1. Session VII WEIGHING IN ON MICROBIOLOGICAL ADI: EXPERIENCES AND PERSPECTIVES Introduction October 26, 2012

2. Significance of Human Intestinal Microbiota An ever-expanding understanding of the roles of human microflora/microbiota A search to PubMed with “ Human Intestinal Microbiota ” identified >3000 articles Important role of human gut flora in maintaining human health: infections, metabolic diseases, diabetes, obesity, cancer, etc Gastroenterology 2008;134(2):577-94

3. Significance of Human Intestinal Microbiota nature 2012;486:208 nature 2012;486:208 nature 2012;488:178 nature 2012;488:178 nature 2012;486:222 nature 2012;486:222 Science 2012;336:1268 Science 2012;336:1268 Science 2012;368:120 Science 2012;368:120 Science 2012;336:1262 Science 2012;336:1262

4. ADI: a Key Parameter in Regulation of Veterinary Drugs for Food Animals Definition of ADI: a measure of the amount of a specific substance (a residue of a veterinary drug, food additive, or pesticide) in food or drinking water that can be ingested (orally) on a daily basis over a lifetime without an appreciable health risk Type of ADI: toxicological (including pharmacological) and microbiological ADI Human food safety assessment of veterinary drugs requires data for establishment of ADI values

5. Human Food Safety Assessment of Veterinary Drugs Microbiological Safety Assessment Toxicity Assessment Metabolism & Residue Chemistry Assessment Lab Animal Toxicity Data AMR /Effect on Gut Microflora No Observed Adverse Effect Level (NOAEL) Toxicological or pharmacological ADI Establishment of MRLs and WP Lowest ADI Microbiological ADI

6. Microbiological ADI Determination - Chronology 1960s: Introduction of ADI concept in EU and JECFA 1990s: JECFA’s guidance on the data requirements and the decision tree approach for mADI determination (1999)  Determination of the most sensitive adverse effects on the human intestinal microflora with three concerns : –Emergence of antimicrobial resistant population –Disruption of the colonization barrier –Changes in enzymatic activities (NOEL determination) 2000s: Development and Implementation of VICH GL-36 (2004): Two endpoints and 5 steps JECFA harmonized with VICH GL-36 (2006) 2012: Implementation of revised VICH GL-36 with new guidance on test systems and assay methodology for assessment of the fraction of oral dose available to microorganisms in the intestine

7. Knowledge Gaps and Research Needs? Effects of antimicrobials on human gut microflora at therapeutic levels (e.g., antimicrobial therapy) are well expected and documented. It is more challenging to address effects at the residual levels (such as those potentially presented in food products) in relation to food safety: What are the effects of low-level antimicrobial residues on public health and the approaches to address them? Human intestinal flora is a relatively stable group of a huge number of bacterial species. Many factors (diets, ages, geography, etc) affect intestinal flora compositions among individuals. What is “normal” flora? How important is it to address the impact of antimicrobial residues in the context of baseline variations in intestinal flora (in individuals or between individuals)? Determination of mADI based on one or two endpoints of concern: Colonization barrier disruption Increase in resistant population What is more concern for potential risk? Which is more sensitive (i.e. lower ADI)? In the era of omics (microbiome), new approaches have emerged. What are the applications of new methodologies (e.g.,new molecular approaches) for establishing mADI?

8. Session Topics Safety Evaluation of Antimicrobial Residues in Food –The microbioogical ADI (Professor P. Silley) –Impact on Human Intestinal Microbiota – Data (Dr. C.E. Cerniglia) Antimicrobial Resistance Surveillance –Update from NARMS (Dr. P. McDermott) Antimicrobial Residues in Food Animals –Findings and Consequences (Dr. P. Basu) Discussion