[Federal Register Volume 67, Number 11 (Wednesday, January 16, 2002)]
[Notices]
[Pages 2210-2214]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-959]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-00658B; FRL-6814-3]


Pesticides; Guidance on Cumulative Risk Assessment of Pesticide 
Chemicals That Have a Common Mechanism of Toxicity

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of availability.

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[[Page 2211]]

SUMMARY: EPA announces the availability of the revised version of the 
pesticide science policy document entitled ``Guidance on Cumulative 
Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of 
Toxicity.'' This notice is one in a series of science policy documents 
related to the implementation of the Federal Food, Drug, and Cosmetic 
Act (FFDCA), as amended by the Food Quality Protection Act of 1996 
(FQPA).

FOR FURTHER INFORMATION CONTACT: Beth Doyle, Environmental Protection 
Agency (7503C), 1200 Pennsylvania Ave., NW., Washington, DC 20460; 
telephone number: (703) 305-2722; fax number: (703) 305-0871; 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 Producers               32532               Pesticide
                                                       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 to this document under 
``Federal Register--Environmental Documents.'' You can go directly to 
the Federal Register listings at http://www.epa.gov/fedrgstr.
    2. In person. The Agency has established an official record for 
this action under docket control number OPP-00658B. 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) under 
docket control number OPP-00557, are considered as part of the official 
record for this action under docket control number OPP-00658B even 
though not placed in the official record. 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 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 Hwy., 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

    On August 3, 1996, FQPA was signed into law. The FQPA significantly 
amended the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 
and 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 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 meet the new FFDCA standard, but that could be revisited if 
additional information became available or as the science evolved. In 
addition, the Agency seeks 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, EPA and the U.S. Department of Agriculture 
(USDA) established a second subcommittee of NACEPT, the Tolerance 
Reassessment Advisory Committee (TRAC) to address FFDCA 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 toward 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.
    As a result of the 1998 and 1999 TRAC process, EPA decided that the 
implementation process and related policies would benefit from 
providing notice and comment on major science policy issues. The TRAC 
identified nine science policy areas it 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) (FRL-6041-5), 
EPA described its intended approach. Since then, EPA has been issuing a 
series of draft documents concerning the nine science policy issues. 
This notice announces the availability of the revised science policy

[[Page 2212]]

document concerning cumulative risk assessment.

III. Summary of ``Guidance on Cumulative Risk Assessment of 
Pesticide Chemicals That Have a Common Mechanism of Toxicity''

    In assessing the potential health risks associated with exposure to 
pesticides, attention has historically focused on single pathways of 
exposure (e.g., from pesticide residues in food, water, or residential/
nonoccupational uses) for individual chemicals, and not on the 
potential for individuals to be exposed to multiple pesticides by all 
pathways concurrently. In 1996, FQPA modified FFDCA to require OPP to 
consider potential human health risks from all pathways of dietary and 
nondietary exposures to more than one pesticide acting through a common 
mechanism of toxicity. This document provides guidance to OPP 
scientists for evaluating and estimating the potential human risks 
associated with such multichemical and multipathway exposures to 
pesticides. This process is referred to as cumulative risk assessment.
    The current guidance has been revised in light of review and 
comment offered by the public on an earlier draft version during the 
public comment period of June through September 2000 (USEPA, 2000a) (65 
FR 40644, June 30, 2000 (FRL-6556-4) and 65 FR 50526, August 18, 2000 
(FRL-6739-3)), by the SAP in September and December 1999, and by 
comments offered by other external parties at the SAP meetings. 
Furthermore, OPP has gained experience in applying the principles of 
the draft guidance itself with actual datasets on pesticides that share 
a common mechanism of toxicity. A pilot analysis was presented to the 
SAP on 24 organophosphorus pesticides illustrating the hazard and dose-
response guidance in September 2000, and on the exposure assessment and 
risk characterization process in December 2000. The SAP comments on 
this pilot analysis have also led to refinements in the process of 
conducting cumulative risk assessments.
    Cumulative risk assessments will play a significant role in the 
evaluation of risks posed by pesticides, and will enable OPP to make 
regulatory decisions that more fully protect public health and 
sensitive subpopulations, including infants and children. The 
cumulative assessment of risks posed by exposure to multiple chemicals 
by multiple pathways (including food, drinking water, and residential/
nonoccupational exposure to air, soil, grass, and indoor surfaces) 
presents a formidable challenge for OPP. This guidance takes into 
account the knowledge and methods available now for assessing 
cumulative risk, and provides flexibility for addressing a variety of 
data situations. Because methods and knowledge are expected to continue 
to evolve in this area, OPP will update specific procedures with peer-
reviewed supplementary technical documentation as needed. Further 
revision of the guidance itself will take place when extensive changes 
are necessary.
    Before undertaking a cumulative risk assessment on pesticides 
sharing a common mechanism of toxicity, OPP will typically perform an 
aggregate risk assessment for each chemical in the common-mechanism 
group. When conducting aggregate assessments, OPP will follow the 
guidance described in the document entitled ``Guidance for Performing 
Aggregate Exposure and Risk Assessments'' (USEPA, 1999b), dated 
November 16, 2001 (66 FR 59428, November 28, 2001) (FRL-6792-8). Using 
this guidance, OPP will simultaneously consider the exposures from 
food, drinking water, and residential/non-occupational uses of each 
pesticide. When the aggregate risk assessments are completed for 
individual chemicals that share a common mechanism of toxicity, OPP 
will perform the cumulative risk assessment in the steps summarized 
below.
    A cumulative risk assessment begins with the identification of a 
group of chemicals, a common mechanism group (CMG), that induce a 
common toxic effect by a common mechanism of toxicity. OPP will follow 
the framework for identifying the chemicals that belong in that group 
(see ``Guidance for Identifying Pesticide Chemicals and Other 
Substances That Have a Common Mechanism of Toxicity,'' USEPA, 1999a (64 
FR 5796, February 5, 1999) (FRL-6060-7)). Once a CMG has been 
established, the next step is to evaluate registered and proposed uses 
for each CMG member in order to identify potential exposure pathways 
(i.e., food, drinking water, residential) and routes (i.e., oral, 
inhalation, dermal). During the hazard characterization phase, the 
various endpoints associated with the common mechanism of toxicity are 
identified, as well as the test species/sex that might serve as a 
uniform basis for determining relative potencies among the chemicals of 
interest. The common effect is also evaluated to determine if it is 
expressed across all exposure routes and durations of interest for each 
CMG member. The temporal aspects (e.g., time to peak effects, time to 
recovery) of the common mechanism toxicity are characterized to 
determine the critical window of its expression.
    Not all cumulative assessments need to be of the same depth and 
scope. Thus, early in the cumulative assessment process, it is 
important to determine the need for, or the capability to perform, a 
comprehensive risk assessment. This is done by considering the number 
and types of possible exposure scenarios in conjunction with the 
associated residue values available. Initial toxicological and exposure 
information is collected. A screening-level assessment may be conducted 
that applies more conservative approaches than would a comprehensive 
and refined cumulative risk assessment. For example, margins of 
exposure may be based on no-observed adverse-effect-levels (NOAELs) for 
the common toxic effect rather than modeling dose-response curves of 
each chemical member to derive more refined relative potencies and 
points of departures. For dietary food risk, treatment of 100% of crops 
is assumed for each CMG chemical registered for use on a crop. 
Tolerance-level residues for the exposure component of the assessment 
may be assumed, rather than producing a refined estimate of actual 
residue levels from monitoring. If a screening-level analysis including 
such overestimates of exposure indicates that there is no risk concern, 
then no further detailed assessment may be necessary. But if this 
conservative approach indicates a potential for unacceptable risk, then 
a refined assessment should be conducted. This may engender the need 
for additional data.
    As the risk assessor proceeds with the cumulative assessment, it is 
important to determine candidate chemicals and uses, routes, and 
pathways from the CMG that may cause cumulative effects. Cumulative 
assessments should not attempt to quantify risk resulting from those 
common-mechanism chemicals that will have a minimal toxic contribution 
to the cumulative hazard, or from minor exposure pathways, routes, or 
uses.
    Exposures from minor pathways should be considered qualitatively. 
Thus, a subset of common-mechanism chemicals to be included in the 
quantification of cumulative risk needs to be identified from the CMG. 
This subgroup is called the cumulative assessment group (CAG). The 
identification of the CAG is done throughout the process as a detailed 
understanding of each group member's hazard and exposure potential 
emerges from the analysis. Although a

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chemical(s) may be removed from the quantification of risk, the 
rationale for such decisions will be explained. Thus, all chemicals 
that were grouped by a common mechanism of toxicity will be accounted 
for (qualitatively or quantitatively) in the final assessment.
    OPP will use dose addition for determining the combined risk of the 
CAG. This approach is consistent with the Agency's approach to 
multichemical assessments that involve chemicals that are 
toxicologically similar and share a common toxic effect. OPP will 
depart from the dose-addition approach if there are data available to 
support an alternative method. A dose-response analysis is performed on 
each CAG member to determine its toxic potency for the common toxic 
effect. The determination of toxic potency should, to the extent 
feasible with available data, be conducted on a uniform basis (i.e., 
same measure of potency, for the same effect, from the same test 
species/sex using studies of comparable methodology).
    Once the toxic potency of each common-mechanism chemical is 
determined, the relative potencies of the CAG members are established. 
To determine relative potency, a chemical from the CAG is selected to 
serve as the index chemical. The index chemical is used as the point of 
reference for standardizing the common toxicity of the other chemical 
members of the CAG. Once the index chemical is selected, relative 
potency factors (RPFs) are calculated (i.e., the ratio of the toxic 
potency of a given chemical relative to that of the index chemical). 
RPFs are used to convert exposures of all chemicals in the CAG into 
exposure equivalents of the index chemical. Given that the RPF method 
portrays risk as exposure equivalents to one chemical (the index 
compound), it is preferred that index chemical (1) have high-quality 
dose-response data, (2) have a toxicological/biological profile for the 
common toxicity that is representative of the common toxic effect(s), 
and (3) be well characterized for the common mechanism of toxicity. The 
last step in the dose-response assessment is to calculate a point of 
departure(s) for the index chemical so that the risk of the CAG can be 
extrapolated to anticipated human exposures.
    Detailed exposure scenarios for all of the uses remaining for each 
pesticide in the CAG must be developed. This includes determination of 
potential human exposures by all relevant pathways, durations, and 
routes that may allow simultaneous exposures, or any sequential 
exposures among the CAG members that could contribute to the same joint 
risk of the common toxic effect (i.e., either by overlapping internal 
doses or by overlapping toxic effects). The framework for estimating 
combined exposures is based on exposure to individuals, representing 
differing attributes of the population (e.g., human activity patterns, 
place of residence, age) that link pathways/route of exposure through 
scenario building. Cumulative risk values for a given common toxic 
effect are calculated separately for each exposure route and duration 
and then combined. To the extent data permit, the temporal and spatial 
linkages should be maintained for the many factors defining a possible 
individual exposure. A decision must be made on the relative importance 
of scenarios and the need for their inclusion in a quantitative 
assessment, as well as on the populations of interest and locations for 
evaluation in the assessment. The potential for co-occurrence of 
possible exposure scenarios is evaluated. Spatial, temporal, and 
demographic considerations are major factors in determining whether a 
concurrent exposure is likely to occur. In other words, all exposure 
events need to occur over a specific interval of time; events need to 
agree in time, place, and demographic characteristics; and an 
individual's dose needs to be matched with relevant toxicological 
values in terms of route and duration.
    Exposure input parameters must be established. The magnitude, 
frequency, and duration for all pertinent exposure pathway/route 
combinations are determined, and appropriate sources of use/usage 
information, residues in all appropriate media, and any modifying 
factors necessary for inclusion in the assessment are identified. Where 
necessary, any appropriate surrogate datasets from other chemical-
specific data, published literature, or generic datasets are 
identified. A trial run of a quantitative cumulative risk is conducted 
by assigning route-specific and duration-specific risk metrics. The 
outputs of this trial run are evaluated and a sensitivity analysis is 
conducted. Subpopulations of concern are assessed.
    The last step of the assessment process is to characterize the 
risk. The results and conclusions of the cumulative risk analysis are 
clearly described, including the relative confidence in toxicity and 
exposure data sources and model inputs. The risk characterization also 
includes a description of the variability. Major areas of uncertainty 
are described both qualitatively and quantitatively. The magnitude and 
direction of likely bias and the impact on the final assessment are 
discussed. Risk contributors are identified with regard to 
pesticide(s), pathway, source, time of year, and impacted subpopulation 
(with particular attention to children). The basis for group 
uncertainty and FQPA safety factors is explained.
    In the event that a cumulative risk assessment indicates that there 
may be risks of concern, OPP would need to develop risk mitigation 
measures and take appropriate regulatory actions. OPP notes that the 
Cumulative Risk Assessment Guidance document does not address the 
process used to decide on the need for or the choice of risk mitigation 
measures. It may be possible to address risk concerns through 
mitigation measures that do not significantly change the use of a 
pesticide (e.g. reducing application rates or changing the timing or 
manner of application). In other cases, however, OPP acknowledges that 
regulatory measures, that reduce or eliminate pesticide uses, may be 
necessary and may result in the use of other pesticides or alternative 
pest control practices, which may have their own risks and benefits. 
While beyond the scope of this science policy document, OPP also 
recognizes that it is important to consider potential risks and 
benefits of such substitutes and alternatives to ensure that decisions 
do not increase net risk, transfer risk unreasonably, and fail to 
preserve important benefits wherever possible. Such consideration would 
be an important part in designing mitigation options for aggregate risk 
assessments for individual chemicals and for cumulative risk 
assessments for chemicals sharing a common mechanism of toxicity. The 
consideration of the risks and benefits of alternatives would 
contribute to an understanding of whether adoption of a possible risk 
mitigation measure might actually result in increased risks. When 
alternative means of reducing risk exist, OPP intends that the risk 
management decisions appropriately take into account which of the 
mitigation measures achieves the necessary reduction in risk in the 
most efficient manner, i.e., the manner that has the highest societal 
benefits. Accordingly, OPP will produce an analysis of alternatives 
when developing risk reduction options so that the net societal risk 
and net societal benefits for the options can be estimated. This 
analysis will enable risk managers to assure that there are not 
significant risk transfers and uses with important benefits are 
maintained, to the extent possible.
    OPP is interested in understanding the views of the public on these 
issues--

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both in the context of making regulatory decisions on specific 
pesticides and more broadly. OPP's ongoing process of public 
participation in individual pesticide tolerance reassessment decisions 
affords ample opportunity for interested stakeholders to comment on 
these issues as they may affect individual chemicals, classes of 
chemicals, and the transfer of risks and benefits. In addition, OPP 
intends to seek public input on broader methodological aspects of these 
issues through its existing federal advisory committee, the Committee 
to Advise on Reassessment and Transition, and/or through other avenues 
that give the public an opportunity to comment. OPP intends to make 
publicly available the comments received, and to use an open and 
participatory process to discuss the analysis, methods, and scientific 
considerations the Agency may use when characterizing changes in net 
risk, and effects of any transfer of risk and benefits associated with 
mitigation options.

IV. 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: January 8, 2002.
Stephen Johnson,
Assistant Administrator for Prevention, Pesticides and Toxic 
Substances.

[FR Doc. 02-959 Filed 1-15-02; 8:45 am]
BILLING CODE 6580-50-S