July 29, 2004
Associate Director for Communications
Office of the Director
National Institutes of Health
Building 1, Room 344
1 Center Drive
Bethesda, Maryland 20892
Subject: Information Quality Appeal - Request for Reconsideration
Dear Madam or Sir;
This letter is submitted by Chemical Products Corporation (CPC) in response to NIH's letter dated July 16, 2004 signed by Susan R. Cornell denying CPC's February 6, 2004 Request for Correction of the National Toxicology Program's 2004 draft of Technical Report 494 (draft TR-494). NIH denied CPC's Request for Correction on the grounds that a draft document disseminated by NIH is not subject to Information Quality Guidelines.
CPC requests that NIH reconsider its denial of CPC's Request for Correction. In this letter CPC will detail the reasons that it believes draft technical documents such as draft TR-494 must be subject to OMB's "Guidelines for Ensuring and Maximizing the Quality, Objectivity, Utility, and Integrity of Information Disseminated by Federal Agencies". A copy of CPC's Request for Correction is enclosed herewith.
NIH has not disputed CPC's contention in its Request for Correction that draft TR-494 fails to meet minimal information quality standards. Draft TR-494 was peer reviewed on February 17, 2004; CPC will demonstrate in this letter that the deficiencies in draft TR-494, coupled with the shortcomings of NIH's peer review procedures, resulted in a peer reviewed document which also fails to meet minimal information quality standards.
We respectfully submit that the results of the peer review of draft TR-494 demonstrate conclusively that draft technical reports must be subject to OMB's Information Quality Guidelines if the objectives of section 515 of the Treasury and General Government Appropriations Act for Fiscal Year 2001 are to be met.
NIH states that CPC's Request for Correction of NTP draft TR-494 was denied because this draft NTP technical report, disseminated for public comment and peer review, is not subject to the NIH "Guidelines for Ensuring the Quality of Information Disseminated to the Public" and the Office of Management and Budget "Guidelines for Ensuring and Maximizing the Quality, Objectivity, Utility, and Integrity of Information Disseminated by Federal Agencies" (OMB Guidelines). CPC requests that NIH reconsider this denial and respectfully submits that the untenable product of NIH's February 17, 2004 peer review of draft TR-494 conclusively demonstrates that the objectives of the OMB Guidelines cannot be met if draft technical reports disseminated to the public by NIH are not subject to the OMB Guidelines.
While the conclusions presented in draft TR-494 are clearly described in the report as being preliminary and subject to change, the scientific information upon which these preliminary conclusions are based must be presented accurately, clearly, and objectively in order for meaningful public comment and scientifically valid peer review to take place. The scientific information presented in draft TR-494 is inaccurate and subjective to such a degree that deliberate obfuscation might be suspected. Both the Abstract of TR-494 presented on NTP's website and the body of draft TR-494 state, "Anthraquinone (97% pure) was mutagenic in S. typhimurium strains TA98 and TA100, with and without rat and hamster S9 metabolic activation enzymes". Inclusion of this statement (placed conspicuously at the beginning of a paragraph) without identifying the mutagenic contaminants making up the other 3% of the sample, or even referring to mutagenic contaminants is confusing at best. Draft TR-494 later states, "a 100% pure anthraquinone sample showed no mutagenic activity in strains TA98, TA100, or TA102, with or without rat liver S9 enzymes". Thus NTP acknowledges in TR-494 that the compound Anthraquinone, CAS # 84-65-1, is not mutagenic, but this vital information is not clearly and objectively presented.
The Anthraquinone test material utilized in the draft TR-494 studies was found to be mutagenic when aliquots of this test material were tested by CPC and then others after the first dissemination of draft TR-494 in 2000 (NTP had not conducted mutagenicity studies on its test material). The test material utilized by NTP in the TR-494 studies is contaminated with mutagenic impurities; this vital piece of information is not presented clearly and transparently in draft TR-494.
NTP now acknowledges that Anthraquinone, chemical formula C14H8O2, CAS # 84-65-1, is not mutagenic. NTP inadvertently employed a test material contaminated with mutagens when it conducted the studies reported in draft TR-494. The mutagenic contaminants in the Anthraquinone test material confounded the results of the TR-494 studies to an unknown (and, we believe, unknowable) extent. In draft TR-494, NTP has inexplicably failed to definitively identify and quantify all contaminants in the TR-494 test material even though NTP was informed by CPC of the presence of mutagenic contaminants in this Anthraquinone test material in 2000.
According to NTP, the contaminated draft TR-494 Anthraquinone test material was derived from Anthracene. The peer review conducted on February 17, 2004 (subsequent to CPC's Request for Correction submission) only required that the term "Anthracene-derived Anthraquinone" be employed in TR-494 to describe the test material, rather than the accurate designation "Mutagen-contaminated Anthraquinone". CPC informed NTP in 2000 that EPA's TSCA file for Anthraquinone contains results of mutagenicity tests conducted on 6 different samples of "Anthracene-derived Anthraquinone" and only one of the 6 showed mutagenicity. "Anthracene-derived Anthraquinone" is not uniformly contaminated with mutagens; the peer reviewed TR-494 derived from draft TR-494 does not conform to the OMB Guidelines.
The outcome of the peer review conducted on draft TR-494 demonstrates that NIH's peer reviewers are committed to finding a "fix" for even the most flawed draft work products rather than refuse to accept the draft technical report as a final technical report. Draft technical reports invariably become final technical reports. Peer reviewers are essentially limited to consideration of the information presented in the draft technical report, thus conformance of draft technical reports to the standards of OMB's Information Quality Guidelines is absolutely essential if high scientific standards are to be maintained.
Draft TR-494 was reviewed by the NTP Board of Scientific Counselors Technical Reports Review Subcommittee on February 17, 2004. NTP's website reports that the peer review of draft TR-494 resulted in a subcommittee recommendation that the title of the report be changed to "Anthracene-derived Anthraquinone" and that it be made clear throughout the report that the material used in the study was anthracene-derived anthraquinone. With these changes, the Subcommittee accepted (7 yes, 6 no) the technical report and the conclusions as written (some evidence of carcinogenic activity of anthraquinone in male rats and clear evidence of carcinogenic activity in female rats and male and female mice). An inaccurate characterization of all anthracene-derived Anthraquinone as contaminated with mutagens was all the peer reviewers required as a condition to acceptance of untenable conclusions based upon a study confounded by the presence of unquantified mutagenic contaminants in a non-mutagenic study material.
EPA's TSCA database contains the results of mutagenicity studies on 6 different Anthraquinone samples derived from at least three different Anthracene oxidation manufacturing processes which were tested for mutagenicity; only one sample was found to be mutagenic. Thus, the characterization of the TR-494 test material contaminated with mutagens as "Anthracene-derived Anthraquinone" does not in any way rectify the uncertainty in interpreting the results of the studies conducted utilizing this mutagen-contaminated Anthraquinone test material. Neither the draft TR-494 disseminated for public comment, nor the peer reviewed TR-494 meets OMB's Information Quality Guidelines.
The study rationale for draft TR-494 is presented as, "Anthraquinones form a large class of commercially important chemicals and constitute the largest class of naturally occurring quinones. Because of the ubiquity of compounds containing the anthraquinone ring system, the National Toxicology Program has been involved in a class study of these compounds. In previous studies, five substituted anthraquinones have exhibited significant carcinogenic potential in long-term rodent studies. Anthraquinone, the parent compound, was selected for this class study to aid in understanding the impact on the carcinogenic response by various substitutions to the anthraquinone ring and because its use pattern suggests the potential for human exposure." (bold typeface and underline added). The peer reviewers on February 17, 2004 failed to recognize that the superficial "fix" of creating an artificial sub-class of the compound Anthraquinone, CAS # 84-65-1 ("Anthracene-derived Anthraquinone") in no way furthers the stated objectives of this study, and would most certainly hinder an understanding of this class of compounds if CPC's Request for Reconsideration were to be denied. The peer review on February 17, 2004 simply created a scientific morass by trying to salvage a sub-standard draft technical report. Given the limited ability of peer reviewers to re-evaluate the conclusions drawn from the information presented in a draft technical report such as TR-494, and their demonstrated reluctance to reject a flawed work product, it is critical that draft work products provided by NIH for public comment and peer review be subject to the OMB Guidelines at the time they are first disseminated.
The NTP Board of Scientific Counselors Technical Reports Review Subcommittee has accepted the untenable conclusions proposed in draft TR-494 regarding the evidence for carcinogenic activity of a non-mutagenic test material contaminated with mutagens on the condition that this material is referred to as "Anthracene-derived Anthraquinone". Is NIH now to create a separate "parallel scientific universe" in which Anthraquinone, CAS # 84-65-1, becomes two compounds with differing carcinogenic activities? Do the five substituted anthraquinones studied previously fall into the "derived from non-Anthracene-derived Anthraquinone" scientific universe, or do they fall into the "derived from Anthracene-derived Anthraquinone" scientific universe? Will NIH assume that the carcinogenic response observed with the mutagen-contaminated Anthraquinone test material was solely the result of Anthraquinone exposure when it studies the impact of substitutions on the anthraquinone ring? We respectfully submit that the scientific dilemma created by the flawed peer review of draft TR-494 is the direct result of NIH's failure to insure that draft technical reports conform to OMB Guidelines before they are disseminated to the public.
The NTP Board of Scientific Counselors Technical Reports Review Subcommittee has plunged NTP into a scientific morass from which the only extrication is withdrawal of draft TR-494 as requested in CPC's February 6, 2004 Request for Correction. We submit that the outcome of the February 17, 2004 peer review demonstrates conclusively the fallacy of NIH's contention that the Department of Health and Human Services "Guidelines for Ensuring and Maximizing the Quality, Objectivity, Utility, and Integrity of Information Disseminated to the Public" and the OMB Guidelines should not apply to draft work products simply because they are disseminated to the public and peer reviewers for comment as "drafts" and contain a disclaimer that interpretations contained therein do not represent the official scientific position of the National Toxicology Program. We submit that the scientific information contained in draft technical reports, as distinct from clearly identified interpretations of scientific information, should meet the same Information Quality standards as any other information disseminated to the public.
If the scientific information disseminated to the public in a draft technical report fails to meet the standards of OMB's Information Quality Guidelines, CPC respectfully submits that that draft technical report should be withdrawn and corrected prior to public comment and peer review. In our Request for Correction, CPC gave many examples of the failure of draft TR-494 to meet the OMB Guidelines; NIH has not disputed that TR-494 fails to conform to the OMB Guidelines. In its Request for Correction, CPC requested that TR-494 be withdrawn and corrected before being submitted for peer review.
We believe that we have demonstrated conclusively that the scientific information contained in draft TR-494 fails to meet the standards in the OMB Guidelines. We believe that we have demonstrated conclusively that the peer reviewed draft TR-494 will yield a final technical report that will fail to meet the standards of the OMB Guidelines unless it is withdrawn as CPC has requested. We request that NIH reconsider its denial of CPC's Request for Correction of draft TR-494. CPC again requests that the 2004 draft TR-494 be withdrawn and brought into conformance with the OMB Guidelines before it is again posted on the NIH web site for public comment and subsequent peer review.
Jerry A. Cook
Cc: Dr. John D. Graham, OIRA
Last Revised: August, 2004