Environmental Exposures and Cancer Risk Maryann Donovan Ph

Environmental Exposures and Cancer Risk Maryann Donovan, Ph. D, MPH March, 2010

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

Cancer is Everyone’s Problem In 2000, approximately 9. 6 million Americans were living with cancer n In 2005, about 1, 368, 030 new cancer cases will be diagnosed and 563, 700 Americans are expected to die of cancer n Cancer affects 1/ 2 men and 1/3 women n In the US, cancer causes 1 of every 4 deaths n NCI Cancer Statistics

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

The axis of ………pollution Unhealthy Food

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

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

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

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

We are Exposed to Mixtures

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

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

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

How can toxic exposures cause cancer?

Cancer Genetics is Complex 20, 000 -25, 000 human genes n n n n 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

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

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

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

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

Epigenetic Patterns Seen in Cancer n n n Genome-wide hypomethylation is one of the earliest events and is a hallmark of cancer cells n Activation of cellular oncogenes and cell growth Tumor suppressor gene methylation n Loss of control of cell division Methylation of DNA mis-match repair enzymes leading to genome instability n 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.

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

Transgenerational Effects Food is Medicine! Yellow Slightly Mottled Heavily Mottled Pseudoagouti Agouti Coat Color Distribution Control Diet Methyl Donor or Genistein Supplementation BPA Exposure ‘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 BPA Exposure plus Methyl Donor or Genistein Supplementation

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

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

Human Evidence for Environmental Role

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

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

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

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

Testicular Cancer Incidence (Men < 30 yrs, 1975 -2006): Age-Specific Rates 10 Incidence (per 100, 000) 8 Age 0 -04 years 05 -09 years 10 -14 years 6 4 2 0 1975 1980 1985 1990 1995 2000 2005 Year of Diagnosis http: //seer. cancer. gov/registries/

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

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

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

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

Childhood Leukemia Incidence (1975 -2006): Age-Specific Rates 10 Incidence (per 100, 000) 8 Age 6 0 -04 years 05 -09 years 4 2 0 1975 1980 1985 1990 1995 2000 2005 Year of Diagnosis http: //seer. cancer. gov/registries/

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

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

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

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

Age of Puberty Falling for Boys and Girls n 1930 to 1970 - Denmark, 5 -6 month decline boys and girls (Aksglaede et al Plos One 2009) n 1940 to 1994 - 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) n endocrine disrupting chemicals and body fat may be important factors.

Environmental Estrogens

Cunningham, Klopman and Rosencranz, 1997.

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

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

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

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

Indoor Air n n Americans spend 90% of their time indoors Dozens of Indoor Air Pollutants n n n n 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

Indoor Air n Health effects n n Allergy, asthma, multiple chemical sensitivity Rashes, dermatitis Chronic health effects, including cancer, but the specific health effects are not known You Can! n n n 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

Heavy Metals Can Act Like Estrogen Lead, Cadmium, Mercury

Lead n Exposure n Contaminated soil and water n from legacy sources: leaded gasoline, lead paint n Household paint - dust n Lead soldered pipes- water n Leaded crystal n Ceramic pottery pre-1970 USA and pottery from other countries (lead glazed) n Hobbies: leaded glass, pottery, furniture refinishing

Lead n n Children and pregnant women are most vulnerable to lead exposure in homes Health effects n n Behavioral disorders, learning disorders Loss of appetite, weight loss, vomiting Pregnancy loss, high blood pressure, violent behavior, seizures You Can! n Buy a lead testing kit and test paint, solder, crystal, dishes n Get tested to determine blood lead levels n there are medical interventions for reducing lead levels

Polychlorinated Biphenyls (PCBs) n n Used 1929 -1970 s in flame retardants, paints, plastics, adhesives, lubricants, sealants, hydraulic and heat transfer fluids, capacitors, transformers, vacuum pumps and gas transition turbines Persistent, remain major global pollutants Indoor air major source of exposure Health effects n n Developmental neurotoxicant Thyroid toxicity Effects on immune, reproductive, nervous, and endocrine systems Cancer, including breast cancer

Polybrominated Diphenyl Ethers (PBDEs) n n n World-wide production- 67, 000 tons in 2001 Flame retardants n found in a variety of consumer products such as plastics, upholstery, construction materials, and electrical appliances n Mattresses, pillows, bedding Persistent, major global pollutant Indoor dust and food major sources of exposure Health effects n Possible developmental neurotoxicant n Thyroid toxicity

Phthalates n n World wide production- 6 million tons per year in 2004 Plasticizer in polyvinyl chloride (PVC) resins (10– 60% of plastic volume) n vinyl upholstery, shower curtains, food containers and wrappers n fragrances, perfumes, air fresheners n toys, floor tiles, lubricants, sealers, and adhesives Cosmetics such as perfume, eye shadow, moisturizer, nail polish, hair spray, and liquid soap Endocrine disruptor

Phthalates n n n Exposure n Food, personal care products, children’s toys Health Effects n Developmental effects in baby boys (anogenital distance; Swan, EHP, 2006) n Sperm quality (Duty, Epidemiology, 2003) You Can! n Purchase non-vinyl products for home renovation projects, shower curtains, childrens toys n Store food in glass not plastic n Eliminate personal care products that contain phthalates

Correlation between plastic metabolites and premature breast development 23 month old girl Colon et al, EHP 2000 Plastic Metabolites in Puerto Rican Girls W/WO Premature Breast Growth

Plasticizers and Pesticides Can Be Endocrine Disruptors Bis-phenol A Pesticides DDT, Methoxychlor, Heptachlor, Dieldrin, Endosulfan Atrazine (weed killer) • EU- banned • US- >70 million pounds applied cornfields, lawns, golf courses • 37 states have atrazine in drinking water

Bis-phenol A n 6 billion pounds 2003 n one of the highest high production volume chemicals n Used to produce plastic polymers used in polycarbonate plastics and epoxy resins n Found in toys, water supply pipes, medical tubing, food container linings, dental sealants, water bottles (#7), sippy cups, baby bottles, white thermal printer receipts

Bis-phenol A n Endocrine disruptor n 2008, National Toxicology Program (NTP) and 2009 Food and Drug Administration (FDA) rule that BPA may pose a threat to humans Science n Rodents (prenatal exposure): increased aggression, memory impairment, changes in maternal behavior , development of preneoplastic mammary lesions n Rodents (prenatal exposure): changes in pubertal age, changes in estrus cycling, changes in brain structure and function n Carr et al, J Toxicol Env Health, 2003; Kawai et al Env Health Perspect, 2003, Miyagawa et al Neuroscience Lett, 2007; Palanza et al Env Res, 2008; Durando et al Env Health Perspect, 2007; reviewed in Patisaul H, American Scientist, 2010

Prenatal exposure to BPA increases the incidence of PIN in male rats and hyperplastic ducts in female mice Ho et al, Cancer Research 2006 Murray et al. Reproductive Toxicology 2006

Bis-phenol A n Human health effects (under investigation) o More than 90% of US population has measurable levels (CDC) o Children 6 -11 had nearly twice the level of 20 yr olds o Aggressive behavior in 2 year old girls Braun et al Env Health Perspect, 2009

Overweight and Obese n n n Epidemic in USA 30% of Adults and 16% of Children are obese Risk factor for heart disease, stroke, diabetes, cancer Energy imbalance; too many calories and not enough exercise Unhealthy calories; prepared foods high in salt, sugar, additives

Questions: Protecting Public Health n n How much and what kind of evidence is required before action is taken to reduce exposures? Are laboratory studies sufficient for demonstrating toxicity? Is population-based evidence demonstrating increased human risk required before taking action? Should the government define and implement safety standards for industry?

Questions: What Standards Should be used to Evaluate Chemical Toxicity? n n Maximizing profit? How do we calculate the cost of production? n n What kind of evidence is required? n n n Laboratory evidence? Population evidence? Human impacts? Ecological Impacts? Is risk-benefit assessment the best option? n n Life cycle costs? Cradle to grave? Cradle to cradle? What endpoints? Effects in children? Chronic disease? Cancer? Does the Precautionary Principle make sense when there is reasonable suspicion of harm?

Some Things You Can ! Do to Reduce Your Risk Lose weight Exercise Avoid animal fats Eat more vegetablesespecially raw Read the newspaper and be informed about these issues Read labels Avoid pesticides and herbicides Minimize exposure to ionizing radiation Wear protective clothing and open windows when using organic solvents Microwave and heat food in glass not plastic Read labels on prepared foods Eat organic food when possible

Center for Environmental Oncology of University of Pittsburgh Cancer Institute Maryann Donovan, Ph. D. , M. P. H. , Director Talal El-Hefnawy, MD, Ph. D Monica Han, Ph. D Steven Bodnar, Amy Eichenberg CEO Funders n Heinz Endowments; Highmark Foundation; The Pittsburgh Foundation, DSF Charitable Trust www. environmentaloncology. org