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

cantork@nih.gov

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.