Environmental Exposures and Cancer Risk

1. Environmental Exposures and Cancer Risk Maryann Donovan, PhD, MPH March, 2010

2. Three Things to Remember • There are many exposures of concern in the environment and we have measurable levels of many chemicals in our bodies • Rates and prevalence of many diseases have been increasing over the last 60 years. • You Can! become aware of environmental risks and, through better and different choices, reduce your exposure.

3. Cancer is Everyone’s Problem • In 2000, approximately 9.6 million Americans were living with cancer • In 2005, about 1,368,030 new cancer cases will be diagnosed and 563,700 Americans are expected to die of cancer • Cancer affects 1/ 2 men and 1/3 women • In the US, cancer causes 1 of every 4 deaths NCI Cancer Statistics

4. Sources of Exposure • Micro-environment • Homes (indoor air, consumer products) • Lifestyle • Personal care products • Food • obesity • Macro-environment • Farming (factory farms vs mid-sized organic) • GMO • Industrial pollution • Air/Water • Regulatory climate/chemicals policy

5. The axis of ………pollution Unhealthy Food

6. Other Sources of Air Pollution • Carcinogens • Endocrine disruptors Benzene Mercury

7. Chemicals- the Facts • 85,000 chemicals used in commerce • 2,200 high production volume (HPV) chemicals • Toxic Substances Control Act (TSCA, 1976) is weak

8. Are We Exposed? • All humans, including newborn babies, have measurable levels of chemicals in their bodies • Laboratory research indicates that some of these pollutants may cause disease • We still don’t know the health effects of mixtures (chemical soup)

9. Water (industrial pollution, lawn chemicals) Occupational Food (pesticides, waxes, preservatives, chemical ingredients) Indoor and outdoor hobbies (golf, wood working, car repair) Personal Care Products (PCPs) Lifestyle (exercise, smoking, drinking, stress) Air Pollution (vehicle exhaust, industrial exhaust, coal fired power plants) Homes, indoors (furniture, paint, pesticides, household hazardous waste) Homes, outdoors (pesticides, paint, home/lawn/garden repair) Neighborhoods (heavy industry, coal fired power plants, superfund sites) Sources of Exposure to Environmental Toxics

10. Furniture Formaldehyde Flame retardants Paint Volatile organics Pigments and metals Organic solvents Carcinogens Pesticides Endocrine disruptors Carcinogens Radon Pets and Dust Mites Allergens Cigarette smoke Endocrine disruptors Carcinogens Mold and bacteria Sources of Exposure - Homes • Food • Pesticides • Sugar • Salt • Artificial sweeteners • Artificial flavors • Artificial colors • Personal Care Products • Allergins • Endocrine disruptors • Carcinogens • Consumer Products (cleaning products, air fresheners) • Allergins • Reproductive and developmental defects • Carcinogens

11. We are Exposed to Mixtures

12. Environment Contributes to Disease Including Cancer Risk Inherited genetic defects account for only 10-30 % of cancerEnvironment plays a role in 70% to 90% of cancers. National Cancer Institute

13. The products that we use Where we work Lifestyle choices The food we eat Where we live Environment is Broadly Defined

14. Genes Environment Genes determine individual susceptibility to toxic environmental exposures Who Gets Sick?

15. How can toxic exposures cause cancer?

16. Cancer Genetics is Complex 20,000-25,000 human genes • Turn on cellular oncogenes • Turn off tumor suppressor genes • Altered expression of growth factor receptors • Loss of cell cycle controls • Loss of surface proteins preventing immune recognition • Loss of cell death response • Loss of contact inhibition • Expression of genes that allow cells to break down tissue and metastasize

17. First hit Second hit Gene Mutation Normal cells • Damage to critical genes • Ionizing radiation, UV radiation

18. Epigenetic changes • Epi·ge·net·ics - “above genetics” • Epigenetics research is the study of heritable changes in gene function that occur without a change in the sequence of the DNA. • DNA methylation • Histone methylation or acetylation Slide courtesy of Dr. Randy Jirtle, Duke University http://www.geneimprint.com

19. Epigenetic Changes Accumulate Over a Lifetime The Epigenome of Young Twins is Identical Chromosome 1 Chromosome 3 3 year old twins Chromosome 12 Fraga, Mario F., et al. (2005) Proc Natl Acad Sci USA 102:10604-10609. Chromosome 17

20. Chromosome 1 Chromosome 3 Chromosome 12 50 year old twins Photo:Maryellen Mark, Ned & Fred Mitchell Chromosome 17 The Epigenomes of 50 year old Twins Look Unrelated Fraga, Mario F., et al. (2005) Proc Natl Acad Sci USA 102:10604-10609.

21. Epigenetic Patterns Seen in Cancer • Genome-wide hypomethylation is one of the earliest events and is a hallmark of cancer cells • Activation of cellular oncogenes and cell growth • Tumor suppressor gene methylation • Loss of control of cell division • Methylation of DNA mis-match repair enzymes leading to genome instability • Inability to repair DNA damage and accumulation of genetic mutations The fetus is especially vulnerable to epigenetic changes resulting from maternal exposures, however, epigenetic changes occur throughout life.

22. Exposure of Pregnant Mice to Chemicals in Diet Produces Differences in Genetically Identical Offspring Bisphenol-A and Agouti Mice Prenatal Exposure Affects Adult Weight and Color Photo courtesy of Dr. Randy Jirtle, Duke University

23. Transgenerational Effects Food is Medicine! Heavily Mottled Yellow Slightly Mottled Pseudo- agouti Mottled Control Diet BPA Exposure Methyl Donor or Genistein Supplementation BPA Exposure plus Methyl Donor or Genistein Supplementation Agouti Coat Color Distribution ‘Let food be thy medicine, and medicine be thy food.’Hippocrates Dolinoy et al., PNAS 104: 13056-13061, 2007 Slide courtesy of Dr. Randy Jirtle, Duke University http://www.geneimprint.com

24. Why are Epigenetic Changes Important? • They turn critical genes on or off and can change • Maternal exposures can change epigenome of offspring in humans and animals • Mechanism to explain how environmental exposure can cause disease including cancer Weidman JR et al. The Cancer Journal 13(1):9-16, 2007

25. Genetic and Epigenetic Changes Contribute to Tumor Progression Resistance to therapy Loss of surface markers recognized by immune cells Blood supply Tumor progression and disease prognosis Increased Mutation Defective DNA repair Movement

26. Human Evidence for Environmental Role

27. Evidence for Environment-Cancer Link • Fewer than half of identical twins get the same cancer • Workers in certain industries have higher rates • Regional increases remain unexplained • Immigrant’s cancer risk parallels that of their new country • The majority of cancer cases have no known risk factors • For many cancers rates are increasing

28. Cancer and Other Adverse Health Effects are on the Rise • For some cancers the rate has continued to increase over the last 50 years • All of the increase cannot be explained by better ascertainment

29. 25 Non-Hodgkin’s lymphoma 20 Melanoma of the skin 15 Incidence per 100,000 10 Kidney and renal pelvis Thyroid 5 0 1975 1980 1985 1990 1995 2000 2005 Year of Diagnosis Cancer Trends Incidence (1975-2006) SEER 9 Registry Age adjusted to US 2000, Tanning beds Flame Retardants http://seer.cancer.gov/registries/

30. Testicular Cancer Trends (Nordic countries) Jacobsen et al., 2005

31. Testicular Cancer Incidence (Men < 30 yrs, 1975-2006): Age-Specific Rates Age http://seer.cancer.gov/registries/

32. 120 120 White 100 2000-04 100 1995-99 1990-94 80 80 1985-89 1980-84 60 60 1975-79 1995-99 2000-04 1985-89 40 40 1990-94 1980-84 1975-79 20 20 0 0 40 50 60 70 80 40 50 60 70 80 Age of Diagnosis Non-Hodgkin’s Lymphoma Incidence US Women (1975-2004) SEER 9 Registry Black Incidence per 100,000 Incidence per 100,000 Age of Diagnosis http://seer.cancer.gov/registries/

33. 160 160 2000-04 1995-99 1990-94 120 120 1985-89 1980-84 80 1995-99 80 1975-79 2000-04 1990-94 1985-89 40 40 1980-84 1975-79 0 0 40 50 60 70 80 40 50 60 70 80 Age of Diagnosis Age of Diagnosis Non-Hodgkin’s Lymphoma Incidence US Men (1975-2004) SEER 9 Registry White Black Incidence per 100,000 Incidence per 100,000 http://seer.cancer.gov/registries/

34. 70 2000-04 60 1995-99 50 1990-94 40 Incidence per 100,000 1985-89 30 1980-84 20 1975-79 10 0 0 10 20 30 40 50 60 70 80 Age of Diagnosis Melanoma Incidence (1975-2004) SEER 9 Registry http://seer.cancer.gov/registries/

35. Thyroid Cancer Incidence (1975-2004) SEER 9 Registry 18 15 12 2000-04 1995-99 Incidence per 100,000 9 1975-79 1985-89 1990-94 1980-84 6 3 0 0 10 20 30 40 50 60 70 80 Age of Diagnosis http://seer.cancer.gov/registries/

36. Childhood Leukemia Incidence (1975-2006): Age-Specific Rates Age http://seer.cancer.gov/registries/

37. Asthma Prevalence by Age (1980-1995) United States Data Source: National Health Interview Survey, National Center for Health Statistics

38. Association between household cleaning products and asthma Occup Environ Med. 2005 Sep;62(9):598-606

39. Autism Prevalence has been Increasing Over Time in the US Newschaffer et al., Pediatrics 2005

40. Prenatal BPA exposure May be Associated with Externalizing (Aggressive) Behaviors in 2-year-old Girls Braun et al., Environ Health Perspec 2009

41. Age of Puberty Falling for Boys and Girls • 1930 to 1970- Denmark, 5-6 month decline boys and girls (Aksglaede et al Plos One 2009) • 1940 to1994- US girls 5-6 month decline for breast development onset and menarche (Euling, et al Examination of US Puberty Timing Data from 1960 to 1994 for Secular Trends: Panel Findings, Pediatrics, 2010) • endocrine disrupting chemicals and body fat may be important factors .

42. Environmental Estrogens

43. Cunningham, Klopman and Rosencranz, 1997.

44. Endocrine Disrupting Chemicals • Compounds in the environment that mimic or block endogenous hormones • Activate the parts of the endocrine system associated with the steroid/retinoid/thyroid super-family of receptors • o,p-DDT (pesticide), PCBs (insulator), bis-phenol A (plasticizer), and p-nonylphenol (detergent) Reviewed in Crews and McLachlan, Endocrinology, 2006

45. Ambient levels of estrogenic chemicals stimulate growth of breast cancer cells in vitro Talal El-Hefnawy, MD, PhD Center for Environmental Oncology

46. Developing Fetus, Babies, and Small Children are Especially Vulnerable Developing Organs

47. Children are not Little Adults • More surface area to absorb toxins through the skin • Put all sorts of things into their mouth • Spend more time on or near the floor • Faster heart rate and respiratory rate • Systems are still developing

48. Indoor Air • Americans spend 90% of their time indoors • Dozens of Indoor Air Pollutants • Allergens: furry pets and dust mites • Volatile Organic Chemicals (paint, furniture, wall board, consumer products, dry cleaning fluid) • Contaminants in dust (lead, asbestos, flame retardants, phthalates) • Cigarette smoke • Combustion contaminants (natural gas, kerosene) like carbon monoxide • Pesticides including banned (in US) pesticides like DDT, chlorpyrifos, chlordane • Mold and bacteria • Radon

49. Indoor Air • Health effects • Allergy, asthma, multiple chemical sensitivity • Rashes, dermatitis • Chronic health effects, including cancer, but the specific health effects are not known • You Can! • Reduce or eliminate use of toxic consumer products and pesticides • Smoke cigarettes outdoors • Purchase paints and stains that do not contain VOCs • Purchase natural flooring materials like cork and linoleum • Purchase natural wood furniture instead of pressed wood or engineered wood • Purchase low-VOC carpeting and upholstered products that do not contain flame retardants

50. Heavy Metals Can Act Like Estrogen Lead, Cadmium, Mercury