UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

DATE: April 12, 2016 

SUBJECT: Response to Comments on the Pesticide Cumulative Risk Assessment: Framework for 

Screening Analysis Purpose 

PC Code: NA DP No.: 0429639 

Decision No.: 480178 Registration No.: NA 

Regu latory Action: NA 

Case No.: 

Petition No.: NA 

Risk Assessment Type: Cumulative 

TXR No.: NA CAS No.: NA 

MRID No.: NA 40 CFR: NA 

FROM: 

THROUGH: 

TO: 

Monique M. Perron, Sc.D., Toxicologist, Risk Assessment Branch 1 ~~./ ~ ( _ 

Hannah Pope-Varsalona, PhD, Risk Assessor & Toxicologist, Risk Assessment Bra ''ftc 

Evisabel Craig, Ph.D.,DABT, Toxicologist, Risk Assessment Branch 6 . · 

Health Effects Division (7509P) 

Office of Pesticide Programs 

CharlesSmith c(__)~ Branch Chief, Risk Assessment Branch 1 

Health Effects Division (7509P) 

Office of Pesticide Programs 

Jessica Rogala/Mark Suarez, Invertebrate and Vertebrate Branch 3 

Andy Ertman/Barbara Madden, Minor Use and Emergency Response Branch 

Registration Division (7SOSP) 

Office of Pesticide Programs 

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Introduction: 

The purpose of this document is to provide the Environmental Protection Agency's (EPA) response to 

the public comments received on an EPA document entitled, Pesticide Cumulative Risk Assessment: 

Framework for Screening Analysis Purpose (see http://www.regulations.gov, EPA-HQ-OPP-2015-0422). 

Each of the comments identified is individually addressed below and is referenced by the docket 

number that is assigned in www.regulations.gov which is the publically available database where 

comments are registered. 

EPA-HQ-OPP-2015-0422-0013 (S. Kunickis, United States Department of Agriculture): 

Comment Summary: Performing a screening-level exposure analysis is equally valuable for candidate 

common mechanism groups (CMGs) under Option 2 as it is for CMGs under Option 3. USDA 

recommends that the screening-level exposure analysis become a standard prerequisite before 

conducting a full cumulative risk assessment (CRA) for both Option 2 and Option 3. 

EPA Response: Under the draft cumulative framework, if pesticides have shared characteristics to 

support a testable hypothesis for a common mechanism of action, but do not have adequate data for 

establishing key events in a pathway as described in the mode of action/adverse outcome pathway 

(MOA/AOP) framework, then the group would be classified as a "candidate CMG" under Option 2. As a 

" candidate CMG", screening-level exposure and aggregate analyses are conducted as described in the 

draft cumulative framework. If the screening-level cumulative risks are below the level of concern, then 

the cumulative screening is complete and no additional MOA/AOP data are needed. On the other hand, 

if screening-level cumulative risks are above the level of concern, additional toxicology and/or exposure 

data are necessary to further evaluate the MOA/ AOP. 

In comparison, if there is sufficient mechanistic data available to support establishing a set of key events 

in a pathway and thus support developing a science policy to establish a CMG, then the group would be 

classified under Option 3 (CMG can be established). The agency would develop a science policy 

according to the 1999 CMG guidance (U.S. EPA, 1999) and a CRA would be conducted following the 

existing CRA guidance (U.S. EPA, 2002a). CRAs may vary in their level of refinement. Not every CRA 

needs to have the same scope or depth. As a result, there is potential to only conduct a screening-level 

assessment for certain CMGs rather than a comprehensive CRA, if appropriate. 

Comment Summary: The statement "it is important to characterize the type of data used to define food 

residues" needs clarity if food residues of a single pesticide chemical also account and estimate for 

parent, metabolites, and/or degradation products. Are processed food products included in the dietary 

exposure assessment? 

EPA Response: The screening framework states that food residues in OPP dietary assessments are 

typically based on tolerance levels, field trial data, or the Pesticide Data Program (PDP) data. Any 

metabolites or degradates are inherently represented in that data. In terms of processed foods, when 

OPP conducts dietary exposure assessments, it includes residues and consumption data for both 

unprocessed and processed foods. For processed foods, OPP incorporates empirical data and/or default 

processing factors, as available, into the Dietary Exposure Evaluation Model-Food Commodity Intake 

Database (DEEM-FCID) under each processed commodity. As such, OPP has not made changes to the 

framework to further describe the type of data used to define food residues. 

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Comment Summary: Regarding the parenthetical "(i.e., turf residues, indoor surface residues, etc.)," if 

residential uses are limited to turf, pet, and indoor residential exposures in the analysis, then 

"etc." should be deleted. If pesticide use also includes greenhouse or nurseries, for example, then other 

residential uses should be specified or defined. 

EPA Response: EPA thanks USDA for this clarification. The parenthetical was not meant to be all 

inclusive, it was meant to list examples of residential uses. The "i.e." will be changed to "e.g." in the final 

cumulative guidance. 

EPA-HQ-OPP-2015-0422-0014 (J. Collins, Croplife America): 

Comment Summary: CLA provided general comments on the level of refinement that should be used or 

the dietary and residential exposure assessments included in a cumulative screen. 

EPA Response: EPA will utilize as many dietary and residential exposure refinements, as described in the 

framework, as necessary on a case-by-case basis. These refinements will be explained in detail in the 

specific cumulative screen documents completed for each candidate CMG. 

Comment Summary: It would be helpful to have a clarification in the final guidance that the reference 

chemical in the screening assessment may be different from that in the existing guidance, and that in 

the screening assessment the most potent chemical should be the reference (which appears to be the 

intent). 

EPA Response: An index chemical may be selected, as appropriate, to derive screening-level relative 

potency factors (RPFs) and points of departure for purposes of a cumulative screening exposure 

analysis. The existing CRA guidance (U.S. EPA 2002a), notes that it is preferred that the 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 (U.S. EPA, 2002a). Similarly in the screening analysis, an index chemical 

will be selected based on an evaluation of the available data in the toxicological databases for all 

chemicals in a candidate CMG. The index chemical does not necessarily need to be the most potent, but 

rather it will have the most robust toxicological database for the common toxic effect via the exposure 

routes of interest. Text has been added to the framework to provide more information on the selection 

of index chemicals. 

Comment Summary: Newly registered chemicals should be considered carefully as they may not 

immediately have data available for refinement. 

EPA Response: If a candidate CMG has not been determined for the class for which the newly registered 

chemical may be a member, screening for a candidate CMG will likely be conducted for that chemical 

during Registration Review. If a new active ingredient is proposed for registration to EPA and the 

chemical is a member of a candidate CMG for which a cumulative screen has previously been completed 

during Registration Review, EPA will conduct a revised cumulative screen incorporating the new active 

ingredient. The available refinements would be used as necessary and on a case-by-case basis (e.g., 

projected percent crop treated/percent crop treated new, etc.) consistent with the framework. 

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EPA-HQ-OPP-2015-0422-0015 (National Resource Defense Council) and EPA-HQ-OPP-2015-0422-0017 

(T. Woodruff, University of California, San Francisco): 

Comment Summary: The pesticide framework should expand the concept of cumulative risk beyond 

MOA/ AOP to include chemicals that contribute to a common adverse health impact. As currently 

drafted, it fails to address true cumulative risk. 

EPA Response: The Federal Food, Drug, and Cosmetic Act (FFDCA) as amended by the Food Quality 

Protection Act (FQPA) requires the agency to take into account "available evidence concerning the 

cumulative effects on infants and children of such residues and other substances that have a common 

mechanism of toxicity." As such the agency has a statutory requirement to assess cumulative risk based 

on common mechanism of toxicity. Accordingly, the agency must first assess cumulative in this way. 

However, OPP is actively engaged with other EPA program offices and regions to develop agency-wide 

CRA guidance that incorporates additional considerations beyond common mechanism of action. As the 

agency wide efforts develop and mature, OPP may participate, if appropriate, in CRA activities with 

broader scope. 

Comment Summary: The CRA framework should include critical elements of a systematic review 

process for evaluating and integrating multiple streams of data. The CRA framework should 

demonstrate that OPP has conducted a comprehensive literature search. The CRA framework should 

include a systematic, transparent, and repeatable process for evaluating confidence in a study that 

addresses study outcome biases (beyond internal validity, reporting quality, or GLP compliance). 

EPA Response: In 2012, OPP published a guidance document to provide guidance procedures for 

considering and using open literature toxicity studies to support human health risk assessment (U.S. EPA 

2012). This guidance assists OPP scientists in their judgement of the scientific quality of open literature 

publications. More specifically, the document discusses how to screen open literature studies for 

journal articles/publications that are relevant to risk assessment, how to review potentially useful 

journal articles/publications and categorize them as to their usefulness in risk assessment, and how the 

studies may be used in the risk assessment. 

In recent years, the agency has been encouraged to move towards systematic review processes to 

enhance the transparency of scientific literature reviews that support chemical-specific risk assessments 

to inform regulatory decision making1

. EPA's Office of Chemical Safety and Pollution Prevention (OCSPP) 

is currently developing policies and procedures in order to employ fit-for-purpose systematic reviews. 

As a result, more recent evaluations of open literature studies, which still employs much of the same 

criteria described in the 2012 open literature review guidance, are starting to reflect this progression in 

the agency's process. Information regarding the agency's efforts to incorporate fit-for-purpose 

systematic reviews has been added to the framework. 

Comment Summary: MOA/AOP frameworks should be used as tools to organize existing in vivo and in 

vitro data and to establish common adverse health impacts, not as a way to overly restrict common 

mechanisms of toxicity and should be interpreted relative to the plausibility of alternate MOA/ AOPs and 

the established default assumption. Before acceptance of a MOA/AOP, OPP's framework should require 

1 NRC 2011. "Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde"; 

NRC 2014. "Review of EPA's Integrated Risk Information System (IRIS) Process" 

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rigorous testing and validation and not use incomplete data sets to downgrade the categorization of 

chemical hazards. 

EPA Response: OPP appreciates the opportunity to clarify the intent of the screening cumulative 

framework. Under the existing CRA guidance (U.S. EPA 2002a), only those groups with fully established 

CM Gs are assessed for CRA. A significant amount of toxicology knowledge is required to fully establish 

key events associated with an adverse outcome. As a result, OPP has, so far, only assessed five CMGs. 

The screening framework provides the opportunity to substantially expand the number of groups 

assessed for cumulative risk. As such, the NRDC's concern that OPP is going to 'downgrade' the groups 

is not warranted and inaccurate. 

The weight-of-evidence analysis described in the draft cumulative framework allows the agency to 

evaluate groups of chemicals for a testable hypothesis for a common mechanism of toxicity. If there is 

any indication that the chemicals have shared characteristics to support a common mechanism of 

toxicity, then the chemicals will be considered a candidate CMG and screening exposure and aggregate 

analyses will be conducted. In this manner, although chemicals may not have data to support a 

MOA/ AOP, they are still conservatively grouped together and evaluated for cumulative risks. If there 

are risks of concern following the screening-level assessment, then additional data are necessary to 

further evaluate the MOA/AOP. These data could further support grouping the chemicals; however, the 

data could also show that a common mechanism of toxicity does not exist for the group of chemicals. 

Therefore, the MOA/ AOP is not necessarily being accepted. For the purposes of the screening-level 

assessment, a common mechanism of toxicity is conservatively assumed. When sufficient MOA/ AOP 

information are available, the MOA/ AOP will be evaluated and validated for acceptance at that time. 

Comment Summary: The pesticide framework should require the defaults be maintained for the steps 

in the risk assessment that require inferences. 

EPA Response: In general, default interspecies and intraspecies uncertainty factors are applied in a 

cumulative assessment in a similar manner as single pesticide risk assessments to account for potential 

human variability and to account for uncertainty in extrapolating animal data to estimate potential 

human risk. As such OPP follows the existing agency guidance and policies on applying uncertainty and 

extrapolation factors (U.S. EPA 2002b; U.S. EPA 2004; U.S. EPA 2014) and text has been added to the 

framework to reflect this. 

Comment Summary: A report of the National Research Council (NRC, 2015) identified some serious 

concerns with the use of predictive toxicology and computational methods at thi.s time. 

EPA Response: The Agency understands the limitations of computational methods, but also 

acknowledges their usefulness in providing additional information, especially when in vivo data are not 

available. As part of the weight-of-evidence, information obtained from these sources is taken into 

context with the rest of the available data. 

EPA-HQ-OPP-2015-0422-0008 (N. Beck, American Chemistry Council): 

Comment Summary: OPP should clearly note that in Option 3, where a CMG can be established, a 

refined CRA should not be conducted unless there is also sufficient exposure information to inform the 

CRA. There may be cases where a CMG can be established, but if there is no exposure, or if exposure 

Page 5 of 7 
information is not sufficient to inform a robust analysis, conducting a refined CRA may not yield 

meaningful results. Sufficient toxicity and exposure information should be available to inform a refined 

CRA. 

EPA Response: Under Option 3 of the framework, sufficient data are available for establishing key 

events and a CMG. Consequently, a CRA would be conducted following the existing CRA guidance (U.S. 

EPA, 2002a). As stated in this guidance, a subset of common mechanism chemicals in the CMG (referred 

to as the cumulative assessment group or CAG) to be included in the quantitative evaluation of 

cumulative risk may be identified. 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 is documented and explained in order to account for all chemical that were grouped by a 

common mechanism of toxicity. Since risk is defined by hazard and exposure, chemicals with no 

exposure would not contribute to the risk of the CMG and, therefore, would not be included in the CAG. 

The data used to evaluate pesticide exposure for single-chemical assessments will constitute the 

majority of the data required to conduct a CRA. As such, strengths and weaknesses inherent in the data 

for each individual chemical assessment will be carried over to the CRA. The data available for each 

route of exposure and/or each individual chemical may vary in quantity as well as in their ability to 

describe the range of exposures likely to be encountered. For further information regarding the 

establishment of exposure input parameters for cumulative assessment, please see the existing CRA 

guidance (U.S. EPA, 2002a). 

Comment Summary: The draft guidance notes that there may be cases where screening-level risks are 

still above a level of concern and in such cases the Agency will consider whether additional toxicology 

data are needed. It would be helpful for OPP to clarify what the next steps will be if the MOA/AOP 

indicates that further information will not be needed. 

EPA Response: Under Option 2 of the framework, screening-level cumulative risks may be below the 

level of concern; therefore, the cumulative screening is complete and no additional data on MOA/AOP 

or exposure are necessary. The candidate CMG may be re-evaluated in the future if the risk profile 

changes. Text has been added to the framework for clarification regarding this situation. 

In instances where the screening-level cumulative risks are above the level of concern for a candidate 

CMG, additional toxicology and/or exposure data are necessary to further evaluate the MOA/ AOP. If 

the data for a candidat~ CMG indicate that a common mechanism does not exist for that group, then 

there wouldn't be support to develop a science policy to establish a CMG. As a result, a CRA would not 

be conducted and the group may be classified as Option 1 under the draft cumulative framework 

(conclusion of no common mechanism). 

Comment Summary: If a chemical does not cause an adverse effect itself, but may have impacts on a 

common pathway (e.g., hormone modulation), would the chemical be included in the CRA? 

EPA Response: Under the draft cumulative framework, a weight-of-evidence analysis, taking into 

consideration dose-response as well as mechanistic data, is used to evaluate all relevant scientific 

information. All chemicals in a group are evaluated simultaneously to determine if a testable hypothesis 

exists to support a candidate CMG. If the toxicological database for a chemical in the group does not 

Page 6 of 7 
support the testable hypothesis for a common mechanism of action for other chemicals evaluated in the 

candidate CMG, then it will not be included in the screening-level cumulative assessment. 

References 

U.S. EPA (Environmental Protection Agency). 1999. "Guidance for Identifying Pesticide Chemicals and 

Other Substances That Have a Common Mechanism of Toxicity." Environmental Protection Agency, 

Office of Pesticide Programs. Fed. Reg. 64:5796-5799. 

U.S. EPA (Environmental Protection Agency). 2002a. "Guidance on Cumulative Risk Assessment of 

Pesticide Chemicals That Have a Common Mechanism of Toxicity"; January 14, 2002. Available: 

h ttps ://www.epa.gov/ pesticide-science-and-a ssessing-pesticide-risks/g u ida nee-cum u I a tive-ris kassessmen t-pesticid e. 

U.S. EPA (Environmental Protection Agency). 2002b. A review of the reference dose and reference 

concentration processes. December. Risk Assessment Forum, Washington, DC; EPA/630/P-02/002F. 

http://www.epa.gov/raf/publications/pdfs/rfd-final.pdf. 

U.S. EPA (Environmental Protection Agency). 2004. An examination of EPA risk assessment principles 

and practices. Staff paper prepared for the U.S. Environmental Protection Agency by members of the 

Risk Assessment Task Force. Office of the Science Advisor, Washington, DC; EPA/100/B-04/001. 

http://www.epa.gov/osa/pdfs/ratf-final.pdf. 

U.S. EPA (Environmental Protection Agency). 2012. Guidance for considering and using open literature 

toxicity studies to support human health risk assessment. http://www.epa.gov/pesticides/science/litstudies.pdf 

U.S. EPA (Environmental Protection Agency). 2014. Guidance for Applying Quantitative Data to Develop 

Data-Derived Extrapolation Factors for Interspecies and lntraspecies Extrapolation. 

http ://www2 .epa .gov I osa/ g u ida nee-applying-qua nti tative-data-deve lop-data-de rived -extrapolationfa cto rs-interspecies-and 

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