Director National Institute of Environmental Health Sciences National Toxicology Program 32 nd International Symposium on Halogenated Persistent Organic Pollutants Monday August 27 2012 ID: 1038227
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1. Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S.DirectorNational Institute of Environmental Health SciencesNational Toxicology Program32nd International Symposium on Halogenated Persistent Organic PollutantsMonday, August 27, 2012Endocrine DisruptorsWhere Do We Go From Here?
2. Sharpe and Irvine, 2004Should We Be Concerned?
3. Data from CDC / National Center for Health StatisticsShould We Be Concerned? Increase in Diabetes (1980-2010)Increase in Autism PrevalenceIncrease in ADHDIncrease in Asthma
4. Why have some diseases increased in incidence over the past 40 years?Genes have not changed over that timeRecent “epidemics” of diabetes, asthma, ADHD, obesity due to environmental, dietary and behavioral changesWe will never understand the etiology of diseases without an understanding of the role of “environmentGene-Environment and Disease
5. “ENVIRONMENT” Includes:Industrial chemicalsAgricultural chemicalsPhysical agents (heat, radiation)By-products of combustion and industrial processes (dioxin)Infectious agentsMicrobiome (gut flora)Foods and nutrientsPrescription drugsLifestyle choices and substance abuseSocial and economic factors
6. Diseases with a Known or Suspected Environmental Component Include:CancersBirth defects (cleft palate, cardiac malformations)Reproductive dysfunction (infertility)Lung dysfunction (asthma, asbestosis)Neurodegenerative diseases (Parkinson’s)Neurodevelopmental disorders (autism)
7. The Endocrine SystemComplex system of hormones and receptorsMultiple receptors (cellular/nuclear)Multiple cofactorsReceptor cross-talkHormones active at pM-nM concentrationsSERMsMultiple modes of action over a wide dose responseNon-monotonic dose responsesHigh doses do not predict low dose effectsHigh doses cause negative feedbackDoses examined must be in the range of agent binding to receptor systemHighly conserved across species
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9. Some Chemicals Disrupt the Endocrine System“Endocrine Disruptors”Exogenous agents that interfere with the production, release, transport, metabolism, binding, action, or elimination of the natural hormones in the body responsible for the maintenance of homeostasis and the regulation of developmental processesEPA definition modified from Crisp et al, “Environmental Endocrine Disruption: An Effects Assessment and Analysis,” EHP 1998.
10. Why We Study Endocrine Disrupting ChemicalsLow doses can have big effectsWide range of effects on our healthEarly life exposures can have persistent effectsEndocrine disrupting chemicals are ubiquitousEffects seen in wildlife, laboratory animals, and people
11. HERBICIDES2,4,-D2,4,5,-TAlachlorAmitroleAtrazineLinuronMetribuzinNitrofenTrifluralinFUNGICIDESBenomylEthylene thioureaFenarimolHexachlorobenzeneMancozebManebMetiram - complexTri-butyl-tinVinclozolinZinebMETALSINSECTICIDESAldicarbbeta-HCHCarbarylChlordaneChlordeconeDBCPDicofolDieldrinDDT and metabolitesEndosulfanHeptachlor / H-epoxideLindane (gamma-HCH)MalathionMethomylMethoxychlorOxychlordaneParathionSynthetic pyrethroidsTransnonachlorToxapheneINDUSTRIAL CHEMICALSBisphenol - A PolycarbonatesButylhydroxyanisole (BHA)CadmiumChloro- & Bromo-diphenylDioxinsFuransLeadManganeseMethyl mercuryNonylphenolOctylphenolPBDEsPCBsPentachlorophenolPenta- to NonylphenolsPerchloratePFOAp-tert-PentylphenolPhthalatesStyreneTestosterone synthesis inhibitor Estrogen receptor agonistThyroid hormone disruptor Androgen receptor antagonistEndocrine Disrupting Chemicals
12. Our endocrine system: tiny amounts of hormones with profound effects on development and normal health Chemical exposures, even at low doses, can disrupt delicate endocrine system and create a mechanism for diseaseFor some endocrine disruptors, biological changes can be seen at low doses, but not at high dosesFor example: BPA, atrazine, DDT, DES, dioxin (TCDD), genistein, nicotine, parathion, PBDE-99, PCB mixtures, perchlorate, sodium fluoride, triclosan, and othersLow Dose
13. Non-Monotonic Dose-Response Curves
14. Non-Monotonic Dose-Response CurvesNMDRCs in hormonesCortisolEstradiolProgesteroneInsulinGrowth HormoneProlactinTestosteroneThyroid HormoneTSHNMDRCs in Endocrine DisruptorsAtrazineBisphenol A (BPA)ChlorpyrifosDDTDESDioxin (TCDD)PBDE-99PCB 180 and PCB MixturesPerchlorateSodium fluorideTributylin oxideTriclosanAnd others…
15. A Practical Example: Tamoxifen FlareNOAELSAFETrueNOAELSAFE“Flare”Modified from Vandenberg et al, “Hormones and EDCs: Low-Dose Effects and Nonmonotonic Dose Responses,” Endocrine Reviews 2012.
16. Example: LeptinModified from Vandenberg et al, “Hormones and EDCs: Low-Dose Effects and Nonmonotonic Dose Responses,” Endocrine Reviews 2012.
17. Wide Range of Health EffectsEndocrine signals govern every organ & process in bodyWhen chemicals interfere, effects can be seen in many different conditions and diseasesRecent work on endocrine disruption shows potential health effects including immune function, metabolism, brain development and behavior. Animal studies identified exposure to environmental endocrine disruptors can cause weight gain later in life. Endocrine Disruptors have also been linked to cancers, altered behavior, diabetes, immune dysfunction, reproductive dysfunction, and cardiovascular disease
18. Decreasing Age of PubertyUS expert panel concluded:Earlier breast development and onset of menarche“Suggest … endocrine-disrupting chemicals …and body fat are important factors associated” with the changeAfrican American and Mexican American girls enter puberty earlier than white girlsEuling et al. Pediatrics 2008.Age of Menarche in Europe and the US from 1790 to 1980
19. Decreasing Age of Puberty The proportion of white girls in the Breast Cancer and the Environment Research Consortium who attained breast stage >2 at age 7 years significantly greater than reported in Pediatric Research in Office Settings (PROS) network in 1997. White girls: 10.4% vs 5.0% (z = 3.72, P = .001)Black non-Hispanic girls: 23.4% vs 15.4% (not significant) The proportion of white girls at breast stage >2 at age 8 also significantly greater than PROS.White girls: 17.9% vs 10.5% (z = 3.77, P < .0002) Black non-Hispanic girls: 37.0% vs 36.6% (not significant) Biro et al, Pediatrics 2010.
20. Decreasing Age of PubertyExposure to three chemical classes (phenols, phthalates, and phytoestrogens) in multiethnic longitudinal study of 1,151 girls:High-molecular-weight phthalate metabolites and triclosan weakly associated with pubic hair development Daidzein with breast stageLow-molecular-weight phthalate biomarkers associated with breast and pubic hair developmentEnterolactone attenuated BMI associations with breast developmentWeak, hormonally active xenobiotic agents had small associations with pubertal development, mainly agents detected at highest concentrations.Wolff et al, EHP 2010
21. Phthalates and Anogenital DistanceHigher exposure to phthalates(phthalate score) results in lower anogenital index (AGI) in boys.Association between AGI and phthalate exposure consistent with phthalate-related syndrome reported in prenatally exposed rodents.Data support hypothesis that prenatal phthalate exposureat environmental levels adverselyaffects male reproductive development.Swann et al, 2005. EHP;113(8):1056–1061
22. Bisphenol A & Diabetes / Obesity (Human Studies)BPA and Diabetes, Glucose Homeostatis, ObesityNTP Review of 8 StudiesStudies range from 2008 – 2011Risk Estimates show:All Odds Ratios > 1.00 for diabetesAll OR > 1.00 for glucose homeostatisAll OR > 1.00 for overweight & obesityNo pooled OR available yet
23. Persistence of Biological EffectsHealth effects of exposure to endocrine disruptors can be observed long after the actual exposure has stopped This is especially true when exposures occur during growth and development, processes that are very sensitive to endocrine regulationEpigenetics: the study of changes in DNA expression that are independent of the DNA sequence.A person’s DNA base sequence doesn’t change, but expression of DNA is affected by changes in DNA “packaging.”Environment is critical factor in DNA expression; we’re born with genes, but environment affects epigenetic changes.
24. Early Prenatal Mid-Late Prenatal PostnatalWeek 1-16 Week 17-40 Birth – 25 yearsCentral nervous system (3 wks - 20 yrs)Ear (4-20 wks)Kidneys (4-40 wks)Heart (3-8 wks)Immune system (8-40 wks; competence & memory birth-10 yrs)Limbs (4-8 wks)Lungs (3-40 wks; alveoli birth-10 yrs)Reproductive system (7-40 wks; maturation in puberty)Skeleton (1-12 wks)Source: Altshuler, K; Berg, M et al. Critical Periods in Development, OCHP Paper Series on Children's Health and the Environment, February 2003.Windows of Susceptibility
25. Developmental ExposuresAGE 2 12 25 40 60 70 Learning Differences/BehaviorAsthmaIncreased Sensitivity to InfectionsTesticular Dysgenesis SyndromeObesityAltered PubertyInfertilityFibroidsPremature MenopauseBreast CancerAtherosclerosisCardiovascular DiseaseProstate CancerAlzheimer'sParkinson'sExamples of Developmental Origins ofHealth and Disease (DOHAD)
26. Maternal Smoking & Children’s ObesityNTP Review of 23 StudiesStudies range from 2001 – 2010Pooled data show:OR=1.5 for obesity (95%CI=1.35-1.65)OR=1.6 for overweight (95%CI=1.42-1.90)Windows of Susceptibility: Tobacco
27. Ubiquitous ExposureChemicals with endocrine disrupting activity are widely dispersed in our environmentEndocrine disruptors often dispersed at biologically effective levels, and exposure to humans is commonCDC’s Report CardAll of us exposed to many different chemicals, and other environmental stressors, at the same timeSynergismGiven exposures can alter the body’s response to later exposuresThe “exposome” is the totality of exposures that a person is subjected to from the environment (“EWAS”)
28. Summary: Where We Go From HereNeed to better characterize:Low dose / nonmonotonic effects Early life exposures may not show effects until later in lifeModes of action change across dose responseWide range of biological effectsAssessment of new endocrine related endpoints may be neededIndividual vs. public health risksEnvironmental health assessments are at individual levelPopulation effects can be much largerRegulatory issues
29. Thank you!NIEHS Strategic Plan Website http://www.niehs.nih.gov/strategicplan