CRE BACKGROUNDER ON PERCHLORATE AND THE HUMAN VOLUNTEER STUDIES ISSUE

Perchlorate is a chemical used in missile fuels, munitions, automobile air bag inflation systems, and lubricating oils, and has been detected in some fertilizers. It is very persistent and mobile in ground and surface waters. In 1997 new analytical methods allowed detection at 4 ppb, about 100 times lower than previously, and it was found to be widespread in ground and surface waters in the Southwest (CA, NV, and AZ), including large metropolitan areas such as Las Vegas, Sacramento, and Los Angeles, as well as in at least 11 other States. Manufacturers or users of perchlorate are located throughout the United States.

Large sums (some of it Congressionally appropriated) are currently being spent by both government agencies and the private sector on research and some remediation, with the potential for additional huge sums being required to be spent to comply with new drinking water regulations and Superfund cleanup levels based on new research and risk assessment.

Perchlorate has been used in the past to treat hyperthyroidism (including Graves' disease) at therapeutic doses hundreds to thousands of times the exposure levels in most areas where it has been found in drinking water. Side effects observed in patients have been limited mainly to gastric irritation. Perchlorate inhibits the uptake of iodide by the thyroid and acts to depress the synthesis of thyroxine (T4). The concern with chronic drinking water intake of low doses of perchlorate by healthy persons, including those with inadequate iodine intake or a marginally functional thyroid, is the possibility of hypothyroidism.

The current review of perchlorate risks began largely in 1997 after an independent peer review group convened by Toxicology Excellence in Risk Assessment ("TERA", www.tera.org), the U.S. Air Force, and the private sector determined that the existing, largely medical, database was inadequate to assess long-term drinking water risks to the general population. The next year, the Federal Government formed the Inter-agency Perchlorate Steering Committee ("IPSC")¹ to coordinate research and stakeholder input. Industry stakeholders, who were not represented on the IPSC, had previously formed the Perchlorate Study Group to design and fund research.

Several States have promulgated interim regulatory levels for perchlorate in drinking water. The levels range from 18 ppb in California and Nevada, to 22 in Texas, and 31 in Arizona. EPA has set a provisional guidance level of 32 ppb.

In 1998, EPA developed a preliminary perchlorate risk assessment, and in 1999 convened a peer review workshop of that document. That peer review found a need for additional studies of various kinds. The latest (2002) revised risk assessment will be reviewed at a March 5-6, 2002 public peer review workshop in Sacramento, CA.² EPA has also requested public comments by February 19. EPA is then expected to finalize the risk assessment, and employ it for decisions on Federal drinking water standards, drinking water advisories to States, and Superfund cleanup levels.

The studies which have been conducted since1998 include several human volunteer studies in which healthy adults ingested doses of perchlorate. The studies have been conducted at a number of academic institutions under IRB³ oversight, both in the United States and Europe. Various Federal agencies, including EPA, DOD, and NIH, have been involved in the design, funding, and conduct of several of the human volunteer studies. One such study has been published, another has been submitted for publication, and another is still in progress.

An additional human volunteer study, apparently the only one without Federal involvement, (being conducted at the Loma Linda Medical Center) has come under attack by environmental groups in a manner similar to the attack mounted against testing of pesticides (principally cholinesterase inhibitors) in human volunteers. ⁴ Those attacks began in 1998. Soon after the attacks began, EPA, in July 1998, expressed concern about the use of such studies for pesticide regulatory decisions, and asked for advice from a joint SAB/SAP panel, many of whom were bioethicists.⁵ The report produced by the panel in September 2000 was equivocal, but it was reported in the press that EPA viewed the report as consistent with an informal interim policy it had instituted of refusing to accept human volunteer studies for use in pesticide decisions.⁶ A formal policy notice was never issued, nor was public comment sought on the policy.⁷

In the last days of the Clinton Administration (January 2001), the press reported that EPA had submitted a proposed policy notice to OMB for review, but that it had been rejected, largely due to objections by other Federal agencies. All was quiet until late November 2001, when major environmental organizations sent briefing papers to the media and there was a sudden barrage of articles in major newspapers reporting that the new Administration planned to accept such studies in a reversal of the (never announced) Clinton Administration policy.⁸ On December 7, 2001, Representative Henry Waxman⁹ sent a letter to EPA based on those articles and expressing concern. He requested that the agency send him virtually all documents pertaining to the issue.¹⁰ A week later, on December 14, 2001, EPA issued a press release announcing that it was referring the general issue of acceptability of "third-party" human volunteer studies to the National Academy of Sciences, and that until it received the NAS recommendations and formalized a new policy through notice and comment it would follow an interim policy of refusing to accept such studies for use in any regulatory decisionmaking (not just pesticide decisions). It could take several years to complete the NAS study and issue a final policy. It has been reported in one press article that the EPA interim rule and NAS referral have White House support¹¹, although the rule never underwent OMB review pursuant to Executive Order 12866, was never announced as proposed for public comment pursuant to the Administrative Procedure Act, and was never sent to Congress under the Congressional Review Act.

The problem EPA and the other Federal agencies now face is trying to articulate a cogent rationale for categorically rejecting human volunteer studies not conducted or supported by Federal agencies while continuing to use similar human volunteer studies conducted or supported by Federal agencies. Many Federal agencies, including EPA, have conducted or supported, and continue to conduct and support, such studies for a wide array of chemicals, and the upcoming perchlorate review might be the first occasion since EPA's December 14, 2001 announcement on which they and independent reviewers will have to confront the issue and its incongruities in a public forum with so much at stake.

1. The IPSC is co-chaired by EPA and DOD, with participation by 22 other Federal and State agencies and Tribal governments.

2. 67 Fed.Reg. 75-76, Jan. 2, 2002.

3. Institutional Review Boards approve and oversee the ethics and scientific merit of human volunteer studies. IRBs are required for Federally supported research by the Federal "Common Rule"; academic institutions also have IRBs to determine compliance with the Declaration of Helsinki and their own guidelines.

4. The HHS Office of Human Research Protections has been conducting an investigation of the Loma Linda study, but not any of the other human volunteer studies.

5. "Comments on the Use of Data from the Testing of Human Subjects", EPA-SAB-EC-00-917, September 2000 (www.epa.gov/sab).

6. See, e.g., The Washington Post, June 7, 2000, p. A2 ("U.S. Rejects Pesticide Tests on Humans").

7. The issue has never been addressed by the National Bioethics Advisory Commission, or the HHS Office of Human Research Protections or its advisory committee, the National Human Research Protections Advisory Committee.

8. Los Angeles Times, Nov. 27, 2001 ("U.S. Will Use Once-Banned Human Tests"); New York Times, Nov. 28, 2001 ("EPA Weighs Pesticide Tests on Humans"); The Washington Post, Nov. 29, 2001 ("EPA Used Data from Human Pesticide Tests").

9. Rep. Waxman (D-CA) is the Ranking Minority Member on the House Committee on Government Reform.

10. The newspaper articles and the Waxman letter contained numerous inaccuracies and misconceptions.

11. Inside EPA, Jan. 11, 2002. The White House reportedly compared this issue to the human cloning issue. The National Academy of Sciences issued a report on human cloning on Jan. 18, 2002. The NAS recommended a temporary ban on human cloning using host mothers. The basis for the recommendation was that such a procedure would be considered "research", and because, based on animal evidence, it would be very dangerous and unlikely to be effective, it could not possibly be approved by IRBs as authorized human volunteer research under existing international codes such as the Declaration of Helsinki and the U.S. "Common Rule".