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Do pesticides cause cancer ?

Michael Alavanja, Dr.P.H. Captain, USPHS Senior Investigator, Division of Cancer Epidemiology and Genetics, NCI 2007 North American Pesticide Applicator Certification & Safety Education Workshop August 20-23, 2007 Portland, Maine.

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Do pesticides cause cancer ?

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  1. Michael Alavanja, Dr.P.H.Captain, USPHSSenior Investigator, Division of Cancer Epidemiology and Genetics, NCI2007 North American Pesticide ApplicatorCertification &Safety Education WorkshopAugust 20-23, 2007Portland, Maine

  2. Agricultural Health Study on Cancer Findings. Session II: Major Cancer ObservationsTuesday, August 21Breakout Session #2

  3. Do pesticides cause cancer ? • Few strong and consistent associations linking a single chemical to a single cancer. • Animal/laboratory studies show most pesticides in current use to be non-genotoxic. • Exposure assessment in previous epidemiologic studies was general weak, they were based on interviews and could suffer from case recall bias. • Studies of pesticide manufactures are generally too small to give meaningful results for cancer • Exposures among the general population in developed countries are relative low and effect hard to measure. • In summary: Neither animal studies nor human studies give a compelling case for an association.

  4. Design AHS(www.aghealth.org) • Prospective cohort study of 89,658 pesticide applicators & spouses (IA and NC). • 82% of target population enrolled 1993-1997. • Little loss to follow-up (<2%). • Cancer incidence and mortality updated annually. • Comprehensive exposure assessment information on 82 pesticides collected at three points in time. • Questionnaire exposure assessment evaluated with field measurements of pesticides. • Buccal cells collected on >35,000 study subjects.

  5. Evaluating the association between estimated exposures with health effects. (Cancer Etiology Studies in the AHS)

  6. Effect • End point of a causal mechanism. • Amount of change in a population’s disease frequency caused by a specific factor. • Incident rate: Number of new cases of disease in a specified period of time. • Absolute effect: I1 – I0 • Relative Effect: I1 / I0

  7. Confounding factors • A confounding factor must be a risk factor for the disease. • A confounding factor must be associated with the exposure under study in the source population (the population from which the cases are derived). • A confounding factor must not be effected by the exposure or the disease. In particular, it cannot be an intermediate step in the causal path between the exposure and the disease. • How do we control confounding? Collect quantitative information on the exposure to the confounder and add the term to the multivariate model: y=b0 + b1x1 + b2 x2

  8. Statistical Interaction-Effect Modification • An effect-modifier is an exposure or host factor that modulates the extent of the effect of the study variable on the disease under investigation. • If a cohort is divided into two or more distinct categories defined by the level of an effect modifier the stratum-specific effect measures may or may not be equal. If they are equal there is no effect modification. If they are significantly different there is effect modification. • How do measure effect modification? Collect quantitative information on the exposure thought to be an effect modifier and add the product term to the multivariate model: y=b0 + b1x1 + b2 x2 + b 3 x1 x2

  9. Typical Sequence of Cancer Etiology Studies in AHS [2003-2007] • SIR analysis (generates general hypothesis) [n=1] • Nested case-control study of specific cancers (generate specific hypotheses [n=6]) • 1 ST COHORT ANALYSIS of specific pesticide (generates or refines specific hypotheses [n=21]) • 2ND COHORT ANALYSIS: (Test Specific Hypotheses [n=1 in progress]) • Molecular epidemiology studies of cancer (Evaluates biological plausibility and mode of action [n=3 in progress])

  10. AHS Research Strategy:Mitigate False Positive Results Biological Initial Replication Evidence in Findings later in time Humans Iowa North Carolina License Type Exposure- Response Exposure- Response Exposure- Response Exposure- Response Exposure- Response Exposure- Response YES YES YES

  11. Mitigate False-Positive Associations and Study Rare Diseases Agricultural Health Cohort Consortium. (NCI organized)

  12. Lung Cancer Excess Observed in AHS Standardized Incidence Ratio (SIR) for private applicators • Overall cancer SIR = 0.87 (95% CI: 0.84-0.91) • Lung cancer SIR = 0.47 (95%CI: 0.4-0.5) (Alavanja et al., SJWE.2005;31:39-45)

  13. Pesticides Associated with Elevated Lung Cancer Risk in Nested Case-Control Study.(Alavanja et al., Am J Epidemiol 2004;160:876-885) • N=240 incident lung cancer cases • Diazinon (OR=1.0, 0.9, 1.4, 2.7 p trend=0.008) • Chlorpyrifos (OR=1.0, 0.9, 1.0, 1.7, 1.7 p trend=0.02) • Carbofuran (OR=1.0, 0.7, 1.1, 1.6 p trend=0.08) • Metolachlor (OR=1.0, 0.6, 0.9, 4.1 p trend=0.015) • Dieldrin (OR=1.0, 1.4, 2.2, 5.3 p trend=0.005)

  14. Pesticides Associated with Elevated Lung Cancer Risk in First Round Cohort Analyses. • Chlorpyrifos (OR=1.0, 0.8, 1.6, 1.4, 2.2 p trend=0.002) • (Lee et al., JNCI, 2004;96:1781-1791) • Diazinon (OR=1.0, 1.0, 0.6, 1.8, 3.5 p trend=0.001) • (Beane-Freeman et al., AJE, 2005;162:1070-1079) • Carbofuran (OR=1.0, 2.4, 1.6, 3.4 p trend=0.23) • (Bonner et al., EHP, 2005; 113:285-289) • Metolachlor (OR=1.0, 1.2, 1.2, 2.4 p trend=0.03) • (Rusiecki et al., Int J Cancer 2006;118:3118-3123)

  15. Lung Cancer Risk in AHS. • Lung cancer risk significantly lower in AHS cohort than that of populations of Iowa and North Carolina due to lower smoking rates. • Several widely used insecticides and herbicides associated with lung cancer risk, these associations not due to smoking or other know lung cancer risk factors. • Reevaluation of these pesticides in 2nd cohort analyses necessary before final conclusions can be made (i.e., 2008).

  16. Prostate Cancer in AHS:Comprehensive Sequence of Studies • N=1450 incident cases (2007). • Buccal cells available from 1,000 cases.

  17. Prostate Cancer Excess Observed in AHS Standardized Incidence Ratio (SIR) • Overall cancer SIR = 0.87 (95% CI: 0.84-0.91) • Prostate cancer SIR = 1.24 (95%CI: 1.2-1.3) (Alavanja et al., SJWE.2005;31:39-45.)

  18. Nested Case-Control study of Prostate Cancer (PC) (2003)(Alavanja et al., AJE, 2003:157:800-814)

  19. Fonofos and Prostate Cancer (PC) (2006)Pesticide Specific Cohort Analysis(Mahajan et al, EHP,2006,114:1833-1842)

  20. Phorate and Prostate Cancer (PC) (2006)Pesticide Specific Cohort Analysis(Mahajan et al., 2006;114:1205-1209)

  21. Butylate and Prostate Cancer (PC) (2006)Pesticide Specific Cohort Analysis(Lynch et al, In preparation)

  22. Pesticide Specific Cohort Analyses • Coumaphos (Analysis in progress) • Chlorpyrifos (Analysis in progress) • Permethrin (Analysis in progress)

  23. Prostate Cancer in AHS: Recommendation of Expert Panel • Expert panel of Extramural/Intramural Investigators(2005): recommends AHS proceeds to molecular epidemiology phase Immediately.

  24. Molecular Epidemiology of Prostate Cancer & Pesticides(Nested Case-Control Study) Biological Plausibility/Mode of Action • Genetic susceptibility • Telomere shortening • Aberrant methylation patterns

  25. Molecular Epidemiology of Prostate Cancer & Pesticides(Nested Case-Control Study) Genetic susceptibility • CGEMS and BPC3 • Metabolic pathway • DNA repair pathway • Hormone regulatory pathway

  26. Excretion GST Candidate Genes from Pesticide Toxicology Literature Metabolic Genes • Xenobiotic substances undergo a series of chemical reactions in order to be eliminated • Phase I and Phase II enzymes catalyze these reaction • Example — Chlorpyrifos metabolism

  27. oxon detox detox GSTM1+ Candidate Genes (e.g., chlorpyrifos)

  28. Epigenetics - Definitions Heritable changes in gene expression that cannot be tied to genetic variation (2006) • Gene-expression states that can be transmitted through cell divisions • Gene-expression modifications that can persist in the absence of the conditions that established them (Richards, Nat Gen 2006)

  29. Epigenetic Mechanisms • DNA Methylation • Histone Modifications • Lysine Acetylation • Lysine and Arginine Methylation • Serine Phosphorylation • Other Chromatine Remodeling Mechanisms (e.g. ATP-Hydrolases)

  30. DNA Methylation

  31. DNA Methylation Modifiers • Aging (cell, individual) • Micronutrients (folate deficiency) • Chemotherapy • Inflammation • Environmental Pollutants

  32. Prostate Cancer Risk in AHS. • Prostate cancer (PC) risk significantly elevated in both Iowa and North Carolina. • PC risk significantly elevated in both private and commercial applicators. • Family history of PC doubles the risk prostate cancer. • Significant interaction between family history PC X pesticide exposure. • Common exposure history or genetic susceptibility may explain results • Prolonged use of Atrazine not associated with PC risk.

  33. Other Cancers Preliminarily Associated with Pesticide Exposures • Melanoma-Carbaryl (Mahajan, et al., IJC, In press) • Colo-Rectal Cancer- Chlorpyrifos (Lee et al., IJC, In press) • Multiple Myeloma – Permethrin (Rusiecki et al., In Preparation)

  34. Agricultural Health StudyCancer Risks from Glyphosate Exposure Tertiles for Exposure Days P for Cancer 1st2nd3rdTrend All cancer 1.0 1.0 1.0 0.57 Colon 1.0 1.4 0.9 0.54 Lung 1.0 0.9 0.7 0.21 Prostate 1.0 0.9 1.1 0.69 NHL 1.0 0.7 0.9 0.73 Myeloma 1.0 1.1 1.9 0.27 From: De Roos et al. Environ Health Perspect 113:49-54, 2005

  35. Influence of pesticide research on public health policy

  36. AHS Research Strategy:Mitigate False Positive Results Biological Initial Replication Evidence in Findings later in time Humans Iowa North Carolina License Type Exposure- Response Exposure- Response Exposure- Response Exposure- Response Exposure- Response Exposure- Response YES YES YES

  37. Pesticides preliminarily identified as possible human carcinogens (2003-2007) • Chlorpyrifos (Alavanja et al., AJE,2004;160:876-855) • Coumaphos (Alavanja et al., AJE,2003:157,876-885) • Permethrin (Alavanja et al.,AJE,2003;157,876-885) • Diazinon (Beane-Freeman et al., AJE, 2005; 162:1070-1079) • Carbofuran (Bonner et al., EHP, 2005; 113:285-289) • Pendimethalin (Hou et al.,Epidemiology,2006;17:1-6) • Alachlor (Lee et al., AJE;159:373-380) • Butylate (Lynch et al., In Review) • Fonofos (Mahajan et al.,EHP,2006,114:1838-1842) • Phorate (Mahajan et al,EHP,2006,114:1205-1209) • Carbaryl (Mahajan, et al., IJC, In press) • Paraquat (Park et al., In Review) • Trifluralin (Kang et al., In Review) • Lindane (Purdue et al., IJC,2007:120:642-649) • Metolachlor (Rusiecki et al., IJC,2006;114:xxx) • Dicamba (Samanic et al.,EHP,114:1521-1526)

  38. Where Are We Going 2007-2010? • Determine the reason we have a significant excess of Multiple Myeloma in the AHS cohort (37%) • examine pyrethrin, atrazine and glyphosate. • MGUS cross-sectional study • Determine the reasons for the diminished risk of breast cancer among spouses who apply pesticides • Determine mechanism responsible for excess prostate cancer in the AHS cohort. • Nested case-control study of Lymphomas • Molecular components (t14:18 translocations)

  39. Where Are We Going 2007-2010? • Re-evaluate/confirm results for 12 pesticides significantly associated with cancer risk • Do acute exposures (HPEE) result in increased cancer risk? • Selected molecular epidemiology studies to better understand biological mode of action. • Role of endotoxin, sunlight and physical activity in cancer risk. • Childhood cancer in the AHS (2nd generation cohort).

  40. Regulatory Implications of AHS Findings • 2007-2008: Reevaluation of chlorpyrifos, alachlor, atrazine, carbofuran, and glyphosate will be completed. • Regulatory action may be required. • Only limited biological evidence from AHS will be available. • 2009: Reevaluation of diazinon, fonofos, paraquat, metolachlor 2,4-D, and trifluralin. • More biological evidence from AHS will be available. • Some regulatory action probably necessary. • 2010-2012: Comprehensive evaluation of between 30-40 pesticides for human carcinogenicity available from AHS. • Substantial regulatory action probably necessary

  41. Regulatory Implications of AHS Findings • International Agency for Research on Cancer. • International recommendations • United States Environmental Protection Agency • Educating pesticide applicators • Label instructions • Limitations of use • Banning use

  42. Thank you for listening. You are invited to participate!: AHS Research Team

  43. Agricultural Health StudyCollaborators Collaborating Institutions • National Cancer Institute • National Institute of Environmental Health Sciences • US Environmental Protection Agency • National Institute for Occupational Safety and Health • Extramural Collaborators (i.e., Universities and Research Institutes) Field Team • University of Iowa • Battelle Centers for Public Health Research and Evaluation • Westat

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