Breast Cancer and Environmental Chemicals: Why is there Concern?

1. 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 Breast Cancer and Environmental Chemicals: Why is there Concern?

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. 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 ???

5. Advancing Age Gender Early Menarche Overweight Hormone Replacement Therapy Alcohol 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., 343:78-85, 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

11. 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

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, 12:279-287, 2001 Davis et al., JNCI, 93:15571562, 2001 Hansen et al., Epidemiology, 12:74-77, 2001 Schernhammer et al, JNCI, 93:1563-1568, 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. 51:499-513, 2001 Rudel et al., Environ. Science and Technol., 37:4543-53, 2003

15. 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

20. 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

21. 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. 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

25. EnviroChem and Cancer Databasehttp://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.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

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

28. 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?

29. 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. 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

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

33. 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

34. 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