Columbia University Superfund Research Program 9/15/2018 Emerging Issues: Arsenic Exposure Joseph H. Graziano, Ph.D. Program Director Columbia University Superfund Research Program 1

Arsenic Presents a Major Public Health Problem Known carcinogen Lung, liver, skin, bladder, kidney, and more Early life exposure → increased risk as adults Multiple potential health effects on essentially every bodily system Skin Respiratory system Cardiovascular system Endocrine system (e.g., diabetes) Immune system Nervous system And more… Arsenic rated #1 on the ATSDR 2011 Substance Priority List as the top chemical of concern as a public health hazard 2

History of SRP Arsenic Research SRP has been committed to arsenic research since the inception of SRP in 1987 SRP takes a “soup-to-nuts” approach to arsenic research and development Detection systems Remediation Identifying and reducing exposures Health effects Training and education of scientists and community partners Community and government engagement Transdisciplinary partnerships to solve problems in communities 3

History of SRP Arsenic Research 9/15/2018 History of SRP Arsenic Research Started funding arsenic research from SRP’s inception in 1987 Currently funding numerous arsenic-related projects at 19 university SRP research centers SRP researchers have published over 150 arsenic- related scientific papers since 2006 4

SRP Activities to Address Arsenic Challenges 9/15/2018 SRP Activities to Address Arsenic Challenges Identifying sources of contamination Characterizing toxic arsenic species and biomarkers of exposure in humans Identifying arsenic-related health effects and mechanisms of toxicity Exploring ways to mitigate health effects Engaging communities, government, and stakeholders as partners in solving real-life problems related to arsenic Training scientists in arsenic research 5

Variable Toxicity of Arsenic Metabolites LD50 (Toxicity) 9/15/2018 Variable Toxicity of Arsenic Metabolites LD50 (Toxicity) Inorganic Arsenic As+3 Arsenite 8 mg/kg As+5 Arsenate 22 mg/kg Mammalian Metabolites MMA+3 Monomethylarsonous Acid 2 mg/kg MMA+5 Monomethylarsonic Acid 916 mg/kg DMA+5 Dimethylarsinic Acid 648 mg/kg Fish Metabolites AsB Arsenobetaine ~10,000 mg/kg AsC Arsenocholine LD50 (Toxicity) 6

What We Have Learned: Arsenic Exposure Naturally occurring element in Earth’s crust Industrial sources (e.g., former smelters) Some types of chemically treated wood Some homeopathic remedies Drinking water Diet (e.g., rice) Soil and dust 7

Arsenic in Groundwater: An International Problem Taiwan China Chile Argentina Mexico United States India Bangladesh Nepal Vietnam Cambodia Mongolia U.S. EPA Maximum Contaminant Level for arsenic: 10 µg/L. Concentrations reported in some regions of many of these countries reached over 3,000 µg/L. 8

Arsenic in Groundwater in the U.S. 9

Global and U.S. Activities Funded by NIEHS SRP 9/15/2018 Global and U.S. Activities Funded by NIEHS SRP Large cohort studies Bangladesh Chile Global/U.S. studies of exposures and health effects Identify and reduce exposures Identify health effects Identify mechanisms of toxicity Explore approaches to mitigating toxicity Taking action at the local level Outreach to encourage private well testing Helping provide safe water sources 10

SRP-funded Cohort Studies Health Effects and Longitudinal Study (HEALS) in Bangladesh • Population exposed via tube wells • Revealing information about exposure, health effects, susceptibilities, and nutritional factors Chilean Cohort • Population exposed for a defined period of time • Population followed for >50 years • Revealing information about health effects and latency 11

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HEALS Cohort Recruitment and Follow-up Baseline HEALS Cohort Recruitment and Follow-up Follow-up 1 7/2000-5/2002 Follow-up 3 HEALS Original Cohort ~12,000 adults Follow-up 2 HEALS Expanded Cohort ~8,000 adults ~20,000 adults: HEALS original and Expanded cohort 113 deaths 120 deaths 174 deaths A validated verbal autopsy was used to classify deaths using WHO’s ICD-10 9/2002-11/2004 12/2004 -9/2006 6/2007-1/2009 4/2010- 6/2006-8/2008 11/2008-11/2009 13

All-cause and Chronic Disease Mortality Table 2. Hazard ratio for mortality of HEALS participants in relation to baseline arsenic exposure, Bangladesh  Arsenic exposure No. of deaths All-cause mortality* Chronic disease mortality* HR 95% CI Well water arsenic (μg/L) 0.1–10 74 1.00 Referent 58 10.1–50 90 1.34 0.99, 1.82 69 1.33 0.94, 1.87 50.1–150 98 1.09 0.81, 1.47 83 1.22 0.87, 1.70 150.1–854 131 1.68 1.26, 2.23 101 1.21, 2.33 P for trend 0.003 0.005   Daily arsenic dose (μg/day) 0.041–35.0 87 66 35.1–163.0 97 1.10 0.83, 1.47 80 1.21 0.88, 1.67 163.1–401.0 91 0.81, 1.46 76 0.88, 1.71 401.1–4898.0 118 1.54 1.17, 2.04 89 1.58 1.15, 2.18 0.004 0.007 Urinary total arsenic (μg/g Cr) 7.0–105.0 64 105.1–199.0 96 1.07 0.80, 1.43 1.17 0.84, 1.62 199.1–352.0 100 0.91, 1.63 1.37 0.98, 1.90 352.1–5000.0 105 1.45 1.09, 1.94 77 1.47 1.05, 2.06 0.008 0.01 HR=hazard ratio; CI=confidence interval; Cr=creatinine. * Multivariate estimates adjusted for age, sex, body mass index, systolic blood pressure, education, and smoking status. All-cause and Chronic Disease Mortality Argos et al. 2010. Lancet 376: 252 14

Early Life Exposure Can Have Effects into Adulthood Increased infant mortality Reduced birthweight Increased infections during infancy and childhood Neurological and motor impairments in children Increased cancer risks as children (liver cancer) Increased cancer risks as adults (lung, bladder, and kidney cancer) Vahter 2008. Basic Clin Pharmacol Toxicol 102(2):204. 15

Early Life Exposure Can Have Life-long Effects Environ Health Perspect 114:1293–1296 (2006). doi:10.1289/ehp.8832 available via ttp://dx.doi.org/ 16

SRP: Making a Difference in the Community Columbia University SRP in Bangladesh Installation of >150 deep community wells that provide low-arsenic water to thousands of residents Providing primary medical care to the >20,000 HEALS participants 17

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Inter-School Art Contest School-Based Educational Intervention in Araihazar, Bangladesh 20

SRP: Making a Difference in the Community Columbia University SRP in Maine Established a Community Engagement Core Disseminating knowledge about the hazards of local well water arsenic contamination Disseminating technologies to filter arsenic 21

Community Engagement in Maine Arsenic concentrations in 1,428 domestic wells from 17 towns central Maine 31% of the wells contain >10 ug/L arsenic (source: Yang 2010). Columbia Community Engagement Core aims to double the testing and treatment rate for arsenic in these towns. A survey is underway to determine the current rates. 22

Assessment of Exposures to High Concentrations of Arsenic in Well Water in Maine [As] >10 ug/L in Maine Total Exposed = 12,458 0-18 yr olds = 3272 (2000 Census) 23

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9/15/2018 Bill Suk, NIEHS 25