IARC Is Not "Authoritative" on Reproductive Toxicity

by F. JayMurray, Ph.D.
President, Murray & Associates

This article appeared in the May 1998 issue of Prop 65 News

The International Agency for Research on Cancer (IARC) in Lyon, France, is well recognized for its contributions to cancer research. IARC was designated by the Scientific Advisory Panel (SAP)(1) as a Proposition 65 "authoritative body" in 1989. Since then, many carcinogens have been listed administratively by OEHHA, based on the results ofIARC evaluations. However, until recently, no chemical had been considered for listing as a reproductive toxicant by citing IARC as "authoritative" for reproductive toxicity.(2) For the reasons detailed in this article, IARC should be regarded as "authoritative" for cancer only, not for reproductive toxicity.

IARC is not "authoritative" on reproductive toxicity issues. IARC carefully examines carcinogenicity data for certain chemicals. IARC's mission does not include a thorough or "authoritative" e~aluation of reproductive effects: "IARC's mission is to coordinate and conduct research on the causes of human cancer, and to develop scientific strategies for cancer control." The preamble to a recent IARC Monograph, Volume 69, describes the IARC "Monograph Programme" as follows:

"The objective of the programme is to prepare, with the help of international working groups of experts, and to publish in the form of monographs. critical reviews and evaluations ofevidence on the carcinogenicity ofa wide range of human exposures. . . . The Monographs represent the first step in carcinogenic risk assessment, which involves examination of all relevant information in order to assess the strength of the available evidence that certain exposures could alter the incidence ofcancer in humans. . . . The IARC Monographs are recognized as an authoritative source ofinformation on the carcinogenicity of a wide range of human exposures."(3)

IARC does not undertake a thorough examination of reproductive toxicity, nor does it purport to be authoritative on reproductive toxicity issues. As part of its examination relating to the carcinogenicit~i ofa chemical, IARC "considers related data," which may include data on reproductive toxicity. In order to consider such related data, IARC typically tries to include on each of its Working Groups one scientist with expertise on reproductive toxicity. Data such as information on reproductive toxicity is used only to assist in IARC's evaluation of the potential carcinogenicity of a chemical. IARC describes its evaluation of reproductive toxicity data in an introductory section to its monograph titled "Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms." The monograph states:

"In coming to an overall evaluation ofcarcinogenicity in humans, the Working Group also considers related data. The nature ofthe information selected for the summary depends on the agent being considered. . . . Data are given on acute and chronic toxic effects (other than cancer), such as organ toxicity, increased cell proliferation, immunotoxicity and endocrine effects. The presence and toxicological significance of cellular receptors is described. Effects on reproduction, teratogenicity, fetotoxicity and embryotoxicity are also summarized briefly. . . . The adequacy of epidemiological studies of reproductive outcome and genetic and related effects in humans is evaluated by the same criteria as are applied to epidemiological studies of cancer."(4)

Senior officials at IARC have confirmed that IARC does not conduct a thorough review of potential reproductive toxicity. In a letter to Cynthia Oshita of OEHHA, dated November 26, 1997, Drs. Jerry Rice (Chief, Unit of Carcinogen Identification and Evaluation, IARC) and Harri Vainio (Chief, Unit of Chemoprevention, IARC)stated:

"Information on developmental and reproductive effects is summarized in the monographs. However, the monographs are not necessarily comprehensive on reproductive and developmental toxicity, and no formal evaluations of the strength of the evidence for reproductive and developmental toxicity are made."(5)

Additional information was provided in a letter to Dr. William Vance ofOEHHA -from Dr. David Longfellow dated December 4, 1997. Longfellow is the Chief of the Chemical and Physical Carcinogenesis Branch in the Division of Cancer Biology at the National Cancer Institute (NCI), as well as the Program Director on NCI's Cooperative Agreement with IARC, which funds the IARC monograph series. Longfellow stated that "These monographs do not critically review developmental and reproductive toxicants (DART). In fact, as stated in the Preamble, 'effects on reproduction, teratogenicity, fetotoxicity, and embryotoxlcity are also summarized briefly. "

Based on his extensive knowledge of IARC, Longfellow also expressed the opinion, in the context of Proposition 65, that " [IARC] should not be considered an 'authoritative body' for DART."

When IARC was designated as an authoritative body in October 1989, the SAP made listing recommendations regarding both carcinogens and reproductive toxi- cants. In examining the relevant transcript,(6) the SAP's focus, when discussing IARC, clearly appears to have been its determinations regarding carcinogenicity. It appears that when the SAP identified IARC as an authoritative body in 1989, it never considered the possibility that IARC might be used as the basis for proposed listings of reproductive toxicants.

To the best ofmy knowledge, no substance has ever been listed as a Proposition 65 reproductive toxicant through the authoritative-body mechanism citing IARC, whereas IARC has been the basis for numerous administrative listings of carcinogens. Thus, OEHHA's practices over the past eight years suggest that OEHHA recognized IARC was authoritative only for carcinogens, not DARTs.

At its December 9, 1997, meeting (see Prop 65 News, January, p. 7), the DART Identification Committee listened to testimony for and against revoking the questionable "authoritative" status ofIARC with respect to reproductive toxicants. While the DART Identification Committee chose not to vote on this issue on December 9, the Committee indicated its desire to consider this and other issues relating to authoritative bodies in a special workshop. Out of a sense of fairness--and out of respect for the scientists on the DART Identification Committee "EHHA should await the outcome of this workshop before reaching a final decision to list any substance as a reproductive toxicant on the basis of an IARC document.

1 Currently termed the Scientific Advisory Board.

2 On December 5, 1997, OEHHA issued a Notice ofIntent to List benzo[a]pyrene as a reproductive toxicant citing IARC as the authoritative body.

3 IARC Monograph Volume 69, 1997, pp. 9-10.

4 IARC Monograph, Volume 69, 1997, pp. 20-21.

5 This letter fiom Rice and Vainio also mentioned a new IARC series, the IARC Hand books of Cancer Prevention, which is expected to critically evaluate evidence ofreprodudive toxicity. When IARC was identified as an authoritative body, this series did not exist. The first volume ofthis series hasjust been published, and it should not be considered authoritative without firrther feview.

6 Transcript of October 20, 1989, Scientific Advisory Panel Meeting pp. 12-23.