National Toxicology Program (NTP); Report on Carcinogens (RoC); Request for Public Comments on the RoC Expert Panel's Recommendations on Listing Status for Aristolochic Acids and Riddelliine in the 12th RoC and the Scientific Justifications for the Recommendations

AGENCY:

National Institute of Environmental Health Sciences (NIEHS); National Institutes of Health (NIH).

ACTION:

Request for public comments.

SUMMARY:

The RoC Office invites public comments on the recommendations from an expert panel on listing status for aristolochic acids and riddelliine in the 12th RoC and the scientific justifications for the recommendations. The recommendation and scientific justification for each candidate substance are available electronically in Part B of the Expert Panel Report ( http://ntp.niehs.nih.gov/go/29682,, see Expert Panel Report Part B) or in printed text from the RoC Office (see FOR FURTHER INFORMATION CONTACT below). The RoC Office convened an eight-member expert panel of scientists from the public and private sectors on January 24-25, 2008, to review aristolochic acid related exposures and riddelliine. The panel was asked (1) to apply the RoC listing criteria to the relevant scientific evidence and make recommendations regarding listing status (i.e., known to be a human carcinogen, reasonably anticipated to be a human carcinogen, or not to list) for aristolochic acids and for riddelliine in the 12th RoC and (2) to provide the scientific justifications for the recommendations.

DATES:

The Expert Panel Report (Part B) for aristolochic acids and for riddelliine will be available for public comment by April 23, 2008. Written comments should be submitted by June 16, 2008.

ADDRESSES:

Comments should be sent to Dr. Ruth Lunn, RoC Office [NIEHS, P.O. Box 12233, MD EC-14, Research Triangle Park, NC 27709, FAX: (919) 541-0144, or lunn@niehs.nih.gov. Courier address: RoC Office, 79 T.W. Alexander Drive, Building 4401, Room 3118, Research Triangle Park, NC 27709].

FOR FURTHER INFORMATION CONTACT:

Dr. Ruth Lunn, RoC Office, (919) 316-4637 or lunn@niehs.nih.gov.

SUPPLEMENTARY INFORMATION:

Background

Aristolochic acid related exposures (which includes “aristolochic acid” and “botanical plants containing aristolochic acid”) and riddelliine are among the candidate substances under review for possible listing in the 12th RoC (see complete list at http://ntp.niehs.nih.gov/go/10091 ). Aristolochic acid is a generic name for a family of nitrophenanthrene carboxylic acids that occurs naturally in plants in the Aristolochiaceae family, primarily of the genera Aristolochia and Asarum. Botanical products from plants containing aristolochic acid are used in traditional folk medicines to treat arthritis, gout, rheumatism, and festering wounds, and have been used inadvertently as part of a weight-loss regimen. Exposure to aristolochic acid has been reported for many countries, including the United States. In 2001, the Food and Drug Administration issued warnings to consumers, health care professionals, and industry associations concerning herbal products containing aristolochic acid. Other countries, including the United Kingdom, Germany, Canada, and Australia, have banned these herbs. Nevertheless, botanical products potentially containing aristolochic acid are still available legally in other countries and can be bought via the Internet.

Riddelliine is a pyrrolizidine alkaloid (PA) of the macrocyclic diester class. Riddelliine and riddelliine N-oxide (a metabolite of riddelliine that can be converted back to riddelliine) occur in plants of the genus Senecio that are found in sandy desert areas of the western United States and other parts of the world. At least 15 Senecio species have been identified that are used in herbal medicines or possibly as food worldwide. Exposure to humans could result from direct contamination of foodstuffs by parts of Senecio plants or from indirect introduction of the alkaloid through products derived from animals that have fed on the plants. PAs have been found in eggs, honey, bee pollen, and milk.

As part of the RoC review process (available at http://ntp.niehs.nih.gov/go/15208 ), the NTP announced the availability of the draft background documents for aristolochic acid related exposures and riddelliine in the Federal Register (72 FR 63900, November 13, 2007), invited public comments on the draft background documents, and announced the expert panel meeting for aristolochic acid related exposures and riddelliine. The RoC Office convened an eight-member expert panel of scientists from the public and private sectors to evaluate these two substances. The expert panel met on January 24-25, 2008, in a public forum at the Chapel Hill Sheraton Hotel in North Carolina. The panel first addressed aristolochic acid related exposures and then riddelliine in its deliberations. The panel was charged to peer review the draft background document for the candidate substance, and then to make a recommendation on its listing status in the 12th RoC and to provide a scientific justification for that recommendation. Details about the meeting, including public comments received and the expert panel reports, are available on the RoC Web site (http://ntp.niehs.nih.gov/go/29682). The expert panel report for each candidate substance contains two parts: Part A has the peer-review comments on the draft background document and Part B is the recommendation on listing status and its scientific justification. The expert panel recommended redefining the two proposed candidate substances: (1) “Aristolochic acid” and (2) “botanical plants containing aristolochic acid” into a single candidate substance, “aristolochic acids.” They concluded that aristolochic acids, the nitrophenanthrene carboxylic acids found primarily in the Aristolochiaceae family of plants, are responsible for the carcinogenic effects observed in humans who consume Aristolochia or herbal remedies prepared from these plants. The expert panel recommended that (1) aristolochic acids be listed in the 12th RoC as known to be human carcinogens and (2) riddelliine be listed in the 12th RoC as reasonably anticipated to be a human carcinogen. The panel's recommendation on listing status and its scientific justification are now being released for public comment.

Next Steps

The RoC Office is in the process of finalizing the background document for each candidate substance based upon the expert panel's peer-review comments and the public comments received (72 FR 63900). Persons can register free-of-charge with the NTP listserve (http://ntp.niehs.nih.gov/go/231) to receive notification when the final background documents are posted on the RoC Web site (http://ntp.niehs.nih.gov/go/10091).

As part of the RoC review process, two government groups will also conduct reviews of aristolochic acids and riddelliine; these meeting are not open to the public. Upon completion of these reviews, the NTP will (1) draft a substance profile for each candidate substance that contains its listing recommendation for the 12th RoC and the scientific information supporting that recommendation, (2) solicit public comments on the draft substance profiles, and (3) convene a meeting of the Board of Scientific Counselors to peer review the draft substance profiles.

Request for Comments

The RoC Office invites written public comments on the expert panel's recommendations on listing status for aristolochic acids and riddelliine and the scientific justifications for the recommendations. All comments received will be posted on the RoC Web site. Persons submitting written comments are asked to include their name and contact information (affiliation, mailing address, telephone and facsimile numbers, e-mail, and sponsoring organization, if any) and send them to Dr. Lunn (see ADDRESSES above). The deadline for submission of written comments is June 16, 2008.

Background Information on the RoC

The RoC is a Congressionally mandated document that identifies and discusses agents, substances, mixtures, or exposure circumstances (collectively referred to as “substances”) that may pose a hazard to human health by virtue of their carcinogenicity. The RoC follows a formal, multi-step process for review and evaluation of selected chemicals. Substances are listed in the report as either known or reasonably anticipated to be human carcinogens. The NTP prepares the RoC on behalf of the Secretary of Health and Human Services. Information about the RoC and the review process are available on its Web site (http://ntp.niehs.nih.gov/go/ roc) or by contacting Dr. Lunn (see FOR FURTHER INFORMATION CONTACT above).