02-959. 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.

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: [phone]; fax number: [phone]; e-mail address: [e-mail].

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:

Categories	NAICS	Examples of 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 [phone].

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 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 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—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.