Non-Hodgkin’s Lymphoma (NHL) and the Agricultural Environment Exploring Environmental Links to...
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Non-Hodgkin’s Lymphoma (NHL) and the Non-Hodgkin’s Lymphoma (NHL) and the Agricultural EnvironmentAgricultural Environment
Exploring Environmental Links to Disease: A Look at Parkinson’s Disease & Non-Hodgkin’s LymphomaSioux Falls, SD, December 5, 2003
Kenneth P. CantorOccupational & Environmental Epidemiology
BranchNational Cancer Institute
Known knownsKnown unknownsUnknown unknowns
Donald Rumsfeld:
Temporal & Temporal & Geographic Patterns of Geographic Patterns of
NHLNHL
0
1
2
3
4
5
6
7
8
9
50 55 60 65 70 75 80 85 90
WM WFBM BF
Non-Hodgkin's lymphoma mortality, 5-year rateswhites (1950-94) and blacks (1970-94)
Trends in NHL mortality among Trends in NHL mortality among US white males, within selected US white males, within selected age groups, 1950-59 to 1990-98age groups, 1950-59 to 1990-98
1
10
100
1950s 1960s 1970s 1980s 1990s
Year of death
Rat
es p
er 1
00,0
00 p
erso
n-ye
ars
Age 80-84Age 70-74Age 60-64Age 50-54Age 40-44Age 30-34
Source: Mortality data provided by NCHS (http://www.cdc.gov/nchs)
NHL Incidence Rates (Age-Adjusted to NHL Incidence Rates (Age-Adjusted to World Standard) by Sex, 1993-97 and World Standard) by Sex, 1993-97 and
1973-771973-77
Source: Cancer Incidence in Five Continents, vols. IV and VIII and Nine SEER Registries
Rates per 100,000 person-years
Males
3.2
3.8
6.0
6.3
7.1
6.0
9.1
4.5
6.3
7.3
10.1
13.2
15.4
16.8
024681012141618
Females
1.7
1.9
2.8
4.3
5.1
3.9
6.9
3.3
3.6
6.0
6.9
9.6
7.3
10.6
0 2 4 6 8 10 12 14 16 18
1993-97*
1973-77
U.S. SEER, Whites
U.S. SEER, Blacks
Varese, Italy
Sweden
Cali, Colombia
Osaka, Japan
Bombay, India
Non-Hodgkin lymphoma mortality Non-Hodgkin lymphoma mortality rates for white males from 1970-rates for white males from 1970-94 by state economic area94 by state economic area
Mortality Rate: 7.03(per 100,000)
# Deaths: 171,267
Non-Hodgkin lymphoma mortality Non-Hodgkin lymphoma mortality rates for white females from 1970-rates for white females from 1970-94 by state economic area94 by state economic area
Mortality Rate: 4.76(per 100,000)
# Deaths: 160,172
0
1
2
3
4
5
6
7
8
50 55 60 65 70 75 80 85 90
WM WFBM BF
Multiple myeloma mortality, 5-year rateswhites (1950-94) and blacks (1970-94)
NHL: known knowns 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
HIGH RISK OCCUPATIONS (from HIGH RISK OCCUPATIONS (from epidemiologic studies)epidemiologic studies)
• Farmers
• Grain handlers
• Rubber industry workers
• Refinery workers
• Dry cleaning workers
• Aircraft maintenance workers
The Agricultural The Agricultural Environment: PesticidesEnvironment: Pesticides
EVALUATION OF PESTICIDES FOR EVALUATION OF PESTICIDES FOR CARCINOGENICITY IN ANIMALSCARCINOGENICITY 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
ORGANIC PESTICIDES CAUSING CANCER IN ANIMALS ACCORDING TO IARC
Pesticide Type Cancer Aldrin I Liver, thyroidAmitrole H Liver, thyroidChlordane I Liver2,4,6-Trichlorophenol H LiverDDT I Liver, lungDiallate H Liver, lung, lymphomaDicol I LiverDieldrin I LiverEthylene dibromide I Liver, breast, lungMirex I Liver, lymphomaToxaphene I Liver, thyroid
I = insecticide; H = herbicide
PESTICIDES WITH LIMITED EVIDENCE FOR PESTICIDES WITH LIMITED EVIDENCE FOR CARCINOGENICITY IN ANIMALS ACCORDING TO CARCINOGENICITY IN ANIMALS ACCORDING TO IARCIARC
Aldrin Chlordane Chlorabenzilate
Dicofol Dieldrin Heptachlor
Calcium Methyl Parathion Tetrachlorvinphos arsenateLindane Carbaryl Diallate
Copper Sodium Chlorothalonil arsenate arsenateCaptan Monuron Arsenic acid
Epidemiologic Designs to Study Pesticides: Epidemiologic Designs to Study Pesticides: Case-Control StudiesCase-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
ISSUES RAISED ABOUT EPIDEMIOLOGIC ISSUES RAISED ABOUT EPIDEMIOLOGIC STUDIES OF PESTICIDESSTUDIES 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
RISK OF NHL IN NEBRASKA 2,4-D USERS RISK OF NHL IN NEBRASKA 2,4-D USERS BY DAYS/YEAR OF APPLICATION BY DAYS/YEAR OF APPLICATION (Zahm et al. Epidemiology (1990))(Zahm et al. Epidemiology (1990))
CASES/ ODDS CONFIDENCECONTROLS RATIO INTERVAL
Non-farmer 54/184 1.01-5 16/44 1.2 0.6-2.46-20 12/25 1.6 0.7-3.621+ 3/4 3.3 0.5-22.1
P for trend: 0.051
DAYS/YEARAPPLIED
NHL AMONG MALE FARMERS FROM NHL AMONG MALE FARMERS FROM NEBRASKA WHO HANDLED 2,4-D, ADJUSTED NEBRASKA WHO HANDLED 2,4-D, ADJUSTED FOR OTHER PESTICIDE USEFOR OTHER PESTICIDE USE
DAYS PER YEAR OF USE EVER 1-5 6-20 20+
Unadjusted for other pest. 1.5 1.2 1.6 3.3 Adjusted for:
Chlor. Hydrocarbons 1.5 1.3 1.5 2.4Carbamates 1.4 1.4 1.7 2.0Organophosphate 1.1 0.9 1.3 1.8Metals 1.8 1.4 2.3 3.4Other 1.7 1.2 2.0 3.1Unknown class 1.8 1.5 2.1 3.8
RISK OF NHL IN NEBRASKA 2,4-D USERS RISK OF NHL IN NEBRASKA 2,4-D USERS BY TIMING OF CHANGING TO CLEAN BY TIMING OF CHANGING TO CLEAN CLOTHES AFTER HANDLING PESTICIDESCLOTHES AFTER HANDLING PESTICIDES (Zahm et al. Epidemiology (1990))(Zahm et al. Epidemiology (1990))
CASES/ ODDS CONFIDENCECONTROLS RATIO INTERVAL
RIGHT AWAY 6/19 1.1 0.4-3.1
AT END OF DAY 31/73 1.5 0.8-2.6
FOLLOWING DAY OR 6/4 4.7 1.1-21.5LATER
RELATIVE RISKS FOR NON-HODGKIN’S LYMPHOMA RELATIVE RISKS FOR NON-HODGKIN’S LYMPHOMA MORTALITY BY HERBICIDE USE* IN A COHORT OF MORTALITY BY HERBICIDE USE* IN A COHORT OF SASKATCHAWAN FARMERSSASKATCHAWAN FARMERS(Wigle DT: J. Natl. Cancer Inst. 1990;82:575-582)(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
RISK OF CANINE MALIGNANT LYMPHOMA RISK OF CANINE MALIGNANT LYMPHOMA BY DOG OWNER’S USE OF 2,4-D BY DOG OWNER’S USE OF 2,4-D (Hayes et al. JNCI (1991))(Hayes et al. JNCI (1991))
APPLICATIONS CASES/ ODDS PER YEAR CONTROLS RATIO
None or dog not in yard 300/641 1.0 1 20/34 1.3
2 28/47 1.33 11/17 1.3
4+ 17/17 2.0
p for trend: 0.02
NHL and Organophosphate PesticidesNHL and Organophosphate Pesticides(Waddell et al., 2001)(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.”
RISK OF NHL IN 4 STATES AND USE OF RISK OF NHL IN 4 STATES AND USE OF DIAZINON DIAZINON (Waddell et al. Ca Causes Ctl 2001)(Waddell et al. Ca Causes Ctl 2001)
CASES/ ODDS CONFIDENCECONTROLS RATIO 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 0.1-32DAYS/YR USED <5 6/11 1.3 0.5-3.9 5+ 6/6 2.4 0.7-8.0
CHROMOSOME BREAKS AMONG CHROMOSOME BREAKS AMONG APPLICATORS EXPOSED TO HERBICIDES, APPLICATORS EXPOSED TO HERBICIDES, INSECTICIDES, OR FUMIGANTSINSECTICIDES, OR FUMIGANTS(Garry et al. Ca.Epi.Biomark.Prev.(1996))(Garry et al. Ca.Epi.Biomark.Prev.(1996))
Chromosome site Non-Exp. Herb. Ins. Fum. (33) (20) (18) (23)
14q32 (oncogene) 0 0 5* 6*
18q21 (oncogene) 0 7* 0 2
A ‘translocation’ involving chromosomes 14 & 18 is common in certain types of NHL.
t(14;18) chromosomal t(14;18) chromosomal translocation & NHLtranslocation & 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)
FACTORS THAT SUPPORT A CAUSAL FACTORS THAT SUPPORT A CAUSAL INFERENCE FROM EPIDEMIOLOGIC INFERENCE FROM EPIDEMIOLOGIC STUDIESSTUDIES
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
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/NEChlordane Cantor (1992) IA/MNCarbaryl “ “DDT Duffie (1992) Canada “ Cantor (1992) IA/MNDiazinon Waddell (2001) IA/MN/KS/NE “ Duffie (2001) CanadaDicamba “ “Lindane “ “Malathion “ “ “ Cantor (1992) IA/MN2,4-D Zahm (1986) Kansas “ Duffie (2001) Canada “ (?) Wigle (1990) Saskatchawan
SUMMARYSUMMARY
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
Agricultural Health StudyAgricultural Health Study(NCI/NIEHS/EPA)(NCI/NIEHS/EPA)
A cohort study A cohort study [www.aghealth.org][www.aghealth.org]
Epidemiologic Designs to Study Pesticides: Epidemiologic Designs to Study Pesticides: Cohort StudiesCohort 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
Phase III
Agricultural Health Study-Timeline
Phase I Phase IV Phase V and Beyond
Phase II
Build the Cohort
Exposure Assessment & Community Support
Validate Exposure
Disease Mechanism
Passive Follow-up
CancerEtiology
1993 1997 2004 2008 2012 2020
Agricultural Health StudyAgricultural Health StudyObjectivesObjectives
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 BranchNational Cancer Institute
Agricultural Health StudyAgricultural Health StudyDesign & StatusDesign & 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 BranchNational Cancer Institute
Agricultural Health Study: HIGH USE PESTICIDES IN IOWA
(1993 or 1994)
Pesticide Type % Using last year 2,4-D H 35.3Glyphosphate H 33.6Imazethapyr H 32.1Atrazine H 29.9Dicamba H 22.4Metolachlor H 19.6Trifluralin H 18.6Chlorpyrifos I 13.6Cyanazine H 13.0Terbufos I 13.0Alachlor H 9.9Permethrin (Animal) I 5.4
H=Herbicide; I=Insecticide
I = insecticide; H = herbicide
Expected Cancer Incidence (2006) in Expected Cancer Incidence (2006) in Agricultural Health Study CohortAgricultural Health Study Cohort
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
2006: approximately 1 million person-years of follow-up
Cancer Cohort Analysis: Cancer Cohort Analysis: Prostate CAProstate CA(1(1stst to be evaluated) 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
Relative Risk (95 % CI) for Methyl Relative Risk (95 % CI) for Methyl Bromide and Incident Prostate Bromide and Incident Prostate CancerCancer
Reference group
(No exposure
)
Exposure Group(cumulative exposure score)
Linear trend
(p value)
I1/3
II1/3
III1/6
IV1/12
V1/12
Odds ratio (95%CI)
1.01.0
(0.7-1.6)
0.8 (0.5-1.3)
0.7(0.4-1.3)
2.7(1.2-6.3)
3.5(1.4-8.8) 0.008
Exposedcases 482 23 22 11 6 5
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.
Plan For Cancer Etiology:Plan For Cancer Etiology: Near Future(2004-2005) Near Future(2004-2005)
Pesticide cohort analysesAlachlor CarbofuranAtrazine CarbarylChlorpyrifos Triazine herbicidesGlyphosate 2,4D Pendimetalin Chlorinated
pesticides
Cancer cohort analysisProstate MelanomaBreast OvarianLung Multiple myelomaColon LeukemiaNHL
The Agricultural The Agricultural Environment: Nitrate in Environment: Nitrate in
Drinking WaterDrinking Water
NITRATE IN DRINKING WATER: NITRATE IN DRINKING WATER: REASONS FOR CONCERN 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.
RISK OF NHL IN NEBRASKA AND NITRATE RISK OF NHL IN NEBRASKA AND NITRATE IN PUBLIC WATER SUPPLIES IN PUBLIC WATER SUPPLIES
NITRATE ODDS CONFIDENCELEVEL 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.
NITRATE IN DRINKING WATER: NITRATE IN DRINKING WATER: LIMITED FINDINGSLIMITED 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.