[Federal Register Volume 65, Number 175 (Friday, September 8, 2000)]
[Notices]
[Pages 54521-54523]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-22820]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-00560A; FRL-6593-6]


Pesticides; Science Policy on Use of Data on Cholinesterase 
Inhibition in Risk Assessment

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of availability.

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SUMMARY: EPA is announcing the availability of the revised version of 
the pesticide science policy document entitled ``The Use of Data on 
Cholinesterase Inhibition for Risk Assessments of Organophosphorus and 
Carbamate Pesticides.'' This notice is one in a series concerning 
science policy documents related to implementation of the Federal Food, 
Drug, and Cosmetic Act, as amended by the Food Quality Protection Act.

FOR FURTHER INFORMATION CONTACT: Dr. Penelope A. Fenner-Crisp, 
Environmental Protection Agency (7501C), 1200 Pennsylvania, Ave., NW., 
Washington, DC 20460; telephone number: (703) 605-0654; fax number: 
(703) 308-4776; e-mail address: [email protected].

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be potentially affected by this action if you manufacture 
or formulate pesticides. Potentially affected categories and entities 
may include, but are not limited to:

 
------------------------------------------------------------------------
                                                        Examples of
             Categories                  NAICS     potentially  affected
                                                          entities
------------------------------------------------------------------------
Pesticide                                  32532   Pesticide
Producers..........................                 manufacturers
                                                   Pesticide formulators
------------------------------------------------------------------------

    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of entities not listed could also be affected. The 
North American Industrial Classification System (NAICS) codes have been 
provided to assist you and others in determining whether or not this 
notice affects certain entities. If you have any questions regarding 
the applicability of this action to a particular entity, consult the 
person listed under FOR FURTHER INFORMATION CONTACT.

B. How Can I Get Additional Information, Including Copies of this 
Document or Other Related Documents?

    1. Electronically. You may obtain electronic copies of this 
document, the science policy documents, and certain other related 
documents that might be available from the Office of Pesticide 
Programs' Home Page at http://www.epa.gov/pesticides/. On the Office of 
Pesticide Programs' Home Page select ``FQPA'' and then look up the 
entry for this document under ``Science Policies.'' You can also go 
directly to the listings at the EPA Home page at http://www.epa.gov. On 
the Home Page select ``Laws and Regulations,'' ``Regulations and 
Proposed Rules,'' and then look up the entry for this document under 
``Federal Register--Environmental Documents.'' You can go directly to 
the Federal Register listings at http://www.epa.gov/fedrgstr/.
    2. Fax-on-Demand. You may request a faxed copy of the science 
policy documents, as well as supporting information, by using a 
faxphone to call (202) 401-0527. Select item 6065 for the document 
entitled ``Office of Pesticide Programs' Science Policy on the Use of 
Data on Cholinesterase Inhibition for Risk Assessments of 
Organophosphorus and Carbamate Pesticides.'' Select item 6066 for the 
document entitled ``Responses to Public Comments on the Office of 
Pesticide Programs' 1997 Science Policy: The Use of Data on 
Cholinesterase Inhibition for Risk Assessments of Organophosphorus and 
Carbamate Pesticides.'' You may also follow the automated menu.
    3. In person. The Agency has established an official record for 
this action under docket control number OPP-00560A which includes a 
document summarizing an objection received during internal EPA review 
and EPA response to the objection. In addition, the documents 
referenced in the framework notice, which published in the Federal 
Register on October 29, 1998 (63 FR 58038) (FRL-6041-5) have also been 
inserted in the docket under docket control number OPP-00557. The 
official record consists of the documents specifically referenced in 
this action, and other information related to this action, including 
any information claimed as Confidential Business Information (CBI). 
This official record includes the documents that are physically located 
in the docket, as well as the documents that are referenced in those 
documents. The public version of the official record does not include 
any information claimed as CBI. The public version of the official 
record, which includes printed, paper versions of any

[[Page 54522]]

electronic comments submitted during an applicable comment period is 
available for inspection in the Public Information and Records 
Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson 
Davis Highway, Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through 
Friday, excluding legal holidays. The PIRIB telephone number is (703) 
305-5805.

II. Background Information About the Tolerance Reassessment 
Advisory Committee

    On August 3, 1996, the Food Quality Protection Act of 1996 (FQPA) 
was signed into law. The FQPA significantly amended the Federal 
Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 
Food, Drug, and Cosmetic Act (FFDCA). Among other changes, FQPA 
established a stringent health-based standard (``a reasonable certainty 
of no harm'') for pesticide residues in foods to assure protection from 
unacceptable pesticide exposure and strengthened health protections for 
infants and children from pesticide risks.
    Thereafter, the Agency established the Food Safety Advisory 
Committee (FSAC) as a subcommittee of the National Advisory Council for 
Environmental Policy and Technology (NACEPT) to assist in soliciting 
input from stakeholders and to provide input to EPA on some of the 
broad policy choices facing the Agency and on strategic direction for 
the Office of Pesticide Programs (OPP). The Agency has used the interim 
approaches developed through discussions with FSAC to make regulatory 
decisions that met FQPA's standard, but that could be revisited if 
additional information became available or as the science evolved. In 
addition, the Agency has sought independent review and public 
participation, generally through presentation of the science policy 
issues to the FIFRA Scientific Advisory Panel (SAP), a group of 
independent, outside experts who provide peer review and scientific 
advice to OPP.
    During 1998 and 1999, as directed by Vice President Albert Gore, 
EPA worked with the U.S. Department of Agriculture (USDA) and a second 
subcommittee of NACEPT, the Tolerance Reassessment Advisory Committee 
(TRAC) to address FQPA issues and implementation. TRAC comprised more 
than 50 representatives of affected user, producer, consumer, public 
health, environmental, states and other interested groups. The TRAC met 
from May 27, 1998 through April 29, 1999.
    In order to continue the constructive discussions about FFDCA, EPA 
and USDA have established, under the auspices of NACEPT, the Committee 
to Advise on Reassessment and Transition (CARAT). The CARAT provides a 
forum for a broad spectrum of stakeholders to consult with and advise 
the Agency and the Secretary of Agriculture on pest and pesticide 
management transition issues related to the tolerance reassessment 
process. The CARAT is intended to further the valuable work initiated 
by the FSAC and TRAC towards the use of sound science and greater 
transparency in regulatory decisionmaking, increased stakeholder 
participation, and reasonable transition strategies that reduce risks 
without jeopardizing American agriculture and farm communities. The 
CARAT held its first meeting on June 23, 2000. As a result of the TRAC 
process, the Agency decided that the FQPA implementation process and 
related policies would benefit from notice and comment on the major 
science policy issues.
    The TRAC identified nine science policy issue areas they believed 
were key to implementation of tolerance reassessment. EPA agreed to 
provide one or more documents for comment on each of the nine issues by 
announcing their availability in the Federal Register. In a notice 
published in the Federal Register of October 29, 1998 (63 FR 58038), 
EPA described its intended approach. Since then, EPA has been issuing a 
series of draft and revised documents concerning the nine science 
policies. This notice announces the availability of the revised version 
of the science policy document entitled ``The Use of Data on 
Cholinesterase Inhibition for Risk Assessments of Organophosphorus and 
Carbamate Pesticides.''

III. Summary of Revised Science Policy Guidance Document

    In 1997, EPA's Office of Pesticide Programs presented a science 
policy document entitled ``The Use of Data on Cholinesterase Inhibition 
for Risk Assessments of Organophosphorus and Carbamate Pesticides'' to 
the FIFRA Scientific Advisory Panel for review and comment. The 1997 
science policy document described the approaches OPP would employ in 
assessing the potential for human health hazard from the cholinergic 
effects on nervous system function following exposure to 
cholinesterase-inhibiting pesticides.
    In 1998, as part of its TRAC review of science policy issues, OPP 
published a draft version of the 1997 TRAC science policy document 
entitled ``Office of Pesticide Programs' Science Policy on the Use of 
Data on Cholinesterase Inhibition for Risk Assessments of 
Organophosphorus and Carbamate Pesticides'' on November 5, 1998 (63 FR 
59780) (FRL-6042-3) and comments were filed under docket control number 
OPP-00560. Many persons also submitted comments on the 1997 policy 
document under docket control number OPP-00480 relative to the 1997 SAP 
meeting (62 FR 19572, April 22, 1997) (FRL-5714-2) and under docket 
control number OPP-00557 relative to the TRAC process. All of the 
comments and recommendations have been reviewed by OPP and incorporated 
into the revised science policy document, as appropriate.
    As did the 1997 policy, this revised science policy document 
emphasizes the weighing of all relevant evidence when selecting 
endpoints for the hazard assessment of anticholinesterase pesticides. 
This ``weight-of-the-evidence'' review, conducted on a case-by-case, 
chemical-by-chemical basis, is accomplished by performing an 
integrative analysis after assessing all the individual lines of 
evidence (including all available data on cholinesterase inhibition in 
all compartments--central nervous system, peripheral nervous system, 
red blood cells, and plasma--as well as data on clinical signs, 
symptoms and other physiological or behavioral effects). Weighing of 
the evidence must include considerations of many factors, including the 
adequacy of study protocols; quality of data; number of studies on each 
endpoint; dose-dependency of responses; time course and duration of 
effects; and similarities or differences of responses observed in all 
the species, strains, and sexes tested for each duration and route of 
exposure evaluated.
    In a weight-of-the-evidence assessment of cholinesterase-inhibiting 
substances, acetylcholinesterase inhibition in the nervous system is 
viewed as a key event in the mechanism of toxicity of these compounds 
and an important critical effect to consider in the hazard assessment. 
Evaluations of the cholinergic effects (i.e., physiological and 
behavioral changes and measures of cholinesterase inhibition in the 
central and peripheral nervous systems) caused by exposure to the 
cholinesterase-inhibiting organophosphorous and carbamate pesticides 
provide direct evidence for characterizing potential human health 
hazard. Because of likely differences in both the chemicals' and the 
cholinesterases' pharmacodynamic properties, measures of cholinesterase 
inhibition in both the central and peripheral nervous systems are 
important for a thorough evaluation of

[[Page 54523]]

potential hazard. However, direct measurement of cholinesterase 
activity in peripheral nervous system tissues is rarely available at 
the present time. When these data are not available, as a matter of 
prudent science policy protective of human health, EPA will treat 
cholinesterase inhibition in the blood as a surrogate measure for the 
peripheral nervous system in animals and for both the peripheral and 
central nervous systems in humans. Information from blood 
cholinesterase inhibition data is considered to provide important 
insights into potential hazard.
    Red blood cell (RBC) measures of acetylcholinesterase (AChE) are 
generally preferred over plasma measures of cholinesterase activity 
because data on red blood cells may provide a better representation of 
the inhibition of the neural target enzyme, acetylcholinesterase. OPP, 
however, may use plasma cholinesterase inhibition data under certain 
circumstances, such as if red blood cell data are insufficient, of poor 
quality, or unavailable; if there is a lack of dose-dependency for the 
red blood cell acetylcholinesterase inhibition; or, if the dose 
responses for inhibition of plasma cholinesterase more closely 
approximate those for AChE inhibition in the nervous system than do the 
dose responses for RBC acetylcholinesterase inhibition.
    It should be noted that the present policy provides guidance only 
on how to deal with data as they relate to the cholinergic endpoints 
associated with nervous system function following exposure to 
organophosphorous and carbamate pesticides. This scope is consistent 
with all earlier descriptions of Agency assessment approaches as well 
as that of other organizations with regard to the evaluation of 
cholinesterase-inhibiting substances (e.g., WHO JMPR (1998), DPR-CalEPA 
(1997) and other national authorities). When applying the weight-of-
the-evidence approach for selecting critical effect(s) for derivation 
of a reference dose (RfD) or concentration (RfC), however, the entire 
toxicological data base on a pesticide must be evaluated (i.e., there 
also must be consideration of endpoints not related to the cholinergic 
consequences of anticholinesterase activity, for instance, liver or 
developmental toxicity or carcinogenicity). It is possible that, for 
one or more of the exposure scenarios being evaluated, the non-
cholinergic effects will be identified as critical or co-critical, and 
they may become a more appropriate basis for deriving RfDs or RfCs.
    Finally, OPP policy documents are meant to be ``living documents,'' 
that is, they are open to periodic updating and revision to reflect 
advances in the science. Thus, this policy, too, will be updated to 
incorporate important new scientific knowledge as it becomes available. 
For example, the routine availability of data on acetylcholinesterase 
activity in the peripheral nervous system may allow for refinements in 
the hazard assessment approach for anticholinesterase chemicals. Also, 
as knowledge increases about the potential roles of the different 
cholinesterases in the developing organism, particularly as they impact 
the development of the nervous system, it may allow for refinements in 
evaluating the potential differential sensitivity and susceptibility of 
the young versus adults. In fact, a substantial research effort has 
been, and continues to be, made to determine what roles acetylcholine-, 
butyrylcholine-, and other esterases may play in the development of the 
nervous system and in cell growth, proliferation, and death in other 
tissues. OPP encourages further discussion of the possible implications 
of the research findings, both for future research planning and for the 
Agency's regulation of cholinesterase-inhibiting pesticides.

IV. Summary of Comments and Responses

    In the public comments referred to under Unit III., some commenters 
addressed the general policy and its rationale as well as all of the 
specific questions posed, while other reviewers provided detailed 
comments only on certain aspects of the policy. A listing of the names 
and affiliations of those who submitted comments is provided at the end 
of the document entitled ``Responses to Public Comments on the Office 
of Pesticide Programs' 1997 Science Policy: The Use of Data on 
Cholinesterase Inhibition for Risk Assessments of Organophosphorus and 
Carbamate Pesticides.'' This document contains a summary of the most 
significant revisions to the 1997 science policy document, followed by 
responses to comments.
    In the draft science policy document, the Agency requested comment 
on ten questions to help focus public commment. In order to organize 
the responses to these questions in the response to comments document, 
the ten specific questions have been combined into six somewhat broader 
topic areas:
    1. General weight-of-the-evidence issues related to the use of 
blood and brain measures as critical effects, differences between 
plasma and RBC measures and their use, and the weight-of-the-evidence 
approach (Questions 1, 2, and 9);
    2. Peripheral nervous system measures (Questions 3 and 4);
    3. Comparative measures in the young and adults (Questions 5 and 
6);
    4. Additional neurochemical measures (Questions 7 and 8);
    5. Other comments.
    6. Editorial comments on the science policy document (Question 10).

V. Policies Not Rules

    The policy document discussed in this notice is intended to provide 
guidance to EPA personnel and decision-makers, and to the public. As a 
guidance document and not a rule, the policy in this guidance is not 
binding on either EPA or any outside parties. Although this guidance 
provides a starting point for EPA risk assessments, EPA will depart 
from its policy where the facts or circumstances warrant. In such 
cases, EPA will explain why a different course was taken. Similarly, 
outside parties remain free to assert that a policy is not appropriate 
for a specific pesticide or that the circumstances surrounding a 
specific risk assessment demonstrate that a policy should not be 
applied.

List of Subjects

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests.

    Dated: August 29, 2000.
Susan H. Wayland,
Acting Assistant Administrator for Prevention, Pesticides and Toxic 
Substances.
[FR Doc. 00-22820 Filed 9-7-00; 8:45 am]
BILLING CODE 6560-50-F