FINAL Report on Carcinogens Background Document for Aristolochic Acids September 2, 2008 U.S. Department of Health and Human Services Public Health Services National Toxicology Program Research Triangle Park, NC 27709 This Page Intentionally Left Blank RoC Background Document for Aristolochic Acids FOREWORD 1 The Report on Carcinogens (RoC) is prepared in response to Section 301 of the Public 2 Health Service Act as amended. The RoC contains a list of identified substances (i) that 3 either are known to be human carcinogens or are reasonably be anticipated to be human 4 carcinogens and (ii) to which a significant number of persons residing in the United 5 States are exposed. The Secretary, Department of Health and Human Services (HHS), has 6 delegated responsibility for preparation of the RoC to the National Toxicology Program 7 (NTP), which prepares the report with assistance from other Federal health and 8 regulatory agencies and nongovernmental institutions. 9 Nominations for (1) listing a new substance, (2) reclassifying the listing status for a 10 substance already listed, or (3) removing a substance already listed in the RoC are 11 reviewed in a multi-step, scientific review process with multiple opportunities for public 12 comment. The scientific peer-review groups evaluate and make independent 13 recommendations for each nomination according to specific RoC listing criteria. This 14 background document was prepared to assist in the review of aristolochic acids. The 15 scientific information used to prepare Sections 3 through 5 of this document must come 16 from publicly available, peer-reviewed sources. Information in Sections 1 and 2, 17 including chemical and physical properties, analytical methods, production, use, and 18 occurrence may come from published and/or unpublished sources. For each study cited in 19 the background document from the peer-reviewed literature, information on funding 20 sources (if available) and the authors’ affiliations are provided in the reference section. 21 The draft background document was peer reviewed in a public forum by an ad hoc expert 22 panel of scientists from the public and private sectors with relevant expertise and 23 knowledge selected by the NTP in accordance with the Federal Advisory Committee Act 24 and HHS guidelines and regulations. This document has been finalized based on the peer- 25 review recommendations of the expert panel and public comments received on the draft 26 document. Any interpretive conclusions, comments, or statistical calculations made by 27 the authors or peer reviewers of this document that are not contained in the original 28 citation are identified in brackets [ ]. 9/2/08 i RoC Background Document for Aristolochic Acids 1 A detailed description of the RoC nomination review process and a list of all substances 2 under consideration for listing in or delisting from the RoC can be obtained by accessing 3 the 12th RoC at http://ntp.niehs.nih.gov/go/9732. The most recent RoC, the 11th Edition 4 (2004), is available at http://ntp.niehs.nih.gov/go/19914. ii 9/2/08 RoC Background Document for Aristolochic Acids CONTRIBUTORS Project Managers, Authors, and Principal Reviewers National Toxicology Program (NTP) and National Institute of Environmental Health Sciences (NIEHS) Ruth Lunn, Dr.P.H. Director, Report on Carcinogens Office C.W. Jameson, Ph.D. Report on Carcinogens Office (former Director; currently at CWJ Consulting, LLC) Gloria D. Jahnke, D.V.M. Report on Carcinogens Office Constella Group, LLC (Support provided through NIEHS Contract Number NO1- ES-35505) Sanford Garner, Ph.D. Principal Investigator Stanley Atwood, M.S., DABT Greg Carter, M.E.M. Consultants Jean-Pierre Cosyns, M.D., D.S.M. Université Catholique de Louvain, Brussels, Belgium Dan Levy, Ph.D. U.S. Food and Drug Administration Administrative Support Shawn Jeter, B.S. NTP/ Report on Carcinogens Office Anna Lee Sabella Kelly Services Ella Darden, B.S. Constella Group, LLC Tracy Saunders, B.S. Constella Group, LLC Editorial Support Susan Dakin, Ph.D. Independent Consultant in Technical & Scientific Writing & Editing 9/2/08 iii RoC Background Document for Aristolochic Acids PEER-REVIEW The draft background document on Riddelliine was peer reviewed by the Report on Carcinogens (RoC) expert panel for Riddelliine and Aristolochic Acid. The panel met in a public forum at the Sheraton Chapel Hill Hotel, Chapel Hill, NC on January 24 – 25, 2008. Members of the expert panel are as follows: Arthur P. Grollman, M.D. (Chair) Albert B. Lowenfels, M.D. Department of Pharmacology Department of Community and Preventive State University of New York at Stony Brook Medicine New York Medical College A. Morrie Craig, Ph.D. College of Veterinary Medicine Joëlle L. Nortier, M.D. Oregon State University Department of Nephrology Erasme Hospital Patricia E. Ganey, Ph.D. Université Libre de Bruxelles Department of Pharmacology and Toxicology Michigan State University Brian T. Schaneberg, Ph.D. Technical Services Yanze Liu, Ph.D. ChromaDex, Inc. Bio-organic and Natural Products Research Laboratory Bryan L. Stegelmeir, D.V.M., Ph.D. McLean Hospital Poisonous Plant Research Laboratory U.S. Department of Agriculture iv 9/2/08 RoC Background Document for Aristolochic Acids Criteria for Listing Agents, Substances or Mixtures in the Report on Carcinogens U.S. Department of Health and Human Services National Toxicology Program The criteria for listing an agent, substance, mixture, or exposure circumstance in the RoC are as follows: Known To Be Human Carcinogen: * There is sufficient evidence of carcinogenicity from studies in humans , which indicates a causal relationship between exposure to the agent, substance, or mixture, and human cancer. Reasonably Anticipated To Be Human Carcinogen: * There is limited evidence of carcinogenicity from studies in humans , which indicates that causal interpretation is credible, but that alternative explanations, such as chance, bias, or confounding factors, could not adequately be excluded, or there is sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors (1) in multiple species or at multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual degree with regard to incidence, site, or type of tumor, or age at onset, or there is less than sufficient evidence of carcinogenicity in humans or laboratory animals; however, the agent, substance, or mixture belongs to a well-defined, structurally related class of substances whose members are listed in a previous Report on Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a human carcinogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans. Conclusions regarding carcinogenicity in humans or experimental animals are based on scientific judgment, with consideration given to all relevant information. Relevant information includes, but is not limited to, dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensitive sub-populations, genetic effects, or other data relating to mechanism of action or factors that may be unique to a given substance. For example, there may be substances for which there is evidence of carcinogenicity in laboratory animals, but there are compelling data indicating that the agent acts through mechanisms which do not operate in humans and would therefore not reasonably be anticipated to cause cancer in humans. * This evidence can include traditional cancer epidemiology studies, data from clinical studies, and/or data derived from the study of tissues or cells from humans exposed to the substance in question that can be useful for evaluating whether a relevant cancer mechanism is operating in people. 9/2/08 v RoC Background Document for Aristolochic Acids This Page Intentionally Left Blank vi 9/2/08 RoC Background Document for Aristolochic Acids Executive Summary 1 Introduction 2 Aristolochic acids are a family of nitrophenanthrene carboxylic acids that occurs 3 naturally in plants in the Aristolochiaceae family, primarily of the genera Aristolochia 4 and Asarum. Botanical products from plants containing aristolochic acids are used in 5 traditional folk medicines, particularly in Chinese herbal medicine, and have been used 6 inadvertently as part of a weight-loss regimen. 7 “Aristolochic acids” were nominated by the National Institute of Environmental Health 8 Sciences (NIEHS) for possible listing in the Report on Carcinogens based on the 9 International Agency for Research on Cancer (IARC) classification that herbal remedies 10 containing plant species of the genus Aristolochia are carcinogenic to humans (Group 1) 11 and that naturally occurring mixtures of aristolochic acid are probably carcinogenic to 12 humans (Group 2A). 13 Human Exposure 14 The risk of human exposure to aristolochic acids remains a global problem. Aristolochia 15 and related plants have been used since ancient times in traditional herbal medicines for 16 obstetrics treatment and for treatment of snakebite, scorpion stings, fever, infection, 17 diarrhea, and inflammation. In contemporary medicine, Aristolochia plant products have 18 been used in therapies for arthritis, gout, rheumatism, and festering wounds. Herbal 19 preparations containing aristolochic acids have also been used inadvertently as part of a 20 weight-loss regimen. Individuals