1 / 44

Non-Hodgkin’s Lymphoma (NHL) and the Agricultural Environment

Non-Hodgkin’s Lymphoma (NHL) and the Agricultural Environment. Kenneth P. Cantor Occupational & Environmental Epidemiology Branch National Cancer Institute cantork@nih.gov. Exploring Environmental Links to Disease: A Look at Parkinson’s Disease & Non-Hodgkin’s Lymphoma

eileen
Download Presentation

Non-Hodgkin’s Lymphoma (NHL) and the Agricultural Environment

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Non-Hodgkin’s Lymphoma (NHL) and the Agricultural Environment Kenneth P. Cantor Occupational & Environmental Epidemiology Branch National Cancer Institute cantork@nih.gov Exploring Environmental Links to Disease: A Look at Parkinson’s Disease & Non-Hodgkin’s Lymphoma Sioux Falls, SD, December 5, 2003

  2. Donald Rumsfeld: • Known knowns • Known unknowns • Unknown unknowns

  3. Temporal & Geographic Patterns of NHL

  4. Non-Hodgkin's lymphoma mortality, 5-year rates whites (1950-94) and blacks (1970-94)

  5. Trends in NHL mortality among US white males, within selected age groups, 1950-59 to 1990-98 Source: Mortality data provided by NCHS (http://www.cdc.gov/nchs)

  6. U.S. SEER, Whites U.S. SEER, Blacks Varese, Italy Sweden 1993-97* Cali, Colombia 1973-77 Osaka, Japan Bombay, India Rates per 100,000 person-years NHL Incidence Rates (Age-Adjusted to World Standard) by Sex, 1993-97 and 1973-77 Source: Cancer Incidence in Five Continents, vols. IV and VIII and Nine SEER Registries

  7. Non-Hodgkin lymphoma mortality rates for white males from 1970-94 by state economic area Mortality Rate: 7.03 (per 100,000) # Deaths: 171,267

  8. Non-Hodgkin lymphoma mortality rates for white females from 1970-94 by state economic area Mortality Rate: 4.76 (per 100,000) # Deaths: 160,172

  9. Multiple myeloma mortality, 5-year rates whites (1950-94) and blacks (1970-94)

  10. NHL: known knowns • Increasing rates over the past 50 years • Risk varies by geographic area: • High in developed world. High in upper midwest & northeast US • Risk higher among males than females • Risk is related to immunedeficiency and/or immunostimulation (immunosuppressent drugs, HIV, autoimmune diseases, genetic conditions) • Risk elevated among certain occupational groups with common exposures: solvents, pesticides, some others

  11. HIGH RISK OCCUPATIONS (from epidemiologic studies) • Farmers • Grain handlers • Rubber industry workers • Refinery workers • Dry cleaning workers • Aircraft maintenance workers

  12. The Agricultural Environment: Pesticides

  13. EVALUATION OF PESTICIDES FOR CARCINOGENICITY IN ANIMALS Of 45 Pesticides reviewed by the International Agency for Research on Cancer (IARC) for carcinogenicity: • 11 (24%) had sufficient evidence • 22 (49%) had limited evidence

  14. ORGANIC PESTICIDES CAUSING CANCER IN ANIMALS ACCORDING TO IARC Pesticide Type Cancer Aldrin I Liver, thyroid Amitrole H Liver, thyroid Chlordane I Liver 2,4,6-Trichlorophenol H Liver DDT I Liver, lung Diallate H Liver, lung, lymphoma Dicol I Liver Dieldrin I Liver Ethylene dibromide I Liver, breast, lung Mirex I Liver, lymphoma Toxaphene I Liver, thyroid I = insecticide; H = herbicide

  15. PESTICIDES WITH LIMITED EVIDENCE FOR CARCINOGENICITY IN ANIMALS ACCORDING TO IARC Aldrin Chlordane Chlorabenzilate Dicofol Dieldrin Heptachlor Calcium Methyl Parathion Tetrachlorvinphos arsenate Lindane Carbaryl Diallate Copper Sodium Chlorothalonil arsenate arsenate Captan Monuron Arsenic acid

  16. Epidemiologic Designs to Study Pesticides: Case-Control Studies • Cases: Patients newly diagnosed with (NHL) in a specified geographic area and time period. • Controls: Healthy individuals matched on age group & sex to cases; Selected randomly from the general population of the study area. • Subjects interviewed directly or by telephone (all characteristics & exposures of interest). • Biologic and/or env’l samples often collected. • Non-Hodgkin’s Lymphoma, Leukemia, Multiple Myeloma, Soft Tissue Sarcoma, Breast, Ovary, Childhood Cancers, Brain, and a few others

  17. ISSUES RAISED ABOUT EPIDEMIOLOGIC STUDIES OF PESTICIDES • Multiple and simultaneous exposures make it difficult to determine what occurred • Inaccuracies in reporting or • Case-bias in reporting • Confounding by other risk factors • Carcinogenic mechanisms for pesticides not well established

  18. RISK OF NHL IN NEBRASKA 2,4-D USERS BY DAYS/YEAR OF APPLICATION (Zahm et al. Epidemiology (1990)) DAYS/YEAR APPLIED CASES/ ODDS CONFIDENCE CONTROLSRATIO INTERVAL Non-farmer 54/184 1.0 1-5 16/44 1.2 0.6-2.4 6-20 12/25 1.6 0.7-3.6 21+ 3/4 3.3 0.5-22.1 P for trend: 0.051

  19. NHL AMONG MALE FARMERS FROM NEBRASKA WHO HANDLED 2,4-D, ADJUSTED FOR OTHER PESTICIDE USE DAYS PER YEAR OF USE EVER1-56-2020+ Unadjusted for other pest. 1.5 1.2 1.6 3.3 Adjusted for: Chlor. Hydrocarbons 1.5 1.3 1.5 2.4 Carbamates 1.4 1.4 1.7 2.0 Organophosphate 1.1 0.9 1.3 1.8 Metals 1.8 1.4 2.3 3.4 Other 1.7 1.2 2.0 3.1 Unknown class 1.8 1.5 2.1 3.8

  20. RISK OF NHL IN NEBRASKA 2,4-D USERS BY TIMING OF CHANGING TO CLEAN CLOTHES AFTER HANDLING PESTICIDES(Zahm et al. Epidemiology (1990)) CASES/ ODDS CONFIDENCE CONTROLSRATIO INTERVAL RIGHT AWAY 6/19 1.1 0.4-3.1 AT ENDOF DAY 31/73 1.5 0.8-2.6 FOLLOWING DAY OR 6/4 4.7 1.1-21.5 LATER

  21. RELATIVE RISKS FOR NON-HODGKIN’S LYMPHOMA MORTALITY BY HERBICIDE USE* IN A COHORT OF SASKATCHAWAN FARMERS(Wigle DT: J. Natl. Cancer Inst. 1990;82:575-582) Acres Sprayed (Farms <1000 Acres) 0 1-99 100-249 250+ Relative Risk 1.0 1.3 1.9 2.2 95% CI 0.7 - 2.4 1.2 - 3.3 1.0-4.6 *75-90% of all herbicides used were 2,4-D BUT OTHER STUDIES, INCLUDING SOME OF OUR OWN, DO NOT SUPPORT AN ASSOCIATION

  22. RISK OF CANINE MALIGNANT LYMPHOMA BY DOG OWNER’S USE OF 2,4-D (Hayes et al. JNCI (1991)) APPLICATIONS CASES/ ODDS PER YEARCONTROLSRATIO None or dog not in yard 300/641 1.0 1 20/34 1.3 2 28/47 1.3 3 11/17 1.3 4+ 17/17 2.0 p for trend: 0.02

  23. NHL and Organophosphate Pesticides(Waddell et al., 2001) Summary from published paper: “Although we found associations [with] several groups and specific organophosphate pesticides, larger risks from proxy respondents complicate interpretation. Associations, however, between … use of diazinon and NHL … among subjects providing direct interviews are not easily discounted.”

  24. RISK OF NHL IN 4 STATES AND USE OF DIAZINON (Waddell et al. Ca Causes Ctl 2001) CASES/ ODDS CONFIDENCE CONTROLSRATIO INTERVAL STATE IA 22/33 1.1 0.6-2.1 KS 1/1 13.0 0.7-230 MN 19/26 1.3 0.4-4.0 NE 16/27 1.4 0.7-2.9 # YRS USED <10 20/40 0.9 0.5-1.7 10-19 10/11 1.8 0.7-4.4 20+ 1/1 1.9 0.1-32 DAYS/YR USED <5 6/11 1.3 0.5-3.9 5+ 6/6 2.4 0.7-8.0

  25. CHROMOSOME BREAKS AMONG APPLICATORS EXPOSED TO HERBICIDES, INSECTICIDES, OR FUMIGANTS(Garry et al. Ca.Epi.Biomark.Prev.(1996)) A ‘translocation’ involving chromosomes 14 & 18 is common in certain types of NHL. Chromosome site Non-Exp. Herb. Ins. Fum. (33) (20) (18) (23) 14q32 (oncogene) 0 0 5* 6* 18q21 (oncogene) 0 7* 0 2

  26. t(14;18) chromosomal translocation & NHL • In a study of NHL, excess risk was found for several pesticides (dieldrin, toxaphene, lindane, atrazine) among patients with t(14;18), but not among t(14;18) negative patients. (Schroeder et al. Epidemiology (2001) 12:701-9)

  27. FACTORS THAT SUPPORT A CAUSAL INFERENCE FROM EPIDEMIOLOGIC STUDIES • A strong association • Dose-response relationship • Can not be explained by other exposures • Similar findings in different populations under various conditions • Concordance of evidence within a study • Experimental support / finding makes biologic & mechanistic sense

  28. SOME PESTICIDES LINKED WITH NHL IN ONE OR MORE STUDIES Pesticide Study Location Aldrin Duffie (2001) Canada (6 Provinces) Atrazine DeRoos (2003) IA/MN/KS/NE Chlordane Cantor (1992) IA/MN Carbaryl “ “ DDT Duffie (1992) Canada “ Cantor (1992) IA/MN Diazinon Waddell (2001) IA/MN/KS/NE “ Duffie (2001) Canada Dicamba “ “ Lindane “ “ Malathion “ “ “ Cantor (1992) IA/MN 2,4-D Zahm (1986) Kansas “ Duffie (2001) Canada “ (?) Wigle (1990) Saskatchawan

  29. SUMMARY • Pesticides can be studied epidemiologically. • Experimental and epidemiologic data indicate that pesticides may pose a risk of non-Hodgkin’s lymphoma and other cancers. • The evidence to date points to some specific pesticides, but uncertainties remain. • Exposure assessment is crucial

  30. Agricultural Health Study(NCI/NIEHS/EPA)A cohort study [www.aghealth.org]

  31. Epidemiologic Designs to Study Pesticides: Cohort Studies • Subjects enter the cohort & are followed over time for disease occurrence. Individual information is recorded at entry & often at later intervals. • Farmers & Other Agricultural Applicators, Commercial Applicators, Pesticide Manufacturers, Grain Workers, Forest Workers

  32. Build the Cohort Exposure Assessment & Community Support Validate Exposure Cancer Etiology Disease Mechanism Passive Follow-up Agricultural Health Study-Timeline Phase V and Beyond Phase I Phase II Phase III Phase IV 1993 1997 2004 2008 2012 2020

  33. Agricultural Health StudyObjectives • Create a prospective cohort of farmers and their spouses to evaluate health issues for a rural population. • Collect exposure information prior to onset of cancer (pesticides, other farm & occ’l exposures, diet, smoking, family medical history, other). • Update information every five years. • Collect biologic material for gene and gene-environment analyses. • Monitor a sample of farm families for pesticide exposures. Occupational & Env’l Epidemiology Branch National Cancer Institute

  34. Agricultural Health StudyDesign & Status • Prospective cohort study of three groups (89,658 persons) • private pesticide applicators (52,395) • spouses of pesticide applicators (32,347) • commercial pesticide applicators (4,916) • Questionnaires completed at enrollment and subsequently [www.aghealth.org] • Cohort is linked annually to the National Death Index and state Cancer Registries • 97% of applicators personally apply pesticides; 50% of spouses also apply. Occupational & Env’l Epidemiology Branch National Cancer Institute

  35. Agricultural Health Study: HIGH USE PESTICIDES IN IOWA (1993 or 1994) Pesticide Type % Using last year 2,4-D H 35.3 Glyphosphate H 33.6 Imazethapyr H 32.1 Atrazine H 29.9 Dicamba H 22.4 Metolachlor H 19.6 Trifluralin H 18.6 Chlorpyrifos I 13.6 Cyanazine H 13.0 Terbufos I 13.0 Alachlor H 9.9 Permethrin (Animal) I 5.4 H=Herbicide; I=Insecticide I = insecticide; H = herbicide

  36. All cancers 4,500 Prostate 1,600 Digestive system 900 Respiratory system 610 Urinary system 273 Melanoma 220 Non-Hodgkin’s lymphoma 168 Leukemia 134 Buccal cavity 120 Ovarian 85 Thyroid and other endocrine 85 Brain and CNS 84 Multiple myeloma 76 Hodgkin’s lymphoma 40 Expected Cancer Incidence (2006) in Agricultural Health Study Cohort 2006: approximately 1 million person-years of follow-up

  37. Cancer Cohort Analysis: Prostate CA(1st to be evaluated) • Evaluate all pesticides • Dose-response analyses • Controlled for age, family history, smoking, other occupational exposures • Look for consistency (state, license type) • Sufficient numbers for cancer of focus

  38. Relative Risk (95 % CI) for Methyl Bromide and Incident Prostate Cancer Logistic regression adjusted for: Age, family history of prostate cancer Alavanja MCR, et al. Prostate Cancer incidence in the AHS Cohort. American Journal of Epidemiology 1993; 157:800-814.

  39. Plan For Cancer Etiology: Near Future(2004-2005) • Pesticide cohort analyses Alachlor Carbofuran Atrazine Carbaryl Chlorpyrifos Triazine herbicides Glyphosate 2,4D Pendimetalin Chlorinated pesticides • Cancer cohort analysis Prostate Melanoma Breast Ovarian Lung Multiple myeloma Colon Leukemia NHL

  40. The Agricultural Environment: Nitrate in Drinking Water

  41. NITRATE IN DRINKING WATER: REASONS FOR CONCERN • Levels are high and increasing in ground water of many agricultural regions. • Nitrate nitrite in the saliva. • Nitrite interacts with secondary amines & amides to form N-nitroso compounds (Vitamin C inhibits formation). • Most N-nitroso compounds are carcinogens in animal tests.

  42. RISK OF NHL IN NEBRASKA AND NITRATE IN PUBLIC WATER SUPPLIES NITRATE ODDS CONFIDENCE LEVEL RATIO INTERVAL (mg/L) <1.6 1.0 referent 1.6-<2.0 1.4 0.8-2.5 2.0-<4.0 1.5 0.7-3.0 4.0+ 2.0 1.1-3.6 Ward et al. Epidemiology 1996; 7: 465-71.

  43. NITRATE IN DRINKING WATER: LIMITED FINDINGS NHL: 1 OF 2 STUDIES POSITIVE. OTHER STUDY IN LOWER EXPOSURE AREA. BLADDER CANCER: 2 STUDIES FROM SAME REGION (IOWA) ARE CONFLICTING. COLON CANCER: OVERALL, NO EXCESS RISK. HIGH RISK IN SUBGROUP WITH HIGH NITRATE & LOW VITAMIN C CONSUMPTION. PANCREAS CANCER: NO ASSOCIATION FOUND.

More Related