Towards 2020: Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S. Director National Institute of Environmental Health Sciences National Toxicology Program

Transcription

1 Towards 2020: What are the Critical Environmental Health Challenges? Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S. Director National Institute of Environmental Health Sciences National Toxicology Program 29 January 2017 Workshop: Environmental Health in Israel 2017: Progress & Challenges Mishkenot Shaananim, Jerusalem

2 Tobacco Smoke Climate Change Non-Ionizing Radiation Indicators of Environmental Chemicals in Food Contaminents Health Trends Pesticides Chemicals in Consumer Products Indoor Air Chemicals in Drinking Water Pollutants in Wastewater Planning Ambient Air Human Biomonitoring

3 Critical Environmental Health Challenges not listed on Slide #2 Developmental Origins of Health and Disease Low-Dose Effects The Exposome Human Microbiome Mixtures Individual variability and susceptibility Transgenerational Effects

4 Low-Dose Low-Dose Effects Shift from high-dose lethality to low-dose subtle effects Constant low-dose exposure to short-lived chemicals Non-monotonic effects Novel exposures to unknown hazards Low Dose Biologic changes that occur in the range of human exposures. NTP, 2001 Three Generalized Truths: 1. Exposures increase over time 2. More effects are identified over time 3. Subtle effects are seen at lower & lower levels...

5 DOHAD Developmental Origin of Adult Disease: Barker Hypothesis 1989 David Barker: inverse relationship between birth weight and death from heart disease in England and Wales Dutch Hunger Winter : food supply to the Netherlands was cut off by Nazis Individuals born during this time had increased insulin-resistance as adults Fetal Origin of Adult Disease (FOAD) confirmed for: Coronary heart disease Hypertension Type II diabetes D. Barker, Trends in Endocrinology and Met. (2010)

6 Endocrine disruptor action is life-stage specific DOHAD Developmental Effects (Organizational) Most sensitive exposure window Persistent effects Latent periods Low Doses of Hormones Can Induce Permanent Alterations in Development Adult Effects (Activational) Usually higher doses Effects as long as EDC present Can augment developmental effects A bad start lasts a lifetime!

7 Certain Chemicals are Particularly Bad Actors Compound Use/Source Disease Links DOHAD Bisphenol-A Phthalates PCBs (polychlorinated biphenyls) Plastics, thermal receipts Plastics, fragrances Electrical coolant and other uses Breast and other cancers, metabolism, puberty, neurobehavioral Low sperm count, metabolism, birth defects, asthma, neurobehavioral Cancer, developmental issues PBDEs Flame retardants Thyroid disruption, neurological issues Lead Drinking water, paint, gasoline Neurological issues, premature birth, kidney disorders Mercury Burning coal, seafood Neurological issues, diabetes Dioxin Formed in industrial processing Cancers, sperm quality, fertility, neurobehavioral DDT/DDE/DDD Pesticides Cancers, developmental toxicity

8 Mixtures Define the exposome An untargeted (hypothesis free) assessment of the totality of environmental exposures External, internal, or both? How to measure it New tools necessary to monitor exposure Can use biomonitoring or untargeted metabolomics to begin to do top-down approach Mixtures Chemical Non-chemical (infectious agents, diet, pyscho-social) Multiple Stressors

9 The Exposome Data Collection and Sharing Epidemiology Mechanistic Research Risk Assessment Citizen Science

10 The Exposome Challenges in epidemiological applications of the exposome Sociological Integration of different stakeholder perspectives Willingness to do untargeted discovery Technological Integration external exposure and internal response Technologies for multi-analyte exposure assessment Logistical Time scale: Lifetime; Windows of Susceptibility; Prospective vs. Retrospective Sample collection, size, power and analysis

11 The Exposome Citizen Science and Community Engaged Research and the exposome Research Partnerships Information / Knowledge Empowerment Public Health Action EH Programs Reduction of exposure Change in health status

12 Human Microbiome The Microbiome: A New Paradigm New genomic technologies have enabled comprehensive identification of the microbial community inhabiting our bodies: the microbiome Studies reveal associations between the composition of the microbiome and health and disease Commensal microbes have a role in metabolism of environmental toxicants Environmental exposures to chemicals, metals, antibiotics, etc., influence the composition of the microbiome

13 Dolinoy et al Variability Types of Variability Binary vs. continuous variation Among Subjects (Interindividual) vs. Within Subject (Intraindividual)

14 Variability Sources of Variability Genetics (e.g., sex, tissue/cell type, etc.) Environment Diet Exposures/Exposome Stress Biological timing Socioeconomic Behavioral Microbiome Infectious agents

15 Variability Interindividual Variability Leads to Health Disparities 10% of asthma patients suffer severe symptoms despite regular use of corticosteroids Identified 2 SNPs in glucocorticoid signaling pathway gene associated with decreased clinical response to inhaled corticosteroids in asthmatic children and young adults Suggests genetic variation contributes to interindividual variability in clinical response Proteomics identified 111 altered proteins in cord blood of infants prenatally exposed to arsenic Interindividual differences: as maternal arsenic levels increased, 60% of infants had above average protein expression (activators); 40% of infants had lower expression (repressors) Activator males had decreased head circumference; no significant difference between activator/repressor females African Americans disproportionately affected by prostate cancer aggressiveness, and lower plasma 25(OH)D3 Those with highest percentage of African American ancestry had lowest mean plasma 25(OH)D3 Higher plasma levels associated with increased odds of aggressive prostate cancer among African Americans, but not European Americans

16 Variability Health Disparities and Vulnerable Populations We need to protect the most vulnerable, not just the average! Children - size, respiration rate, and development stage all create vulnerabilities Elderly compromised immune systems, less able to compensate Race genetics, behaviors, and medicine can all influence individual susceptibility Socio-Economics - may dictate where you live, what you eat, and thus your exposure Occupation influences not only your exposure but also your family s

17 Transgenerational Inheritance: Does it exist? What is its significance for human health? Primordial Germ Cell Developmental Window Gestating mother exposed to an endocrine disruptor (sex-determination period) Transgenerational Effects F 0 F 1 F 2 germ line Male embryo (F 2 ) F 2 F 3

18 Transgenerational Effects Chemicals Causing Transgenerational Changes Chemical Transgenerational Effects Mechanism BPA Behavioral changes through F4 Obesity Alteration of neuropeptide genes. DNA methylation Methoxychlor Steroid biosynthesis, ovarian effects Unclear DES Uterine and mammary gland changes Expression of Hox genes, ER signaling Vinclozolin Sperm counts DNA methylation on imprinted genes Dioxins AhR expression in prostate, liver, and sperm DNA methylation on imprinted genes TBT Obesity, hepatic steatosis Mesenchymal stem cell changes, epimutations Xin F, et al. 2015

19 TODAH RABA! תודה רבה