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With advances in analytical chemistry, scientists are increasingly detecting unintended chemicals at low levels in food, drink, pharmaceuticals, and consumer products.For many of these low level substances, there are little or no toxicological data available and it is not always possible, nor is it needed, to generate toxicological data on every single substance.The Threshold of Toxicological Concern (TTC) approach has been developed to qualitatively assess low level exposures and is now used widely as a science-based approach for prioritizing assessment of those chemicals with low-level exposures that require further analysis over those that can be presumed to present no appreciable human health risk.The origins of TTC trace back to the Threshold of Regulation established by the U.S.Food and Drug Administration in 1995 as a tool to evaluate chemicals migrating at low levels from food packaging materials.In the years that followed, this approach was expanded for broader use, and multiple TTC-based exposure limits were established.Using the tiered TTC approach, chemicals are placed into different potency bins that are determined based on the chemical structure; publically-available software is available to make this determination.Chemicals that have structural alerts for DNA-reactivity are presumed to pose a potential cancer risk and are assigned the lowest TTC value.The next bin is for organophosphates and carbamates, which generally exhibit a higher degree of toxicity than most organic chemicals.Chemicals that are not expected to be DNA reactive are binned into broad categories of high, moderate or low toxicity, with increasing TTC exposure limits established for each bin.In all, the current tiered TTC approach covers over fours orders of magnitude, ranging from 0.0025 ug/kg/day to 0.03 mg/kg/day.If human exposure to a substance is below the TTC value, the likelihood of adverse effects is considered to be very low, and it is generally agreed that no further analysis is needed for those exposures.This talk will provide a brief history of the development of TTC, its scientific underpinnings, and its current application by global regulatory agencies.More recent advances will be described, including the development of a cosmetics-related database to support the extension of TTC to dermal exposures from cosmetics.Highlights from the 2016 State-of the-Science report issued jointly by the European Food Safety Authority and the World Health Organization will be described, with a focus on some of the more challenging questions that have been raised for application of TTC (e.g., application to mixtures,to endocrine active substances, exposures to infants, and consideration of nongenotoxic carcinogens).Finally, ongoing work by the U.S.Food and Drug Administration to update the TTC decision tree as well as a recently initiated project to update the genotoxic/carcinogenic TTC database will be discussed.