Research Phorate Exposure and Incidence of Cancer in the Agricultural Health Study Rajeev Mahajan,1 Matthew R. Bonner,1 Jane A. Hoppin,2 and Michael C.R. Alavanja1 1Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, USA; 2Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA BACKGROUND: We recently reported a link between use of the organophosphate pesticide phorate and risk of prostate cancer among applicators with a family history of prostate cancer in the Agricultural Health Study (AHS). OBJECTIVE: This finding, together with findings of associations between other organophosphate pesticides and cancer more broadly, prompted us to examine phorate exposure and overall cancer incidence in the AHS. Adding 3 years of follow-up and using more detailed exposure information allowed us to see whether the prostate cancer ﬁnding held. METHODS: The AHS is a prospective study of licensed restricted-use pesticide applicators from North Carolina and Iowa. To our knowledge, this is the largest examination of workers occupa- tionally exposed to phorate. Pesticide exposure and other information was collected using two self- administered questionnaires completed from 1993 to 1997. Poisson regression was used to calculate rate ratios (RR) and 95% conﬁdence intervals (CI), adjusting for potential confounders. RESULTS: Phorate use was not related to the incidence of all cancers combined or to any individual cancer, although we had insufﬁcient numbers to study non-Hodgkin lymphoma or leukemia, which have been linked to organophosphates in other studies. Although prostate cancer risk was not sig- niﬁcantly related to phorate use overall or among those without a family history, the risk tended to increase among applicators with a family history of prostate cancer. The interaction RR was 1.53 (95% CI, 0.99–2.37). CONCLUSION: The observed statistical interaction suggests a gene–environment interaction between family history and phorate exposure in the incidence of prostate cancer, but other explanations are also possible. KEY WORDS: agriculture, insecticides, neoplasms, occupational exposure, organophosphorus com- pounds, organothiophosphorus compounds, pesticides, prostate, phorate. Environ Health Perspect 114:1205–1209 (2006). doi:10.1289/ehp.8911 available via http://dx.doi.org/ [Online 18 April 2006] Phorate {O,O-diethyl S-[(ethylthio)methyl] phosphorothioate; trade name: thimet} is an organophosphate compound used agricultur- ally, primarily in the production of corn, cot- ton, and potatoes, to control sap-feeding insects including various beetles, mites, grubs, and worms. There are no registered residential uses. Phorate was ﬁrst registered for use in the United States in 1959 [U.S. Environmental Protection Agency (EPA) 2001]. In the United States, almost 2.5 million acres are treated annually with 2–3 million pounds of phorate, making it the sixth most common organophosphate used (Donaldson et al. 2002). The currently limited body of literature does not provide evidence to suggest that phorate is mutagenic, genotoxic, or carcino- genic (Bingham et al. 2001; California Department of Pesticide Regulation 1996; Lin et al. 1987; Pandita 1986). However, several epidemiologic studies have found associations between exposure to organophosphate pesti- cides and non-Hodgkin lymphoma (NHL) (Cantor et al. 1992; Zahm et al. 1993) as well as leukemia (Brown et al. 1990; Clavel et al. 1996), and the International Agency for Research on Cancer (IARC) considers insecti- cide application to be an exposure that is prob- ably carcinogenic in humans (Group 2A) (IARC 1991). Recent findings from the Agricultural Health Study (AHS) linking lung cancer with exposure to diazinon and chlor- pyrifos (Alavanja et al. 2004) and prostate can- cer with exposure to chlorpyrifos, coumaphos, fonofos, and phorate among applicators with a family history of prostate cancer (Alavanja et al. 2003) prompted us to examine risk for all can- cers among phorate users in the same cohort over a longer follow-up period. The aforemen- tioned insecticides belong to the organothio- phosphate subgroup, are similar to phorate in chemical structure, and must be converted in the body to their bioactive, neurotoxic oxon forms, which irreversibly inhibit acetylcholine esterase by phosphorylating a serine hydroxyl group in the active site of the enzyme (Pope 1999; Sultatos 1994). Little is known of the carcinogenicity of the oxon species. To our knowledge, this is the largest epidemiologic examination of an occupational group exposed to phorate. Methods Cohort enrollment and follow-up. The AHS has been described elsewhere (Alavanja et al. 1996). It is a prospective cohort including 52,395 private applicators (farmers) from Iowa and North Carolina and 4,916 commer- cial applicators (employees of pest control Environmental Health Perspectives • VOLUME 114 | NUMBER 8 | August 2006 companies or persons who apply pesticides as employees of businesses whose primary function is not pesticide application) from Iowa licensed to apply restricted-use pesticides (82.4% of eligible applicators). Incident tumors diagnosed between enrollment (31 December 1993 to 31 December 1997) and 31 December 2002 were identiﬁed using population-based tumor registries of both states. Subjects were censored in the year they moved out of the state, as determined by an extensive search of address records, or the year they died, as determined using the National Death Index and state death registry records. Less than 2% of the cohort was lost to follow- up. The average follow-up time of 7.5 years represents an increase of 3.2 years over the previously published prostate cancer paper. All participants provided informed consent and the protocol was approved by all appropriate institutional review boards. Exposure assessment. Applicators were given two self-administered questionnaires upon enrollment. The enrollment question- naire collected information on days of use per year, years of use, and decade of ﬁrst use for 22 pesticides, as well as information on ever/never use of 28 additional pesticides (including phor- ate); application methods; use of personal pro- tective equipment (PPE); smoking; alcohol consumption; farm activities; cancer history in first-degree relatives; and basic demographic data. A supplemental take-home questionnaire collected information on days of use per year, years of use, and decade of ﬁrst use for the 28 pesticides for which only ever/never use infor- mation was collected in the enrollment ques- tionnaire. The take-home questionnaire, which was completed by 25,291 (44%) of the participants, also collected additional informa- tion on work practices, physical activity, med- ical conditions, and occupational exposures from nonfarming jobs. Both questionnaires are Address correspondence to M.C.R. Alavanja, 6120 Executive Blvd., EPS 8000, Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20852 USA. Telephone: (301) 435-4720. Fax: (301) 402-1819. E-mail: alavanjm@mail.nih.gov This research was supported by the Intramural Research Program of the National Cancer Institute and National Institute of Environmental Health Sciences, National Institutes of Health. The authors declare they have no competing ﬁnancial interests. Received 8 December 2005; accepted 18 April 2006. 1205