How is Arsenic in Rice affecting our health? Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon How is Arsenic in Rice affecting our health? Tracy Punshon Ph.D. Dartmouth College Dan Leffler Celiac Center at BIDMC

Very poor: purely hypothetical Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon Scale of Scientific Certainty Good, lots of data Arsenic as an environmental pollutant: The different forms of arsenic, from safe to toxic forms Sources of arsenic pollution Arsenic in rice How much arsenic is in our food? How much arsenic should we eat? Detailed look at arsenic in rice Poor: not much data Health effects from dietary arsenic exposure Nutrients important for arsenic metabolism What do we do now? Study arsenic exposure in Celiac Disease patients on gluten-free diets Partner with the community to reduce exposure and enhance nutritional intake to address arsenic exposure Very poor: purely hypothetical

Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon What is arsenic? A naturally-occurring metalloid found in rock, soil, water, plants, animals and air.

DIMETHYLARSINIC ACID (DMA) Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon The many forms of arsenic The toxicity of arsenic is a function of its chemical form (‘species’) µg mg g per serving µg mg g per serving ARSENITE & DIMETHYLARSINIC ACID (DMA) ARSENOBETAINE Median lethal dose: Arsenite: 10-20 mg/kg DMA: 700 -2,600 mg/kg NONE FOUND

The many forms of arsenic Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon The many forms of arsenic Acute toxicity The toxicity of arsenic is a function of its chemical form (‘species’) HIGH Inorganic Arsenic No carbon Organic Arsenic Carbon Arsenic LOW Dimethylarsinic acid: DMA Monomethylarsonic acid: MMA 3 chemical bonds Arsenite Arsenate 5 chemical bonds Arsenobetaine; AsB Arsenosugars Arsenolipids 16 chemical forms relevant to biological systems 100 found in nature

Where does arsenic come from? Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon Where does arsenic come from? NATURE HUMAN ACTIVITIES Burning coal for energy Mining metals Metal smelting operations Pesticide application Glass manufacture Disposal of wastewater sludges Pharmaceutical waste Livestock dips Phosphate fertilizer application Wood preservatives Chemotherapeutic drugs Bedrock 568 known arsenic containing minerals Groundwater Drilling of groundwater tube wells in SE Asia “largest mass poisoning in history”

99% 1% How are we exposed to arsenic? Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon How are we exposed to arsenic? 99% 1%

“USA long grain rice had the highest mean arsenic level…” Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon Rice is an arsenic-accumulating plant Environmental Science & Technology 39: 2005 “USA long grain rice had the highest mean arsenic level…” “arsenic in rice contributes considerably to arsenic ingestion in subsistence rice diets”

A detailed look at arsenic in rice Processed ingredient Common name Anatomy husk rice bran oil brown rice syrup brown rice flour brown rice bran pericarp tegumen aleurone rice flour rice starch rice syrup puffed rice rice protein concentrate white rice grain endosperm Organic arsenic germ embryo Inorganic arsenic ‘embryo rice’ rice germ rice germ oil ovular vascular trace A detailed look at arsenic in rice

Parboiling bran grain Nutrients germ Common name Anatomy Parboiled rice (also called ‘converted rice’) is rice that has been partially boiled in the husk. The three basic steps of parboiling are soaking, steaming and drying. These steps make rice easier to process by hand, boost its nutritional profile and change its texture. Common name Anatomy husk bran pericarp tegumen aleurone Nutrients grain endosperm germ embryo ovular vascular trace

Arsenic regulation in drinking water and food Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon Arsenic regulation in drinking water and food Drinking water: EPA limit 10 µg/L (ppb) REGULATION mg/kg = parts per million ‘ppm’ or 1¼ soda bottles/Olympic sized swimming pool µg/kg = parts per billion ‘ppb’ ½ teaspoon/Olympic sized swimming pool European Union INORGANIC ARSENIC White rice 0.2 ppm Infant rice 0.1 ppm EPA Integrated Risk Information System Currently under revision Oral reference dose (daily exposure range for no appreciable risk over a lifetime exposure) 0.3 μg inorganic arsenic/kg body weight/day Range = 0.1-0.8 μg Asi/kg bw/day California Proposition 65 Daily intake level for 1:100,000 cancer risk No significant risk level for daily intake of inorganic arsenic is 10 μg FDA Proposed action limit Infant rice cereal should not contain more than 0.1 ppm (100 ppb) inorganic arsenic REGULATION

The amount of arsenic in serving from eating whole grain rice Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon The amount of arsenic in serving from eating whole grain rice

Inorganic arsenic per serving in common rice-containing products Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon Inorganic arsenic per serving in common rice-containing products 10 µg http://www.fda.gov/downloads/Food/FoodborneIllnessContaminants/Metals/UCM352467.pdf

Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon

Bladder cancer in New England related to drinking water arsenic Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon Bladder cancer in New England related to drinking water arsenic

Low level exposure and decreased IQ Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon Low level exposure and decreased IQ Exposure to drinking water As > 5 µg/L was associated with decrease in IQ of 5 -6 points http://files.centralmaine.com/uploads/2014/04/20140403_63865.xml-arsenic+brennan.jpg Wassermann et al. Environ Health. 2014 Apr 1;13(1):23. doi: 10.1186/1476-069X-13-23.

MONOMETHYLARSONIC ACID Annual Meeting of the New England Celiac Organization, October 16, 2016 Tracy Punshon ‘One Carbon’ arsenic metabolism: Nutrients and genes arsenic-3 methyl transferase (AS3MT) INORGANIC ARSENIC FOLATE METHIONINE BETAINE CHOLINE CH3 AS3MT B12 MONOMETHYLARSONIC ACID (MMA) CH3 Iron Zinc Selenium DIMETHYLARSINIC ACID (DMA)

C-FARR Charge Develop a set of policy-relevant questions or uncertainties for scientists to consider