Pesticides and Cancer

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Pesticides and Cancer

• Mary H. Ward, Ph.D.
• Occupational Epidemiology Branch
• National Cancer Institute

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Overview

• Exposure
• Mechanisms of carcinogenicity
• Animal studies
• Epidemiologic studies
• Occupational groups
• General population
• Ongoing studies, research needs

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Pesticides any agent used to kill or control
undesired insects, weeds, rodents, fungi,
bacteria, or other organisms

• Insecticides
• Fumigants Insects
• Herbicides Weeds
• Fungicides Fungi
• Rodenticides Rodents
• Nematicides Roundworms
• Acaricides Spiders, mites, ticks
• Wood preservatives
• Disinfectants
• Biocides

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Pesticide Use in the United States (U.S.
Geological Survey Circular 1225 conventional
pesticides only)
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Pesticide Use Trends

• Use increased dramatically post-WWII in
  developed and developing countries
• Changes in use by chemical classes over time
• eg. organophosphates, carbamates, pyrethroids
  insecticides replaced organochlorines
• Currently (1997)
• highest agricultural use atrazine
• highest non-ag use 2,4-D

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Pesticide Use in the United States

• 890 active ingredients registered lt50 account
  for 75 of use
• 11.9 billion spent on pesticides in U.S. in 1997
  (70 for agriculture)
• 1/3 of world market 1/5 of active ingredient use
  worldwide

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Occupational groups exposed to pesticides

• Farmers, farmworkers
• Pesticide manufacturers
• Pesticide applicators
• Crop dusters
• Ag extension agents
• Food processors
• Packing house workers
• Fumigation workers
• Grain millers
• Forestry workers
• Pet groomers

• Structural pest control
• Custodians
• Nursery/greenhouse workers
• Chemical lawn care
• Golf course workers
• Park, landscape, highway maintenance
• Mosquito abatement
• Paint manufacturers
• Military personnel

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Sources of Pesticide ExposureRural/agricultural
populations

• Exposures to agricultural pesticides are
  intermediate between occupational groups and
  general population
• Agricultural drift, overspray, off-gassing,
  volatilization
• Occupational carry home exposure
• Ground surface water contamination
• Soil contamination
• Food contamination
• Estimated that more than 50 of population in
  Iowa lives within distance likely to be affected
  by pesticide drift

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Residential exposures to agricultural pesticides
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Sources of Pesticide Exposure-General population

• Homeowner indoor pest control application
• Homeowner lawn and garden application
• Drift from lawn and garden application
• Drift from public land maintenance insect
  control
• Indoor air contamination at home, school,
  offices, aircraft, other buildings
• Recreational areas, such as golf courses parks
• Insecticidal shampoos
• Pet products

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Home and garden use

• 1990 EPA Home and Garden Pesticide Use Survey
• 82 U.S. households use pesticides
• 66 treat primary living area 1/year
• 22-33 use herbicides on yard or garden annually
• Application rate/acre for household lands is FIVE
  times rate for agricultural land

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Pesticide Exposure

• Most occupational and environmental pesticide
  exposure/absorption is through skin, can be high
• Exposures through food and water, though common,
  are typically very low
• Exposure to pesticides by the largest number of
  persons probably occurs in and around the home
  (Nigg et al.,1990)

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Pesticides and Water

• 10 community water systems and 4 of rural wells
  had one or more pesticide or pesticide degradate
  (EPA)
• Tap water in 27 of 29 cities tested contained 2-9
  different pesticides (Env. Working Group)
• 14.1 million people routinely drink water
  contaminated with 5 herbicides tested (Env.
  Working Group)
• Monitoring of public water supplies only required
  since late 1980s herbicides/atrazine most
  commonly detected

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Pesticides and Diet

• Dougherty et al., 2000 calculated average
  exposure to 30 pesticides
• Although much uncertainty in approach, benchmark
  concentrations (for carcinogenic and
  noncarcinogenic effects) were exceeded for
  chlordane, DDT, dieldrin
• Fish consumption accounted for large percent of
  food exposure

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Possible Mechanisms of Carcinogenicity

• Genotoxicity Captan, dichlorvos, ethylene
• dibromide, parathion, toxaphene,
  sulfallate, etc.
• Tumor promotion Chlordane, DDT, heptachlor,
  lindane, mirex, hexachlorobenzene
• Immunotoxicity Aldicarb, chlordane, 2,4-D, DDT,
• dieldrin, malathion, mirex
• Peroxisome Chlorophenols, 2,4,5-T, 2,4-D, MCPA
  Proliferation
• Hormonal action DDT, methoxychlor, atrazine,
  ziram,
• aminotriazoles

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Evidence of Carcinogenicity of Pesticides from
Animal studies

• National Toxicology Program (2002)107
  Pesticides, pesticide intermediates, or
  solvent carriers have been tested in animals
• 54 Had at least some carcinogenicity at one
  or more sites (pesticides with suspicion are
  tested)
• Int. Agency for Research on Cancer (1997)
• 26 pesticides with sufficient evidence
• 8 still registered for use in U.S.
• 19 pesticides with limited evidence
• 15 still registered for use in U.S.

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Evidence of Carcinogenicity of Pesticides from
Animal Studies

• Includes all types herbicides, insecticides,
  fungicides, some still in use
• Several chemical classes
• Triazines
• Organophospates
• Organochlorines
• Among each type and class there are pesticides
  that do not appear to be carcinogens
• Pesticides that are not genotoxic are less likely
  to be regulated

• National Toxicology Program (2002)107
  Pesticides, pesticide intermediates, or
  solvent carriers have been tested

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Epidemiologic studies of pesticides and cancer

• Surveys of causes of mortality/morbidity by
  occupation showed farmers have increased risk of
  certain (mostly rare) cancers
• Non-Hodgkins lymphoma, Leukemia, Multiple
  myeloma
• Soft-tissue sarcoma
• Melanoma, Other skin, Lip
• Stomach
• Brain
• Prostate, testes

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Epidemiologic studies of pesticides and cancer

• Some of these cancers rates are also rising in
  developed countries
• Non-Hodgkins lymphoma,
• Multiple myeloma
• Melanoma, other skin
• Brain
• Prostate

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Studies of Pesticides Exposures among Farmers

• Most knowledge of pesticides and human cancer
  comes from studies of farmers, pesticide
  applicators
• Case-control studies of cancers excessive among
  farmers
• Personal use of herbicides, insecticides
  days/year, years, use on crops, livestock
• Protective equipment use
• Collected information on confounders

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Studies of Pesticides Exposures among Farmers

• Farmers, pesticide applicators have multiple
  exposures
• Most studies evaluated exposure one-by-one did
  not control for other exposures

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Phenoxy acid herbicides

• 2,4-D
• 2,4,5-T
• MCPA

• Non-Hodgkins lymphoma (NHL)
• Soft tissue sarcoma
• Soft tissue sarcoma

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Organochlorine insecticides

• DDT
• Chlordane
• Lindane
• Dieldrin
• Toxaphene
• Methoxychlor

• NHL, leukemia, STS, pancreas, lung, liver, mm,
  skin, breast
• Lymphoma, lung, neuroblastoma
• Lymphoma, breast
• Breast
• Lymphoma
• Leukemia

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Organophosphate insecticides

• Crotoxyphos
• Diazinon
• Dichlorvos
• Famphur
• Malathion

• Leukemia
• NHL
• NHL, leukemia
• Leukemia
• NHL

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Other pesticides

• Glyphosate
• Atrazine
• Specific carbamates

• NHL
• NHL, ovary
• NHL

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Analysis of multiple exposures

• Pooled analysis of 3 NHL case-control studies
  evaluated exposure to 47 pesticides adjusted for
  use of other pesticides (DeRoos et al.)
• Different results from individual analysis and
  from analyses that controlled for general classes
  of pesticides
• Organophosphates Herbicides
• Coumaphos 1.7 (0.9, 3.3) Atrazine 1.5 (1.0,
  2.2)
• Fonofos 1.5 (0.9, 2.7) Glyphosate 1.6 (0.9,
  2.8)
• Diazinon 1.7 (1.0, 2.8) Sod. chlorate 1.9
  (0.8,4.1)
• Organochlorines Other insecticide
• Chlordane 1.3 (0.8, 2.1) Copper
  acetoarsenite
• Dieldrin 1.4 (0.8, 2.6) 1.4 (0.9, 2.1)

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Analysis of multiple exposures

• Elevated NHL incidence with exposure to
  increasing numbers of high-risk
  pesticides OR (95 CI)
• 0 pesticides 1
• 1 pesticide only 1.6 (0.8-3.1)
• 2-4 pesticides 2.7 (0.7-10.8)
• 5 or more 25.9 (1.5-450.2)
• _________________________________
  
  
• 3 OPs dieldrin, chlordane, atrazine,
  glyphosate
• From DeRoos et al. Integrative Analysis of
  Multiple Pesticides as Risk Factors for
  Non-Hodgkins Lymphoma

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Environmental exposure to pesticides and adult
cancer

• Few cancers studied
• Residential proximity to cranberry bogs linked to
  brain cancer
• Higher rates of lymphoma in agricultural counties
  of Michigan
• Prostate cancer and home use of pesticides in
  Canada
• Studies lacked detailed exposure information

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Studies of DDT and Breast Cancer

• Many studies of DDT/DDE in serum or adipose
• DDT, other OCs have estrogenic activity
• Serum or adipose levels of DDE assoc. with risk
  in early case-control studies (Falck 1992 Wolff
  1993 Dewailly 1994)
• Recent cohort, case-control studies in Mexico,
  Europe, and U.S. found no association
• Combined analysis of 5 U.S. studies (1400 cases,
  1642 controls) Laden et al., 2001
• --OR (fifth quintile vs. first) 0.99
  (0.77-1.27)

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Studies of DDT and Breast Cancer

• Issues (Snedeker EHP 2001)
• Measured persistent metabolite p,p-DDE but
  o,p-DDT most estrogenic
• Western women exposure (DDE) primarily through
  diet vs. occupational/environmental exposure to
  o,p-DDT
• Timing of exposure (in utero, prepuberty,etc)
• Multiple exposures and genetic polymorphisms not
  evaluated
• More recent studies investigating DDT effects on
  stage, lymph node involvement, size of breast
  tumors

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Breast cancer and Dieldrin

• Danish study measured serum levels of kepone,
  dieldrin, DDT, hexachlorobenzene, PCBs
• Found positive association with levels of
  dieldrin Q4 vs. Q1 adjusted OR2.05 (1.2-3.6)
• Survival also affected by dieldrin levels after
  adjusting for tumor size, grade, lymph node
  involvement
• U.S. study (Missouri) found no association
  lower exposure
• Not strongly estrogenic may act as an
  antiandrogen

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Childhood Cancer and Pesticides

• About 40 studies
• Leukemia associated with household use of
  pesticides, maternal and paternal exposures
  during pregnancy
• Brain cancer associated with household exposure
  to insecticides and paternal exposure during
  pregnancy
• Other cancers linked to pesticides
• NHL, Ewings sarcoma, Wilms tumor

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Childhood Cancer and Pesticides

• Risks stronger when more detailed pesticide
  information obtained
• Children/fetus may be uniquely sensitive
• Study design issues controls, evaluation of time
  windows
• Exposure assessment need more details of
  exposure evaluation of recall bias
  environmental measures
• Evaluate genetic polymorphisms specific genetic
  subtypes of disease eg. MLL gene

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Pesticides and Cancer

• Strength of the evidence depends on the quality
  of the studies
• Criteria strength of the association,
  dose-response, consistency across studies,
  biologic plausibility
• Large individual-based studies with good exposure
  data evaluate multiple exposures genetic
  subgroups, polymorphisms

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Agricultural Health Study

• Cohort study of farmers and pesticides
  applicators and their spouses
• Pesticide info obtained prospectively
• Detailed questions about agricultural use, PPE,
  etc,
• Pesticide storage, hygiene practices
• Cancer and other health effects can be evaluated

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Case-control study of NHL(L.A., Detroit,
Seattle, Iowa)

• 1200 living cases 1100 controls ages 20-74
• Occupational, home/garden use of pesticides at
  each residence gt2 years 1970 onwards
• Carpet dust collection to measure in-home
  exposure to persistent pesticides
• Tap water sample for private wells
• Genetic polymorphisms e.g., paraoxanase
  (PON)-organophosphates
• Serum levels of organochlorines, PCBs

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Case-control study of child leukemia in 35
California counties

• Parental occupational, home/garden use of
  pesticides
• Carpet dust samples
• GPS locations of homes
• Field staff map crops within 1200 meters of home
  within 3 weeks of dust collection
• Pesticide Use Reporting (PUR) database, 1990
• All agricultural pesticide use
• 1 sq. mile reporting unit
• Date of application, crop, application rates,
  acres treated

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Pesticide use based on PUR data only
SECTION 1
SECTION 2
Residence Location
Improved spatial resolution of pesticide use
Sugar Beets
grapes
grapess
corn
MTRS1
grapes
Residence Location
beans
Corn
ABeans