.7)  Other 655 (2.7) 140 (2.2) 114 (1.7) 118 (1.9) 149 (2.3) Educational attainment  High school or less 13 245 (55.1) 3267 (52.0) 3537 (53.6) 3324 (53.6) 3661 (55.9)  More than high school 10 208 (42.5) 2863 (45.6) 2936 (44.5) 2757 (44.5) 2754 (42)  Missing 592 (2.5) 152 (2.4) 129 (2.0) 121 (2.0) 139 (2.1) Family history of cancer  No 14 464 (60.2) 3435 (54.7) 3588 (54.3) 3421 (55.2) 3590 (54.8)  Yes 8814 (36.7) 2683 (42.7) 2861 (43.3) 2638 (42.5) 2802 (42.8)  Missing/don't know 767 (3.2) 164 (2.6) 153 (2.3) 143 (2.3) 162 (2.5) Smoking status and pack-years  Never 12 796 (53.2) 3507 (55.8) 3659 (55.4) 3300 (53.2) 3151 (48.1)  Former, <4 pack-years 2237 (9.3) 709 (11.3) 720 (10.9) 608 (9.8) 672 (10.3)  Former, 4–15 pack-years 2064 (8.6) 575 (9.2) 619 (9.4) 565 (9.1) 598 (9.1)  Former, >15 pack-years 1855 (7.7) 477 (7.6) 544 (8.2) 557 (9.0) 644 (9.8)  Current, <11.5 pack-years 1568 (6.5) 295 (4.7) 285 (4.3) 335 (5.4) 365 (5.6)  Current, 11.5–29 pack-years 1293 (5.4) 260 (4.1) 290 (4.4) 332 (5.4) 405 (6.2)  Current, >29 pack-years 1230 (5.1) 255 (4.1) 289 (4.4) 327 (5.3) 498 (7.6)  Missing 1002 (4.2) 204 (3.2) 196 (3.0) 178 (2.9) 221 (3.4) Smokeless tobacco use  Never 19 478 (81.0) 5235 (83.3) 5494 (83.2) 5120 (82.6) 5311 (81.0)  Ever 4567 (19.0) 1047 (16.7) 1108 (16.8) 1082 (17.4) 1243 (19.0) Alcohol use  Never 8001 (33.3) 1729 (27.5) 1813 (27.5) 1686 (27.2) 1983 (30.3)  <1 drink/wk 7501 (31.2) 2185 (34.8) 2261 (34.2) 2083 (33.6) 1989 (30.3)  ≥1 drink/wk 8087 (33.6) 2268 (36.1) 2458 (37.2) 2367 (38.2) 2518 (38.4)  Missing 456 (1.9) 100 (1.6) 70 (1.1) 66 (1.1) 64 (1.0) Use of selected pesticides†  Atrazine use   None 10 690 (44.5) 890 (14.2) 755 (11.4) 582 (9.4) 413 (6.3)   Low (≤2720) 7821 (32.5) 4119 (65.6) 3623 (54.9) 2020 (32.6) 790 (12.1)   High (>2720) 4966 (20.7) 1197 (19.1) 2159 (32.7) 3548 (57.2) 5304 (80.9)   Missing 568 (2.4) 76 (1.2) 65 (1) 52 (0.8) 47 (0.7)  Cyanazine use   None 18 366 (76.4) 2667 (42.5) 2771 (42) 2480 (40.0) 2516 (38.4)   Low (≤1120) 2831 (11.8) 2652 (42.2) 2138 (32.4) 1282 (20.7) 680 (10.4)   High (>1120) 2590 (10.8) 745 (11.9) 1510 (22.9) 2251 (36.3) 3128 (47.7)   Missing 258 (1.1) 218 (3.5) 183 (2.8) 189 (3.0) 230 (3.5)  Metolachlor use   None 16 070 (66.8) 2351 (37.4) 2384 (36.1) 2096 (33.8) 1836 (28.0)   Low (≤1456) 3984 (16.6) 2753 (43.8) 2454 (37.2) 1346 (21.7) 796 (12.1)   High (>1456) 3574 (14.9) 956 (15.2) 1591 (24.1) 2576 (41.5) 3719 (56.7)   Missing 417 (1.7) 222 (3.5) 173 (2.6) 184 (3.0) 203 (3.1)  2,4-D use   None 7737 (32.2) 769 (12.2) 711 (10.8) 655 (10.6) 560 (8.5)   Low (≤3270) 9562 (39.8) 3909 (62.2) 3461 (52.4) 2220 (35.8) 1140 (17.4)   High (>3270) 6082 (25.3) 1507 (24) 2346 (35.5) 3243 (52.3) 4778 (72.9)   Missing 664 (2.8) 97 (1.5) 84 (1.3) 84 (1.4) 76 (1.2)  Terbufos use   None 18 029 (75.0) 3262 (51.9) 3326 (50.4) 2832 (45.7) 2726 (41.6)   Low (≤1322) 3060 (12.7) 2124 (33.8) 1919 (29.1) 1271 (20.5) 744 (11.4)   High (>1322) 2289 (9.5) 629 (10.0) 1132 (17.1) 1892 (30.5) 2832 (43.2)   Missing 667 (2.8) 267 (4.3) 225 (3.4) 207 (3.3) 252 (3.8) Characteristic Cumulative intensity-weighted days of alachlor exposure None ≤560 561–1762 1763–5075 >5075 (n = 24 045) (n = 6282) (n = 6602) (n = 6202) (n = 6554) No. (%)* No. (%)* No. (%)* No. (%)* No. (%)* Attained age, y  <50 4701 (19.6) 766 (12.2) 733 (11.1) 711 (11.5) 560 (8.5)  50–59.9 7044 (29.3) 1863 (29.7) 1940 (29.4) 1900 (30.6) 2148 (32.8)  60–69.9 6107 (25.4) 1875 (29.8) 2022 (30.6) 1864 (30.1) 2085 (31.8)  ≥70 6193 (25.8) 1778 (28.3) 1907 (28.9) 1727 (27.8) 1761 (26.9) State  Iowa 15 088 (62.7) 4996 (79.5) 5098 (77.2) 4480 (72.2) 3898 (59.5)  North Carolina 8957 (37.3) 1286 (20.5) 1504 (22.8) 1722 (27.8) 2656 (40.5) Applicator type  Private 21 546 (89.6) 5952 (94.7) 6246 (94.6) 5744 (92.6) 5734 (87.5)  Commercial 2499 (10.4) 330 (5.3) 356 (5.4) 458 (7.4) 820 (12.5) Sex  Male 22 972 (95.5) 6198 (98.7) 6542 (99.1) 6165 (99.4) 6518 (99.5)  Female 1073 (4.5) 84 (1.3) 60 (0.9) 37 (0.6) 36 (0.5) Race  White 23 390 (97.3) 6142 (97.8) 6488 (98.3) 6084 (98.1) 6405 (97.7)  Other 655 (2.7) 140 (2.2) 114 (1.7) 118 (1.9) 149 (2.3) Educational attainment  High school or less 13 245 (55.1) 3267 (52.0) 3537 (53.6) 3324 (53.6) 3661 (55.9)  More than high school 10 208 (42.5) 2863 (45.6) 2936 (44.5) 2757 (44.5) 2754 (42)  Missing 592 (2.5) 152 (2.4) 129 (2.0) 121 (2.0) 139 (2.1) Family history of cancer  No 14 464 (60.2) 3435 (54.7) 3588 (54.3) 3421 (55.2) 3590 (54.8)  Yes 8814 (36.7) 2683 (42.7) 2861 (43.3) 2638 (42.5) 2802 (42.8)  Missing/don't know 767 (3.2) 164 (2.6) 153 (2.3) 143 (2.3) 162 (2.5) Smoking status and pack-years  Never 12 796 (53.2) 3507 (55.8) 3659 (55.4) 3300 (53.2) 3151 (48.1)  Former, <4 pack-years 2237 (9.3) 709 (11.3) 720 (10.9) 608 (9.8) 672 (10.3)  Former, 4–15 pack-years 2064 (8.6) 575 (9.2) 619 (9.4) 565 (9.1) 598 (9.1)  Former, >15 pack-years 1855 (7.7) 477 (7.6) 544 (8.2) 557 (9.0) 644 (9.8)  Current, <11.5 pack-years 1568 (6.5) 295 (4.7) 285 (4.3) 335 (5.4) 365 (5.6)  Current, 11.5–29 pack-years 1293 (5.4) 260 (4.1) 290 (4.4) 332 (5.4) 405 (6.2)  Current, >29 pack-years 1230 (5.1) 255 (4.1) 289 (4.4) 327 (5.3) 498 (7.6)  Missing 1002 (4.2) 204 (3.2) 196 (3.0) 178 (2.9) 221 (3.4) Smokeless tobacco use  Never 19 478 (81.0) 5235 (83.3) 5494 (83.2) 5120 (82.6) 5311 (81.0)  Ever 4567 (19.0) 1047 (16.7) 1108 (16.8) 1082 (17.4) 1243 (19.0) Alcohol use  Never 8001 (33.3) 1729 (27.5) 1813 (27.5) 1686 (27.2) 1983 (30.3)  <1 drink/wk 7501 (31.2) 2185 (34.8) 2261 (34.2) 2083 (33.6) 1989 (30.3)  ≥1 drink/wk 8087 (33.6) 2268 (36.1) 2458 (37.2) 2367 (38.2) 2518 (38.4)  Missing 456 (1.9) 100 (1.6) 70 (1.1) 66 (1.1) 64 (1.0) Use of selected pesticides†  Atrazine use   None 10 690 (44.5) 890 (14.2) 755 (11.4) 582 (9.4) 413 (6.3)   Low (≤2720) 7821 (32.5) 4119 (65.6) 3623 (54.9) 2020 (32.6) 790 (12.1)   High (>2720) 4966 (20.7) 1197 (19.1) 2159 (32.7) 3548 (57.2) 5304 (80.9)   Missing 568 (2.4) 76 (1.2) 65 (1) 52 (0.8) 47 (0.7)  Cyanazine use   None 18 366 (76.4) 2667 (42.5) 2771 (42) 2480 (40.0) 2516 (38.4)   Low (≤1120) 2831 (11.8) 2652 (42.2) 2138 (32.4) 1282 (20.7) 680 (10.4)   High (>1120) 2590 (10.8) 745 (11.9) 1510 (22.9) 2251 (36.3) 3128 (47.7)   Missing 258 (1.1) 218 (3.5) 183 (2.8) 189 (3.0) 230 (3.5)  Metolachlor use   None 16 070 (66.8) 2351 (37.4) 2384 (36.1) 2096 (33.8) 1836 (28.0)   Low (≤1456) 3984 (16.6) 2753 (43.8) 2454 (37.2) 1346 (21.7) 796 (12.1)   High (>1456) 3574 (14.9) 956 (15.2) 1591 (24.1) 2576 (41.5) 3719 (56.7)   Missing 417 (1.7) 222 (3.5) 173 (2.6) 184 (3.0) 203 (3.1)  2,4-D use   None 7737 (32.2) 769 (12.2) 711 (10.8) 655 (10.6) 560 (8.5)   Low (≤3270) 9562 (39.8) 3909 (62.2) 3461 (52.4) 2220 (35.8) 1140 (17.4)   High (>3270) 6082 (25.3) 1507 (24) 2346 (35.5) 3243 (52.3) 4778 (72.9)   Missing 664 (2.8) 97 (1.5) 84 (1.3) 84 (1.4) 76 (1.2)  Terbufos use   None 18 029 (75.0) 3262 (51.9) 3326 (50.4) 2832 (45.7) 2726 (41.6)   Low (≤1322) 3060 (12.7) 2124 (33.8) 1919 (29.1) 1271 (20.5) 744 (11.4)   High (>1322) 2289 (9.5) 629 (10.0) 1132 (17.1) 1892 (30.5) 2832 (43.2)   Missing 667 (2.8) 267 (4.3) 225 (3.4) 207 (3.3) 252 (3.8) * Percentages may not sum to 100 due to rounding. † Five pesticides most highly correlated with alachlor; classified as no use, low use (≤median), or high use (>median) based on cumulative intensity-weighted lifetime days. Four point seven percent of applicators who applied alachlor at enrollment continued to apply alachlor at follow-up; very few (0.9%) applicators first reported alachlor use during follow-up (Figure 1). Applicators who reported greater alachlor use at enrollment were more likely to report use of alachlor and other chloroacetanilides such as acetochlor or metolachlor at follow-up; 13.4% of applicators in the cohort had stopped applying pesticides on the farm at follow-up, while virtually all applicators reported pesticide use at enrollment (not shown). Figure 1. View largeDownload slide Use of alachlor at enrollment (A) and chloroacetanilide herbicides at follow-up interview (B) among Agricultural Health Study applicators who completed follow-up interview (n = 31 822). Figure 1. View largeDownload slide Use of alachlor at enrollment (A) and chloroacetanilide herbicides at follow-up interview (B) among Agricultural Health Study applicators who completed follow-up interview (n = 31 822). Table 2 displays model results for cumulative intensity-weighted days of alachlor use and cancer risk. We saw no association for all cancer sites combined. Laryngeal cancer was associated with alachlor exposure in the second (RR = 4.68, 95% CI = 1.95 to 11.23), third (RR = 6.04, 95% CI = 2.44 to 14.99), and fourth (RR = 7.10, 95% CI = 2.58 to 19.53) quartiles of use compared with unexposed, with a statistically significant exposure-response trend (Ptrend = .001). Alachlor intensity-weighted days of use in the third quartile was associated with cancers of the small intestine (RR = 3.41, 95% CI = 1.26 to 9.25); risk estimates in other quartiles were elevated but not statistically significant, and there was no evidence for exposure-response trend (Ptrend = .48). Alachlor intensity-weighted days of use in the first quartile of exposure was associated with increased risk of melanoma (RR = 1.44, 95% CI = 1.01 to 2.06, Ptrend = .94); risk estimates remained unchanged after further adjustment for sun protection and sensitivity (not shown). We also noted a non–statistically significant inverse association with stomach cancer for alachlor exposure in the fourth quartile (RR = 0.53, 95% CI = 0.23 to 1.23, Ptrend = .14). There was no association for lymphohematopoietic cancers combined (Ptrend = .44). However, myeloid leukemia was elevated among applicators in the fourth quartile of use (RR = 1.82, 95% CI = 0.85 to 3.87, Ptrend = .17) based on 48 exposed cases. Of these, 34 were acute myeloid leukemia (AML), for which similar results were observed in the fourth quartile of alachlor exposure (RR = 1.73, 95% CI = 0.73 to 4.13, Ptrend = .22, not shown). There were not enough chronic myeloid leukemia (CML) cases to evaluate separately. For comparison with Lee et al., we examined total leukemia including chronic lymphocytic leukemia (CLL; now classified as an NHL subtype) (18). We noted a non–statistically significantly elevated relative risk in the fourth quartile of intensity-weighted days of exposure (RR = 1.25, 95% CI = 0.78 to 2.02, Ptrend = .29) compared with unexposed (not shown). Results for models examining alachlor days of exposure were similar (Supplementary Table 1, available online); a statistically significant trend for lifetime days of exposure and laryngeal cancer was apparent (Ptrend = .004). Table 2. Adjusted* relative risks and 95% confidence intervals for cancer incidence associated with cumulative alachlor intensity-weighted days of exposure, compared with no alachlor use, in the Agricultural Health Study Cancer site No use Quartile 1 Quartile 2 Quartile 3 Quartile 4 Ptrend† (ref) ≤560 561–1762 1763–5075 >5075 No. No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Any cancer‡ 3037 884 1.07 (0.98 to 1.16) 883 1.00 (0.92 to 1.08) 884 1.07 (0.98 to 1.16) 883 1.00 (0.91 to 1.09) .77 Oral cavity§ 76 19 0.86 (0.50 to 1.48) 26 1.08 (0.67 to 1.73) 11 0.48 (0.25 to 0.94) 26 1.10 (0.64 to 1.87) .65  Lip 19 8 1.30 (0.53 to 3.21) 11 1.72 (0.77 to 3.84) 3 0.54 (0.15 to 1.90) 7 1.34 (0.49 to 3.65) .76 Esophagus‡,‖ 36 13 1.38 (0.68 to 2.81) 10 0.87 (0.41 to 1.88) 15 1.33 (0.68 to 2.59) 16 1.16 (0.56 to 2.41) .77 Stomach 45 10 0.85 (0.41 to 1.79) 13 0.98 (0.50 to 1.91) 12 0.89 (0.44 to 1.77) 8 0.53 (0.23 to 1.23) .14 Small intestine 14 6 2.25 (0.77 to 6.57) 5 1.87 (0.61 to 5.68) 8 3.41 (1.26 to 9.25) 4 1.93 (0.53 to 7.00) .48 Colon 221 60 1.04 (0.76 to 1.42) 48 0.79 (0.57 to 1.11) 64 1.12 (0.82 to 1.53) 63 1.07 (0.77 to 1.49) .58 Rectum 98 33 1.35 (0.86 to 2.13) 20 0.77 (0.46 to 1.29) 27 1.06 (0.66 to 1.69) 23 0.80 (0.47 to 1.36) .35 Liver‖ 16 4 1.27 (0.40 to 4.09) 6 1.58 (0.57 to 4.36) 9 1.91 (0.75 to 4.89) 9 1.23 (0.42 to 3.62) 1.00 Pancreas‡ 71 15 0.89 (0.48 to 1.65) 20 1.05 (0.61 to 1.81) 17 0.90 (0.50 to 1.64) 15 0.76 (0.39 to 1.48) .42 Lung‡ 293 69 1.14 (0.86 to 1.53) 72 1.06 (0.80 to 1.40) 87 1.28 (0.98 to 1.67) 78 0.94 (0.69 to 1.27) .47  Small cell 86 22 1.24 (0.73 to 2.11) 20 1.01 (0.60 to 1.72) 26 1.36 (0.83 to 2.22) 22 0.92 (0.52 to 1.62) .64  Squamous cell 67 21 1.33 (0.76 to 2.34) 14 0.83 (0.45 to 1.53) 23 1.30 (0.76 to 2.22) 23 0.99 (0.55 to 1.78) .84  Adenocarcinoma 86 18 1.03 (0.59 to 1.80) 24 1.18 (0.72 to 1.94) 27 1.37 (0.84 to 2.22) 22 1.02 (0.59 to 1.78) .96 Larynx‡,‖ 15 4 1.60 (0.49 to 5.24) 11 4.68 (1.95 to 11.23) 10 6.04 (2.44 to 14.99) 9 7.10 (2.58 to 19.53) .001 Melanoma 129 51 1.44 (1.01 to 2.06) 29 0.78 (0.50 to 1.19) 47 1.35 (0.94 to 1.96) 40 1.06 (0.69 to 1.62) .94 Prostate 1138 355 1.04 (0.92 to 1.19) 391 1.07 (0.95 to 1.22) 341 1.02 (0.89 to 1.16) 357 1.03 (0.89 to 1.18) .91  Aggressive prostate 618 198 1.01 (0.94 to 1.08) 198 0.94 (0.88 to 1.01) 173 0.94 (0.88 to 1.01) 188 0.94 (0.87 to 1.01) .14 Testis 24 8 1.15 (0.49 to 2.73) 8 1.18 (0.50 to 2.77) 7 1.10 (0.43 to 2.76) 1 0.17 (0.02 to 1.35) .08 Bladder‡ 150 57 1.31 (0.93 to 1.84) 39 0.86 (0.59 to 1.26) 44 1.04 (0.72 to 1.49) 42 0.91 (0.61 to 1.37) .55 Kidney‡ 110 32 1.04 (0.67 to 1.62) 29 0.91 (0.59 to 1.41) 37 1.17 (0.78 to 1.78) 26 0.79 (0.48 to 1.29) .34 Brain 39 13 1.08 (0.54 to 2.18) 9 0.76 (0.36 to 1.64) 10 0.89 (0.41 to 1.91) 9 0.83 (0.35 to 1.97) .71 Thyroid 35 10 1.31 (0.61 to 2.78) 15 1.69 (0.85 to 3.36) 8 1.09 (0.47 to 2.52) 8 1.14 (0.46 to 2.83) .98 Lymphohematopoietic 307 84 0.92 (0.71 to 1.20) 83 0.85 (0.65 to 1.10) 86 0.98 (0.75 to 1.27) 94 1.07 (0.81 to 1.40) .44  Non-Hodgkin lymphoid  malignancies 251 70 0.86 (0.65 to 1.15) 61 0.70 (0.52 to 0.95) 72 0.93 (0.70 to 1.24) 79 1.02 (0.76 to 1.38) .50    CLL/SLL/PLL/MCL 74 17 0.67 (0.38 to 1.18) 14 0.51 (0.28 to 0.95) 25 1.14 (0.69 to 1.87) 23 1.15 (0.66 to 1.99) .31    Diffuse large B cell    lymphoma 62 13 0.73 (0.39 to 1.39) 18 0.84 (0.47 to 1.51) 12 0.64 (0.33 to 1.24) 17 0.81 (0.43 to 1.54) .68    Follicular lymphoma 28 9 0.94 (0.42 to 2.13) 5 0.52 (0.19 to 1.42) 6 0.57 (0.21 to 1.57) 11 1.22 (0.52 to 2.85) .43    Multiple myeloma 52 17 1.26 (0.68 to 2.32) 13 0.84 (0.44 to 1.61) 15 0.94 (0.50 to 1.78) 14 0.77 (0.39 to 1.55) .43  Myeloid leukemia 40 11 1.28 (0.62 to 2.66) 13 1.42 (0.72 to 2.81) 11 1.46 (0.69 to 3.09) 13 1.82 (0.85 to 3.87) .17 Cancer site No use Quartile 1 Quartile 2 Quartile 3 Quartile 4 Ptrend† (ref) ≤560 561–1762 1763–5075 >5075 No. No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Any cancer‡ 3037 884 1.07 (0.98 to 1.16) 883 1.00 (0.92 to 1.08) 884 1.07 (0.98 to 1.16) 883 1.00 (0.91 to 1.09) .77 Oral cavity§ 76 19 0.86 (0.50 to 1.48) 26 1.08 (0.67 to 1.73) 11 0.48 (0.25 to 0.94) 26 1.10 (0.64 to 1.87) .65  Lip 19 8 1.30 (0.53 to 3.21) 11 1.72 (0.77 to 3.84) 3 0.54 (0.15 to 1.90) 7 1.34 (0.49 to 3.65) .76 Esophagus‡,‖ 36 13 1.38 (0.68 to 2.81) 10 0.87 (0.41 to 1.88) 15 1.33 (0.68 to 2.59) 16 1.16 (0.56 to 2.41) .77 Stomach 45 10 0.85 (0.41 to 1.79) 13 0.98 (0.50 to 1.91) 12 0.89 (0.44 to 1.77) 8 0.53 (0.23 to 1.23) .14 Small intestine 14 6 2.25 (0.77 to 6.57) 5 1.87 (0.61 to 5.68) 8 3.41 (1.26 to 9.25) 4 1.93 (0.53 to 7.00) .48 Colon 221 60 1.04 (0.76 to 1.42) 48 0.79 (0.57 to 1.11) 64 1.12 (0.82 to 1.53) 63 1.07 (0.77 to 1.49) .58 Rectum 98 33 1.35 (0.86 to 2.13) 20 0.77 (0.46 to 1.29) 27 1.06 (0.66 to 1.69) 23 0.80 (0.47 to 1.36) .35 Liver‖ 16 4 1.27 (0.40 to 4.09) 6 1.58 (0.57 to 4.36) 9 1.91 (0.75 to 4.89) 9 1.23 (0.42 to 3.62) 1.00 Pancreas‡ 71 15 0.89 (0.48 to 1.65) 20 1.05 (0.61 to 1.81) 17 0.90 (0.50 to 1.64) 15 0.76 (0.39 to 1.48) .42 Lung‡ 293 69 1.14 (0.86 to 1.53) 72 1.06 (0.80 to 1.40) 87 1.28 (0.98 to 1.67) 78 0.94 (0.69 to 1.27) .47  Small cell 86 22 1.24 (0.73 to 2.11) 20 1.01 (0.60 to 1.72) 26 1.36 (0.83 to 2.22) 22 0.92 (0.52 to 1.62) .64  Squamous cell 67 21 1.33 (0.76 to 2.34) 14 0.83 (0.45 to 1.53) 23 1.30 (0.76 to 2.22) 23 0.99 (0.55 to 1.78) .84  Adenocarcinoma 86 18 1.03 (0.59 to 1.80) 24 1.18 (0.72 to 1.94) 27 1.37 (0.84 to 2.22) 22 1.02 (0.59 to 1.78) .96 Larynx‡,‖ 15 4 1.60 (0.49 to 5.24) 11 4.68 (1.95 to 11.23) 10 6.04 (2.44 to 14.99) 9 7.10 (2.58 to 19.53) .001 Melanoma 129 51 1.44 (1.01 to 2.06) 29 0.78 (0.50 to 1.19) 47 1.35 (0.94 to 1.96) 40 1.06 (0.69 to 1.62) .94 Prostate 1138 355 1.04 (0.92 to 1.19) 391 1.07 (0.95 to 1.22) 341 1.02 (0.89 to 1.16) 357 1.03 (0.89 to 1.18) .91  Aggressive prostate 618 198 1.01 (0.94 to 1.08) 198 0.94 (0.88 to 1.01) 173 0.94 (0.88 to 1.01) 188 0.94 (0.87 to 1.01) .14 Testis 24 8 1.15 (0.49 to 2.73) 8 1.18 (0.50 to 2.77) 7 1.10 (0.43 to 2.76) 1 0.17 (0.02 to 1.35) .08 Bladder‡ 150 57 1.31 (0.93 to 1.84) 39 0.86 (0.59 to 1.26) 44 1.04 (0.72 to 1.49) 42 0.91 (0.61 to 1.37) .55 Kidney‡ 110 32 1.04 (0.67 to 1.62) 29 0.91 (0.59 to 1.41) 37 1.17 (0.78 to 1.78) 26 0.79 (0.48 to 1.29) .34 Brain 39 13 1.08 (0.54 to 2.18) 9 0.76 (0.36 to 1.64) 10 0.89 (0.41 to 1.91) 9 0.83 (0.35 to 1.97) .71 Thyroid 35 10 1.31 (0.61 to 2.78) 15 1.69 (0.85 to 3.36) 8 1.09 (0.47 to 2.52) 8 1.14 (0.46 to 2.83) .98 Lymphohematopoietic 307 84 0.92 (0.71 to 1.20) 83 0.85 (0.65 to 1.10) 86 0.98 (0.75 to 1.27) 94 1.07 (0.81 to 1.40) .44  Non-Hodgkin lymphoid  malignancies 251 70 0.86 (0.65 to 1.15) 61 0.70 (0.52 to 0.95) 72 0.93 (0.70 to 1.24) 79 1.02 (0.76 to 1.38) .50    CLL/SLL/PLL/MCL 74 17 0.67 (0.38 to 1.18) 14 0.51 (0.28 to 0.95) 25 1.14 (0.69 to 1.87) 23 1.15 (0.66 to 1.99) .31    Diffuse large B cell    lymphoma 62 13 0.73 (0.39 to 1.39) 18 0.84 (0.47 to 1.51) 12 0.64 (0.33 to 1.24) 17 0.81 (0.43 to 1.54) .68    Follicular lymphoma 28 9 0.94 (0.42 to 2.13) 5 0.52 (0.19 to 1.42) 6 0.57 (0.21 to 1.57) 11 1.22 (0.52 to 2.85) .43    Multiple myeloma 52 17 1.26 (0.68 to 2.32) 13 0.84 (0.44 to 1.61) 15 0.94 (0.50 to 1.78) 14 0.77 (0.39 to 1.55) .43  Myeloid leukemia 40 11 1.28 (0.62 to 2.66) 13 1.42 (0.72 to 2.81) 11 1.46 (0.69 to 3.09) 13 1.82 (0.85 to 3.87) .17 * Adjusted for attained age, state, applicator type, smoking status, family history of cancer, correlated pesticides (atrazine, cyanazine, metolachlor, 2,4-D, terbufos). CI = confidence interval; CLL = chronic lymphocytic leukemia; MCL = mantle cell lymphoma; PLL = prolymphocytic leukemia; RR = relative risk; SLL = small lymphocytic lymphoma. † Two-sided Wald chi-square test. ‡ Additionally adjusted for pack-years smoked. § Additionally adjusted for smokeless tobacco use. ‖ Additionally adjusted for alcohol use. Table 2. Adjusted* relative risks and 95% confidence intervals for cancer incidence associated with cumulative alachlor intensity-weighted days of exposure, compared with no alachlor use, in the Agricultural Health Study Cancer site No use Quartile 1 Quartile 2 Quartile 3 Quartile 4 Ptrend† (ref) ≤560 561–1762 1763–5075 >5075 No. No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Any cancer‡ 3037 884 1.07 (0.98 to 1.16) 883 1.00 (0.92 to 1.08) 884 1.07 (0.98 to 1.16) 883 1.00 (0.91 to 1.09) .77 Oral cavity§ 76 19 0.86 (0.50 to 1.48) 26 1.08 (0.67 to 1.73) 11 0.48 (0.25 to 0.94) 26 1.10 (0.64 to 1.87) .65  Lip 19 8 1.30 (0.53 to 3.21) 11 1.72 (0.77 to 3.84) 3 0.54 (0.15 to 1.90) 7 1.34 (0.49 to 3.65) .76 Esophagus‡,‖ 36 13 1.38 (0.68 to 2.81) 10 0.87 (0.41 to 1.88) 15 1.33 (0.68 to 2.59) 16 1.16 (0.56 to 2.41) .77 Stomach 45 10 0.85 (0.41 to 1.79) 13 0.98 (0.50 to 1.91) 12 0.89 (0.44 to 1.77) 8 0.53 (0.23 to 1.23) .14 Small intestine 14 6 2.25 (0.77 to 6.57) 5 1.87 (0.61 to 5.68) 8 3.41 (1.26 to 9.25) 4 1.93 (0.53 to 7.00) .48 Colon 221 60 1.04 (0.76 to 1.42) 48 0.79 (0.57 to 1.11) 64 1.12 (0.82 to 1.53) 63 1.07 (0.77 to 1.49) .58 Rectum 98 33 1.35 (0.86 to 2.13) 20 0.77 (0.46 to 1.29) 27 1.06 (0.66 to 1.69) 23 0.80 (0.47 to 1.36) .35 Liver‖ 16 4 1.27 (0.40 to 4.09) 6 1.58 (0.57 to 4.36) 9 1.91 (0.75 to 4.89) 9 1.23 (0.42 to 3.62) 1.00 Pancreas‡ 71 15 0.89 (0.48 to 1.65) 20 1.05 (0.61 to 1.81) 17 0.90 (0.50 to 1.64) 15 0.76 (0.39 to 1.48) .42 Lung‡ 293 69 1.14 (0.86 to 1.53) 72 1.06 (0.80 to 1.40) 87 1.28 (0.98 to 1.67) 78 0.94 (0.69 to 1.27) .47  Small cell 86 22 1.24 (0.73 to 2.11) 20 1.01 (0.60 to 1.72) 26 1.36 (0.83 to 2.22) 22 0.92 (0.52 to 1.62) .64  Squamous cell 67 21 1.33 (0.76 to 2.34) 14 0.83 (0.45 to 1.53) 23 1.30 (0.76 to 2.22) 23 0.99 (0.55 to 1.78) .84  Adenocarcinoma 86 18 1.03 (0.59 to 1.80) 24 1.18 (0.72 to 1.94) 27 1.37 (0.84 to 2.22) 22 1.02 (0.59 to 1.78) .96 Larynx‡,‖ 15 4 1.60 (0.49 to 5.24) 11 4.68 (1.95 to 11.23) 10 6.04 (2.44 to 14.99) 9 7.10 (2.58 to 19.53) .001 Melanoma 129 51 1.44 (1.01 to 2.06) 29 0.78 (0.50 to 1.19) 47 1.35 (0.94 to 1.96) 40 1.06 (0.69 to 1.62) .94 Prostate 1138 355 1.04 (0.92 to 1.19) 391 1.07 (0.95 to 1.22) 341 1.02 (0.89 to 1.16) 357 1.03 (0.89 to 1.18) .91  Aggressive prostate 618 198 1.01 (0.94 to 1.08) 198 0.94 (0.88 to 1.01) 173 0.94 (0.88 to 1.01) 188 0.94 (0.87 to 1.01) .14 Testis 24 8 1.15 (0.49 to 2.73) 8 1.18 (0.50 to 2.77) 7 1.10 (0.43 to 2.76) 1 0.17 (0.02 to 1.35) .08 Bladder‡ 150 57 1.31 (0.93 to 1.84) 39 0.86 (0.59 to 1.26) 44 1.04 (0.72 to 1.49) 42 0.91 (0.61 to 1.37) .55 Kidney‡ 110 32 1.04 (0.67 to 1.62) 29 0.91 (0.59 to 1.41) 37 1.17 (0.78 to 1.78) 26 0.79 (0.48 to 1.29) .34 Brain 39 13 1.08 (0.54 to 2.18) 9 0.76 (0.36 to 1.64) 10 0.89 (0.41 to 1.91) 9 0.83 (0.35 to 1.97) .71 Thyroid 35 10 1.31 (0.61 to 2.78) 15 1.69 (0.85 to 3.36) 8 1.09 (0.47 to 2.52) 8 1.14 (0.46 to 2.83) .98 Lymphohematopoietic 307 84 0.92 (0.71 to 1.20) 83 0.85 (0.65 to 1.10) 86 0.98 (0.75 to 1.27) 94 1.07 (0.81 to 1.40) .44  Non-Hodgkin lymphoid  malignancies 251 70 0.86 (0.65 to 1.15) 61 0.70 (0.52 to 0.95) 72 0.93 (0.70 to 1.24) 79 1.02 (0.76 to 1.38) .50    CLL/SLL/PLL/MCL 74 17 0.67 (0.38 to 1.18) 14 0.51 (0.28 to 0.95) 25 1.14 (0.69 to 1.87) 23 1.15 (0.66 to 1.99) .31    Diffuse large B cell    lymphoma 62 13 0.73 (0.39 to 1.39) 18 0.84 (0.47 to 1.51) 12 0.64 (0.33 to 1.24) 17 0.81 (0.43 to 1.54) .68    Follicular lymphoma 28 9 0.94 (0.42 to 2.13) 5 0.52 (0.19 to 1.42) 6 0.57 (0.21 to 1.57) 11 1.22 (0.52 to 2.85) .43    Multiple myeloma 52 17 1.26 (0.68 to 2.32) 13 0.84 (0.44 to 1.61) 15 0.94 (0.50 to 1.78) 14 0.77 (0.39 to 1.55) .43  Myeloid leukemia 40 11 1.28 (0.62 to 2.66) 13 1.42 (0.72 to 2.81) 11 1.46 (0.69 to 3.09) 13 1.82 (0.85 to 3.87) .17 Cancer site No use Quartile 1 Quartile 2 Quartile 3 Quartile 4 Ptrend† (ref) ≤560 561–1762 1763–5075 >5075 No. No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Any cancer‡ 3037 884 1.07 (0.98 to 1.16) 883 1.00 (0.92 to 1.08) 884 1.07 (0.98 to 1.16) 883 1.00 (0.91 to 1.09) .77 Oral cavity§ 76 19 0.86 (0.50 to 1.48) 26 1.08 (0.67 to 1.73) 11 0.48 (0.25 to 0.94) 26 1.10 (0.64 to 1.87) .65  Lip 19 8 1.30 (0.53 to 3.21) 11 1.72 (0.77 to 3.84) 3 0.54 (0.15 to 1.90) 7 1.34 (0.49 to 3.65) .76 Esophagus‡,‖ 36 13 1.38 (0.68 to 2.81) 10 0.87 (0.41 to 1.88) 15 1.33 (0.68 to 2.59) 16 1.16 (0.56 to 2.41) .77 Stomach 45 10 0.85 (0.41 to 1.79) 13 0.98 (0.50 to 1.91) 12 0.89 (0.44 to 1.77) 8 0.53 (0.23 to 1.23) .14 Small intestine 14 6 2.25 (0.77 to 6.57) 5 1.87 (0.61 to 5.68) 8 3.41 (1.26 to 9.25) 4 1.93 (0.53 to 7.00) .48 Colon 221 60 1.04 (0.76 to 1.42) 48 0.79 (0.57 to 1.11) 64 1.12 (0.82 to 1.53) 63 1.07 (0.77 to 1.49) .58 Rectum 98 33 1.35 (0.86 to 2.13) 20 0.77 (0.46 to 1.29) 27 1.06 (0.66 to 1.69) 23 0.80 (0.47 to 1.36) .35 Liver‖ 16 4 1.27 (0.40 to 4.09) 6 1.58 (0.57 to 4.36) 9 1.91 (0.75 to 4.89) 9 1.23 (0.42 to 3.62) 1.00 Pancreas‡ 71 15 0.89 (0.48 to 1.65) 20 1.05 (0.61 to 1.81) 17 0.90 (0.50 to 1.64) 15 0.76 (0.39 to 1.48) .42 Lung‡ 293 69 1.14 (0.86 to 1.53) 72 1.06 (0.80 to 1.40) 87 1.28 (0.98 to 1.67) 78 0.94 (0.69 to 1.27) .47  Small cell 86 22 1.24 (0.73 to 2.11) 20 1.01 (0.60 to 1.72) 26 1.36 (0.83 to 2.22) 22 0.92 (0.52 to 1.62) .64  Squamous cell 67 21 1.33 (0.76 to 2.34) 14 0.83 (0.45 to 1.53) 23 1.30 (0.76 to 2.22) 23 0.99 (0.55 to 1.78) .84  Adenocarcinoma 86 18 1.03 (0.59 to 1.80) 24 1.18 (0.72 to 1.94) 27 1.37 (0.84 to 2.22) 22 1.02 (0.59 to 1.78) .96 Larynx‡,‖ 15 4 1.60 (0.49 to 5.24) 11 4.68 (1.95 to 11.23) 10 6.04 (2.44 to 14.99) 9 7.10 (2.58 to 19.53) .001 Melanoma 129 51 1.44 (1.01 to 2.06) 29 0.78 (0.50 to 1.19) 47 1.35 (0.94 to 1.96) 40 1.06 (0.69 to 1.62) .94 Prostate 1138 355 1.04 (0.92 to 1.19) 391 1.07 (0.95 to 1.22) 341 1.02 (0.89 to 1.16) 357 1.03 (0.89 to 1.18) .91  Aggressive prostate 618 198 1.01 (0.94 to 1.08) 198 0.94 (0.88 to 1.01) 173 0.94 (0.88 to 1.01) 188 0.94 (0.87 to 1.01) .14 Testis 24 8 1.15 (0.49 to 2.73) 8 1.18 (0.50 to 2.77) 7 1.10 (0.43 to 2.76) 1 0.17 (0.02 to 1.35) .08 Bladder‡ 150 57 1.31 (0.93 to 1.84) 39 0.86 (0.59 to 1.26) 44 1.04 (0.72 to 1.49) 42 0.91 (0.61 to 1.37) .55 Kidney‡ 110 32 1.04 (0.67 to 1.62) 29 0.91 (0.59 to 1.41) 37 1.17 (0.78 to 1.78) 26 0.79 (0.48 to 1.29) .34 Brain 39 13 1.08 (0.54 to 2.18) 9 0.76 (0.36 to 1.64) 10 0.89 (0.41 to 1.91) 9 0.83 (0.35 to 1.97) .71 Thyroid 35 10 1.31 (0.61 to 2.78) 15 1.69 (0.85 to 3.36) 8 1.09 (0.47 to 2.52) 8 1.14 (0.46 to 2.83) .98 Lymphohematopoietic 307 84 0.92 (0.71 to 1.20) 83 0.85 (0.65 to 1.10) 86 0.98 (0.75 to 1.27) 94 1.07 (0.81 to 1.40) .44  Non-Hodgkin lymphoid  malignancies 251 70 0.86 (0.65 to 1.15) 61 0.70 (0.52 to 0.95) 72 0.93 (0.70 to 1.24) 79 1.02 (0.76 to 1.38) .50    CLL/SLL/PLL/MCL 74 17 0.67 (0.38 to 1.18) 14 0.51 (0.28 to 0.95) 25 1.14 (0.69 to 1.87) 23 1.15 (0.66 to 1.99) .31    Diffuse large B cell    lymphoma 62 13 0.73 (0.39 to 1.39) 18 0.84 (0.47 to 1.51) 12 0.64 (0.33 to 1.24) 17 0.81 (0.43 to 1.54) .68    Follicular lymphoma 28 9 0.94 (0.42 to 2.13) 5 0.52 (0.19 to 1.42) 6 0.57 (0.21 to 1.57) 11 1.22 (0.52 to 2.85) .43    Multiple myeloma 52 17 1.26 (0.68 to 2.32) 13 0.84 (0.44 to 1.61) 15 0.94 (0.50 to 1.78) 14 0.77 (0.39 to 1.55) .43  Myeloid leukemia 40 11 1.28 (0.62 to 2.66) 13 1.42 (0.72 to 2.81) 11 1.46 (0.69 to 3.09) 13 1.82 (0.85 to 3.87) .17 * Adjusted for attained age, state, applicator type, smoking status, family history of cancer, correlated pesticides (atrazine, cyanazine, metolachlor, 2,4-D, terbufos). CI = confidence interval; CLL = chronic lymphocytic leukemia; MCL = mantle cell lymphoma; PLL = prolymphocytic leukemia; RR = relative risk; SLL = small lymphocytic lymphoma. † Two-sided Wald chi-square test. ‡ Additionally adjusted for pack-years smoked. § Additionally adjusted for smokeless tobacco use. ‖ Additionally adjusted for alcohol use. We further explored the relationship between intensity-weighted alachlor days and laryngeal cancer (Table 3). Using low exposure as the referent, high alachlor exposure was statistically nonsignificantly associated with laryngeal cancer (RR = 2.03, 95% CI = 0.92 to 4.49). Adjusting for occupational exposures potentially associated with laryngeal cancer generally did not impact the overall associations, though adjustment for exposure to grain dusts did result in slight attenuation of the relative risk. Among never smokers, there was only one laryngeal cancer case who had never applied alachlor, though even with limited power we observed that increasing alachlor use was associated with laryngeal cancer (not shown). To increase precision, we stratified by pack-years of cigarette smoking. Compared with those with fewer than five pack-years of cigarette smoking and no use of alachlor, risk of laryngeal cancer increased with increasing alachlor exposure regardless of smoking status (Pinteraction = .45). High alachlor use was associated with laryngeal cancer among never (RR = 9.87, 95% CI = 2.94 to 33.14) and ever drinkers (RR = 5.72, 95% CI = 1.69 to 19.31), compared with never drinkers who did not apply alachlor. In our study, there was no interaction between smoking and alcohol use, and adjusting for combined smoking and alcohol use did not impact the risk estimates for alachlor exposure and laryngeal cancer (not shown). High alachlor exposure was associated with laryngeal cancer among both atrazine-unexposed (RR = 4.15, 95% CI = 1.02 to 16.93) and -exposed (RR = 3.21, 95% CI = 1.22 to 8.46) individuals, compared with individuals exposed to neither herbicide (Pinteraction = .47). Table 3. Adjusted* relative risks and 95% confidence intervals for low (≤median) and high (>median) intensity-weighted days of alachlor exposure for laryngeal cancer in the Agricultural Health Study Analysis No use Low use High use ≤1762 >1762 No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Ptrend† Overall‡,§,‖ 15 1.00 (ref) 15 3.15 (1.38 to 7.19) 19 6.28 (2.73 to 14.45) <.001 Low exposure as referent‡,§,‖ –¶ –¶ 15 1.00 (ref) 19 2.03 (0.92 to 4.49) Adjusted for occupational exposures‡,§,‖  Dusts (wood, cotton, sand, silica) 15 1.00 (ref) 15 3.19 (1.40 to 7.29) 19 6.33 (2.75 to 14.57) <.001  Dusts (grain) 15 1.00 (ref) 15 2.94 (1.29 to 6.71) 19 5.72 (2.49 to 13.15) <.001  Asbestos 15 1.00 (ref) 15 3.15 (1.38 to 7.18) 19 6.26 (2.72 to 14.41) <.001  Solvents 15 1.00 (ref) 15 3.18 (1.39 to 7.25) 19 6.30 (2.74 to 14.50) <.001  Engine exhaust 15 1.00 (ref) 15 3.18 (1.39 to 7.26) 19 6.33 (2.75 to 14.56) <.001  Work in swine/poultry confinement areas 15 1.00 (ref) 15 3.14 (1.38 to 7.16) 19 6.30 (2.74 to 14.49) <.001  Metal grinding 15 1.00 (ref) 15 3.16 (1.38 to 7.23) 19 6.25 (2.72 to 14.38) <.001 Pinteraction# ≤5 cigarette pack-years§,‖ 5 1.00 (ref) 3 1.57 (0.36 to 6.96) 6 5.58 (1.57 to 19.80) .45  >5 cigarette pack-years 9 0.88 (0.26 to 2.93) 12 3.89 (1.16 to 13.07) 13 6.40 (1.85 to 22.15) Never drinkers‡,‖ 5 1.00 (ref) 5 4.06 (1.10 to 14.93) 8 9.87 (2.94 to 33.14) .69  Ever drinkers 9 1.11 (0.36 to 3.47) 10 3.14 (0.94 to 10.45) 11 5.72 (1.69 to 19.31) Atrazine never use‡,§ 12 1.00 (ref) 3 2.05 (0.56 to 7.57) 3 4.15 (1.02 to 16.93) .47  Ever use 3 0.36 (0.10 to 1.34) 12 2.00 (0.74 to 5.38) 16 3.21 (1.22 to 8.46) Analysis No use Low use High use ≤1762 >1762 No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Ptrend† Overall‡,§,‖ 15 1.00 (ref) 15 3.15 (1.38 to 7.19) 19 6.28 (2.73 to 14.45) <.001 Low exposure as referent‡,§,‖ –¶ –¶ 15 1.00 (ref) 19 2.03 (0.92 to 4.49) Adjusted for occupational exposures‡,§,‖  Dusts (wood, cotton, sand, silica) 15 1.00 (ref) 15 3.19 (1.40 to 7.29) 19 6.33 (2.75 to 14.57) <.001  Dusts (grain) 15 1.00 (ref) 15 2.94 (1.29 to 6.71) 19 5.72 (2.49 to 13.15) <.001  Asbestos 15 1.00 (ref) 15 3.15 (1.38 to 7.18) 19 6.26 (2.72 to 14.41) <.001  Solvents 15 1.00 (ref) 15 3.18 (1.39 to 7.25) 19 6.30 (2.74 to 14.50) <.001  Engine exhaust 15 1.00 (ref) 15 3.18 (1.39 to 7.26) 19 6.33 (2.75 to 14.56) <.001  Work in swine/poultry confinement areas 15 1.00 (ref) 15 3.14 (1.38 to 7.16) 19 6.30 (2.74 to 14.49) <.001  Metal grinding 15 1.00 (ref) 15 3.16 (1.38 to 7.23) 19 6.25 (2.72 to 14.38) <.001 Pinteraction# ≤5 cigarette pack-years§,‖ 5 1.00 (ref) 3 1.57 (0.36 to 6.96) 6 5.58 (1.57 to 19.80) .45  >5 cigarette pack-years 9 0.88 (0.26 to 2.93) 12 3.89 (1.16 to 13.07) 13 6.40 (1.85 to 22.15) Never drinkers‡,‖ 5 1.00 (ref) 5 4.06 (1.10 to 14.93) 8 9.87 (2.94 to 33.14) .69  Ever drinkers 9 1.11 (0.36 to 3.47) 10 3.14 (0.94 to 10.45) 11 5.72 (1.69 to 19.31) Atrazine never use‡,§ 12 1.00 (ref) 3 2.05 (0.56 to 7.57) 3 4.15 (1.02 to 16.93) .47  Ever use 3 0.36 (0.10 to 1.34) 12 2.00 (0.74 to 5.38) 16 3.21 (1.22 to 8.46) * Adjusted for attained age, state, applicator type, smoking status, family history of cancer, correlated pesticides (cyanazine, metolachlor, 2,4-D, terbufos). CI = confidence interval; RR = relative risk. † Two-sided Wald chi-square test. ‡ Additionally adjusted for pack-years smoked. § Additionally adjusted for alcohol use. ‖ Additionally adjusted for atrazine. ¶ Low alachlor-exposed as the referent category; individuals with no use excluded from analysis. # Two-sided likelihood ratio test. Table 3. Adjusted* relative risks and 95% confidence intervals for low (≤median) and high (>median) intensity-weighted days of alachlor exposure for laryngeal cancer in the Agricultural Health Study Analysis No use Low use High use ≤1762 >1762 No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Ptrend† Overall‡,§,‖ 15 1.00 (ref) 15 3.15 (1.38 to 7.19) 19 6.28 (2.73 to 14.45) <.001 Low exposure as referent‡,§,‖ –¶ –¶ 15 1.00 (ref) 19 2.03 (0.92 to 4.49) Adjusted for occupational exposures‡,§,‖  Dusts (wood, cotton, sand, silica) 15 1.00 (ref) 15 3.19 (1.40 to 7.29) 19 6.33 (2.75 to 14.57) <.001  Dusts (grain) 15 1.00 (ref) 15 2.94 (1.29 to 6.71) 19 5.72 (2.49 to 13.15) <.001  Asbestos 15 1.00 (ref) 15 3.15 (1.38 to 7.18) 19 6.26 (2.72 to 14.41) <.001  Solvents 15 1.00 (ref) 15 3.18 (1.39 to 7.25) 19 6.30 (2.74 to 14.50) <.001  Engine exhaust 15 1.00 (ref) 15 3.18 (1.39 to 7.26) 19 6.33 (2.75 to 14.56) <.001  Work in swine/poultry confinement areas 15 1.00 (ref) 15 3.14 (1.38 to 7.16) 19 6.30 (2.74 to 14.49) <.001  Metal grinding 15 1.00 (ref) 15 3.16 (1.38 to 7.23) 19 6.25 (2.72 to 14.38) <.001 Pinteraction# ≤5 cigarette pack-years§,‖ 5 1.00 (ref) 3 1.57 (0.36 to 6.96) 6 5.58 (1.57 to 19.80) .45  >5 cigarette pack-years 9 0.88 (0.26 to 2.93) 12 3.89 (1.16 to 13.07) 13 6.40 (1.85 to 22.15) Never drinkers‡,‖ 5 1.00 (ref) 5 4.06 (1.10 to 14.93) 8 9.87 (2.94 to 33.14) .69  Ever drinkers 9 1.11 (0.36 to 3.47) 10 3.14 (0.94 to 10.45) 11 5.72 (1.69 to 19.31) Atrazine never use‡,§ 12 1.00 (ref) 3 2.05 (0.56 to 7.57) 3 4.15 (1.02 to 16.93) .47  Ever use 3 0.36 (0.10 to 1.34) 12 2.00 (0.74 to 5.38) 16 3.21 (1.22 to 8.46) Analysis No use Low use High use ≤1762 >1762 No. RR (95% CI) No. RR (95% CI) No. RR (95% CI) Ptrend† Overall‡,§,‖ 15 1.00 (ref) 15 3.15 (1.38 to 7.19) 19 6.28 (2.73 to 14.45) <.001 Low exposure as referent‡,§,‖ –¶ –¶ 15 1.00 (ref) 19 2.03 (0.92 to 4.49) Adjusted for occupational exposures‡,§,‖  Dusts (wood, cotton, sand, silica) 15 1.00 (ref) 15 3.19 (1.40 to 7.29) 19 6.33 (2.75 to 14.57) <.001  Dusts (grain) 15 1.00 (ref) 15 2.94 (1.29 to 6.71) 19 5.72 (2.49 to 13.15) <.001  Asbestos 15 1.00 (ref) 15 3.15 (1.38 to 7.18) 19 6.26 (2.72 to 14.41) <.001  Solvents 15 1.00 (ref) 15 3.18 (1.39 to 7.25) 19 6.30 (2.74 to 14.50) <.001  Engine exhaust 15 1.00 (ref) 15 3.18 (1.39 to 7.26) 19 6.33 (2.75 to 14.56) <.001  Work in swine/poultry confinement areas 15 1.00 (ref) 15 3.14 (1.38 to 7.16) 19 6.30 (2.74 to 14.49) <.001  Metal grinding 15 1.00 (ref) 15 3.16 (1.38 to 7.23) 19 6.25 (2.72 to 14.38) <.001 Pinteraction# ≤5 cigarette pack-years§,‖ 5 1.00 (ref) 3 1.57 (0.36 to 6.96) 6 5.58 (1.57 to 19.80) .45  >5 cigarette pack-years 9 0.88 (0.26 to 2.93) 12 3.89 (1.16 to 13.07) 13 6.40 (1.85 to 22.15) Never drinkers‡,‖ 5 1.00 (ref) 5 4.06 (1.10 to 14.93) 8 9.87 (2.94 to 33.14) .69  Ever drinkers 9 1.11 (0.36 to 3.47) 10 3.14 (0.94 to 10.45) 11 5.72 (1.69 to 19.31) Atrazine never use‡,§ 12 1.00 (ref) 3 2.05 (0.56 to 7.57) 3 4.15 (1.02 to 16.93) .47  Ever use 3 0.36 (0.10 to 1.34) 12 2.00 (0.74 to 5.38) 16 3.21 (1.22 to 8.46) * Adjusted for attained age, state, applicator type, smoking status, family history of cancer, correlated pesticides (cyanazine, metolachlor, 2,4-D, terbufos). CI = confidence interval; RR = relative risk. † Two-sided Wald chi-square test. ‡ Additionally adjusted for pack-years smoked. § Additionally adjusted for alcohol use. ‖ Additionally adjusted for atrazine. ¶ Low alachlor-exposed as the referent category; individuals with no use excluded from analysis. # Two-sided likelihood ratio test. Results for models examining alachlor exposure with a 10-year exposure lag were similar compared with standard models (Supplementary Table 2, available online). Associations for laryngeal, stomach, small intestine cancer, and myeloid leukemia were consistent with unlagged results. We noted inverse associations with aggressive prostate cancer in the second (RR = 0.91, 95% CI = 0.85 to 0.98) and third (RR = 0.91, 95% CI = 0.85 to 0.98) quartiles of exposure, with no exposure-response trend (Ptrend = .32). Discussion Our study is the largest and most comprehensive analysis of occupational alachlor exposure and cancer risk to date. The most striking finding was a strong positive monotonic association with laryngeal cancer, with a sevenfold risk in the highest quartile of exposure compared with unexposed. This association remained after lagging exposure, stratifying by important potential effect modifiers (eg, tobacco and alcohol use) and adjusting for known and suspected occupational risk factors (22). In these data, atrazine is inversely associated with laryngeal cancer (21) and correlated with alachlor; however, we observed elevated risks for alachlor use and laryngeal cancer among both atrazine-unexposed and -exposed applicators, compared with those reporting use of neither. Lee et al. previously reported a non–statistically significant association between ever use of alachlor and risk of laryngeal cancer based on seven exposed cases (13). The only other epidemiologic study directly assessing alachlor exposure and multiple cancer outcomes did not examine laryngeal cancer (12). Occupation as a farmer or agricultural worker has been associated with laryngeal cancer (23–27); however, there is no clear consensus in the literature regarding this association (22,28–30). Furthermore, with little or no information on participants’ farming activities, it is not possible to attribute the observed associations in these studies to pesticide exposure or alachlor specifically. There is ample evidence for alachlor’s carcinogenicity in vivo and in vitro, including formation of tumors (1), DNA adducts (8), and single-strand DNA breaks (9), as well as epidemiologic evidence for telomere effects in the AHS (31,32). In alachlor chronic feeding studies, another upper respiratory tract cancer, nasal olfactory tumor, occurs consistently (33,34). Rats are obligate nasal breathers; in humans, mouth breathing involves bypassing filtration by the nasal passages and may result in effects on more distant respiratory tract organs such as the larynx (35). Furthermore, it has been posited that elevated expression of cytochrome P450 isoforms that metabolize alachlor to its reactive intermediate, particularly in target tissues (ie, nasal tissue), may play a role in carcinogenesis in animal models (36). Taken together, this literature suggests that the larynx may not only be a point of direct access for inhaled pesticide exposures, but may be more susceptible than other tissue due to increased bioactivation of alachlor. These mechanisms are not well studied in humans; however, there is evidence that CYP2B6, known to metabolize and bioactivate alachlor in vitro (37), is expressed at high levels in human larynx tissue (38). In the previous AHS analysis of alachlor, the authors noted a statistically significant exposure-response trend for alachlor use and all lymphohematopoietic cancers combined, elevated associations for leukemia and multiple myeloma, and no association with NHL (13). We found no association with lymphohematopoietic cancers overall, nor did we see an association for NHL, multiple myeloma, CLL, or other NHL subtypes based on extended follow-up. However, we observed elevated risks for myeloid leukemia in all exposure categories, though associations were not statistically significant, with limited evidence for exposure-response trend. Results for AML (70.8% of alachlor-exposed myeloid leukemias) were similar. For consistency with the previous AHS analysis, we examined total leukemia, combining all subtypes including CLL (grouped with NHL in the primary analyses) (18). Combined, we noted an elevated association in the fourth quartile of exposure, likely driven by the myeloid subtypes. A case–control study examining pesticides and leukemia found no association with alachlor, though leukemia subtypes were not examined (10). Alachlor manufacturing workers with any or high alachlor exposure had elevated incidence of CML (among two exposed cases); there was no association with total leukemia (12). It is possible that the relevant period to capture associations in this cohort has passed, with declining use of alachlor and short latency for certain lymphohematopoietic cancers. In addition, our analysis was underpowered to examine many rare NHL and leukemia subtypes, even with extended follow-up. Additional studies are needed to understand this possible association, examining finer subtypes. Trends in the use of specific herbicides change over time, as more effective chemicals come on the market and/or pesticides of known concern are phased out of use. Alachlor use has declined in the United States since its peak in the 1980s, and it has been replaced by newer chloroacetanilide chemicals (ie, S-metolachlor, acetochlor) with the same mechanism of action and closely related chemical structures. As of 2012, S-metolachlor and acetochlor account for more 10% of the agricultural herbicides sold in the United States by volume; in recent years alachlor is no longer reported among the most highly used chemicals by the US EPA (39). Despite similarity in chemical structure, there is often discordance between observed cancer associations for pesticides in the same chemical class. Previously in the AHS, metolachlor use has been associated with increased risk of liver cancer and acetochlor use has been associated with a suggestive increased risk of lung cancer, particularly when applied as a product mixture with atrazine (40,41). Laryngeal cancer was not evaluated for associations with either pesticide due to few exposed cases. Strengths of our analysis include longitudinal study design with regular follow-up of participants for cancer and mortality outcomes and detailed and validated self-reported pesticide exposure and intensity information (42). Although there is potential for misclassification of self-reported alachlor use, because of the prospective study design, exposure misclassification will be nondifferential with respect to cancer outcome, which would bias relative risks toward the null (43). Participants with missing information on alachlor use were excluded (11%), which is potentially a biased sample that may not be representative of the larger cohort. Although overall very similar to the general cohort, individuals who were missing alachlor use information were more likely to be older, from North Carolina, private applicators, and to report a race/ethnicity other than white. To date, this is the largest study to examine alachlor exposure and cancer risk, with a total of 3534 exposed cases (2729 additional accrued cases since the previous analysis within the cohort). Because of the high prevalence of alachlor use, we could examine many rarer cancer sites and subtypes. However, due to few exposed female applicators, we were unable to evaluate cancer sites such as breast (n = 8) and endometrial cancer (n = 1). We were able to control for potential confounders including tobacco use (smoking and smokeless tobacco), alcohol consumption, family history of cancer, ultraviolet radiation, and other farming and agricultural exposures. Laryngeal cancer shares risk factors with other respiratory tract cancers, such as tobacco use, and head and neck cancers, such as alcohol use. We saw no associations with alachlor exposure and cancers of the lung, oral cavity, or esophagus, or any other respiratory tract cancers, indicating that unmeasured confounding by these shared risk factors is unlikely responsible for the laryngeal cancer finding. We controlled for use of other pesticides that were most highly correlated with alachlor to minimize confounding. Because of its inverse association with laryngeal cancer, we also examined alachlor use among applicators never exposed to atrazine, with these stratified analyses indicating that confounding by atrazine is unlikely to explain this association. In conclusion, we observed increased risk of laryngeal cancer with increasing alachlor exposure. We also noted a suggestive association for myeloid leukemia, consistent with excess CML in a study of alachlor manufacturing workers and prior findings in AHS for total leukemia. This is the first epidemiologic study to evaluate the association with alachlor and laryngeal cancer. However, the relatively large risk estimates, coupled with the consistent associations after extensive adjustment for potential confounders, examination of lagged exposure, and stratification by potential effect modifiers, indicate that occupational alachlor exposure may play a role in larynx carcinogenesis. Replication in other studies with detailed pesticide exposure assessment is needed. Funding This work was supported by the intramural research program of the National Institutes of Health, the National Cancer Institute at the National Institutes of Health (Z01-CP010119), and the National Institute of Environmental Health Sciences at the National Institutes of Health (Z01-ES049030). Notes Affiliations of authors: Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (CCL, GA, SK, JNH, AB, LEBF); Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea (WJL); National Institute of Environmental Health Sciences, Research Triangle Park, NC (DPS, CGP); Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (JHL). 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Journal

JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Sep 1, 2018

References

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