Non Hodgkin’s Lymphoma (NHL) and the Agricultural Environment Kenneth P. Cantor Occupational & Environmental Epidemiology Branch National Cancer Institute [email protected]

Exploring Environmental Links to Disease: A Look at Parkinson’s Disease & Non-Hodgkin’s Lymphoma Sioux Falls, SD, December 5, 2003

Donald Rumsfeld:



Known knowns



Known unknowns



Unknown unknowns

Temporal & Geographic Patterns of NHL

1 0 4 3 2 9 8 7 6 5 50 Non-Hodgkin's lymphoma mortality, 5-year rates whites (1950-94) and blacks (1970-94) WM BM WF BF 55 60 65 70 75 80 85 90

Trends in NHL mortality among US white males, within selected age groups, 1950-59 to 1990-98

100 10 Age 80-84 Age 70-74 Age 60-64 Age 50-54 Age 40-44 Age 30-34 Source: Mortality data provided by NCHS (http://www.cdc.gov/nchs) 1 1950s 1960s 1970s 1980s Year of death 1990s

NHL Incidence Rates (Age-Adjusted to World Standard) by Sex, 1993-97 and 1973-77

16.8

18

15.4

16

13.2

14 12

10.1

9.1

10

Males

U.S. SEER, Whites

7.1

6.0

U.S. SEER, Blacks Varese, Italy Sweden

3.9

6.3

7.3

6.0

6.3

4.5

3.8

3.2

8 6 4 Cali, Colombia Osaka, Japan Bombay, India 2 0 0 2 Rates per 100,000 person-years

1.9

2.8

3.6

3.3

1.7

4

4.3

5.1

6

6.0

6.9

7.3

6.9

8

Females 9.6

10

10.6

12 1993-97* 1973-77 14 16 18 Source: Cancer Incidence in Five Continents Registries , vols. IV and VIII and Nine SEER

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

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

2 1 0 8 7 6 5 4 3 50 WM BM Multiple myeloma mortality, 5-year rates whites (1950-94) and blacks (1970-94) WF BF 55 60 65 70 75 80 85 90

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 epidemiologic studies)

• • • • • •

Farmers Grain handlers Rubber industry workers Refinery workers Dry cleaning workers Aircraft maintenance workers

The Agricultural Environment: Pesticides

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

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

PESTICIDES WITH LIMITED EVIDENCE FOR CARCINOGENICITY IN ANIMALS ACCORDING TO IARC

Aldrin Dicofol Calcium arsenate Lindane Copper arsenate Captan Chlordane Dieldrin Methyl Parathion Carbaryl Sodium arsenate Monuron Chlorabenzilate Heptachlor Tetrachlorvinphos Diallate Chlorothalonil Arsenic acid

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

ISSUES RAISED ABOUT EPIDEMIOLOGIC STUDIES OF PESTICIDES



Multiple and simultaneous exposures make it difficult to determine what occurred

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Inaccuracies in reporting or



Case-bias in reporting

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Confounding by other risk factors

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Carcinogenic mechanisms for pesticides not well established

RISK OF NHL IN NEBRASKA 2,4-D USERS BY DAYS/YEAR OF APPLICATION (Zahm et al. Epidemiology (1990)) DAYS/YEAR APPLIED Non-farmer 1-5 6-20 21+ CASES/ ODDS CONTROLS RATIO CONFIDENCE INTERVAL 54/184 16/44 12/25 1.0

1.2

1.6

0.6-2.4

0.7-3.6

3/4 3.3 0.5-22.1

P for trend: 0.051

NHL AMONG MALE FARMERS FROM NEBRASKA WHO HANDLED 2,4-D, ADJUSTED FOR OTHER PESTICIDE USE Unadjusted for other pest. Adjusted for: Chlor. Hydrocarbons Carbamates Organophosphate Metals Other Unknown class DAYS PER YEAR OF USE EVER 1-5 6-20 20+ 1.5

1.2

1.6 3.3

1.5

1.4

1.1

1.8

1.7

1.8

1.3

1.4

0.9

1.5 2.4

1.7 2.0

1.3 1.8

1.4 2.3 3.4

1.2 2.0 3.1

1.5 2.1 3.8

RISK OF NHL IN NEBRASKA 2,4-D USERS BY TIMING OF CHANGING TO CLEAN CLOTHES AFTER HANDLING PESTICIDES (Zahm et al. Epidemiology (1990)) RIGHT AWAY AT END OF DAY CASES/ ODDS CONTROLS RATIO CONFIDENCE INTERVAL 6/19 31/73 1.1

1.5

FOLLOWING DAY OR 6/4 4.7

LATER 0.4-3.1

0.8-2.6

1.1-21.5

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) Relative Risk 95% CI 0 1.0

1-99 1.3

0.7 - 2.4

100-249 1.9

1.2 - 3.3

*75-90% of all herbicides used were 2,4-D 250+ 2.2

1.0-4.6

BUT OTHER STUDIES, INCLUDING SOME OF OUR OWN, DO NOT SUPPORT AN ASSOCIATION

RISK OF CANINE MALIGNANT LYMPHOMA BY DOG OWNER’S USE OF 2,4-D (Hayes et al. JNCI (1991)) APPLICATIONS CASES/ PER YEAR ODDS CONTROLS RATIO None or dog not in yard 1 2 3 4+ 300/641 20/34 28/47 11/17 17/17 1.0

1.3

1.3

1.3

2.0

p for trend: 0.02

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.”

RISK OF NHL IN 4 STATES AND USE OF DIAZINON (Waddell et al. Ca Causes Ctl 2001) STATE IA KS MN NE # YRS USED <10 10-19 20+ DAYS/YR USED <5 5+ CASES/ ODDS CONTROLS RATIO CONFIDENCE INTERVAL 22/33 1/1 19/26 16/27 20/40 10/11 1/1 6/11 6/6 1.1

13.0

1.3

1.4

0.9

1.8

1.9

1.3

2.4

0.6-2.1

0.7-230 0.4-4.0

0.7-2.9

0.5-1.7

0.7-4.4

0.1-32 0.5-3.9

0.7-8.0

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

t(14;18) chromosomal translocation & NHL

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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 INFERENCE FROM EPIDEMIOLOGIC STUDIES

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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 Atrazine Duffie (2001) DeRoos (2003) Canada (6 Provinces) IA/MN/KS/NE Chlordane Cantor (1992) Carbaryl “ DDT Duffie (1992) “ Cantor (1992) IA/MN “ Canada IA/MN Diazinon Waddell (2001) IA/MN/KS/NE “ Duffie (2001) Canada Dicamba “ “ Lindane Malathion “ “ “ “ “ Cantor (1992) IA/MN 2,4-D Zahm (1986) “ Duffie (2001) Canada “ (?) Kansas Wigle (1990) Saskatchawan

SUMMARY

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Pesticides can be studied epidemiologically.

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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 Study (NCI/NIEHS/EPA) A cohort study

[www.aghealth.org]

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

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

Agricultural Health Study

Objectives

  

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

Agricultural Health Study

Design & 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

Agricultural Health Study: HIGH USE PESTICIDES IN IOWA (1993 or 1994) Pesticide 2,4-D Glyphosphate Imazethapyr Atrazine Dicamba Metolachlor Trifluralin Chlorpyrifos Cyanazine Terbufos Alachlor Permethrin (Animal) Type H H H I H H H H H I H I H=Herbicide; I=Insecticide % Using last year 35.3

33.6

32.1

29.9

22.4

19.6

18.6

13.6

13.0

13.0

9.9

5.4

Expected Cancer Incidence (2006) in Agricultural Health Study Cohort

             

All cancers Prostate 4,500 1,600 Digestive system Respiratory system 900 610 Urinary system 273 Melanoma 220 Non Hodgkin’s lymphoma 168 Leukemia Buccal cavity Ovarian 134 120 85 Thyroid and other endocrine 85 Brain and CNS 84 Multiple myeloma Hodgkin’s lymphoma 76 40

2006: approximately 1 million person-years of follow-up

Cancer Cohort Analysis: Prostate CA (1

st

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 Bromide and Incident Prostate Cancer

Odds ratio (95%CI) Exposed cases Reference group (No exposure)

1.0

482

I 1/3 Exposure Group

(cumulative exposure score)

II 1/3 III 1/6 IV 1/12 V 1/12

1.0 (0.7 1.6) 23 0.8 (0.5 1.3) 22 0.7

(0.4 1.3) 11 2.7

(1.2 6.3) 6 3.5

(1.4 8.8) 5

Linear trend (p value)

0.008

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: Near Future(2004-2005)



Pesticide cohort analyses Alachlor Atrazine Chlorpyrifos Glyphosate Pendimetalin Carbofuran Carbaryl Triazine herbicides 2,4D Chlorinated pesticides



Cancer cohort analysis Prostate Melanoma Breast Lung Ovarian Multiple myeloma Colon NHL Leukemia

The Agricultural Environment: Nitrate in Drinking Water

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.

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

4.0+ 1.5

0.7-3.0

2.0

1.1-3.6

Ward et al. Epidemiology 1996; 7: 465-71.

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.