Breast Cancer and Environmental Chemicals: Why is there Concern?

1. Suzanne Snedeker, Ph.D. Assoc. Director of Translational Research Cornell University Sprecher Institute for Comparative Cancer Research Program on Breast Cancer and Environmental Factors (BCERF) http://envirocancer.cornell.edu Breast Cancer and Environmental Chemicals: Why is there Concern? 2003 National Pesticide Applicator Certification and Safety Education Workshop

2. Education & Income 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 ???

3. Advancing Age Gender Early Menarche Overweight Hormone Replacement Therapy Alcohol Exposure to Hormones Late Menopause Some Chemicals -Work -Home -Garden -Recreation Lack of Exercise

4. Geographical differences • Rates differ world-wide • Highest – North America, Europe, Australia • Lowest – Africa, India, Asia • Suggested explanations • Differences in screening practices, childbearing, breastfeeding, diet, lifestyle, and exposure to chemicals • Rising rates of breast cancer • In Japan, as they adopt Western-lifestyles • In Asians who migrate to the US

5. 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., 343:78-85, 2000

6. How are we exposed to environmental chemicals? • Routes of exposure • Air we breath • Food we eat & beverages we drink • Contact with our skin • Some chemicals cross the placenta • Some can appear in breast milk

7. 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 • Some may act as anti-cancer agents • Others may be hormone mimics and support breast tumor growth

8. 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

9. Some evidence of higher breast cancer risk Acid mists Benzene Carbon tetrachloride Ethylene Oxide Formaldehyde Lead oxide Methylene chloride Styrene Chemicals in the workplace–what do we know? • Refs: Blair and Kazerouni, Cancer Causes & Control, 8:473-490, 1997 • Cantor et al., J. Occup. Environ. Med., 37:336-348, 1995 • Goldberg and Labreche, Occup. Environ. Med., 53:145-156, 1996 • Hansen, Am. J. Ind. Med., 36:43-47, 1999 • Norman et al., Int. J. Epidemiology, 24:276-284, 1995 • Spiritas et al., Br. J. Ind. Med., 48:515-530, 1991

10. 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

11. Chemicals in the home–what are we exposed to? • Cape Cod Breast Study Silent Spring Institute • Measuring household exposures to hormone-like and cancer-causing chemicals in air and dust samples • Will help identify types of chemicals in the home that may affect breast cancer risk • Will help prioritize chemicals that should be studied Ref: Rudel et al., J. Air Waste Manage. Assoc. 51:499-513, 2001 Rudel et al., Environ. Science and Technol., (in press), Sept. 2003 publication

12. Pesticides and cancer risk–exposure concerns

13. 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.

14. 1999 Estimates of U.S. Pesticide Usage -Conventional pesticide active ingredients Ref: Donaldson et al., Pesticide industry sales and usage, 1998 and 1990 market estimates, Figure 3.3, US EPA, August 2002

15. 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

16. 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)

17. 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

18. 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, 11:523-531, 2000

19. 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

20. Pesticides and breast cancer risk –DDT/DDE possible explanations • Exposure Issues - Chemical form matters • Predominant exposure in western white women • is to very weak estrogenic form (p,p’-DDE) in food • not to estrogenic form that was sprayed (o,p’-DDT ) • 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

21. 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

22. 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 Chemicals and breast cancer risk–National Toxicology Program • Types of compounds that cause mammary (breast) tumors in laboratory animals • Refs: Dunnick et al., Carcinogenesis, 16:173-170, 1995 • Bennett and Davis, Environ. Mol. Mutagen. 39:150-157, 2002

23. Chemicals and breast cancer risk–National Toxicology Program • Pesticides and fumigants that cause mammary tumors in laboratory animals • Clonitralid • 1,2-Dibromo-3-chloropropane (DBCP) • 1,2-Dibromoethane • 1,2-Dichloroethane • 1,2-Dichloropropane • Dichlorvos • Ethylene Oxide • Sulfallate Ref: Dunnick et al., Carcinogenesis, 16:173-170, 1995

24. Hormones and growth factors -dual roles • Many hormones and local growth factors play a role in normal breast growth and in the cancer process • Hormones (endocrine chemical messengers) • Estrogen • Progesterone • Prolactin • Growth Hormone • Growth Factors (local chemical messengers) • Epidermal Growth Factor family • Insulin Growth Factor (IGFs)

25. Endocrine disrupting chemicals–What’s 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

26. 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?

27. 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

28. Endocrine disrupting chemicals–How can we screen chemicals? • 1996 Food Quality Protection Act • Mandates testing of ALL pesticide active ingredients for endocrine disrupting effects • Also will test high volume production inerts • EPA is currently validating screening tests and prioritizing chemicals to be screened • Screening to begin in 2003-04 Ref. http://www.epa.gov/scipoly/oscpendo/

29. TEB, CD-1 mouse, 45 days old Photo whole mount collection of Snedeker and DiAugustine, 1987 TEB, Human, 13 yrs. old Ref: Howard and Gusterson, J. Mam. Gland Biol. Neoplasia, 5:119-137, 2000 Early exposures to chemicals–can they affect breast cancer risk? • Terminal end buds (TEBs) • Target for cancer-causing chemicals

30. Early exposures to chemicals–targets and susceptibility factors • Direct effect - start tumors • Dividing cells in TEBs are targets for carcinogens • TEB cells more susceptible to chemical carcinogens • TEB cells less able to repair damage to DNA • Mature mammary glands (post-lacation) are better able to repair DNA damage • Indirect effect - susceptibility • Chemicals that affect early breast development can influence how breast cells handle other cancer causing chemicals later in life • TEBs that persist are targets for other carcinogens • Chemicals that causes TEBs to persist include: • Atrazine (herbicide used in agriculture) • TCDD (type of dioxin) Refs: Brown et al., Carcinogenesis 19:1623-1629, 1998 Birnbaum and Fenton, Envir. Health Perspect. 111:389-394, 2003

31. 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

32. cancer and environment 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

33. Acknowledgements • Grants: • CSREES, US Department of Agriculture • NYS Depts. of Environmental Conservation and Health • Graphics: • Marie Stewart and Sean Gardener • Library Research Assistants: • Elizabeth Murphy and Laura Obijuru • TEB mammary gland studies: • Collaborator, Richard DiAugustine, NIEHS