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Reg WeekSM: CRE Regulatory Action of the Week

CRE Files Human Test Data Petition at EPA
EPA's Pesticides Office has refused to consider clinical human test data in establishing No Observed Adverse Effects Levels during pesticide review and registration. On August 30, 2001, CRE petitioned EPA to return to its prior practice of considering clinical human test data when establishing pesticide NOAELs. CRE's petition explains that the Pesticides Office cannot refuse to consider clinical human test data without a rulemaking in accordance with all applicable laws and executive orders.

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    August 30, 2001

    Hon. Christine Todd Whitman
    Administrator
    United States Environmental Protection Agency
    Ariel Rios Building
    1200 Pennsylvania Avenue, N.W.
    Washington, D.C. 20460

    Dear Ms. Whitman:

    Attached is a Petition for EPA action submitted by the Center for Regulatory Effectiveness. This Petition asks EPA's Office of Pesticides Programs to stop applying an invalid rule banning the use of clinical human test data to establish No Observed Adverse Effect Levels during pesticide review and registration. EPA could not apply such a rule until and unless the Agency complies with:

    • the public-notice-and-comment requirements of the Administrative Procedure Act;
    • the OMB review requirements of Executive Order 12866; and
    • the congressional review requirements of the Congressional Review Act.

    This matter is urgent. Consequently, we request that EPA respond to the attached Petition within 90 days of your receipt of it.

    Sincerely

    Jim J. Tozzi
    Member, CRE Board of Advisors



    PETITION FOR EPA COMPLIANCE WITH EXECUTIVE ORDER 12866 AND THE ADMINISTRATIVE PROCEDURE ACT

    The Center for Regulatory Effectiveness petitions the United States Environmental Protection Agency to perform its duties under the Administrative Procedure Act and Executive Order 12866 with regard to the EPA rule described below.

    EPA 's Office of Pesticides Programs (OPP) has developed and is enforcing a rule barring the use of clinical human test data to determine and establish No Observed Adverse Effects Levels ("NOAEL") during EPA/OPP's regulation of pesticides. This EPA rule is binding and inflexible. It has a significant impact on the legal rights and duties of pesticides manufacturers. It is inconsistent with and could interfere with the practice of other EPA Offices and other federal agencies. It endangers the environment, public health and safety by arbitrarily excluding the best available scientific data on pesticide safety. It is a "significant regulatory action" for purposes of OMB's review duties under Executive Order 12866.

    EPA developed and is enforcing its No-NOAEL rule in violation of Executive Order 12866, the Administrative Procedure Act (APA), and the Congressional Review Act. EPA is enforcing this rule without ever having submitted it for public notice and comment; without ever have submitted it for OMB review under Executive order 12866; and without ever sent it with the required supporting package for congressional review under the Congressional Review Act.

    EPA cannot apply and enforce this rule unless and until it has complied with the OMB review required by Executive Order 12866; the public notice and comment requirements required by the APA; and the congressional review requirements imposed by the Congressional Review Act. Until and Unless EPA complies with theses requirements, the Agency must return to its prior practice of considering clinical human test data when establishing pesticide NOAELs.

    BACKGROUND ON THE EPA RULE

    On July 27, 1998, EPA issued a "Statement on Human Testing" that read, in its entirety, as follows:

    EPA is deeply concerned that some pesticide manufacturers seem to be engaging in health-effects studies on human subjects as a way to avoid more protective results from animal tests under the new Food Quality Protection Act. The government has in place very stringent standards that apply to federally funded research to ensure the protection of human subjects. EPA will be asking its independent Science Advisory Board to apply these same standards to pesticide data submitted to EPA by companies for review. No human test data has been used by EPA for any final decisions about acceptable levels of pesticide under the new food safety law. The protection of public health from adverse effects of pesticides can be achieved through reliance on animal testing and use of the highest ethical standards.

    EPA did not publish this Statement in the Federal Register and invite comment.

    Prior to its July 1998 statement on its interim policy , EPA had consistently accepted clinical human pesticide safety data for all purposes during pesticide review and registration. There is no indication that such data were ever excluded from consideration on the basis of general policy.

    Shortly after the above Statement was issued, EPA convened a joint committee of its FIFRA Science Advisory Panel ("SAP") and its Science Advisory Board ("SAB") for the purpose of obtaining advice on an explicit policy for acceptance of such non-federally-funded research. At the initial SAP/SAB Subcommittee meeting on this issue in December 1998, EPA representatives presented information on the agency's acceptance of such studies for the period from January 1, 1990 through August 31, 1998. During that period, 26 human effects studies based on intentional clinical exposure were submitted that addressed metabolism, pharmacokinetics, and absorption, and 8 that addressed a NOAEL.

    In preparation for one of these SAB/SAP meetings, EPA issued, in addition to its "charge" to the Subcommittee (i.e., specific questions to be addressed), a "Staff Background Paper" in which it amplified on its July 27, 1998 statement. The Background Paper made clear that the agency viewed the original Statement as having put in place a moratorium on acceptance of human volunteer data submitted to the pesticide program, stating:

    The Agency's policy continues as it was first articulated in July 1998: we will not rely on these studies to support final decisions under the Food Quality Protection Act [FQPA] until a policy is in place that can ensure they meet the highest scientific and ethical standards.1

    EPA's Background Paper expressed, as one of the agency's "abiding concerns":

    We have never defined guidelines for testing pesticide effects or establishing NOAELs in human subjects. We do not require such studies; we do not encourage them; we do not believe them to be necessary to good risk assessments. Nevertheless the argument is made [apparently by others outside the agency] that human studies are more appropriate to an assessment of human health risk than animal studies, that they are more reliable than animal studies, and that they support more accurate assessments of potential risk.

    EPA's Background Paper also contained the following points or statements:

    • The FQPA "calls for an additional tenfold safety factor to protect children", and use of human subject studies in place of animal studies could "eliminate" the tenfold inter-species uncertainty factor. This could result in pesticide residue tolerance levels higher than would otherwise be allowed, thus allowing use of more of a particular pesticide, meaning that the FQPA requirement for the additional uncertainty factor for children might have unintentionally created an incentive to test pesticides on humans. [Emphasis in quotations as in original.]

    • Various offices within EPA have "continued to perform or to support many kinds of research with human subjects, with the oversight and subject protection required by the Common Rule ."

    • Since passage of the FQPA, the agency had received fourteen new studies on ten different pesticides that were "all intended to define a human systemic NOAEL"

    A joint report on this issue was published by EPA's SAB and EPA's FIFRA Scientific Advisory Committee in September 2000. The majority of the members on the joint review committee agreed that human test data could be used during pesticides regulation, subject to the usual rigorous protections of the test subjects. The Report also expressed some scientific concerns about whether some human test data that had been submitted to EPA have a sufficient number of subjects and were of sufficient duration to have statistical validity when determining NOAELs.

    In recent weeks, EPA representatives have repeatedly stated that the Pesticides Office's current position is that it will consider human test data on a case-by-case basis for some unidentified purposes, but that the Pesticides Office will not consider or use human test data to determine and establish NOAELs.

    EPA'S NO-NOAEL RULE VIOLATES THE APA BECAUSE EPA IS ENFORCING IT WITHOUT HAVING FIRST COMPLIED WITH THE APA'S PUBLIC NOTICE AND COMMENT RULEMAKING REQUIREMENTS

    In refusing to consider and use clinical human test data to identify and establish NOAELs, EPA'S Pesticides Office has made an "agency statement of general or particular applicability and future effect designed to implement, interpret, or prescribe law or policy...." 5 U.S.C. 551(4). This is a "rule" as defined by the APA; the Congressional Review Act, and Executive Order 12866. 5 U.S.C. 551; 5 U.S.C. 804(3); Executive Order 12866, 3(d).

    In its 1998 written statement, EPA admitted that this is a new standard governing the regulation of pesticides. EPA's new regulatory standard is binding, and it has a significant impact on the legal rights and duties of pesticide manufacturers and others. EPA's new regulatory standard could be outcome determinative for some pesticides being reviewed under the FQPA. EPA is not just interpreting an existing rule or statute. Instead, EPA is modifying or adding to a legal norm based on the agency's own alleged authority. Consequently, this new regulatory standard is a substantive rule that cannot be applied or enforced without first going through the public notice and comment required by the APA. E.g., 5 U.S.C. 553; Molycorp, Inc. v. EPA, 197 F.3d 543 (D.C. Cir. 1999); Syncor Intern. Corp. v. Shalala, 127 F.3d 90 (D.C. Cir. 1997); McLouth Steel Products Corp. v. Thomas, 838 F.2d 1317, 1320 (D.C. Cir. 1988); Lee v. Kemp, 731 F. Supp. 1101 (D.D.C. 1989).

    EPA'S NO-NOAEL RULE VIOLATES EXECUTIVE ORDER 12866

    Section 6(b) of the Executive Order requires OMB, acting through OIRA, to "provide meaningful guidance and oversight so that each agency's regulatory actions are consistent with applicable law, the President's priorities, and the principles set forth in this Executive order and do not conflict with the policies or actions of another agency." Section 6(b)(1) of Executive Order 12866 limits OMB's review duties to "significant regulatory actions."

    As discussed in more detail below, EPA's No-NOAEL is a significant regulatory action, and it violates Executive Order 12866 and other applicable laws for at least the following reasons:

    • This rule has never been in EPA's published regulatory agenda of all regulations under development or review, as required by Section 4(b) of the Executive order.

    • This rule has never been included in EPA's Regulatory Plan forwarded to OIRA pursuant to Section 4(c) of the Executive Order.

    • This rule has never been submitted to OMB for review along with the supporting package required by Section 6(a)(1)(B) of the Executive Order.

    • EPA has never provided the public with the information regarding this rule that is required to be disclosed by Section 6(a)(3)(E) of the Executive Order.

    • EPA is enforcing this rule despite the fact that it has never been proposed for public comment in accordance with the requirements of the Administrative Procedure Act.

    • EPA is enforcing this rule despite the fact that it has never been sent to Congress with the required supporting package (including compliance with Executive Order 12866) for review under the Congressional Review Act.

    EPA's No-NOAEL Rule Violates Executive Order 12866 Because It Is Inconsistent With the Practice of Other Agencies and other Offices within EPA and with the Common Rule

    One of the most prominent examples of human volunteer tests for toxicity that are expressly permitted and used by the federal government are the Phase I clinical studies for investigating potential new drugs and food and color additives regulated by FDA. At the November 30, 1999 meeting of the joint SAB/SAP subcommittee on this issue, an FDA official acting as a consultant to the subcommittee made a detailed presentation on pertinent aspects of Phase I testing for INDs. Those points included the following:

    • The purpose of the trial is to establish safety, not therapeutic benefits. Very few substances tested ever make it to therapeutic trials or final approval.

    • Subjects do not anticipate direct personal benefits.

    • Administered substances are biologically active and therefore inherently toxic at some dose.

    • The studies attempt to establish a NOAEL, meaning a level at which pharmacodynamic effects are seen short of frank adverse effects and considered acceptable. The investigators will also be looking for variations from the animal data and factors such as reversibility of effects.

    • The number of human subjects at each dose level will usually range between 3 and 10, with gradual escalation of doses until the relevant effect is observed.

    • Foreign data is acceptable if considered to have been properly obtained.

    EPA noted in the Background Paper prepared for the 1999 SAB/SAP Subcommittee meeting that the agency has itself conducted and supported a considerable number of human volunteer experiments with potentially toxic substances. Agency and SAB/SAP sources have cited agency testing of the following substances:

    • MTBE (methyl tertiary butyl ether, a gasoline additive)
    • ozone
    • SO2 (sulphur dioxide)
    • NO2 (nitrogen dioxide)
    • CO (carbon monoxide)
    • air particulate matter and acidic particles
    • methyl mercury
    • hydrofluorocarbons

    EPA's own use of human volunteer data to set exposure standards apparently continues to the present. For example -

    • EPA operates "inhalation chambers" at Chapel Hill, North Carolina, where the Agency tests exposes volunteers to various air pollutants. The most recent annual report for the Agency's National Health and Environmental Effects Research Laboratory discusses the Agency's use of human volunteers to test for levels at which concentrated ambient air particles cause lung inflammation and factors associated with blood clotting, and ongoing studies using human volunteers suffering from asthma or chronic obstructive pulmonary disease.2

    • In March 2000, the Agency's Office of Pollution Prevention and Toxics issued for public comment Acute Exposure Guideline Levels ("AEGL"s) proposed by the AEGL National Advisory Committee. The proposed AEGL-1 , AEGL-2, and AEGL-3 for Cis-1,2-Dichloroethylene and Trans-1,2-Dichloroethylene were all NOAELs based on human volunteer tests.3

    • In June 2000, the same EPA office issued a proposed AEGL-1 for Dimethyldichlorosilane that was based on a NOAEL in exercising asthmatics4. The same notice proposed an AEGL-1 for 2,4 and 2,6 Toluene Diisocyanate (TDI) based on reduced lung function in asthmatic human volunteers.5

    EPA has not been willing to attempt to explain how it can rationalize using data from federally-funded human volunteer studies while refusing to consider data from privately-funded human volunteer studies.

    The "Common Rule" sets out a "Federal Policy for the Protection of Human Subjects". The policy was developed by the Department of Health and Human Services and the National Commission for the Protection of Human Subjects between 1974 and 1991. The Rule was then adopted by the 16 other Federal agencies that conduct, support, or otherwise regulate human subject research, including EPA. The EPA codification of the Common Rule is set out in 40 CFR Part 26. The Common Rule has been uniformly applied by all Federal agencies in conducting, sponsoring, and regulating human volunteer research used for many years to set a variety of regulatory standards under Federal programs.

    The Common Rule set up a system whereby Institutional Review Boards ("IRBs") would evaluate and oversee human volunteer research in order to ensure that there was informed consent and minimization of risks. The Common Rule does not contain any specific restrictions on types of research that can be conducted with human subjects; it contains only a definition of "research", and general "criteria for IRB approval of research".

    "Research" allowable under the Common Rule is defined as "a systematic investigation, including research development, testing, and evaluation designed to develop or contribute to generalizable knowledge." 40 CFR 26.102(d). This definition clearly can encompass human subject research involving pesticidal substances.

    The "Criteria for IRB approval of research" state simply, in relevant part, that risks to the subjects must be minimized "[b]y using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk . . . ." 40 CFR 26.111(a)(1).

    Applying the principles of the Common Rule, as noted above, EPA has previously utilized human volunteer research data to determine NOAELs and set regulatory limits for pesticides, and has also used such research similarly in other programs.

    EPA's No-NOAEL rule violates Executive Order 12866 because it conflicts with the practice of other agencies, such as FDA; with the practice of other EPA offices; and with the Common Rule.

    EPA's Rule Is a Significant Regulatory Action Under Executive Order 12866

    Under Section 3(f) of the Executive Order, a "'significant regulatory action' means any regulatory action that is likely to result in a rule that may:

    1. Have an annual effect on the economy of $100 million or more or adversely affect in a material way the economy, a sector of the economy, productivity, competition, jobs, the environment, public health or safety, or State, local, or tribal governments or communities;

    2. Create a serious inconsistency or otherwise interfere with an action taken or planned by another agency;...

    3. Raise novel legal or policy issues arising out of legal mandates, the President's priorities, or principles set forth in this Executive order."

    EPA's rule will adversely affect in a material way the environment, public health or safety. Attached is a report entitled Using Human Data to Protect the Public's Health (Dourson et al., Feb. 23, 2001). This Report reviewed the Reference Doses (RFDs) on EPA's Integrated Risk Information System (IRIS). It concluded that use of human data resulted in significantly lower RFDs than just use of animal test data for 23% of the IRIS substances. In other words, EPA's rule increases the risk to the environment, public health and safety because it arbitrarily excludes the best scientific data on pesticide safety. This increased risk violates Executive Order 12866.

    EPA's rule also creates a serious inconsistency or otherwise interferes with action taken or planned by another agency. EPA's No-NOAEL rule for its Pesticides Office is irreconcilable with the actions of other federal agencies and other EPA program offices. For example, the FDA routinely uses human test data to determine and establish NOAELs. Other EPA program offices routinely use human test data to determine and establish NOAELs. It is arbitrary and capricious to have conflicting federal standards on this issue. This conflict violates Executive Order 12866.

    EPA Is Violating the Congressional Review Act Because It Is enforcing the No-NOAEL rule Without First Sending the Rule to Congress for Review

    The Congressional Review Act provides that no rule can take effect until the agency promulgating it has sent the rule, and information regarding the agency's compliance with Executive Order 12866 and other relevant Executive orders, to Congress and the Comptroller General. 5 U.S.C. 801(a)(1)(A),(B). The Congressional Review Act defines the term rule in the same manner as the APA, with some exceptions that are not relevant to EPA's No-NOAEL rule. 5 U.S.C. 804 (3).

    EPA's No-NOAEL rule is a rule subject to the Congressional Review Act. EPA is violating the Congressional Review Act by enforcing this rule without ever sending it to Congress with the statutorily required supporting package.

    Relief Requested

    1. Any rule barring the use of clinical human test data to establish pesticide NOAELs is arbitrary, capricious, an abuse of discretion and not otherwise in accordance with applicable law. If EPA nevertheless wishes to proceed with consideration of such a rule, it must before promulgating it comply withs duties under the APA; Executive Order 12866; and the Congressional Review Action.

    2. EPA should announce publicly that it will not apply and enforce its No-NOAEL rule until and unless EPA has complied with the APA's public-notice-and-comment requirements; OMB has completed the Executive Order 12866 review; and the rule has been reviewed by Congress under the Congressional Review Act, along with the required certification of compliance with Executive Order 12866. EPA's public announcement should include a statement that it will consider clinical human test data in establishing pesticide NOAELs until and unless it promulgates a new rule in accordance with these and all other applicable requirements.


    1A very similar statement was made to the SAB/SAP Subcommittee at its November 30, 1999 meeting by the Director of the agency's pesticides program office.

    2"National Health and Environmental Effects Research Laboratory: An Annual Report of Accomplishments for Fiscal Year 2000 (EPA 600/R-00/101, November 2000).

    365 Fed.Reg. 14186, 14187-88, March 15, 2000. (See also p. 4189.)

    465 Fed.Reg.39264, 39266, June 23, 2000.

    5Id. at 39268.