ABSTRACT:

Objective:

To update findings of observational analytical studies on the association between occupational exposure to organophosphates and hematologic malignancies.

Methodology:

Systematic literature review, including cohort and case-control studies, without limitation of publication time, in Portuguese and English. The articles were traced from June 2017 to July 2019 in PubMed, MEDLINE, LILACS, Web of Science, and Scopus databases. The qualitative bias risk assessment was performed using the Newcastle-Ottawa Scale and the Downs and Black Checklist. Results were presented according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).

Results:

Seventeen studies evaluated as good/high methodological quality were eligible. Exposure to diazinon (1 cohort), phonophos (1 cohort), dichlorvos, crotoxiphos and famphur (1 case control) was associated with leukemia, while exposure to organophosphate was associated to lymphomas (6 case control); the risk of non-Hodgkin’s lymphoma was higher in those exposed to diazinon (1 control case) and malathion (3 control case) than non-exposed ones. Multiple myeloma occurred more commonly in organophosphate exposed than in non-exposed individuals (1 case-control).

Conclusion:

Occupational exposure to organophosphates increases the risk of hematologic malignancies, especially among individuals with longer exposure periods. Worker monitoring and exposure control measures are recommended.

Keywords:
Hematologic neoplasms; Agrochemicals; Risk factors; Epidemiology; Review; Occupational health

INTRODUCTION

Occupational exposure to some types of chemical compounds used in pesticides is common. Among these compounds, those belonging to the chemical group of organophosphates (OP) are the most studied ones, consisted of insecticides widely used in agriculture, such as Acephate, the fourth most active ingredient commercialized in Brazil in 2017¹1. Instituto Brasileiro do Meio Ambiente e dos Recursos Naturais Renováveis. Relatórios de comercialização de agrotóxicos [Internet]. 2019 [acessado em 23 jul. 2019]. Disponível em: Disponível em: https://www.ibama.gov.br/agrotoxicos/relatorios-de-comercializacao-de-agrotoxicos
https://www.ibama.gov.br/agrotoxicos/rel... . Many studies have shown that OP associate with hematologic neoplasms (HN)²2. Colt JS, Davis S, Severson RK, Lynch CF, Cozen W, Camann D, et al. Residential insecticide use and risk of non-Hodgkin’s lymphoma. Cancer Epidemiol Biomarkers Prev 2006; 15(2): 251-7. http://doi.org/10.1158/1055-9965.EPI-05-0556
https://doi.org/http://doi.org/10.1158/1... ^,33. Van Maele-Fabry G, Duhayon S, Mertens C, Lison D. Risk of leukaemia among pesticide manufacturing workers: a review and meta-analysis of cohort studies. Environ Res 2008; 106(1): 121-37. http://doi.org/10.1016/j.envres.2007.09.002
https://doi.org/http://doi.org/10.1016/j... ^,44. Orsi L, Delabre L, Monnereau A, Delval P, Berthou C, Fenaux P, et al. Occupational exposure to pesticides and lymphoid neoplasms among men: results of a French case-control study. Occup Environ Med 2009; 66(5): 291-8. https://doi.org/10.1136/oem.2008.040972
https://doi.org/https://doi.org/10.1136/... ^,55. Bertrand KA, Spiegelman D, Aster JC, Altshul LM, Korrick SA, Rodig SJ, et al. Plasma organochlorine levels and risk of non-Hodgkin lymphoma in a cohort of men. Epidemiology 2010; 21(2): 172-80. http://doi.org/10.1097/EDE.0b013e3181cb610b
https://doi.org/http://doi.org/10.1097/E... ^,66. Zakerinia M, Namdari M, Amirghofran S. The relationship between exposure to pesticides and the occurrence of lymphoid neoplasm. Iran Red Crescent Med J 2012; 14(6): 337-44.^,77. Boccolini PMM, Boccolini CS, Chrisman JR, Markowitz SB, Koifman S, Koifman RJ, et al. Pesticide use and non-Hodgkin’s lymphoma mortality in Brazil. Int J Hyg Env Health 2013; 216(4): 461-6. http://doi.org/10.1016/j.ijheh.2013.03.007
https://doi.org/http://doi.org/10.1016/j... ^,88. Kachuri L, Demers PA, Blair A, Spinelli JJ, Pahwa M, McLaughlin JR, et al. Multiple pesticide exposures and the risk of multiple myeloma in Canadian men. Int J Cancer 2013; 133(8): 1846-58. http://doi.org/10.1002/ijc.28191
https://doi.org/http://doi.org/10.1002/i... ^,99. Navaranjan G, Hohenadel K, Blair A, Demers PA, Spinelli JJ, Pahwa P, et al. Exposures to multiple pesticides and the risk of Hodgkin lymphoma in Canadian men. Cancer Causes Control 2013; 24(9): 1661-73. http://doi.org/10.1007/s10552-013-0240-y
https://doi.org/http://doi.org/10.1007/s... ^,1010. Schinasi L, Leon ME. Non-Hodgkin lymphoma and occupational exposure to agricultural pesticide chemical groups and active ingredients: a systematic review and meta-analysis. Int J Environ Res Public Health 2014; 11(4): 4449-527. https://doi.org/10.3390/ijerph110404449
https://doi.org/https://doi.org/10.3390/... , when analyzing specific substances, as well as different types of HN. These analyses rely on a synthesis of the knowledge produced through systematic reviews of the findings.

In recent years, systematic reviews (SR) such as the one by Weichenthal et al.¹¹11. Weichenthal S, Moase C, Chan P. A review of pesticide exposure and cancer incidence in the agricultural health study cohort. Ciên Saúde Colet 2012; 17(1): 255-70. http://dx.doi.org/10.1590/S1413-81232012000100028
https://doi.org/http://dx.doi.org/10.159... have been published, focusing on exposure to chlorpyrifos, phonophos, and diazinon and the association of this exposure with leukemia and HN, in the studies of the Agricultural Healthy Study (AHS) cohort. Schinasi and Leon¹⁰10. Schinasi L, Leon ME. Non-Hodgkin lymphoma and occupational exposure to agricultural pesticide chemical groups and active ingredients: a systematic review and meta-analysis. Int J Environ Res Public Health 2014; 11(4): 4449-527. https://doi.org/10.3390/ijerph110404449
https://doi.org/https://doi.org/10.3390/... showed an increase in non-Hodgkin’s lymphoma (NHL) through exposure to chlorpyrifos, diazinon, malathion, phorate, and terbufos. Hu et al.¹²12. Hu L, Luo D, Zhou T, Tao Y, Feng J, Mei S. The association between non-Hodgkin lymphoma and organophosphate pesticides exposure: A meta-analysis. Environ Pollut 2017; 231(Parte 1): 319-28. http://doi.org/10.1016/j.envpol.2017.08.028
https://doi.org/http://doi.org/10.1016/j... reviewed the association between terbufos, malathion, diazinon, and NHL.

In addition, the International Agency for Research on Cancer (IARC) classified the OP tetrachlorvinphos and paration insecticides as possibly carcinogenic to humans (group 2B) and malathion and diazinon as probably carcinogenic to humans (group 2A), making it possible to associate malathion to NHL, and diazinon to NHL and leukemia¹³13. Guyton KZ, Loomis D, Grosse Y, Ghissassi FE, Benbrahim-Tallaa L, Guha N, et al. Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. Lancet Oncol 2015; 16(5): 490-1. http://doi.org/10.1016/S1470-2045(15)70134-8
https://doi.org/http://doi.org/10.1016/S... .

Analytical studies relate individual exposures to the occurrence of cancer and provide effect estimates (odds ratio or relative risk) as the main association measure. Therefore, investigating the association between HN and exposure to OP through these studies allows us to understand the impact of exposure to these compounds on humans, especially on the agricultural worker, as potential risks can be assessed, as well as it is possible to subsidize implementing exposure reduction strategies in agricultural regions.

Thus, considering that the previously published SR described the association between OP and HN, leukemia and NHL, this study aims to update the findings of studies that estimated the association between occupational exposure to OP and HN, taking into account the publications after the SR of Hu et al.¹²12. Hu L, Luo D, Zhou T, Tao Y, Feng J, Mei S. The association between non-Hodgkin lymphoma and organophosphate pesticides exposure: A meta-analysis. Environ Pollut 2017; 231(Parte 1): 319-28. http://doi.org/10.1016/j.envpol.2017.08.028
https://doi.org/http://doi.org/10.1016/j... and including the results of the association between OP and multiple myeloma (MM).

METHODS

Publications with results of cohort and case-control studies, with full text, in Portuguese and English, which presented estimates of the association between occupational exposure to some chemical compound in the OP and HN group (leukemias, lymphomas, and MM). No limits were set for publication time. Other eligibility criteria were those recommended in the PICO strategy (acronym for Patient or Problem, Intervention, Comparison and Outcomes)¹⁴14. Akobeng A. Principles of evidence based medicine. Arch Dis Child 2005; 90(8): 837-40. http://doi.org/10.1136/adc.2005.071761
https://doi.org/http://doi.org/10.1136/a... :

Exclusion criteria were:

SEARCH STRATEGIES

The search for publications was carried out from June 14th, 2017 to July 23rd, 2019, in the databases of Public Medline (PubMed), Medical Literature Analysis and Retrieval System Online (MEDLINE), Latin American and Caribbean Literature in Health Sciences (LILACS), Web of Science, and Scopus, using a combination of descriptors in English related to occupational exposure to pesticides (pesticides, pesticide exposure, organophosphorus compounds, organophosphate pesticides) and neoplasms (neoplasms, hematologic neoplasms, leukemia, lymphoma, multiple myeloma). An example of a search strategy was (“hematologic neoplasms” OR leukemia OR lymphoma OR multiple myeloma) AND (pesticides OR “organophosphate pesticides”).

Two reviewers performed the search independently, in cases of disagreement a third reviewer would evaluate the studies; however, there was no divergence in the selection process. An initial screening followed, after reading the article’s title and abstract, with elimination of duplications. After reading the full text, the eligible publications were identified and selected, from which the variables required for the analysis of this review were extracted.

The study variables were:

ANALYSIS

For the qualitative assessment of bias in the methodology of the studies, the Newcastle-Ottawa Scale (NOS)¹⁵15. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Otawa Quality Assessment Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [Internet]. 2009 [acessado em 28 jul. 2018]. Disponível em: Disponível em: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
http://www.ohri.ca/programs/clinical_epi... and the Downs and Black Checklist¹⁶16. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998; 52(6): 377-84. https://doi.org/10.1136/jech.52.6.377
https://doi.org/https://doi.org/10.1136/... were employed, which are used in the analysis of systematic reviews of non-randomized studies included in SR¹⁷17. Higgins JPT, Green S., editores. Cochrane handbook for systematic reviews of interventions [Internet]. Version 5.1.0. Austrália: The Cochrane Collaboration, 2011 [acessado em 9 maio 2018]. Disponível em: Disponível em: http://handbook-5-1.cochrane.org
http://handbook-5-1.cochrane.org... . NOS is a qualitative assessment tool for non-randomized studies that allows judgment in three dimensions: the selection of groups (four items), the comparability of groups (one item), and the verification of exposure or outcome of interest (three items) adapted according to the type of study (case control or cohort). The scoring system is based on the quality of the selection and the exposure/outcome measure, whose scores range from zero to nine stars. The higher the score, the better the quality of the study¹⁵15. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Otawa Quality Assessment Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [Internet]. 2009 [acessado em 28 jul. 2018]. Disponível em: Disponível em: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
http://www.ohri.ca/programs/clinical_epi... .

The Downs and Black Checklist is validated for qualitative assessment of randomized clinical trials and non-randomized studies. It comprises 27 questions based on the following domains: information or report (ten items), external validity (three items), internal validity/measurement bias (seven items), internal validity/selection bias (six items), and statistical power (one item). Answers are scored with a value of zero or one, except for a question in the “information or report” domain that can be scored from zero to two and the question in the “power” domain that can receive from zero to five points. The maximum score of the checklist is 32 points, there is a higher methodological quality when a higher score is reached¹⁶16. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998; 52(6): 377-84. https://doi.org/10.1136/jech.52.6.377
https://doi.org/https://doi.org/10.1136/... . It should be noted that only 19 questions are fully applicable to observational studies, while eight are specific to randomized controlled trials (questions 4, 8, 13, 14, 15, 19, 23, and 24). In this study, the adapted version of the Downs and Black Checklist was used (only with specific questions for cohort and case control studies) and a maximum score of 24 points¹⁸18. Vieira MCS, Boing L, Machado Z, Guimarães ACA. Sintomas do envelhecimento masculino relacionados à atividade física e qualidade de vida: uma revisão sistemática. Rev Bras Ciênc Mov 2017; 25(1): 183-98..

The protocol for this SR was registered on the International Prospective Register of Systematic Reviews Platform (PROSPERO). The presentation of the results followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA)¹⁹19. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration. PLoS Med 2009; 6(7): e1000100. https://doi.org/10.1371/journal.pmed.1000100
https://doi.org/https://doi.org/10.1371/... .

RESULTS

823 articles published between 1986 and 2019 were identified, of which, after screening, 17 publications from 1990 to 2015 were eligible for analysis (Figure 1). The methods employed (population, sampling, exposure measurement, and adjustment variables) and the results of the studies (adjusted OR and RR) are described in Tables 1 and 2. Six cohort articles derived from the same study (Agricultural Health Study, United States) and 11 case-control articles with data from the United States, Canada, Australia, Czech Republic, Germany, France, Italy, Ireland, and Spain. Most of the articles were limited to the male population of pesticide applicators, and the exhibition comprised diazinon, phonophos, malathion, terbufos, phorate, coumaphos, dichlorvos, tetrachlorvinphos, famphur, crotoxiphos, dimethoate, and methyl parathion.

Most studies (n = 16:94.1%) were classified as having good/high methodological quality according to NOS and Downs and Black Checklist. NOS identified a selection bias due to the self-report on exposure in cohort studies²⁰20. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. Am J Epidemiol 2005; 162(11): 1070-9. http://doi.org/10.1093/aje/kwi321
https://doi.org/http://doi.org/10.1093/a... ^,2121. Mahajan R, Blair A, Lynch CF, Schroeder P, Hoppin JA, Sandler DP, et al. Fonofos exposure and cancer incidence in the agricultural health study. Environ Health Perspect 2006; 114(12): 1838-42. http://doi.org/10.1289/ehp.9301
https://doi.org/http://doi.org/10.1289/e... ^,2222. Mahajan R, Bonner MR, Hoppin JA, Alavanja MCR. Phorate exposure and incidence of cancer in the Agricultural Health Study. Environ Health Perspect 2006; 114(8): 1205-9. http://doi.org/10.1289/ehp.8911
https://doi.org/http://doi.org/10.1289/e... ^,2323. Bonner MR, Coble J, Blair A, Beane Freeman LE, Hoppin JA, Sandler DP, et al. Malathion Exposure and the Incidence of Cancer in the Agricultural Health Study. Am J Epidemiol 2007; 166(9): 1023-34. https://doi.org/10.1093/aje/kwm182
https://doi.org/https://doi.org/10.1093/... ^,2424. Koutros S, Mahajan R, Zheng T, Hoppin JA, Ma X, Lynch CF, et al. Dichlorvos exposure and human cancer risk: results from the Agricultural Health Study. Cancer Causes Control 2008; 19(1): 59-65. http://doi.org/10.1007/s10552-007-9070-0
https://doi.org/http://doi.org/10.1007/s... ^,2525. Bonner MR, Williams BA, Rusiecki JA, Blair A, Beane Freeman LE, Hoppin JA, et al. Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study. Cancer Causes Control 2010; 21(6): 871-7. https://doi.org/10.1007/s10552-010-9514-9
https://doi.org/https://doi.org/10.1007/... and when the case definition was based only on records²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... , without second confirmation, for example the review of the anatomopathological exam. There were gaps in the measurement of exposure, such as in the use of unblinded interviews for cases and controls⁸8. Kachuri L, Demers PA, Blair A, Spinelli JJ, Pahwa M, McLaughlin JR, et al. Multiple pesticide exposures and the risk of multiple myeloma in Canadian men. Int J Cancer 2013; 133(8): 1846-58. http://doi.org/10.1002/ijc.28191
https://doi.org/http://doi.org/10.1002/i... ^,2727. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... ^,2828. Hohenadel K, Harris SA, McLaughlin JR, Spinelli JJ, Pahwa P, Dosman JA, et al. Exposure to Multiple Pesticides and Risk of Non-Hodgkin Lymphoma in Men from Six Canadian Provinces. Int J Environ Res Public Health 2011; 8(6): 2320-30. http://doi.org/10.3390/ijerph8062320
https://doi.org/http://doi.org/10.3390/i... ^,2929. Costas L, Infante-Rivard C, Zock JP, Van Tongeren M, Boffetta P, Cusson A, et al. Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study. Brit J Cancer 2015; 112(7): 1251-6. http://doi.org/10.1038/bjc.2015.83
https://doi.org/http://doi.org/10.1038/b... ^,3030. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91.^,3131. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55.^,3232. Nanni O, Amadori D, Lugaresi C, Falcini F, Scarpi E, Saragoni A, et al. Chronic lymphocytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breeding workers: a population case-control study based on a priori exposure matrices. Occup Environ Med 1996; 53(10): 652-7. https://doi.org/10.1136/oem.53.10.652
https://doi.org/https://doi.org/10.1136/... ^,3333. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. Non-Hodgkin’s Lymphoma and specific pesticide exposures in men. Cancer Epidemiol Biomarkers Prevent 2001; 10(11): 1155-63.^,3434. Fritschi L, Benke G, Hughes AM, Kricker A, Turner J, Vajdic CM, et al. Occupational exposure to pesticides and risk of Non-Hodgkin’s Lymphoma. Am J Epidemiol 2005; 162(9): 849-57. https://doi.org/10.1093/aje/kwi292
https://doi.org/https://doi.org/10.1093/... ^,3535. Cocco P, Satta G, Dubois S, Pili C, Pilleri M, Zucca M, et al. Lymphoma risk and occupational exposure to pesticides: results of the Epilymph study. Occup Environ Med 2013; 70: 91-8. http://doi.org/10.1136/oemed-2012-100845
https://doi.org/http://doi.org/10.1136/o... , in the written self-report on exposure²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... and in the proportion of different non-response or not described between the case and control groups⁸8. Kachuri L, Demers PA, Blair A, Spinelli JJ, Pahwa M, McLaughlin JR, et al. Multiple pesticide exposures and the risk of multiple myeloma in Canadian men. Int J Cancer 2013; 133(8): 1846-58. http://doi.org/10.1002/ijc.28191
https://doi.org/http://doi.org/10.1002/i... ^,2626. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... ^,2727. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... ^,2828. Hohenadel K, Harris SA, McLaughlin JR, Spinelli JJ, Pahwa P, Dosman JA, et al. Exposure to Multiple Pesticides and Risk of Non-Hodgkin Lymphoma in Men from Six Canadian Provinces. Int J Environ Res Public Health 2011; 8(6): 2320-30. http://doi.org/10.3390/ijerph8062320
https://doi.org/http://doi.org/10.3390/i... ^,2929. Costas L, Infante-Rivard C, Zock JP, Van Tongeren M, Boffetta P, Cusson A, et al. Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study. Brit J Cancer 2015; 112(7): 1251-6. http://doi.org/10.1038/bjc.2015.83
https://doi.org/http://doi.org/10.1038/b... ^,3232. Nanni O, Amadori D, Lugaresi C, Falcini F, Scarpi E, Saragoni A, et al. Chronic lymphocytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breeding workers: a population case-control study based on a priori exposure matrices. Occup Environ Med 1996; 53(10): 652-7. https://doi.org/10.1136/oem.53.10.652
https://doi.org/https://doi.org/10.1136/... ^,3333. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. Non-Hodgkin’s Lymphoma and specific pesticide exposures in men. Cancer Epidemiol Biomarkers Prevent 2001; 10(11): 1155-63.^,3434. Fritschi L, Benke G, Hughes AM, Kricker A, Turner J, Vajdic CM, et al. Occupational exposure to pesticides and risk of Non-Hodgkin’s Lymphoma. Am J Epidemiol 2005; 162(9): 849-57. https://doi.org/10.1093/aje/kwi292
https://doi.org/https://doi.org/10.1093/... ^,3535. Cocco P, Satta G, Dubois S, Pili C, Pilleri M, Zucca M, et al. Lymphoma risk and occupational exposure to pesticides: results of the Epilymph study. Occup Environ Med 2013; 70: 91-8. http://doi.org/10.1136/oemed-2012-100845
https://doi.org/http://doi.org/10.1136/o... .

Information and selection biases were observed, such as the omission of reference to losses²⁷27. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... , which compromises the understanding of external validity, for example the degree of representativeness of the sample⁸8. Kachuri L, Demers PA, Blair A, Spinelli JJ, Pahwa M, McLaughlin JR, et al. Multiple pesticide exposures and the risk of multiple myeloma in Canadian men. Int J Cancer 2013; 133(8): 1846-58. http://doi.org/10.1002/ijc.28191
https://doi.org/http://doi.org/10.1002/i... ^,2828. Hohenadel K, Harris SA, McLaughlin JR, Spinelli JJ, Pahwa P, Dosman JA, et al. Exposure to Multiple Pesticides and Risk of Non-Hodgkin Lymphoma in Men from Six Canadian Provinces. Int J Environ Res Public Health 2011; 8(6): 2320-30. http://doi.org/10.3390/ijerph8062320
https://doi.org/http://doi.org/10.3390/i... ^,2929. Costas L, Infante-Rivard C, Zock JP, Van Tongeren M, Boffetta P, Cusson A, et al. Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study. Brit J Cancer 2015; 112(7): 1251-6. http://doi.org/10.1038/bjc.2015.83
https://doi.org/http://doi.org/10.1038/b... according to the Downs and Black Checklist.

GROUPED HEMATOLOGIC NEOPLASMS

Six cohort studies investigated the pooled HN²⁰20. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. Am J Epidemiol 2005; 162(11): 1070-9. http://doi.org/10.1093/aje/kwi321
https://doi.org/http://doi.org/10.1093/a... ^,2121. Mahajan R, Blair A, Lynch CF, Schroeder P, Hoppin JA, Sandler DP, et al. Fonofos exposure and cancer incidence in the agricultural health study. Environ Health Perspect 2006; 114(12): 1838-42. http://doi.org/10.1289/ehp.9301
https://doi.org/http://doi.org/10.1289/e... ^,2222. Mahajan R, Bonner MR, Hoppin JA, Alavanja MCR. Phorate exposure and incidence of cancer in the Agricultural Health Study. Environ Health Perspect 2006; 114(8): 1205-9. http://doi.org/10.1289/ehp.8911
https://doi.org/http://doi.org/10.1289/e... ^,2323. Bonner MR, Coble J, Blair A, Beane Freeman LE, Hoppin JA, Sandler DP, et al. Malathion Exposure and the Incidence of Cancer in the Agricultural Health Study. Am J Epidemiol 2007; 166(9): 1023-34. https://doi.org/10.1093/aje/kwm182
https://doi.org/https://doi.org/10.1093/... ^,2424. Koutros S, Mahajan R, Zheng T, Hoppin JA, Ma X, Lynch CF, et al. Dichlorvos exposure and human cancer risk: results from the Agricultural Health Study. Cancer Causes Control 2008; 19(1): 59-65. http://doi.org/10.1007/s10552-007-9070-0
https://doi.org/http://doi.org/10.1007/s... ^,2525. Bonner MR, Williams BA, Rusiecki JA, Blair A, Beane Freeman LE, Hoppin JA, et al. Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study. Cancer Causes Control 2010; 21(6): 871-7. https://doi.org/10.1007/s10552-010-9514-9
https://doi.org/https://doi.org/10.1007/... , all derived from AHS, a study conducted with 89,658 people, 57,311 pesticide applicators, and 32,347 spouses³⁶36. Alavanja MCR, Sandler DP, Lynch CF, Knott C, Lubin JH, Tarone R, et al. Cancer incidence in the Agricultural Health Study. Scand J Work Environ Health 2005; 31(Supl. 1): 39-45., which is distinguished by the type of OP studied. Exposure to diazinon²⁰20. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. Am J Epidemiol 2005; 162(11): 1070-9. http://doi.org/10.1093/aje/kwi321
https://doi.org/http://doi.org/10.1093/a... was associated with HN (RR = 1.84; 95%CI 0.89 - 3.82) in general, however, among those with a greater number of days and greater intensity of exposure throughout their working lives (RR = 2.01; 95%CI 1.02 - 3.94) this association was more evident, with the risk being twice as high. Exposure to phorate²²22. Mahajan R, Bonner MR, Hoppin JA, Alavanja MCR. Phorate exposure and incidence of cancer in the Agricultural Health Study. Environ Health Perspect 2006; 114(8): 1205-9. http://doi.org/10.1289/ehp.8911
https://doi.org/http://doi.org/10.1289/e... , phonophos²¹21. Mahajan R, Blair A, Lynch CF, Schroeder P, Hoppin JA, Sandler DP, et al. Fonofos exposure and cancer incidence in the agricultural health study. Environ Health Perspect 2006; 114(12): 1838-42. http://doi.org/10.1289/ehp.9301
https://doi.org/http://doi.org/10.1289/e... , malathion²³23. Bonner MR, Coble J, Blair A, Beane Freeman LE, Hoppin JA, Sandler DP, et al. Malathion Exposure and the Incidence of Cancer in the Agricultural Health Study. Am J Epidemiol 2007; 166(9): 1023-34. https://doi.org/10.1093/aje/kwm182
https://doi.org/https://doi.org/10.1093/... , dichlorvos²⁴24. Koutros S, Mahajan R, Zheng T, Hoppin JA, Ma X, Lynch CF, et al. Dichlorvos exposure and human cancer risk: results from the Agricultural Health Study. Cancer Causes Control 2008; 19(1): 59-65. http://doi.org/10.1007/s10552-007-9070-0
https://doi.org/http://doi.org/10.1007/s... , and terbufos²⁵25. Bonner MR, Williams BA, Rusiecki JA, Blair A, Beane Freeman LE, Hoppin JA, et al. Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study. Cancer Causes Control 2010; 21(6): 871-7. https://doi.org/10.1007/s10552-010-9514-9
https://doi.org/https://doi.org/10.1007/... was not associated with HN.

LEUKEMIA

Two case-control studies²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... ^,3030. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91. and four cohort studies²⁰20. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. Am J Epidemiol 2005; 162(11): 1070-9. http://doi.org/10.1093/aje/kwi321
https://doi.org/http://doi.org/10.1093/a... ^,2121. Mahajan R, Blair A, Lynch CF, Schroeder P, Hoppin JA, Sandler DP, et al. Fonofos exposure and cancer incidence in the agricultural health study. Environ Health Perspect 2006; 114(12): 1838-42. http://doi.org/10.1289/ehp.9301
https://doi.org/http://doi.org/10.1289/e... ^,2323. Bonner MR, Coble J, Blair A, Beane Freeman LE, Hoppin JA, Sandler DP, et al. Malathion Exposure and the Incidence of Cancer in the Agricultural Health Study. Am J Epidemiol 2007; 166(9): 1023-34. https://doi.org/10.1093/aje/kwm182
https://doi.org/https://doi.org/10.1093/... ^,2525. Bonner MR, Williams BA, Rusiecki JA, Blair A, Beane Freeman LE, Hoppin JA, et al. Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study. Cancer Causes Control 2010; 21(6): 871-7. https://doi.org/10.1007/s10552-010-9514-9
https://doi.org/https://doi.org/10.1007/... investigated the association between exposure to OP and leukemia. In one of these case control studies, there was an association between dichlorvos (OR = 2.0; 95%CI 1.2 - 3.5), crotoxiphos (OR = 11.1; 95%CI 2.2 - 55.0), and famphur (OR = 11.6; 95%CI 1.2 - 107.0) and leukemia in insecticide applicators in animals³⁰30. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91., although the strength of association found is limited by the small number of participants in the study, which is evidenced by the ample confidence intervals for crotoxiphos and famphur.

Exposure to diazinon was analyzed in three studies: a cohort²⁰20. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. Am J Epidemiol 2005; 162(11): 1070-9. http://doi.org/10.1093/aje/kwi321
https://doi.org/http://doi.org/10.1093/a... that estimated the association with leukemia (RR = 3.36; 95%CI 1.08 - 10.49) exclusively among individuals with exposure time greater than 38 days during the working life. However, in two case-control studies, no association was found²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... ^,3030. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91..

The phonophos was associated with leukemia only in the categories with the greatest number of days and the greatest intensity of exposure throughout a working life, according to the findings of the cohort of Mahajan et al.²¹21. Mahajan R, Blair A, Lynch CF, Schroeder P, Hoppin JA, Sandler DP, et al. Fonofos exposure and cancer incidence in the agricultural health study. Environ Health Perspect 2006; 114(12): 1838-42. http://doi.org/10.1289/ehp.9301
https://doi.org/http://doi.org/10.1289/e... (RR = 2.67; 95%CI 1.06 - 6.70). Unlike Brown et al.³⁰30. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91. who found no association between this chemical agent and leukemia. There was also no association between exposure to malathion²³23. Bonner MR, Coble J, Blair A, Beane Freeman LE, Hoppin JA, Sandler DP, et al. Malathion Exposure and the Incidence of Cancer in the Agricultural Health Study. Am J Epidemiol 2007; 166(9): 1023-34. https://doi.org/10.1093/aje/kwm182
https://doi.org/https://doi.org/10.1093/... ^,2626. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... ^,3030. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91., methyl parathion²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... , terbufos²⁵25. Bonner MR, Williams BA, Rusiecki JA, Blair A, Beane Freeman LE, Hoppin JA, et al. Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study. Cancer Causes Control 2010; 21(6): 871-7. https://doi.org/10.1007/s10552-010-9514-9
https://doi.org/https://doi.org/10.1007/... ^,3030. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91., phorate, coumaphos, tetrachloryinphos³⁰30. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91., and leukemia.

LYMPHOMAS

The association between exposure to OP and lymphomas has been the target of the largest number of publications, nine case control studies²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... ^,2727. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... ^,2828. Hohenadel K, Harris SA, McLaughlin JR, Spinelli JJ, Pahwa P, Dosman JA, et al. Exposure to Multiple Pesticides and Risk of Non-Hodgkin Lymphoma in Men from Six Canadian Provinces. Int J Environ Res Public Health 2011; 8(6): 2320-30. http://doi.org/10.3390/ijerph8062320
https://doi.org/http://doi.org/10.3390/i... ^,2929. Costas L, Infante-Rivard C, Zock JP, Van Tongeren M, Boffetta P, Cusson A, et al. Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study. Brit J Cancer 2015; 112(7): 1251-6. http://doi.org/10.1038/bjc.2015.83
https://doi.org/http://doi.org/10.1038/b... ^,3131. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55.^,3232. Nanni O, Amadori D, Lugaresi C, Falcini F, Scarpi E, Saragoni A, et al. Chronic lymphocytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breeding workers: a population case-control study based on a priori exposure matrices. Occup Environ Med 1996; 53(10): 652-7. https://doi.org/10.1136/oem.53.10.652
https://doi.org/https://doi.org/10.1136/... ^,3333. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. Non-Hodgkin’s Lymphoma and specific pesticide exposures in men. Cancer Epidemiol Biomarkers Prevent 2001; 10(11): 1155-63.^,3434. Fritschi L, Benke G, Hughes AM, Kricker A, Turner J, Vajdic CM, et al. Occupational exposure to pesticides and risk of Non-Hodgkin’s Lymphoma. Am J Epidemiol 2005; 162(9): 849-57. https://doi.org/10.1093/aje/kwi292
https://doi.org/https://doi.org/10.1093/... ^,3535. Cocco P, Satta G, Dubois S, Pili C, Pilleri M, Zucca M, et al. Lymphoma risk and occupational exposure to pesticides: results of the Epilymph study. Occup Environ Med 2013; 70: 91-8. http://doi.org/10.1136/oemed-2012-100845
https://doi.org/http://doi.org/10.1136/o... and three cohort studies²⁰20. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. Am J Epidemiol 2005; 162(11): 1070-9. http://doi.org/10.1093/aje/kwi321
https://doi.org/http://doi.org/10.1093/a... ^,2323. Bonner MR, Coble J, Blair A, Beane Freeman LE, Hoppin JA, Sandler DP, et al. Malathion Exposure and the Incidence of Cancer in the Agricultural Health Study. Am J Epidemiol 2007; 166(9): 1023-34. https://doi.org/10.1093/aje/kwm182
https://doi.org/https://doi.org/10.1093/... ^,2525. Bonner MR, Williams BA, Rusiecki JA, Blair A, Beane Freeman LE, Hoppin JA, et al. Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study. Cancer Causes Control 2010; 21(6): 871-7. https://doi.org/10.1007/s10552-010-9514-9
https://doi.org/https://doi.org/10.1007/... . In general, OP have been associated with:

There were five studies that found no association between OP and subtypes of lymphoma³⁵35. Cocco P, Satta G, Dubois S, Pili C, Pilleri M, Zucca M, et al. Lymphoma risk and occupational exposure to pesticides: results of the Epilymph study. Occup Environ Med 2013; 70: 91-8. http://doi.org/10.1136/oemed-2012-100845
https://doi.org/http://doi.org/10.1136/o... , NHL²⁷27. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... ^,3131. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55.^,3434. Fritschi L, Benke G, Hughes AM, Kricker A, Turner J, Vajdic CM, et al. Occupational exposure to pesticides and risk of Non-Hodgkin’s Lymphoma. Am J Epidemiol 2005; 162(9): 849-57. https://doi.org/10.1093/aje/kwi292
https://doi.org/https://doi.org/10.1093/... , and HL²⁹29. Costas L, Infante-Rivard C, Zock JP, Van Tongeren M, Boffetta P, Cusson A, et al. Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study. Brit J Cancer 2015; 112(7): 1251-6. http://doi.org/10.1038/bjc.2015.83
https://doi.org/http://doi.org/10.1038/b... .

The findings for diazinon showed an association with NHL³¹31. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55. in those with more than 15 years of exposure (OR = 2.6; 95%CI 1.2 - 5.9), but no associations were found in three case-control studies²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... ^,2727. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... ^,3333. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. Non-Hodgkin’s Lymphoma and specific pesticide exposures in men. Cancer Epidemiol Biomarkers Prevent 2001; 10(11): 1155-63. and in one cohort one²⁰20. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. Am J Epidemiol 2005; 162(11): 1070-9. http://doi.org/10.1093/aje/kwi321
https://doi.org/http://doi.org/10.1093/a... .

The measure of association between the time of exposure to malathion and NHL was greater in the studies by Cantor et al.³¹31. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55. (OR = 2.9; 95%CI 1.0 - 7.4), with more than 15 years of exposure, by McDuffie et al.³³33. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. Non-Hodgkin’s Lymphoma and specific pesticide exposures in men. Cancer Epidemiol Biomarkers Prevent 2001; 10(11): 1155-63. (OR = 1.75; 95%CI 1.02 - 3.03), with use greater than 2 days/year, and by Waddell et al.²⁷27. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... (OR = 1.7/; 95%CI 1.1 - 2.9), with use for more than 20 years. However, other studies do not corroborate these results for malathion²³23. Bonner MR, Coble J, Blair A, Beane Freeman LE, Hoppin JA, Sandler DP, et al. Malathion Exposure and the Incidence of Cancer in the Agricultural Health Study. Am J Epidemiol 2007; 166(9): 1023-34. https://doi.org/10.1093/aje/kwm182
https://doi.org/https://doi.org/10.1093/... ^,2626. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... . Other OP such as phonophos, phorate²⁷27. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... ^,3131. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55., terbufos²⁵25. Bonner MR, Williams BA, Rusiecki JA, Blair A, Beane Freeman LE, Hoppin JA, et al. Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study. Cancer Causes Control 2010; 21(6): 871-7. https://doi.org/10.1007/s10552-010-9514-9
https://doi.org/https://doi.org/10.1007/... ^,2727. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... ^,3131. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55., coumaphos, dichlorvos, famphur³¹31. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55., dimethoate³³33. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. Non-Hodgkin’s Lymphoma and specific pesticide exposures in men. Cancer Epidemiol Biomarkers Prevent 2001; 10(11): 1155-63.^,3535. Cocco P, Satta G, Dubois S, Pili C, Pilleri M, Zucca M, et al. Lymphoma risk and occupational exposure to pesticides: results of the Epilymph study. Occup Environ Med 2013; 70: 91-8. http://doi.org/10.1136/oemed-2012-100845
https://doi.org/http://doi.org/10.1136/o... , and methyl parathion²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... were not associated with lymphoma.

MULTIPLE MYELOMA

Only three case control studies investigated exposure to OP and risk of MM. There was a higher risk of MM in those exposed to OP in general²⁹29. Costas L, Infante-Rivard C, Zock JP, Van Tongeren M, Boffetta P, Cusson A, et al. Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study. Brit J Cancer 2015; 112(7): 1251-6. http://doi.org/10.1038/bjc.2015.83
https://doi.org/http://doi.org/10.1038/b... compared to the references (OR = 1.22; 95%CI 1.06 - 1.41). This result differs from the findings by Kachuri et al.⁸8. Kachuri L, Demers PA, Blair A, Spinelli JJ, Pahwa M, McLaughlin JR, et al. Multiple pesticide exposures and the risk of multiple myeloma in Canadian men. Int J Cancer 2013; 133(8): 1846-58. http://doi.org/10.1002/ijc.28191
https://doi.org/http://doi.org/10.1002/i... , who found no association between OP and malathion and MM. As well as no association was found between exposure to diazinon, malathion, methyl parathion and MM²⁶26. Mills PK, Yang R, Riordan D. Lymphohematopoietic Cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes Control 2005; 16(7): 823-30. http://doi.org/10.1007/s10552-005-2703-2
https://doi.org/http://doi.org/10.1007/s... .

DISCUSSION

The results of this SR show that in two cohort²⁰20. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. Am J Epidemiol 2005; 162(11): 1070-9. http://doi.org/10.1093/aje/kwi321
https://doi.org/http://doi.org/10.1093/a... ^,2222. Mahajan R, Bonner MR, Hoppin JA, Alavanja MCR. Phorate exposure and incidence of cancer in the Agricultural Health Study. Environ Health Perspect 2006; 114(8): 1205-9. http://doi.org/10.1289/ehp.8911
https://doi.org/http://doi.org/10.1289/e... and four case control studies²⁷27. Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F, Burmeister LF, et al. Agricultural use of organophosphate pesticides and the risk of non-Hodgkin’s lymphoma among male farmers (United States). Cancer Causes Control 2001; 12(6): 509-17. http://doi.org/10.1023/A:1011293208949
https://doi.org/http://doi.org/10.1023/A... ^,3030. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide Exposures and Other Agricultural Risk Factors for Leukemia among Men in Iowa and Minnesota. Cancer Res 1990; 50(20): 6585-91.^,3131. Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for Non-Hodgkin’s Lymphoma among men in Iowa and Minnesota. Cancer Res 1992; 52(9): 2447-55.^,3333. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. Non-Hodgkin’s Lymphoma and specific pesticide exposures in men. Cancer Epidemiol Biomarkers Prevent 2001; 10(11): 1155-63. the findings were of a positive association between occupational exposure to OP and HN, in which the time of exposure to pesticides appeared as a modifying variable effect on these causal relationships.

Among the investigated OP, individuals exposed to diazinon for a longer period, compared to those not exposed, had a higher risk of HN, leukemia, and NHL. This association was estimated regardless of methodological differences in the measurement of time - in days of working life, days per year or years of exposure to pesticides.

Leukemia was the neoplasm associated with a greater diversity of OP, such as famphur, crotoxiphos, dichlorvos, diazinon, and phonophos among the studied compounds. The increased risk from exposure to diazinon and phonophos occurred among those who had the longest exposure time.

There were divergences in some results, which may be due to differences in design and methods of analysis. For example, only in the cohort studies was there a uniformity of the variables used for adjustment and of the strategies used to assess the intensity of occupational exposure. However, in most articles there was an adjustment for age, family history of cancer, exposure to other pesticides, smoking, among others; Regarding the exposure assessment, some studies considered time in days or years and others used matrices according to the toxicity of pesticides, methods of applying the substances, use of personal protective equipment (PPE), exposure time, among others. None of the studies had quantitative measures of exposure with biomonitoring of residues or enzymatic activity.

Measuring exposure to chemicals is a complex task and comprises:

Other aspects to be considered are the windows of susceptibility and the time of metabolism or persistence in the body. To obtain measures of these dimensions in epidemiological studies, data from environmental or biological monitoring, records from workplaces or other sources, expert evaluations, exposure-work matrices and questionnaires or interviews with subjects or family members can be used³⁷37. International Agency for Research of Cancer. Monographs on the Identification of Carcinogenic Hazards to Humans PREAMBLE [Internet]. Lyon: IARC; 2019 [acessado em 20 jan. 2019]. Disponível em: Disponível em: https://monographs.iarc.fr/wp-content/uploads/2019/01/Preamble-2019.pdf
https://monographs.iarc.fr/wp-content/up... . All of these secondary-based measures, obtained through access to company data records, can be biased.

The qualitative analysis of the articles showed selection bias such as: definition of cases based on registration of information systems and exposure assessment considering only the self-report of the participants. Specifically, the measurement of exposure based on self-report has a series of gaps linked to memory bias, since individuals may have difficulties in accurately reporting the types of chemicals used and the frequency of application throughout life³⁸38. International Agency for Research of Cancer. Some organophosphate insecticides and herbicides. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans [Internet]. Lyon: IARC , 2015 [acessado em 25 jul. 2018]. v. 112. 464 p. Disponível em: Disponível em: http://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Evaluation-Of-Carcinogenic-Risks-To-Humans/Some-Organophosphate-Insecticides-And-Herbicides-2017
http://publications.iarc.fr/Book-And-Rep... .

COMPARISON WITH OTHER SR

The SR that summarized the results of studies from the AHS cohort estimated a higher risk of HN among those exposed to diazinon and chlorpyrifos in the categories with the highest exposure intensity, in addition to the association between diazinon, chlorpyrifos and phonophos and leukemia in individuals exposed for the longest time throughout working life¹¹11. Weichenthal S, Moase C, Chan P. A review of pesticide exposure and cancer incidence in the agricultural health study cohort. Ciên Saúde Colet 2012; 17(1): 255-70. http://dx.doi.org/10.1590/S1413-81232012000100028
https://doi.org/http://dx.doi.org/10.159... .

In two SR with meta-analysis, it was observed that in the first, Schinasi and Leon¹⁰10. Schinasi L, Leon ME. Non-Hodgkin lymphoma and occupational exposure to agricultural pesticide chemical groups and active ingredients: a systematic review and meta-analysis. Int J Environ Res Public Health 2014; 11(4): 4449-527. https://doi.org/10.3390/ijerph110404449
https://doi.org/https://doi.org/10.3390/... reviewed 44 studies and found an association between OP in general, malathion and diazinon and NHL, while in the second, Hu et al.¹²12. Hu L, Luo D, Zhou T, Tao Y, Feng J, Mei S. The association between non-Hodgkin lymphoma and organophosphate pesticides exposure: A meta-analysis. Environ Pollut 2017; 231(Parte 1): 319-28. http://doi.org/10.1016/j.envpol.2017.08.028
https://doi.org/http://doi.org/10.1016/j... demonstrated the association between diazinon and NHL after meta-analysis of ten observational studies.

The results of this SR, updated until July 2019, corroborate the findings of the previous SR for NHL and leukemia and include the results of the multicenter case study conducted in Europe by Costas et al.²⁹29. Costas L, Infante-Rivard C, Zock JP, Van Tongeren M, Boffetta P, Cusson A, et al. Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study. Brit J Cancer 2015; 112(7): 1251-6. http://doi.org/10.1038/bjc.2015.83
https://doi.org/http://doi.org/10.1038/b... , which describes the association between OP and MM, not explored in the other SR. Such findings reinforce the evidence of the carcinogenicity of OP to HN.

ADVANCES AND LIMITS OF THE STUDY

In the NOS guidance manual, the distinction between the scores of good studies and those of low quality is not clear. Thus, in this review, the classification used in a meta-analysis¹²12. Hu L, Luo D, Zhou T, Tao Y, Feng J, Mei S. The association between non-Hodgkin lymphoma and organophosphate pesticides exposure: A meta-analysis. Environ Pollut 2017; 231(Parte 1): 319-28. http://doi.org/10.1016/j.envpol.2017.08.028
https://doi.org/http://doi.org/10.1016/j... was adopted, which considered low from zero to three stars, moderate from four to six stars and high quality from seven to nine stars. The criticisms of NOS are directed to case definition, since there is no specification of the need for validation by two different examiners, and the difficulty of guaranteeing the interviewer’s blindness to the case control status, as some diseases are visually identified, for example, signs of neurological damage³⁹39. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25(9): 603-5. http://doi.org/10.1007/s10654-010-9491-z
https://doi.org/http://doi.org/10.1007/s... . Nonetheless, NOS has been recommended to verify the methodological quality and the risk of bias in observational analytical studies⁴⁰40. Zeng X, Zhang Y, Kwong JSW, Zhang C, Li S, Sun F, et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med 2015; 8(1): 2-10. http://doi.org/10.1111/jebm.12141
https://doi.org/http://doi.org/10.1111/j... .

It is important to highlight the role of epidemiological studies in the process of evaluating the carcinogenicity of pesticides. By integrating the results of observational studies with the findings of experimental animal studies and mutagenic tests, the OP insecticides tetrachloryinphos and paration were classified by the IARC as possibly carcinogenic to humans (group 2B), and malathion and diazinon as probably carcinogenic to humans (group 2A) , with a possible association between malathion and NHL, and between diazinon and NHL and leukemia¹³13. Guyton KZ, Loomis D, Grosse Y, Ghissassi FE, Benbrahim-Tallaa L, Guha N, et al. Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. Lancet Oncol 2015; 16(5): 490-1. http://doi.org/10.1016/S1470-2045(15)70134-8
https://doi.org/http://doi.org/10.1016/S... . However, even with this classification, some of these products continue to be used in agriculture. The process of regulating active ingredients of pesticides is fundamental to reduce risks to human health and the environment resulting from the use of these substances, however the regulation occurs differently between regions of the world.

In Brazil, diazinon and malathion are authorized for use, paration was already banned in 2015, and there is no record of pesticides using tetrachloryinphos⁴¹41. Agência Nacional de Vigilância Sanitária. Regularização de produtos agrotóxicos- Monografias de agrotóxicos [Internet]. Brasil: Agência Nacional de Vigilância Sanitária; 2019 [acessado em 22 ago. 2019]. Disponível em: Disponível em: http://portal.anvisa.gov.br/registros-e-autorizacoes/agrotoxicos/produtos/monografia-de-agrotoxicos
http://portal.anvisa.gov.br/registros-e-... . In the United States, all of these active ingredients are in use, but in the process of reevaluation⁴²42. United States Environmental Protection Agency. Pesticide chemical search [Internet]. Estados Unidos: United States Environmental Protection Agency; 2019 [acessado em 22 ago. 2019]. Disponível em: Disponível em: https://iaspub.epa.gov/apex/pesticides/f?p=CHEMICALSEARCH:1:
https://iaspub.epa.gov/apex/pesticides/f... . While only malathion is allowed for use in agriculture in the European Union, the rest has been banned⁴³43. European Commission. Plants: EU pesticides database [Internet]. Europa: EU; 2019 [acessado em 22 ago. 2019]. Disponível em: Disponível em: http://ec.europa.eu/food/plant/pesticides/eu-pesticides-database/public/?event=activesubstance.selection&language=EN
http://ec.europa.eu/food/plant/pesticide... .

In 2017, the Human Rights Council of the United Nations issued a warning on the lack of standardization in the laws that regulate the use of pesticides worldwide, especially in developing countries, where the pressure to increase the production generated by the export of agricultural products has the consequence of increasing the use of agrochemicals without adequate security to control the risks associated with these products. Gaps in legislation in these countries may result in a higher risk of toxicity due to the permission to commercialize highly toxic products already banned in industrialized countries⁴⁴44. Office of the United Nations High Commissioner for Human Rights (OHCHR). Human Rights Council. Thirty-fourth session 27 February-24 March 2017. Report of the special rapporteur on the right to food [Internet]. Genebra: OHCHR; 2017 [acessado em 13 jun. 2018]. Disponível em: Disponível em: https://documents-dds-ny.un.org/doc/UNDOC/GEN/G17/017/85/PDF/G1701785.pdf?OpenElement
https://documents-dds-ny.un.org/doc/UNDO... .

Considering the issue of increasing agricultural production in developing countries, the scarcity of studies from these regions discussing the risks of chronic exposure to these products to human health, particularly neoplasms, draws attention.

In relation to Brazil, the third largest producer of soybeans and corn in the world in 2016 and the second country with the highest proportion of pesticide use by planted area in 2014⁴⁵45. Food and Agriculture Organization of the United Nations. FAOSTAT Countries by commodity [Internet]. Estados Unidos: Food and Agriculture Organization of the United Nations; 2018 [acessado em 13 jun. 2018]. Disponível em: Disponível em: http://www.fao.org/faostat/en/#rankings/countries_by_commodity
http://www.fao.org/faostat/en/#rankings/... ^,4646. Food and Agriculture Organization of the United Nations. FAOSTAT Compare data agri-environmental Indicators - Pesticides [Internet]. Estados Unidos: Food and Agriculture Organization of the United Nations ; 2018 [acessado em 13 jun. 2018]. Disponível em: Disponível em: http://www.fao.org/faostat/en/#compare
http://www.fao.org/faostat/en/#compare... , the article screening process identified three studies, which were not selected in the review for being of ecological design⁷7. Boccolini PMM, Boccolini CS, Chrisman JR, Markowitz SB, Koifman S, Koifman RJ, et al. Pesticide use and non-Hodgkin’s lymphoma mortality in Brazil. Int J Hyg Env Health 2013; 216(4): 461-6. http://doi.org/10.1016/j.ijheh.2013.03.007
https://doi.org/http://doi.org/10.1016/j... ^,4747. Meyer A, Chrisman J, Moreira JC, Koifman S. Cancer mortality among agricultural workers from Serrana Region, state of Rio de Janeiro, Brazil. Environ Res 2003; 93(3): 264-71. http://doi.org/10.1016/s0013-9351(03)00065-3
https://doi.org/http://doi.org/10.1016/s... ^,4848. Chrisman JR, Koifman S, Sarcinelli PN, Moreira JC, Koifman RJ, Meyer A. Pesticide sales and adult male cancer mortality in Brazil. Int J Hyg Environ Health 2009; 212(3): 310-21. http://doi.org/10.1016/j.ijheh.2008.07.006
https://doi.org/http://doi.org/10.1016/j... .

The findings of this study coincide with those of other systematic reviews, but they must be evaluated with caution due to the number of selected studies, in addition to the small number of participants. It is noteworthy that diazinon is an OP that has been associated with HN, leukemia, and NHL. In addition, there is a relationship between the time of exposure to pesticides and the occurrence of HN. In this sense, future studies should analyze this exposure using standardized time measurement, in order to allow a more accurate comparison between the findings obtained in different populations.

The importance of increasing research that identifies health risks, especially in the most vulnerable groups, such as farmers and residents of developing countries with significant agricultural production, is emphasized.

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