Breast Cancer and Environmental Chemicals: Why is there Concern

1
Breast Cancer and Environmental Chemicals Why
is there Concern?

• Suzanne Snedeker, Ph.D.
• Associate Director of Translational Research
• Cornell University Sprecher Institute for
• Comparative Cancer Research
• Program on Breast Cancer and Environmental
  Factors (BCERF)
• http//envirocancer.cornell.edu

2
Lesson Outline

• Why is there a concern about environmental links
  to breast cancer risk?
• Which chemicals in the workplace and home are
  associated with increased risks of breast cancer?
• What do we know about pesticides and breast
  cancer risk?
• What can we learn from animal cancer bioassays?
• What is known about endocrine disrupting
  chemicals?
• What are the challenges do we face in evaluating
  linkages between environmental chemicals and
  cancer risk?

3
How does cancer occur?
Initiated cell
Invasive Tumor
4
Risks Related to Breast Cancer
Close Relative
Advancing Age
Genetics
Gender
Age at First Birth
Early Menarche
Passive Smoke
Late Menopause
Diet
Overweight
Lack of Exercise
Chemicals -Work -Home -Garden -Recreation
Ionizing Radiation
Hormone Replacement Therapy
Benign Breast Disease
Alcohol
???
5
Exposure to Hormones
Late Menopause
Some Chemicals -Work -Home -Garden
-Recreation
Lack of Exercise
6
Breast cancer rates worldwide
7
Environmental links to breast cancer
Scandinavian Twins Study

• Contribution of inherited vs. environmental
  factors to breast cancer risk
• Inherited factors, 27 of risk
• Environmental factors, 73 of risk
• Suggests environmental factors play a
• major role in determining breast cancer risk
• Ref Lichtenstein et al., N. Engl. J. Med.,
  34378-85, 2000

8
How are we exposed to environmental
chemicals?

• Routes of exposure
• Air we breath
• Food we eat beverages we drink
• Contact with our skin
• Contact with eyes
• Some chemicals cross the placenta
• Some can appear in breast milk

9
Exposure to environmental chemicals

• Each chemical is unique
• Some can be stored in body fat
• Others quickly eliminated
• Some need to activated by the body
• Others are quickly detoxified
• Some pose no cancer risk
• Some are potent carcinogens
• Others may be hormone mimics and support breast
  tumor growth
• Some may act as anti-cancer agents

10
Chemicals in the workplace problems with many
studies

• Few high quality cancer studies of women in the
  workplace
• Many studies very small
• Follow-up time often too short
• Records of actual exposures often lacking
• Methods for estimating exposures often crude
• Frequently have exposures to multiple chemicals

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Chemicals in the workplace what do we know?

• Some evidence of higher breast cancer risk
• Acid mists
• Benzene
• Carbon tetrachloride
• Ethylene Oxide

• Formaldehyde
• Lead oxide
• Methylene chloride
• Styrene

Refs Blair and Kazerouni, Cancer Causes
Control, 8473-490, 1997 Cantor et al., J.
Occup. Environ. Med., 37336-348, 1995 Goldberg
and Labreche, Occup. Environ. Med., 53145-156,
1996 Hansen, Am. J. Ind. Med., 3643-47,
1999 Norman et al., Int. J. Epidemiology,
24276-284, 1995 Spiritas et al., Br. J. Ind.
Med., 48515-530, 1991
12
Chemicals in the workplace -light at night

• Light at night
• May disrupt the synthesis of the hormone
  melatonin
• Changes in melatonin may affect levels of
  estrogen
• Breast cancer risk is higher in women who worked
  the grave yard shift for many years
• Refs Steven and Rea, Cancer Causes Control,
  12279-287, 2001
• Davis et al., JNCI, 9315571562, 2001
• Hansen et al., Epidemiology, 1274-77, 2001
• Schernhammer et al, JNCI, 931563-1568, 2001

13
Chemicals in the workplace what do we need to
know?

• Workers that need further evaluation
• Chemical manufacturing workers
• Pharmaceutical industry workers
• Laboratory and biomedical workers
• Cosmetologists and hairdressers
• Printers and dye workers
• Health care workers
• Metal plate workers
• Airline personnel

14
Chemicals in the home what are we exposed to?

• Cape Cod Breast Study
• Silent Spring Institute
• Measured household exposures to 89 hormone-like
  and cancer-causing chemicals in air and dust
  samples of 120 Cape Cod homes
• Chemicals identified included plasticizers,
  disinfectants, certain flame retardants,
  persistent organochlorine pesticides and
  contemporary (permethrin) pesticides
• Exposure is one step in the risk assessment
  process
• Results will help prioritize chemicals that
  should be studied further
• Refs Rudel et al., J. Air Waste Manage.
  Assoc. 51499-513, 2001
• Rudel et al., Environ. Science and
  Technol., 374543-53, 2003

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Pesticides and cancer risk exposure concerns
16
U.S. Conventional Pesticide Use historical
trends1964-1996
Ref Aspelin and Grub, Pesticide industry sales
and usage, 1996 and 1997 market estimates, Figure
10.b, US EPA, November 1999.
17
Pesticides and cancer risk why is there concern?

• Higher cancer risk in male farmers
• Lip
• Skin
• Stomach
• Brain
• Lymphoma
• Prostate
• Ref Blair and Zahm, Environ. Health Perspect.
  103 (Suppl 8)205-208, 1995

18
Pesticides and cancer risk cancer risks on the
farm

• Environmental exposures on the farm
• Sunlight / UV radiation
• Nitrates
• Pesticides
• Solvents
• Fuel exhaust
• Mycotoxins (toxins formed by mold on crops some
  are cancer-causing)

19
Pesticides and cancer risk cancer risks on the
farm

• Agricultural Health Study
• Evaluating health effects of agricultural
  chemicals in a 10 year, prospective study
• 55,300 men and 30,000 women
• Cancer risks
• Prostate cancer risk elevated 14 in male
  pesticide applicators
• http//aghealth.org/index.html
• Ref Alavanja et al., Am. J. Epidemiology, vol.
  157, pp. 800-814, 2003

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Breast cancer risk of farm women

• Few studies on cancer risks of farm women most
  studies on men
• North Carolina Study
• Overall, breast cancer rates lower in women
  living on or near farms
• In farm women who applied pesticides, breast
  cancer risk 2X higher if protective clothing or
  gloves not worn
• Reducing exposure reduces risk
• Ref Duell et al., Epidemiology, 11523-531, 2000

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Pesticides and breast cancer risk
-organochlorine (OC) pesticides

• DDT and DDE
• Early descriptive studies suggested a positive
  association between blood or adipose tissue DDE
  levels and breast cancer risk
• Over 20 of the recent, well controlled,
  large-scale studies have not shown that levels of
  DDT or DDE predict breast cancer risk in North
  American or European white women

22
Pesticides and breast cancer risk DDT/DDE
possible explanations

• Exposure Issues - Chemical form matters
• Predominant exposure in western white women
• Was not to estrogenic form that was sprayed
  (o,p-DDT)
• But to very weak estrogenic form (p,p-DDE) in
  food
• Heavily exposed populations less studied
• Few studies of breast cancer risk in countries
  that currently use DDT (estrogenic form) for
  malaria control
• Critical windows of exposure
• Little information on whether exposure to DDT
  during early breast development affects breast
  cancer risk
• Ref Snedeker, Environ. Health Perspect., 109
  (suppl 1) 3547, 2001

23
Chemicals and breast cancer risk laboratory
animal studies

• Why use laboratory animal studies?
• Human studies have the most weight when
  evaluating cancer risk
• For most chemicals we have no information on
  human exposures and later cancer risk
• Use controlled animal laboratory studies to
• Identify the hazard
• Estimate cancer risks to humans
• National Toxicology Program Animal
  cancer bioassays
• Of 509 chemicals tested, 42 (8) cause mammary
  (breast) tumors in laboratory animals

24
Chemicals and breast cancer risk National
Toxicology Program

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

• Organic solvents
• Dyes and dye intermediates
• Chemicals used in manufacture of rubber,
  neoprene, vinyl and polyurethane foams
• Flame retardants
• Food additive
• Gasoline additives / lead scavengers

• Metals use in microelectronics
• Medical instrument sterilizing agent
• Mycotoxin (toxin produced by a type of mold)
• Pesticides and fumigants
• Pharmaceuticals
• Rocket fuel

Refs Dunnick et al., Carcinogenesis, 16173-170,
1995 Bennett and Davis, Environ. Mol. Mutagen.
39150-157, 2002
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EnviroChem 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 use
• http//envirocancer.cornell.edu/ECCD/chemsearch.cf
  m
• Includes information on the chemicals
• 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

26
Endocrine disrupting chemicals (Hormonally
Active Agents)

• We know that many hormones and local growth
  factors play a role both in normal breast growth
  and in the cancer process
• Hormones (chemical messengers)
• Estrogen
• Progesterone
• Prolactin
• Growth Hormone
• Growth Factors (local chemical messengers)
• Epidermal Growth Factor family
• Insulin Growth Factor (IGFs)

27
Endocrine disrupting chemicals Whats the
evidence?

• What we know
• Pharmaceuticals that act like estrogen or
  estrogen / progesterone (E P) can increase
  breast cancer risk
• Diethylstilbestrol
• Prescribed to 5 to10 million women
• In mothers - moderate increase in BC risk
• In daughters - data not in yet
• E P post-menopausal hormone therapy
• Risk increases with duration of use
• Small risk (8 cases per 10,000), but widely
  prescribed
• May increase risk of more aggressive tumors

http//www.desaction.org/ http//www.cdc.gov/DES/
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Endocrine disrupting chemicals -(hormonally
active agents)

• Hormonally active agents
• may affect breast cancer risk by
• Affecting the delicate balance that controls cell
  division
• Supporting the growth of a hormone-dependent
  breast tumor
• The Concern
• Do low levels of environmental chemicals that act
  like hormones or disrupt hormone pathways affect
  breast cancer risk?

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Endocrine Disrupting Chemicals Need to know more

• Polybrominated diphenyl ethers (PBDEs)
• Flame retardant
• Used in plastics, textiles, carpets, furniture
  foam
• Detected in marine life and human breast milk
  globally
• Can stimulate breast tumors cells to grow in the
  lab
• Plasticizers
• Nonyl phenol, bisphenol A - estrogenic
• Phthalates - some may cause premature breast
  development in children (studies from Puerto
  Rico)
• Heavy Metals
• Cadmium and arsenite - environmental estrogens
• Pesticides

30
Endocrine disrupting chemicals How can we
screen chemicals?

• 1996 Food Quality Protection Act
• Mandates testing of ALL pesticide active
  ingredients for endocrine disrupting effects
• EPA is currently validating screening tests and
  prioritizing chemicals to be screened
• Ref. http//www.epa.gov/scipoly/oscpendo/

31
Early exposures to chemicals can they affect
breast cancer risk?

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

32
Genes influence response to environmental
chemicals

• Gene-environmental interactions
• Many chemicals need to be activated to become
  cancer-causing agents
• Certain genes control important enzymes involved
  in activation pathways
• Variations in these genes can affect the
  activation pathway
• This affects the level of cancer-causing chemical

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Challenges

• Complexity of the disease
• Many risk factors involved
• Complex biology of breast tumors
• Takes long time for breast tumors to develop
• Exposure issues
• Difficult to measure low-level exposures to
  multiple chemicals from the distant past
• Few chemicals have validated biomarkers
• Levels of exposure to chemicals at critical
  periods of breast development (in utero through
  puberty) is lacking
• Exposures to many chemicals in the home and
  workplace are not well characterized

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BCERF on the web

• http//envirocancer.cornell.edu
• Fact Sheets and Tip Sheets
• Critical Evaluations of chemicals
• A Place For Women site
• Newsletters and News You Can Use
• Bibliographies on environmental factors
• Cancer Maps
• Endocrine Disrupting Chemical Information
• Companion Animal Tumor Registry