### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D.C. 20460
OFF ICE OF CHEM ICAL SAFETY AND POLLUTI ON 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 Assess ment Type: Cumulative TXR No .: NA CAS No .: NA 40 CFR: NA MRID No. : 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** Evisabe l 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 Res po nse Branch Registration Division (7SOSP) Office of Pesticide Programs

Page 1 of 7Int rodu cti o n: 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, 

### Pest icide Cumulative RiskAssessment : Frameworkfor 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-20 15-0422-0013 (S. K un ickis, United States Department of Agricult u re) : Comm ent Summar y : 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 R esponse: 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 avai lab le 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. C

omment S ummary: 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, whe n 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. Page 2 of 7Comment Summary: Regarding the parenthetical "(i.e., turf residues, indoor surface residues, etc.), " if residential uses are limited to turf, pet, and indoo r 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 cla rifi cation. 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. Th ese 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 necessari ly 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 Respon se: 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.
Page 3 of 7EPA-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 co ncept 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 Respon se: 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 oftoxicity. " 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 shou ld 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 Respon se: In 2012 , OPP published a guidance document to provide guidance procedures for conside rin g 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 art icles/publications that are relevant to risk assessment, how to review potentially useful journal articles/pub lications 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 making 1

. EPA's Office of Chemical Safety and Pollution Prevention (OCSPP) is cu rrently developing pol icies 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 . I nformation 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 assumptio n . Before acceptance of a MOA/AOP, OPP's framework should require

1 NRC 2011. "Review of th e Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde"; NRC 2014. " R eview of EPA's Integrated Risk Information Sys tem (IRIS) Process" Page 4 of 7rigorous 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 screeni ng cumu lative framework. Under the existing CRA guidance (U.S. EPA 2002a), only those groups with fully established CMGs are assessed for CRA. A significant amount of toxico logy 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 framewo rk provides the opportunity to substantially expandthe number of groups assessed for cumu lative 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 fo r a testable hypothesis for a co mmon 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 conse rvatively grouped together and evaluated for cumu lative risks. If there are ris ks of concern foll owing the screen ing-level assessment, the n 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 necessa ri ly being accepted. For the purposes ofthe screening-level assessment, a common mechanism of toxicity is conservatively assumed
. When sufficient MOA/ AOP information are ava i lable, the MOA/ AOP will be eval uated and validated for acceptance at that time. Comm ent 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 an d 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 Resea rch Council (NRC, 2015) identified some serious concerns with the use of predictive toxicology and com putational methods at thi
. s ti me. 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 availab le data. EPA-HQ-OPP-2015-0422-0008 (N
. Beck, American Chemi stry Council) : Comment Summary: OPP should clea rl y 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 7information 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. EP A Respo nse : Under Option 3 of the framework, sufficient data are available for establishing key events and a CMG
. Consequently, a CRA wou ld be conducted following the existing CRA guidance (U
.S. EPA, 2002a)
. As stated in this guidance, a subset of common mechan ism 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 requi red 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 exposu res 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). Comm ent S ummary: 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 toxico logy 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). Com me nt 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 R esponse: 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 chemica ls 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 7support the testable hypothesis for a common mechanism of action for other chemicals evaluated in the cand idate 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." Environm ental Protection Agency, Office of Pesticide Programs
. Fed
. Reg
. 64:5796-5799. U .S. EPA (Environmental Protection Agency)
. 2002a. "Guidance on Cumu lative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity" ; January 14, 2002. Available: https://www.epa.gov/pesticide-scie nce-and -assessing-pesticide-risks/guida nee-cum uIative-riskassessment-pesticide. 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-fina l
.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 Advi so r, Wash ington, DC; EPA/100/B-04/001. http://www.epa.gov/osa/pdfs/ratf-final.pdf. U.S. EPA (Environmenta l Protection Agency)
. 2012. Guidance for considering and using open literature toxicity studies to support human health risk assessment. http://www.epa .gov/pesticides/science/litstu dies .pdf U.S. EPA (Environmental Protection Agency). 2014
. Guidance for Applying Quantitative Data to Deve lop Data-Derived Extrapolation Factors for Interspecies and lntraspecies Extrapolation. http://www2.epa .gov

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