Breast Cancer and Environmental Chemicals: Why is there Concern? Suzanne Snedeker, Ph.D. Associate Director of Translational Research Cornell University.

Breast Cancer and Breast Cancer and Environmental Chemicals: Environmental Chemicals:

Why is there Concern?Why is there Concern?Suzanne Snedeker, Ph.D.Suzanne Snedeker, Ph.D.Associate Director of Translational ResearchAssociate Director of Translational Research

Cornell University Sprecher Institute for Cornell University Sprecher Institute for

Comparative Cancer Research Comparative Cancer Research Program on Breast Cancer and Environmental Factors (BCERF) Program on Breast Cancer and Environmental Factors (BCERF)

http://envirocancer.cornell.eduhttp://envirocancer.cornell.edu

Lesson OutlineLesson Outline

Why is there a concern about environmental links to Why is there a concern about environmental links to breast cancer risk?breast cancer risk?

Which chemicals in the workplace and home are Which chemicals in the workplace and home are associated with increased risks of breast cancer?associated with increased risks of breast cancer?

What do we know about pesticides and breast cancer What do we know about pesticides and breast cancer risk?risk?

What can we learn from animal cancer bioassays?What can we learn from animal cancer bioassays? What is known about endocrine disrupting chemicals?What is known about endocrine disrupting chemicals? What are the challenges do we face in evaluating What are the challenges do we face in evaluating

linkages between environmental chemicals and cancer linkages between environmental chemicals and cancer risk? risk?

How does cancer occur?How does cancer occur?

Initiated cell

Invasive Tumor

AdvancingAdvancingAgeAge GeneticsGenetics

AlcoholAlcohol

Lack of Lack of ExerciseExercise

HormoneHormoneReplacemenReplacementtTherapyTherapy

OverweightOverweight

GenderGender

??????

PassivePassive

SmokeSmokeLateLateMenopauseMenopause

CloseCloseRelativeRelative

Age atAge atFirst BirthFirst Birth

BenignBenignBreast DiseaseBreast Disease

EarlyEarlyMenarcheMenarche

Risks Related to Breast CancerRisks Related to Breast Cancer

IonizingIonizingRadiationRadiation

ChemicalsChemicals -Work-Work

-Home-Home

-Garden-Garden

-Recreation-Recreation

DietDiet

Education Education & Income & Income

LateLateMenopauseMenopause

AdvancingAdvancingAgeAge

Lack of Lack of ExerciseExercise

Early Early MenarcheMenarche

OverweightOverweight

HormoneHormoneReplacementReplacementTherapyTherapy

Some Some ChemicalsChemicals

-Work-Work

-Home-Home

-Garden-Garden

-Recreation-Recreation

GenderGender

Exposure to HormonesExposure to Hormones

AlcoholAlcohol

0 10 20 30 40 50 60 70 80 90 100

Netherlands

U.S.A.

Denmark

Canada

Israel

UK

Germany

Italy

Portugal

Philipines

Mexico

Japan

Peru

Kenya

India

China

Chad

Korea

Gambia

Breast Cancer Incidence Rates

Breast cancer rates worldwideBreast cancer rates worldwide

Environmental links to breast cancerEnvironmental links to breast cancer –Scandinavian Twins Study –Scandinavian Twins Study

Contribution of inherited vs. environmental Contribution of inherited vs. environmental factors to breast cancer riskfactors to breast cancer risk

• Inherited factors, 27% of riskInherited factors, 27% of risk

• Environmental factors, 73% of riskEnvironmental factors, 73% of risk

• Suggests environmental factors play aSuggests environmental factors play a

major rolemajor role in determining breast cancer risk in determining breast cancer risk

Ref: Lichtenstein et al., N. Engl. J. Med., 343:78-85, 2000Ref: Lichtenstein et al., N. Engl. J. Med., 343:78-85, 2000

How are we exposed to How are we exposed to environmental chemicals?environmental chemicals?

Routes of exposureRoutes of exposure• Air we breathAir we breath• Food we eat & beverages we drinkFood we eat & beverages we drink• Contact with our skinContact with our skin• Contact with eyesContact with eyes• Some chemicals cross the placentaSome chemicals cross the placenta• Some can appear in breast milkSome can appear in breast milk

Exposure toExposure toenvironmental chemicalsenvironmental chemicals

Each chemical is uniqueEach chemical is unique• Some can be stored in body fatSome can be stored in body fat• Others quickly eliminatedOthers quickly eliminated• Some need to “activated” by the bodySome need to “activated” by the body• Others are quickly detoxifiedOthers are quickly detoxified• Some pose no cancer riskSome pose no cancer risk• Some are potent carcinogensSome are potent carcinogens• Others may be hormone mimics and support Others may be hormone mimics and support

breast tumor growthbreast tumor growth• Some may act as anti-cancer agentsSome may act as anti-cancer agents

Chemicals in the workplaceChemicals in the workplace–problems with many studies–problems with many studies

Few high quality cancer studies of Few high quality cancer studies of women in the workplacewomen in the workplace• Many studies very smallMany studies very small• Follow-up time often too short Follow-up time often too short • Records of actual exposures often lackingRecords of actual exposures often lacking• Methods for estimating exposures often Methods for estimating exposures often

crudecrude• Frequently have exposures to multiple Frequently have exposures to multiple

chemicalschemicals

Chemicals in the workplaceChemicals in the workplace–what do we know?–what do we know?

Some evidence of higher breast cancer riskSome evidence of higher breast cancer risk• Acid mistsAcid mists• BenzeneBenzene• Carbon tetrachlorideCarbon tetrachloride• Ethylene OxideEthylene Oxide

• Formaldehyde Formaldehyde • Lead oxide Lead oxide • Methylene chlorideMethylene chloride• StyreneStyrene

Refs: Blair and Kazerouni, Cancer Causes & Control, 8:473-490, 1997 Cantor et al., J. Occup. Environ. Med., 37:336-348, 1995Goldberg and Labreche, Occup. Environ. Med., 53:145-156, 1996Hansen, Am. J. Ind. Med., 36:43-47, 1999Norman et al., Int. J. Epidemiology, 24:276-284, 1995Spiritas et al., Br. J. Ind. Med., 48:515-530, 1991

Chemicals in the workplaceChemicals in the workplace-light at night-light at night

Light at night Light at night • May disrupt the synthesis of the hormone melatonin May disrupt the synthesis of the hormone melatonin • Changes in melatonin may affect levels of estrogenChanges in melatonin may affect levels of estrogen• Breast cancer risk is higher in women who worked Breast cancer risk is higher in women who worked

the “grave yard” shift for many yearsthe “grave yard” shift for many years

Refs: Steven and Rea, Cancer Causes Control, 12:279-287, 2001Refs: Steven and Rea, Cancer Causes Control, 12:279-287, 2001

Davis et al., JNCI, 93:15571562, 2001Davis et al., JNCI, 93:15571562, 2001

Hansen et al., Epidemiology, 12:74-77, 2001Hansen et al., Epidemiology, 12:74-77, 2001

Schernhammer et al, JNCI, 93:1563-1568, 2001Schernhammer et al, JNCI, 93:1563-1568, 2001

Chemicals in the workplaceChemicals in the workplace–what do we need to know?–what do we need to know?

Workers that need further evaluationWorkers that need further evaluation• Chemical manufacturing workersChemical manufacturing workers• Pharmaceutical industry workersPharmaceutical industry workers• Laboratory and biomedical workersLaboratory and biomedical workers• Cosmetologists and hairdressersCosmetologists and hairdressers• Printers and dye workersPrinters and dye workers• Health care workersHealth care workers• Metal plate workersMetal plate workers• Airline personnelAirline personnel

Chemicals in the homeChemicals in the home–what are we exposed to?–what are we exposed to?

Cape Cod Breast StudyCape Cod Breast Study Silent Spring InstituteSilent Spring Institute

• Measured household exposures to 89 hormone-like and Measured household exposures to 89 hormone-like and cancer-causing chemicals in air and dust samples of 120 cancer-causing chemicals in air and dust samples of 120 Cape Cod homesCape Cod homes

• Chemicals identified included plasticizers, disinfectants, Chemicals identified included plasticizers, disinfectants, certain flame retardants, persistent organochlorine certain flame retardants, persistent organochlorine pesticides and contemporary (permethrin) pesticidespesticides and contemporary (permethrin) pesticides

• Exposure is one step in the risk assessment processExposure is one step in the risk assessment process• Results will help prioritize chemicals that should be Results will help prioritize chemicals that should be

studied furtherstudied further

Refs: Rudel et al., J. Air Waste Manage. Assoc. 51:499-513, 2001Refs: Rudel et al., J. Air Waste Manage. Assoc. 51:499-513, 2001

Rudel et al., Environ. Science and Technol., 37:4543-53, Rudel et al., Environ. Science and Technol., 37:4543-53, 20032003

Pesticides and cancer riskPesticides and cancer risk–exposure concerns–exposure concerns

U.S. Conventional Pesticide UseU.S. Conventional Pesticide Use–historical trends1964-1996–historical trends1964-1996

Ref: Aspelin and Grub, Pesticide industry sales and usage, 1996 and 1997 market estimates, Figure 10.b, US EPA, November 1999.

Pesticides and cancer riskPesticides and cancer risk–why is there concern?–why is there concern?

HHigher cancer risk in male igher cancer risk in male farmersfarmers• LipLip• SkinSkin• StomachStomach• BrainBrain• LymphomaLymphoma• ProstateProstate

Ref: Blair and Zahm, Environ. Health Perspect. 103 Ref: Blair and Zahm, Environ. Health Perspect. 103 (Suppl 8):205-208, 1995(Suppl 8):205-208, 1995

Pesticides and cancer riskPesticides and cancer risk–cancer risks on the farm–cancer risks on the farm

Environmental exposures on the Environmental exposures on the farmfarm• Sunlight / UV radiationSunlight / UV radiation• NitratesNitrates• PesticidesPesticides• SolventsSolvents• Fuel exhaustFuel exhaust• Mycotoxins (toxins formed by mold Mycotoxins (toxins formed by mold

on crops; some are cancer-on crops; some are cancer-causing)causing)

Pesticides and cancer riskPesticides and cancer risk–cancer risks on the farm–cancer risks on the farm

Agricultural Health StudyAgricultural Health Study• Evaluating health effects of agricultural Evaluating health effects of agricultural

chemicals in a 10 year, prospective studychemicals in a 10 year, prospective study– 55,300 men and 30,000 women55,300 men and 30,000 women

• Cancer risksCancer risks– Prostate cancer riskProstate cancer risk elevated 14% in elevated 14% in

male pesticide applicatorsmale pesticide applicators

http://aghealth.org/index.htmlhttp://aghealth.org/index.html

Ref: Alavanja et al., Am. J. Epidemiology, vol. 157, pp. 800-814, 2003Ref: Alavanja et al., Am. J. Epidemiology, vol. 157, pp. 800-814, 2003

Breast cancer risk of farm womenBreast cancer risk of farm women

Few studies on cancer risks of farm Few studies on cancer risks of farm women; most studies on men women; most studies on men

North Carolina StudyNorth Carolina Study• Overall, breast cancer rates Overall, breast cancer rates lowerlower in in

women living on or near farmswomen living on or near farms• In farm women who In farm women who applied pesticidesapplied pesticides, ,

breast cancer risk 2X higher if protective breast cancer risk 2X higher if protective clothing or gloves not wornclothing or gloves not worn

• Reducing exposure reduces riskReducing exposure reduces risk Ref: Duell et al., Epidemiology, 11:523-531, 2000Ref: Duell et al., Epidemiology, 11:523-531, 2000

Pesticides and breast cancer risk Pesticides and breast cancer risk -organochlorine (OC) pesticides-organochlorine (OC) pesticides

DDT and DDEDDT and DDE• Early descriptive studies suggested a Early descriptive studies suggested a

positive association between blood or positive association between blood or adipose tissue DDE levels and breast adipose tissue DDE levels and breast cancer riskcancer risk

• Over 20 of the recent, well controlled, large-Over 20 of the recent, well controlled, large-scale studies scale studies have not shown have not shown that levels that levels of DDT or DDE predict breast cancer risk in of DDT or DDE predict breast cancer risk in North American or European white womenNorth American or European white women

Pesticides and breast cancer risk Pesticides and breast cancer risk

–DDT/DDE possible explanations–DDT/DDE possible explanations

Exposure Issues - Chemical form mattersExposure Issues - Chemical form matters• Predominant exposure in western white womenPredominant exposure in western white women

– Was not to estrogenic form that was sprayed (o,p’-Was not to estrogenic form that was sprayed (o,p’-DDTDDT))

– But to very weak estrogenic form (p,p’-DDE) in foodBut to very weak estrogenic form (p,p’-DDE) in food Heavily exposed populations less studiedHeavily exposed populations less studied

• Few studies of breast cancer risk in countries that Few studies of breast cancer risk in countries that currently use DDT (estrogenic form) for malaria controlcurrently use DDT (estrogenic form) for malaria control

Critical windows of exposureCritical windows of exposure • Little information on whether exposure to DDT during Little information on whether exposure to DDT during

early breast development affects breast cancer riskearly breast development affects breast cancer risk

Ref: Snedeker, Environ. Health Perspect., 109 (suppl 1): 3547, 2001Ref: Snedeker, Environ. Health Perspect., 109 (suppl 1): 3547, 2001

Chemicals and breast cancer riskChemicals and breast cancer risk–laboratory animal studies–laboratory animal studies

Why use laboratory animal studies?Why use laboratory animal studies?• Human studies have the most weight when Human studies have the most weight when

evaluating cancer riskevaluating cancer risk• For most chemicals we have For most chemicals we have no informationno information on on

human exposures and later cancer riskhuman exposures and later cancer risk• Use controlled animal laboratory studies to:Use controlled animal laboratory studies to:

– Identify the hazardIdentify the hazard– Estimate cancer risks to humansEstimate cancer risks to humans

National Toxicology ProgramNational Toxicology Program Animal cancer bioassaysAnimal cancer bioassays

– Of 509 chemicals tested, 42 (8%) cause Of 509 chemicals tested, 42 (8%) cause mammary (breast) tumors in laboratory mammary (breast) tumors in laboratory animalsanimals

Chemicals and breast cancer riskChemicals and breast cancer risk–National Toxicology Program–National Toxicology Program

• Organic solventsOrganic solvents• Dyes and dye intermediates Dyes and dye intermediates • Chemicals used in Chemicals used in

manufacture of rubber, manufacture of rubber, neoprene, vinyl and neoprene, vinyl and polyurethane foams polyurethane foams

• Flame retardantsFlame retardants• Food additiveFood additive• Gasoline additives / lead Gasoline additives / lead

scavengersscavengers

• Metals use in Metals use in microelectronics microelectronics

• Medical instrument Medical instrument sterilizing agentsterilizing agent

• Mycotoxin (toxin produced Mycotoxin (toxin produced by a type of mold)by a type of mold)

• Pesticides and fumigantsPesticides and fumigants• PharmaceuticalsPharmaceuticals• Rocket fuelRocket fuel

Types of compounds that cause mammary Types of compounds that cause mammary (breast) tumors in laboratory animals(breast) tumors in laboratory animals

Refs: Dunnick et al., Carcinogenesis, 16:173-170, 1995Refs: Dunnick et al., Carcinogenesis, 16:173-170, 1995Bennett and Davis, Environ. Mol. Mutagen. 39:150-157, 2002Bennett and Davis, Environ. Mol. Mutagen. 39:150-157, 2002

EnviroChem and Cancer DatabaseEnviroChem and Cancer Database http://environcancer.cornell.edu/chemstart.cfm

On-line Information on 42 chemicals that cause mammary gland tumors in laboratory animals in NTP bioassays

Searchable by chemical name, CAS #, or major usehttp://envirocancer.cornell.edu/ECCD/chemsearch.cfm

Includes information on the chemical’s:• Major uses• Cancer classification• Whether the chemical is currently produced• If / when it was taken off the market • Use in manufacturing processes• Consumer products• Exposures of concern• Overview of workplace regulations and advisories by OSHA

Endocrine disrupting chemicalsEndocrine disrupting chemicals(Hormonally Active Agents)(Hormonally Active Agents)

We know that many hormones and local growth factors play We know that many hormones and local growth factors play a role a role bothboth in normal breast growth and in the cancer process in normal breast growth and in the cancer process• Hormones (chemical messengers)Hormones (chemical messengers)

– EstrogenEstrogen– ProgesteroneProgesterone– ProlactinProlactin– Growth HormoneGrowth Hormone

• Growth Factors (local chemical messengers)Growth Factors (local chemical messengers)– Epidermal Growth Factor familyEpidermal Growth Factor family– Insulin Growth Factor (IGFs)Insulin Growth Factor (IGFs)

Endocrine disrupting chemicalsEndocrine disrupting chemicals–What’s the evidence?–What’s the evidence?

What we knowWhat we know• Pharmaceuticals that act like estrogen or estrogen / Pharmaceuticals that act like estrogen or estrogen /

progesterone (E + P) can increase breast cancer riskprogesterone (E + P) can increase breast cancer risk– DiethylstilbestrolDiethylstilbestrol

• Prescribed to 5 to10 million womenPrescribed to 5 to10 million women• In mothers - moderate increase in BC riskIn mothers - moderate increase in BC risk• In daughters - data not in yetIn daughters - data not in yet

– E + P post-menopausal hormone therapyE + P post-menopausal hormone therapy• Risk increases with duration of useRisk increases with duration of use• Small risk (8 cases per 10,000), but widely Small risk (8 cases per 10,000), but widely

prescribedprescribed• May increase risk of more aggressive tumorsMay increase risk of more aggressive tumors

http://www.desaction.org/http://www.cdc.gov/DES/

Endocrine disrupting chemicalsEndocrine disrupting chemicals-(hormonally active agents)-(hormonally active agents)

Hormonally active agents Hormonally active agents may affect breast cancer risk may affect breast cancer risk

by:by:• Affecting the delicate balance that Affecting the delicate balance that

controls cell divisioncontrols cell division• Supporting the growth of a Supporting the growth of a

hormone-dependent breast tumorhormone-dependent breast tumor The ConcernThe Concern

• Do low levels of environmental Do low levels of environmental chemicals that act like hormones chemicals that act like hormones or disrupt hormone pathways or disrupt hormone pathways affect breast cancer risk?affect breast cancer risk?

Endocrine Disrupting ChemicalsEndocrine Disrupting Chemicals–Need to know more–Need to know more

Polybrominated diphenyl ethers (PBDEs)Polybrominated diphenyl ethers (PBDEs)• Flame retardantFlame retardant• Used in plastics, textiles, carpets, & furniture foamUsed in plastics, textiles, carpets, & furniture foam• Detected in marine life and human breast milk globallyDetected in marine life and human breast milk globally• Can stimulate breast tumors cells to grow in the labCan stimulate breast tumors cells to grow in the lab

PlasticizersPlasticizers• Nonyl phenol, bisphenol A - estrogenicNonyl phenol, bisphenol A - estrogenic• Phthalates - some may cause premature breast Phthalates - some may cause premature breast

development in children (studies from Puerto Rico)development in children (studies from Puerto Rico) Heavy MetalsHeavy Metals

• Cadmium and arsenite - environmental estrogens Cadmium and arsenite - environmental estrogens PesticidesPesticides

Endocrine disrupting chemicalsEndocrine disrupting chemicals–How can we screen chemicals?–How can we screen chemicals?

1996 Food Quality Protection Act1996 Food Quality Protection Act• Mandates testing of ALL pesticide active Mandates testing of ALL pesticide active

ingredients for endocrine disrupting effectsingredients for endocrine disrupting effects• EPA is currently validating screening tests EPA is currently validating screening tests

and prioritizing chemicals to be screenedand prioritizing chemicals to be screened

Ref. http://www.epa.gov/scipoly/oscpendo/Ref. http://www.epa.gov/scipoly/oscpendo/

Early exposures to chemicalsEarly exposures to chemicals–can they affect breast cancer risk?–can they affect breast cancer risk?

Terminal end buds (TEBs)Terminal end buds (TEBs)• Target for cancer-causing chemicalsTarget for cancer-causing chemicals

TEB, CD-1 mouse, TEB, CD-1 mouse,

45 days old45 days old

Photo whole mount collection of Photo whole mount collection of Snedeker and DiAugustine, 1987Snedeker and DiAugustine, 1987

TEB, Human, 13 yrs. old

Ref: Howard and Gusterson, J. Mam. Gland Biol. Neoplasia, 5:119-137, 2000

Genes influence response to Genes influence response to environmental chemicalsenvironmental chemicals

Gene-environmental interactionsGene-environmental interactions• Many chemicals need to be “activated” Many chemicals need to be “activated”

to become cancer-causing agentsto become cancer-causing agents• Certain genes control important Certain genes control important

enzymes involved in activation pathwaysenzymes involved in activation pathways• Variations in these genes can affect the Variations in these genes can affect the

activation pathwayactivation pathway• This affects the level of cancer-causing This affects the level of cancer-causing

chemicalchemical

ChallengesChallenges Complexity of the diseaseComplexity of the disease

• Many risk factors involvedMany risk factors involved• Complex biology of breast tumorsComplex biology of breast tumors• Takes long time for breast tumors to developTakes long time for breast tumors to develop

Exposure issuesExposure issues• Difficult to measure low-level exposures to Difficult to measure low-level exposures to

multiple chemicals from the distant past multiple chemicals from the distant past • Few chemicals have validated biomarkersFew chemicals have validated biomarkers• Levels of exposure to chemicals at critical periods Levels of exposure to chemicals at critical periods

of breast development (of breast development (in uteroin utero through puberty) through puberty) is lackingis lacking

• Exposures to many chemicals in the home and Exposures to many chemicals in the home and workplace are not well characterizedworkplace are not well characterized

BCERF on the webBCERF on the web

http://envirocancer.cornell.eduhttp://envirocancer.cornell.edu Fact Sheets and Tip SheetsFact Sheets and Tip Sheets Critical Evaluations of chemicalsCritical Evaluations of chemicals ““A Place For Women” siteA Place For Women” site Newsletters and “News You Can Use”Newsletters and “News You Can Use” Bibliographies on environmental factorsBibliographies on environmental factors Cancer MapsCancer Maps Endocrine Disrupting Chemical Endocrine Disrupting Chemical

InformationInformation Companion Animal Tumor RegistryCompanion Animal Tumor Registry

ccancer and ancer and eenvironmentnvironment