Maida P. Galvez, MD, MPH - Mount Sinai Hospital

Maida P. Galvez, MD, MPHAssistant Professor, Region 2 PEHSU DirectorDepartments of Preventive Medicine and PediatricsMount Sinai School of Medicine

Breast Cancer Risk Factors• Gender• Increasing Age• Family History of Breast CA• Genetic Factors (BRCA1, BRCA2)• Radiation Exposure• Obesity• Late menopause >55 years• 1 st child after age 35 years

Risk Factors through the LifespanPregnancy Birth Infancy Childhood Adolescence AdulthoodNot well characterizedWell characterized

Objectives• To describe trends in early puberty in girls, apotential risk factor for Breast Cancer• To describe the role of environmental factors inearly puberty• To describe how the BCERC NationalConsortium is addressing questions about therole of the environment on early childhood riskfactors for breast CA.

Onset of Puberty

Puberty in Girls• In the US, first breast development occurs:– 8.9 years of age in Black girls– 10 years of age in White girls• Average age at menarche is– 12.1 years of age in Black girls– 12.6 years of age in White girlsHermans-Giddens et al, 1997

Ages at Puberty in US Girls n=1623born 1988-1994 in NHANES IIIB2 MenarcheAfrican-American 9.5 12.1 yCaucasian 10.3 12.7 yHispanic (Mex-Amer) 9.8 12.2 yWu, 2002

Copenhagen Puberty StudyB2 Menarche1991 (n=1100) 10.88 13.42 y2006 (n=995) 9.86 13.13 yAksglaede 2009. Findings remained significant after adjusting for BMI.

Age at Menarche• Historical decline in age at menarcheamong Caucasians:–17 yr in 1800–14 yr in 1900–12.7 yr in 1960’s• Among black girls, average age atmenarche has been 0.4 yr younger thanamongst Caucasians since 1900

Early Menarche and Breast Cancer• Early menarche increases risk for breastcancer by 30%• Early menarche defined as age atmenarche 15 years

Early Puberty and Breast CancerAre other pubertal milestones risk factors forBreast Cancer?Hypothesis:• If age at Menarche is relatively stable over thepast few decades, and age at B2 is declining– Suggests tempo is increasing– Developing breast may be more vulnerable toenvironmental exposures– Increased hormone exposure over a lifetimepromotes development of breast cancer– May help explain in part recent trends in Breast CA

Estrogen levels throughout life10000pregnancyEstrogen levels,pg/mL100010010birthOC usemenopauseHRT10 10 20 30 40 50 60 70 80menarchepubertyAge, yearsMost breast cancer studies

Selected EnvironmentalExposures related to EstrogenEstrogenic activityPhytoestrogens (anti-estrogenic) ++Alkylphenols ++Phthalates +

Environmental Exposures and Puberty• Delayed Puberty– lead: Selevan et al., 2003; Wu et al., 2003– phytoestrogens: Wolff et al., 2008• Advanced Puberty– pcbs: Denham et al., 2005; Gladen et al., 2000– pesticides: Vasilu et al 2004; Oyuang et al 2005

Environment and PubertyEndocrine disruptors may influence:– the onset of puberty– the duration of time in puberty “tempo”Age at 1st Menses

Where are Phthalates found?

Phthalates Findings• What we know about phthalates is largelyfrom animal studies• These studies demonstrate that the malereproductive tract is particularly sensitiveto the anti-androgenic effects of phthalates

Phthalates Findings in HumansThough the data is limited, some humanstudies demonstrate an associationbetween phthalates and:– Alterations in hormone levels– Male Infertility– Asthma, puberty and body size– Decreased anogenital distance

Product Phthalate MetaboliteToysMedicalsuppliesToysPVC, vinylfloors,cosmeticsCosmetics: eg,nail polish andperfumesDEHP: di-(2-ethylhexyl) phthalateDINP: di-isononyl phthalateDIDP: di-isodecyl phthalateDNOP: Di-n-octylphthalateBBzP: benzyl butyl phthalateDEHP: di-(2-ethylhexyl) phthalateDEP: diethyl phthalateDBP: dibutyl phthalateDMP: dimethyl phthalateMEHP: mono-(2-ethylhexyl) phthalateMEOHP: Mono(2-ethy-5-oxolhexyl) phthalateMEHHP: Mono(2-ethyl-5-hydroxyhexyl) phthalateMECPP: Mono(2-ethy-5-carboxypentyl) phthalateMINP: monoisononyl phthalateMCIOP: mono(carboxy-isooctyl) phthalateMOINP: mono(oxoisononyl)phthalateMHINP: mono (hydroxy-isononyl)phthalateMIDP: monoisodecyl phthalateMnOP: :mono-n-octyl phthalateMBzP: monobenzyl phthalateMEHP: mono-(2-ethylhexyl)phthalateMEOHP: Mono(2-ethy-5-oxolhexyl)phthalateMEHHP: Mono(2-ethyl-5-hydroxyhexyl)phthalateMECPP: Mono(2-ethy-5-carboxypentyl)phthalateMEP: monoethyl phthalateMBP: monobutyl phthalate

Centers for Disease Control (CDC)3 rd Report on Human ExposuresGeometric Means of Phthalates (ug/g) by agePHTHALATE 6-11yo 12-19yo 20yo+mEP 96.9 152 181mEHHP 38.3 19.2 17.2mEOHP 26.6 13.5 11.4mBP 35.5 19.4 16.1mBzP 38.1 17.9 12miBP 4.8 2.7 2.3mEHP 5.02 3.5 4.0

Bisphenol A (BPA)

BPA and Early Puberty in Animals• Low dose exposures in pregnancy:– Shortened pubertal tempo (Howdeshell et al, 1999)– Irregular cycles (Rubin et al, 2001)• Low and high dose postnatal exposures:– Early puberty (Ashby and Tinwell, 1998; Kato et al, 2003)– Irregular cycles (Laws et al, 2001)Rasier G, 2006

BPA Exposures are Widespread• NHANES 2003-2004 Calafat et al.– US population ages 6-85 years (n=2517)– BPA present in 95% of population– Children 6-11 years (n=217)• geometric mean BPA=4.3 ug/gram creatinine• children >6 years old (p < 0.001) and adolescents(p < 0.003) had higher levels than adults

Summary of BPA FindingsBPA is a weak estrogen• Animal studies:– Neurocognitive disorders: hyperactivity and impaired learning– Early puberty– Increased body size– Breast, Uterine and Prostate Cancer• Human studies limited– Neuro-developmental effects– Cardiovascular disease and Type 2 Diabetes– Liver function (GGT, LDH, Alk Phos)– Cancer classification controversial

BCERCIn 2003, a consortium of Breast Cancer and the Environment ResearchCenters (BCERC) were developed through a partnership betweenNIEHS and NCI• New York and Pennsylvania– Mount Sinai School of Medicine, NY– Fox Chase Cancer Center, Philadelphia, PA• Cincinnati, Ohio– Division of Adolescent Medicine, Cincinnati Children's Hospital,Cincinnati, Ohio– Department of Environmental Health, University of Cincinnati College ofMedicine and Academic Health Center, Cincinnati, Ohio• California Bay Area– Kaiser Permanente Health Maintenance Organization, Oakland,California– UCSF Comprehensive Cancer Care Center, University of California atSan Francisco, California

Outcomes of Interest• Breast and hair development• Age at Menarche• Tempo• Obesity

Exposures of Interest• Developmental and lifestyle factors– Food intake and physical activity levels– Growth patterns, birthweight, etc.• Environmental exposures– Phytoestrogens– Phthalates– Alkyl phenols including bisphenol A– PBDEs, PCBs, and pesticides– PFOAs– Heavy metals such as lead and cadmium– Cotinine• Genetic Factors

BCERC Cohort• Mean ages at baseline– 7.34 years (NY)– 7.13 years (OH)– 7.38 years (CA)• Parent or guardian reported Race/ethnicity– 34% White, non-Hispanic– 30% Hispanic– 25% Black, non-Hispanic– 4% Black, Hispanic– 5% Asian– 2% Other

BCERC Cohort: Percent of 7 yearolds at Breast Stage 2+White,non-HispanicBlack,non-HispanicBlack,HispanicNY OH CA ALLn=191 n=303 n=432 n=92614% 4% 9%14% 31% 21% 23%8% 8%Hispanic 18% 13% 11% 14%Total 15% 18% 9% 13%

Mount Sinai Growing Up HealthyBreast Stage 2+ by BMI (n=412)BMIpercentileBlack,non-Hispanicn=21Hispanicn=56Black,Hispanicn=12

Exposures are Ubiquitous in 6-8-yo BCERC GirlsGeometric means in μg/g creatinine N=950 (2004-07)1000Phthalate monoesters(medians 45-98 ug/L)Median Urinary Biomarkers among 1151 BCERC Girls at BaselinePhenols(medians

Results• There were significant differences inpubertal status by race/ethnicity across thethree sites.• Overall, 13% of 7 year old girls (n=919)attained breast stage 2 or greater– 20% of Black, non-Hispanic girls– 19% of Hispanic girls– 9% of White girls

Clinical Implications• Families are concerned about early puberty ingirls• Health Care providers need to considercounseling on pubertal development at earlierages• Until more is known, there are simple stepsfamilies can take to reduce exposures

What Can You Do to ReducePhthalates and BPA Exposures?• Arm yourselves with evidence basedinformation so that you may makeinformed decisions about what is best foryour family• In the absence of scientific certainty, erron the side of caution and take aprecautionary approach

In the Absence of Mandated Labeling,Look to Recycling LabelsFront of cardBack of cardClaudio L.

What Can You Do to ReducePhthalates and BPA Exposures?Take a Precautionary Approach• Wet mop and dust frequently• Choose fragrance free products• Seek phthalates and bpa free products– Glass food containers– Stainless Steel• For #3 and #7 plastics:– Avoid use in microwave– Avoid use in dishwasherNY Times, 2009

Implications• Longitudinal analyses of the BCERCcohort data may– define more precisely the factors associatedwith onset of puberty, a potential early life riskfactor for breast cancer– Elucidate potential interventions targetingprimary prevention efforts for breast cancer

BCERC 2003-2010• Long term federal investment in thesenovel approaches to elucidating breastcancer risk factors through the life span• Renewed commitment for 2010-2015

The Mount Sinai NIEHS/EPA Center for Children’sEnvironmental Health and Disease Prevention ResearchThe NIEHS/NCI Breast Cancer and the EnvironmentResearch CenterBarbara BrennerJulie BrittonJia ChenLuz ClaudioStephanie EngelJoel FormanJim GodboldJessica GutierrezLouisa HongPhil LandriganLaura LiaoAna MejiaKim MorlandArkeyris RichiezSusan TeitelbaumNita VangeepuramSarah WilliamsJames WetmurMary WolffChenbo Zhu

BCERC Consortium• Fox Chase Cancer Center• Michigan State University• University of Cincinnati• Cincinnati Children’s Hospital• UCSF Comprehensive Cancer Center• Kaiser Permanente• Lawrence Berkeley National Laboratory• University of Alabama Birmingham

Acknowledgements• Breast Cancer and Environment Research Centers– http://www.bcerc.org/index.htm• National Institute of Environmental Health Sciences– #2 P01 ES009584• National Cancer Institute– #U01 ES012771• Environmental Protection Agency– #P50 RD8317101• National Center for Research Resources– #MO1-RR-00071• Agency for Toxic Substances and Disease Registry– #ATU 300014• Centers for Disease Control– #5U58DP001010-02• NYS Department of Health Empire Clinical Research Investigator Program– ECRIP