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Occupational exposure to pesticides and risk of leukemia among offspring in Costa Rica

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From the Department of Public Health Sciences, Division of Occupational Medicine Karolinska Institutet, SE-171 Stockholm, Sweden Occupational exposure to pesticides and risk of leukemia among offspring
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From the Department of Public Health Sciences, Division of Occupational Medicine Karolinska Institutet, SE-171 Stockholm, Sweden Occupational exposure to pesticides and risk of leukemia among offspring in Costa Rica Patricia Monge Stockholm 2006 All previously published papers were reproduced with permission from the publishers. Published and printed by Karolinska University Press Box 200, SE Stockholm, Sweden Patricia Monge, 2006 ISBN To Jose, Tati, Pauli and Fiore 3 ABSTRACT Background. Leukemias are the most common childhood cancers, accounting for 25-35% of the incidence of all childhood cancer in most populations. In early reports on cancer, Costa Rica ranks among the highest incidence of childhood leukemia in the world. Agriculture is an important economic activity in Costa Rica and is characterized by intensive use of pesticides. In this thesis we present a descriptive epidemiologic study of childhood leukemias, two methodological studies on parental pesticide exposure assessment and an etiological analysis based on a population based-control study. Objective. The main objective of this study was to increase the understanding of potential risk factors of childhood leukemia in Costa Rica, propose improved methods for exposure assessment in cancer research in developing country conditions, and provide epidemiological evidence of association between childhood leukemia and parental occupational pesticide exposure during the prenatal and early postnatal periods of children. Methods. Childhood leukemia incidence during was analyzed by histology, gender, birth year, time period of diagnosis, age at diagnosis and region. Case data were extracted from the National Cancer Registry of Costa Rica. Person-years at risk were calculated from census data and annual sample survey data. International comparison of rates was performed (Paper I). We describe an icon-calendar interview form (ICF) for assessing retrospective parental exposure to pesticides, collecting data on agricultural pesticide use, job tasks, frequency of exposure and major determinants of pesticide exposure (Paper II). ICF data were combined with external data of pesticide application rates for the country, in two retrospective exposure assessment models (Paper III). Associations between parental exposure to pesticides and the risk of leukemia in the offspring were examined in a population-based case-control study in Costa Rica. All cases of childhood leukemia (N=334), ages 0-14 at diagnosis, during , were identified at the Cancer Registry and the Children s Hospital of Costa Rica (ICD-0-1). Population controls (N=579), were drawn from the National Birth Registry (Paper IV). Results. The reported cases of childhood leukemia between represented an overall age-standardized incidence rate of 55 per million personyears. Acute lymphocytic leukemia (ALL) accounted for 79% of all leukemias. A Poisson regression model identified significant excesses of ALL for boys, groups of 1-4 and 5-9 years of age and for three out of seven geographical regions. Based on the first 100 ICF, recall was acceptable in 90% of the interviews, successful identification of special events in 84%, good recovery of pesticide names, frequency of use and application techniques in 90%, report of changes in pesticide use patterns in 63%. Numbers of exposed mothers and fathers for each prioritized pesticide and its exposure intensities for five time windows, were estimated with the exposure assessment models. A sensitivity analysis suggested satisfactory robustness of the model weights. In the case-control 4 study, 876 mothers and 762 fathers were included in the analysis. Mothers exposures to any pesticides anytime and during year before conception and 1st and 2nd trimesters, and fathers exposures to any pesticides during 2nd trimester were associated with excess risks. Excesses of total leukemia were found for mothers and fathers exposed to organophosphates and for fathers exposed to benzimidazoles. There was a suggestion of exposure-response gradients for fathers for picloram, benomyl and paraquat. Age at diagnosis was positively associated with fathers exposures and inversely with mothers. Mothers exposures seemed more important than fathers. Conclusions. Based on worldwide epidemiologic data, including ours, we believe that parental and early childhood exposure to pesticides may be associated with risk of leukemia in the offspring. The most likely candidates for etiologically important pesticidal compounds appear to be organophosphates as group and still with considerable uncertainty picloram, benomyl, paraquat, foxim, mancozeb, malathion, dichlorvos and sodium monomethyldithiocarbamate (metam sodium). Epidemiological research on childhood cancer needs to be further conducted in developing countries, including etiological research on pesticides. There is a need to study biomarkers for assessing biological processes in leukaemogenesis, susceptibility and exposure. We recommend prevention of pesticide hazards, especially in the population stratum reproductively active and among children. Key words: agriculture, agricultural workers, cancer epidemiology, casecontrol, childhood cancer, childhood leukemia, children, Costa Rica, developing countries, exposure assessment, fetal exposures, offspring, prenatal exposures, icons, interview, occupational exposure, pesticides, questionnaire, pregnancy, reproductive effects, tropics. 5 RESUMEN Antecedentes. Las leukemias son las enfermedades malignas más frecuentes en la infancia y representan entre un 25-35% de la incidencia total de cáncer infantil en la mayoría de la poblaciones. La incidencia de leucemia en niños en Costa Rica, se encuentra entre las más altas en el mundo. La agricultura es una actividad económica muy importante en el país, caracterizada por el uso intensivo de plaguicidas. En esta tesis se presentan un estudio descriptivo epidemiológico de leucemias en niños, dos estudios metodológicos sobre evaluación de exposición de padres a plaguicidas y un estudio analítico de casos y controles de base poblacional sobre la asociación entre la exposición paterna ocupacional a plaguicidas y el riesgo de leucemia en los hijos. Objetivo. El objetivo principal del estudio fue incrementar el conocimiento de los factores de riesgo asociados al desarrollo de leucemias infantiles en Costa Rica, proponer métodos de evaluación de exposición en cáncer para países en desarrollo y evaluar la asociación entre las leucemias en niños y la exposición paterna ocupacional a plaguicidas durante el período prenatal y postnatal temprano. Métodos. La incidencia de leucemia en niños durante el período fue analizado por histología, sexo, año de nacimiento, año de diagnóstico, edad al diagnóstico y región geográfica. La información de los casos fue extraída del Registro Nacional de Tumores (RNT). Los años-persona en riesgo fueron calculados del censo y de las estimaciones de población para estos años. Se establecieron comparaciones internacionales de incidencias (Artículo I). Presentamos un cuestionario pictórico (calendario de imágenes) (ICF) para evaluar la exposición retrospectiva de exposición a plaguicidas de ambos padres, que se utilizó para recopilar la información sobre uso de plaguicidas en agricultura, puestos de trabajo y los principales determinantes de exposición (Artículo II). Los datos obtenidos con el ICF fueron combinados con datos externos de tasas de aplicación de plaguicidas, en dos modelos de evaluación de exposición retrospectiva (Artículo III). Adicionalmente se analizó la asociación entre la exposición paterna y materna a plaguicidas y el riesgo de desarrollar leucemia en los niños, a través de un estudio de casos y controles. Todos los casos de leucemia (N=334) con edades entre 0-14 años en al momento del diagnóstico, durante fueron identificados en el RNT y el Hospital Nacional de Niños de Costa Rica. Los controles fueron escogidos del Registro Civil (Manuscrito IV). Resultados. Los casos reportados de leucemia infantil en el período representaron una incidencia estandarizada por edad de 55 por millón de añospersona. El 79% correspondió a leucemia linfocítica aguda (LLA). Un modelo de regresión de Poisson identificó excesos significativos de LLA para niños, los grupos de edad 1-4 y 5-9 y para tres de las siete regiones geográficas. Con base en los primeros ICF completados: la capacidad de recordar fue aceptable en 90% de las entrevistas, la identificación exitosa de los eventos especiales en 6 un 84%, la recopilación general de uso de plaguicidas en un 90%, y el reporte de cambios en los patrones de uso de plaguicidas en un 63%. Los modelos de evaluación de exposición identificaron la cantidad de madres y padres expuestos a los plaguicidas priorizados y sus intensidades de exposición para 5 ventanas de tiempo. Un análisis de sensibilidad del modelo cuantitativo sugirió una adecuada fuerza de los pesos utilizados. En el estudio de casos y controles, 876 madres y 762 padres fueron incluidos en el análisis. La exposición de las madres a plaguicidas en general, durante el año antes de la concepción, 1º y 2º trimestres de embarazo y durante todo el período fue asociada con el riesgo de leucemia infantil. También se identificó riesgo para los padres expuestos a plaguicidas en general, durante el 2º trimestre de embarazo del niño. Se identificaron asociaciones en madres y padres expuestos a organofosforados y riesgos de leucemia, así como padres expuestos a benzimidazoles. Es posible que hubiera una gradiente de exposición-respuesta para padres expuestos a picloram, benomil y paraquat. La edad del niño al diagnóstico estuvo asociada positivamente con los padres y en forma inversa con las madres. Las exposiciones maternas parecen más importantes que las de los padres. Conclusiones. En base a los datos epidemiológicos internacionales, incluidos los nuestros, consideramos que hay razones que apoyan la asociación entre la exposición paterna a plaguicidas pre-concepción y temprana en la niñez y el riesgo de leucemia infantil. Los plaguicidas que podrían ser agentes etiológicos son organosforados como grupo y -aún con alguna incertidumbre- benomil, paraquat, picloram, foxim, mancozeb, malatión, diclorvos y metilditiocarbamato sódico. Investigaciones epidemiológicas en cáncer infantil son necesarias en países en desarrollo, incluyendo la investigación etiológica en plaguicidas. Es importante el desarrollo de biomarcadores para evaluar los procesos biológicos de leuquemogénesis, susceptibilidad y exposición en Costa Rica. Recomendamos la prevención de riesgos asociados con plaguicidas, especialmente en la población en edad reproductiva y en los niños. Palabras clave: agricultura, cáncer infantil, casos y controles, Costa Rica, cuestionario embarazo, efectos reproductivos, epidemiología de cáncer, entrevista, evaluación de exposición, exposiciones fetales, exposición ocupacional, íconos, leucemia, niños, países en desarrollo, plaguicidas, trabajador agrícola, trópico. 7 LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numeral (I-IV): I. Monge P, Wesseling C, Rodríguez AC, Cantor K, Weiderpass E, Reutfors J, Ahlbom A, Partanen T. Childhood leukemia in Costa Rica, Paediatr Perinat Epidemiol 2002;16: II. Monge P, Wesseling C, Engel L, Keifer M, Zuurbier M, Rojas M, Partanen T. An icon-based interview for the assessment of occupational pesticide exposure in a case-control study of childhood leukemia. Int J Occup Environ Health 2004;10: III. Monge P, Partanen T, Wesseling C, Bravo V, Ruepert C, Burstyn I. Assessment of pesticide exposure assessment in the agricultural population of Costa Rica. Ann Occup Hyg 2005;49:1-10. IV. Monge P, Wesseling C, Guardado J, Lundberg I, Ahlbom A, Cantor K, Weiderpass E, Partanen T. Parental occupational exposure to pesticides and risk of childhood leukemia in Costa Rica. Submitted. Papers I, II and III are reprinted with permission of the respective journals. 8 CONTENTS Abstract Resumen List of publications List of abbreviations 1 INTRODUCTION BACKGROUND Leukemias Epidemiology of childhood leukemias Occupational and environmental exposures and childhood leukemias Costa Rica Population, health indicators and health care Registration of leukemia cases Pesticide use in Costa Rica Methodological issues in research in childhood leukemia and pesticides Exposure assessment Exposure models Data sources on pesticide use Epidemiological research in a developing country OBJECTIVES MATERIALS AND METHODS Paper I Paper II Paper III Paper IV Study population and study design Data collection Epidemiological data analysis RESULTS Childhood leukemia in Costa Rica: international comparison (Paper I) Performance of the ICF (Paper II) Exposure intensities of parents exposed to pesticides (Paper III) Risk of childhood leukemia associated with parental occupational exposure to pesticides (Paper IV) 6 GENERAL DISCUSSION Childhood leukemia incidence (Paper I) Evaluation of ICF calendar for assessing past parental occupational pesticide exposure (Paper II) Evaluation of the exposure assessment model (Paper III) Validity of the case-control study (Paper IV) Consolidated evidence CONCLUSIONS AND RECOMMENDATIONS ACKNOWLEDGEMENTS REFERENCES APPENDIX LIST OF ABBREVIATIONS a.i. ALL ANLL CCSS CI DDT DBCP EPA HNN IARC ICCC ICD-O ICF INEC IRET-UNA NA NEC NOS OR PPP RNT Active ingredient Acute lymphocytic leukemia Acute non-lymphocytic leukemia Social Security System of Costa Rica (Caja Costarricense de Seguro Social) Confidence interval Dichloro-diphenyl-trichloroethane Dibromochloropropane U.S. Environmental Protection Agency National Children s Hospital (Hospital Nacional de Niños) International Agency for Research on Cancer International Classification of Childhood Cancer International Classification of Diseases for Oncology Icon-calendar form National Institute of Statistics and Censuses (Instituto Nacional de Estadística y Censo) Central American Institute for Studies on Toxic Substances (Instituto Regional de Estudios en Sustancias Tóxicas, Universidad Nacional, Heredia, Costa Rica) Not applicable Number of exposed cases Not otherwise specified Odds ratio Purchasing power parity National Cancer Registry (Registro Nacional de Tumores) 11 1 INTRODUCTION Childhood leukemias are the most common cancers among children, accounting for 25-35% of the incidence of all childhood cancers in most populations (Little 1999, Parkin 1998). The etiology of childhood leukemia is still to a large extent unknown. A number of risk factors have been proposed in the literature, such as gender, age, genetic factors, ethnicity, socio-economic status, high birth weight, exposure to ionizing radiation, spores, infections, dust, fumes, and chemical agents. Epidemiological cancer data from developing countries are scarce and much needed. During the 1980s, the newly established cancer registry in Costa Rica permitted the identification of childhood leukemia as the most common childhood malignancy (39% in 1987), with incidence rates among the highest in the world: 59 per million for total leukemia, and 45 per million for acute lymphocytic leukemia in 1987 (Little 1999, Parkin et al. 1998, Linet et al. 1991, Sierra et al. 1995). Associations of childhood leukemia with parents exposure to pesticides were proposed in medical discussions, and a cluster associated with pesticide exposure in the late 1980s caused considerable public concern, but no formal investigations were possible at that time. An increased risk of leukemia in children associated with parental occupational exposure to pesticides prior and during pregnancy has been suggested by a number of epidemiologic studies (Shu et al. 1988, Infante-Rivard et al. 1999, Petridou et al. 2000, Meinert et al. 2000, Alexander et al. 2005). Agriculture is an important economic activity in Costa Rica and is characterized by intensive and inappropriate use of pesticides, many of them mutagenic, genotoxic and possibly carcinogenic (Wesseling et al. 2001). An epidemiologic study examining the relation between parental pesticide exposures and cancer in the offspring emerged therefore as a priority, in spite of challenges to carry out cancer epidemiology in a developing country. In this thesis we present a descriptive epidemiologic study of childhood leukemias, two methodological studies on parental pesticide exposure assessment, and an etiologic analysis based on a population-based case-control study. 12 2 BACKGROUND 2.1 Leukemias Leukemias are a group of heterogeneous neoplastic disorders of white blood cells, a clonal disorder of stem cell, primary at the bone marrow. Leukemic cells usually spill into the blood, and may also infiltrate lymph nodes, liver, spleen and other tissues. Leukemias can be subdivided into lymphoid (originating from a precursor of B- or T- lymphocytes) and myeloid (originating from a precursor of granulocytes, monocytes, erythrocytes, or megakaryocytes). According to the International Classification of Childhood Cancer (ICCC), adapted from the International Classification of Diseases (ICD-0-3), leukemias are classified into five groups: lymphoid leukemias, acute myeloid leukemias, chronic myeloproliferative diseases, myelodysplastic syndrome and other myeloproliferative diseases, and unspecified and other specified leukemias. Table 1 shows the classification (Steliarova-Foucher et al. 2005). Table 1. International classification of childhood leukemias 1. Diagnostic groups Morphology Ia: Lymphoid leukemia 9820, 9823, 9826, 9827, , 9940, 9948 Ib: Acute myeloid leukemias 9840, 9861, 9866, 9867, , 9891, , 9910, 9920, 9931 Ic: Chronic myeloproliferative diseases 9863, 9875, 9876, 9950, Id: Myelodysplastic syndrome and other myeloproliferative diseases 9945, 9946, 9975, 9980, , 9989 Ie: Unspecified leukemia 9800, 9801, 9805, 9860, Based on the International Classification of Childhood Cancer (ICCC-3). Steliarova-Foucher E, Stiller, C, Lacour B, Kaatshc P. International Classification on Childhood Cancer, Third Edition. International Agency for Research on Cancer (IARC). Cancer 2005;7: Epidemiology of childhood leukemias Leukemias are the most common childhood cancers, especially among white populations in Europe, America, Oceania and in most of Eastern Asia, with an age-standardized rate of per million. Acute lymphocytic leukemia (ALL) comprises around 80% of the total leukemias in most populations (Little 1999, Parkin 1998). The highest incidence have been reported in Hispanic populations of California (Glazer et al. 1999), Florida (Wilkinson et al. 2001), and Costa Rica (Linet 1991). 13 The etiology of childhood leukemia is not well understood. Known or suspected risk factors include gender, age, genetic factors, ethnicity, socio-economic status, small families; parental, child and prenatal exposure to ionizing radiation, electromagnetic fields, chemical agents, dusts, fumes, medications, infections, and other events in the medical history of parents and the child (Little 1999, Ries et al. 1999) Occupational and environmental exposures and childhood leukemias Exposures to occupational and environmental hazards may contribute to the risk of leukemia in offspring through different mechanisms: intrauterine and early extrauterine exposure via maternal or paternal route of exposure to toxic compounds. Metabolites of parental exposures have been proposed through transplacental transmission during gestation. Children may be exposed during the postnatal period by take-home exposure through contaminated person or work clothes (Savitz et al. 1990, Ries et al. 1999, Curl et al. 2002, Buffler et al. 2005). Environmental exposures during development and childhood also may place children at higher cancer risk than adults at the same level of exte
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