Environmental Exposures and Cancer Risk

Maryann Donovan, PhD, MPHMarch, 2010

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.

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

deathsNCI Cancer Statistics

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

                                                                                                                                          

Unhealthy Unhealthy FoodFood

Unhealthy Unhealthy FoodFood

The axis of ………pollution

Other Sources of Air Pollution

•Carcinogens•Endocrine disruptors

Mercury

Benzene

Chemicals- the Facts

85,000 chemicals used in commerce

2,200 high production volume (HPV) chemicals

Toxic Substances Control Act (TSCA, 1976) is weak

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)

Sources of Exposure to Environmental Toxics

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

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

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

We are Exposed to Mixtures

Inherited genetic defects account for only 10-30 % of cancer

Environment plays a role in 70% to 90% of cancers.National Cancer InstituteNational Cancer Institute

Environment Contributes to DiseaseIncluding Cancer Risk

Environment is Broadly Defined

Where we work

Where we live

The products

that we use

The food we eat

Lifestyle choices

Who Gets Sick?

Genes Environment

Genes determine individual susceptibility to toxic environmental

exposures

How can toxic exposures cause cancer?

Cancer Genetics is Complex Cancer Genetics is Complex 20,000-25,000 human genes20,000-25,000 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

Gene Mutation

Normal cells

• Damage to critical genes• Ionizing radiation, UV radiation

First hit Second hit

http://www.geneimprint.com

EpigeneticEpigenetic changes 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

Epigenetic Changes Accumulate Over a Lifetime

Chromosome 1

Chromosome 3

Chromosome 17

Chromosome 123 year old

twinsFraga, Mario F., et al. (2005) Proc Natl Acad Sci USA 102:10604-10609.

The Epigenome of Young Twins is Identical

Chromosome 1

Chromosome 3

Chromosome 17

Chromosome 12

50 year old twins

Photo:Maryellen Mark, Ned & Fred MitchellFraga, Mario F., et al. (2005) Proc Natl Acad Sci USA 102:10604-10609.

The Epigenomes of 50 year old Twins Look Unrelated

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.

Epigenetic Patterns Seen in Epigenetic Patterns Seen in CancerCancer

Exposure of Pregnant Mice to Chemicals in Diet Produces Differences in Genetically Identical Offspring

Photo courtesy of Dr. Randy Jirtle, Duke University

Bisphenol-A and Agouti Mice

Prenatal Exposure Affects Adult Weight and Color

Methyl Donor or GenisteinSupplementation

Transgenerational EffectsTransgenerational EffectsFood is Medicine!Food is Medicine!

BPA Exposure plusMethyl Donor or Genistein

Supplementation

BPA Exposure

Control Diet

Agouti Coat ColorDistribution

Dolinoy et al., PNAS 104: 13056-

13061, 2007

‘Let food be thy medicine, and medicine be thy food.’ Hippocrates

Pseudo-agouti

HeavilyMottled

MottledSlightlyMottled

Yellow

Slide courtesy of Dr. Randy Jirtle, Duke Universityhttp://www.geneimprint.com

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

Tumor progression and disease prognosis

Blood supply

Resistance to therapy

Defective DNA repair

Movement

Genetic and Epigenetic Changes Contribute to Tumor Progression

Increased Mutation

Loss of surface markers

recognized by immune cells

Human Evidence for Environmental Role

• 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

Evidence for Environment-Cancer Link

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

Inci

den

ce p

er

10

0,0

00

0

5

10

15

20

25

1975 1980 1985 1990 1995 2000 2005

Year of Diagnosis

Melanoma of the skin

Kidney and renal pelvisThyroi

d

Non-Hodgkin’s lymphoma

Age adjusted to US 2000,

Cancer Trends Incidence (1975-2006)SEER 9 Registry

http://seer.cancer.gov/registries/

Tanning beds

Flame Retardants

Testicular Cancer Trends (Nordic countries)

Jacobsen et al., 2005

Age

Testicular Cancer Incidence (Men < 30 yrs, 1975-2006): Age-Specific Rates

http://seer.cancer.gov/registries/

Non-Hodgkin’s Lymphoma Incidence US Women (1975-2004) SEER 9 Registry

0

20

40

60

80

100

120

40 50 60 70 80Age of Diagnosis

2000-041995-99

1990-941985-89

1980-84

1975-79

0

20

40

60

80

100

120

40 50 60 70 80

1975-79

1980-84

1985-89

1990-94

1995-99

2000-04

White

Inci

den

ce p

er

10

0,0

00

Inci

den

ce p

er

10

0,0

00

Age of Diagnosis

Black

http://seer.cancer.gov/registries/

0

40

80

120

160

40 50 60 70 80

Age of Diagnosis

1975-79

1980-84

1985-891990-94

1995-99

2000-04

0

40

80

120

160

40 50 60 70 80

Age of Diagnosis

2000-04

1995-99

1990-941985-89

1980-841975-79

Inci

den

ce p

er

10

0,0

00

Inci

den

ce p

er

10

0,0

00

Non-Hodgkin’s Lymphoma IncidenceUS Men (1975-2004) SEER 9 Registry

http://seer.cancer.gov/registries/

White Black

0

10

20

30

40

50

60

70

0 10 20 30 40 50 60 70 80Age of Diagnosis

1975-79

1980-84

1985-89

1990-94

1995-99

2000-04

Inci

den

ce p

er

10

0,0

00

Melanoma Incidence (1975-2004) SEER 9 Registry

http://seer.cancer.gov/registries/

0

3

6

9

12

15

18

0 10 20 30 40 50 60 70 80Age of Diagnosis

1975-79

1980-84

1985-891990-94

1995-99

2000-04

Inci

den

ce p

er

10

0,0

00

http://seer.cancer.gov/registries/

Thyroid Cancer Incidence (1975-2004) SEER 9 Registry

Age

Childhood Leukemia Incidence (1975-2006): Age-Specific Rates

http://seer.cancer.gov/registries/

Data Source: National Health Interview Survey, National Center for Health Statistics

Asthma Prevalence by Age (1980-1995) United States

Association between household cleaning products and asthma

Occup Environ Med. 2005 Sep;62(9):598-606

Newschaffer et al., Pediatrics 2005

Autism Prevalence has been Increasing Over Time in the US

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

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 .

Environmental Estrogens

Cunningham, Klopman and Rosencranz, 1997.

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

Ambient levels of estrogenic chemicalsstimulate growth of breast cancer cells in vitro

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

cont

rol

E 8

0

E40

0

endo

80

endo

400

endo

200

0

BP

A 8

0

BP

A 4

00

BP

A 2

000

DD

E 8

0

DD

E 4

00

DD

E 2

000

BaP

80

BaP

400

BaP

200

0

Cou

m 8

0

Cou

m 4

00

Cou

m 2

000

ZO

L 80

ZO

L 40

0

ZO

L 20

00

MC

F7

pro

life

rati

on

(F

old

in

crea

se /

Co

ntr

ol)

Talal El-Hefnawy, MD, PhD

Center for Environmental Oncology

Developing Fetus, Babies, and Small Children are Especially Vulnerable

Developing Organs

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

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

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

Heavy Metals Can Act Like Estrogen

Lead, Cadmium, Mercury

Lead

Exposure Contaminated soil and water

from legacy sources: leaded gasoline, lead paint Household paint - dust Lead soldered pipes- water Leaded crystal Ceramic pottery pre-1970 USA and pottery from other

countries (lead glazed) Hobbies: leaded glass, pottery, furniture refinishing

Lead

Children and pregnant women are most vulnerable to lead exposure in homes

Health effects Behavioral disorders, learning disorders Loss of appetite, weight loss, vomiting Pregnancy loss, high blood pressure, violent behavior, seizures

You Can! Buy a lead testing kit and test paint, solder, crystal,

dishes Get tested to determine blood lead levels

there are medical interventions for reducing lead levels

Polychlorinated Biphenyls (PCBs)

Used 1929-1970s 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

Developmental neurotoxicant Thyroid toxicity Effects on immune, reproductive, nervous, and endocrine systems Cancer, including breast cancer

Polybrominated Diphenyl Ethers (PBDEs)

World-wide production- 67,000 tons in 2001 Flame retardants

found in a variety of consumer products such as plastics, upholstery, construction materials, and electrical appliances

Mattresses, pillows, bedding Persistent, major global pollutant Indoor dust and food major sources of exposure Health effects

Possible developmental neurotoxicant Thyroid toxicity

Phthalates

World wide production- 6 million tons per year in 2004 Plasticizer in polyvinyl chloride (PVC) resins (10–60% of

plastic volume) vinyl upholstery, shower curtains, food containers and

wrappers fragrances, perfumes, air fresheners toys, floor tiles, lubricants, sealers, and adhesives

Cosmetics such as perfume, eye shadow, moisturizer, nail polish, hair spray, and liquid soap

Endocrine disruptor

Phthalates

Exposure Food, personal care products, children’s toys

Health Effects Developmental effects in baby boys (anogenital

distance; Swan, EHP, 2006) Sperm quality (Duty, Epidemiology, 2003)

You Can! Purchase non-vinyl products for home renovation

projects, shower curtains, childrens toys Store food in glass not plastic Eliminate personal care products that contain phthalates

Plastic Metabolites in Puerto Rican Girls W/WO Premature Breast Growth

Correlation between plastic metabolites and premature breast development

Colon et al, EHP 2000

23 month old girl

Plasticizers and Pesticides Can Be Endocrine Disruptors

Bis-phenol A

Atrazine (weed killer)Atrazine (weed killer)•EU- banned •US- >70 million pounds applied cornfields, lawns, golf courses•37 states have atrazine in drinking water

PesticidesPesticidesDDT, Methoxychlor, Heptachlor, Dieldrin, Endosulfan

Bis-phenol A

6 billion pounds 2003 one of the highest high production volume chemicals

Used to produce plastic polymers used in polycarbonate plastics and epoxy resins

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

Endocrine disruptor

2008, National Toxicology Program (NTP) and 2009 Food and Drug Administration (FDA) rule that BPA may pose a threat to humans

Science Rodents (prenatal exposure): increased aggression,

memory impairment, changes in maternal behavior , development of preneoplastic mammary lesions

Rodents (prenatal exposure): changes in pubertal age, changes in estrus cycling, changes in brain structure and function

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

Murray et al. Reproductive Toxicology 2006Ho et al, Cancer Research 2006

Prenatal exposure to BPA increases the incidence of PIN in male rats and hyperplastic ducts in female mice

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 oldso Aggressive behavior in 2 year old girls

Bis-phenol A

Braun et al Env Health Perspect, 2009

Overweight and Obese

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 Questions: Protecting Public HealthHealth

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?

Maximizing profit? How do we calculate the cost of production?

Life cycle costs? Cradle to grave? Cradle to cradle? What kind of evidence is required?

Laboratory evidence? Population evidence? Human impacts? Ecological Impacts?

Is risk-benefit assessment the best option? 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

vegetables-especially 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

CEO Funders Heinz Endowments; Highmark Foundation; The Pittsburgh Foundation, DSF Charitable Trust

www.environmentaloncology.org

Center for Environmental Oncology of Center for Environmental Oncology of University of Pittsburgh Cancer InstituteUniversity of Pittsburgh Cancer Institute

Maryann Donovan, Ph.D., M.P.H., DirectorMaryann Donovan, Ph.D., M.P.H., DirectorTalal El-Hefnawy, MD, PhD

Monica Han, PhDSteven Bodnar, Amy Eichenberg