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Pesticide Cumulative Risk Assessment: 

Framework for Screening Analysis Purpose

Office of Pesticide Programs

Office of Chemical Safety and Pollution Prevention

U.S. Environmental Protection Agency

Washington, DC

April 12, 2016
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Table of Contents

1.0. BACKGROUND ............................................................................................................... 3

2.0. KEY TERMS IN ESTABLISHING A COMMON MECHANISM GROUPING & IN CRA................ 4

3.0. CUMULATIVE RISK SCREENING ANALYSIS ....................................................................... 5

3.1. TOXICOLOGICAL DETERMINATION OF WHETHER A CMG OR CANDIDATE CMG CAN BE 

ESTABLISHED......................................................................................................................... 5

3.1.1. TOXICOLOGICAL CONSIDERATIONS IN DETERMINING A CANDIDATE CMG.................... 5

3.1.1.1. CHEMICAL STRUCTURAL SIMILARITY......................................................................... 5

3.1.1.2. HAZARD PROFILE...................................................................................................... 6

3.1.1.3. MOA/AOP/COMMON MECHANISM OF TOXICITY...................................................... 7

3.1.2. DRAWING CONCLUSIONS FROM CMG SCREENING ANALYSIS AND OPTIONS FOR 

FURTHER CRA........................................................................................................................ 7

3.2. CRA SCREENING ON A CANDIDATE CMG....................................................................... 10

3.2.1. TOXICOLOGY EVALUATION IN CRA SCREENING.......................................................... 10

3.2.2. EXPOSURE CONSIDERATIONS IN CRA SCREENING ...................................................... 10

3.2.2.1. USE PATTERN......................................................................................................... 11

3.2.2.2. LEVEL OF REFINEMENT FOR SINGLE PESTICIDE CHEMICAL RISK ASSESSMENT .......... 11

3.2.2.3. SINGLE PESTICIDE CHEMICAL AGGREGATE ASSESSMENT RISK PROFILE.................... 11

3.2.3. TIERED APPROACH FOR CUMULATIVE SCREENING-LEVEL DIETARY EXPOSURE ANALYSIS

........................................................................................................................................... 11

3.2.4. TIERED APPROACH FOR CUMULATIVE SCREENING-LEVEL RESIDENTIAL EXPOSURE

ANALYSIS ............................................................................................................................ 13

3.2.5. CUMULATIVE SCREENING-LEVEL MULTI-PATHWAY EXPOSURE ANALYSIS................... 14

4.0. SCREENING-LEVEL CUMULATIVE ANALYSIS & RECOMMENDATIONS FOR NEXT STEPS ... 14

5.0. REFERENCES................................................................................................................. 16
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This document provides guidance on how to screen groups of pesticides for cumulative 

evaluation using a two-step approach beginning with the evaluation of available toxicological 

information and if necessary followed by a risk-based screening approach. This framework

supplements the existing guidance documents for establishing common mechanism groups

(CMGs) and conducting cumulative risk assessments (CRA). 

1.0. Background

Section 408(b)(2)(D)(v) of the Federal Food, Drug, and Cosmetic Act (FFDCA) requires EPA to 

take into account “available evidence concerning the cumulative effects of such [pesticide] 

residues and other substances that have a common mechanism of toxicity”. The Office of 

Pesticide Programs (OPP) has developed two guidance documents:

• Guidance For Identifying Pesticide Chemicals and Other Substances that have a 

Common Mechanism of Toxicity (USEPA, 1999) which describes the process for 

establishing CMGs;

• Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a 

Common Mechanism of Toxicity (USEPA, 2002) which describes the steps used in 

conducting CRA.

The process described in these documents results in a highly refined CRA but requires an 

extensive amount of resources, large amounts of toxicology and exposure data, and may 

involve sophisticated modelling. The process involves developing science policy documents 

that establish a CMG before conducting a highly refined CRA. To date, OPP has established five 

CMGs: organophosphates (OPs), N-methyl carbamates (NMCs), chloracetanilides, triazines, and 

naturally occurring pyrethrins and synthetic pyrethroids1. CRAs have been conducted on each 

group (http://www.epa.gov/oppsrrd1/cumulative/). 

The level of refinement provided by this approach is not necessary or even feasible for all 

existing pesticide classes. The 2002 CRA guidance notes that not all cumulative assessments 

need to be of the same depth and scope and that it is important to determine the need for a 

comprehensive risk assessment by considering the exposure profile. The 2011 WHO IPCS2

guidance on CRA describes a screening approach involving tiered analysis with increasing levels 

of refinement. (Meek et al, 2011). The Agency is developing this guidance to assist scientists 

and decision-makers in screening pesticides for potential common mechanism groupings and 

conducting screening-level CRAs, neither of which is provided for in either guidance document 

listed above. Specifically, this document provides guidance for screening available information 

to identify groups of pesticides that may have a common mechanism of toxicity (i.e., candidate 

CMGs). In addition, this document provides guidance for screening available information on 

 1 The agency has evaluated the thiocarbamates & dithiocarbamates and found that these pesticides did not share a 

common mechanism. http://epa.gov/pesticides/cumulative/thiocarb.pdf; 

http://epa.gov/oppsrrd1/cumulative/dithiocarb.pdf

2 IPCS: International Programme on Chemical Safety, http://www.who.int/ipcs/en/
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those candidate groups for potential cumulative risks, which may lead to more refined CRAs.

This document relies on the policies and principles provided in the CMG and CRA guidance 

documents along with expertise and knowledge gained by OPP in the conduct of the five CRAs 

noted above. 

2.0. Key Terms in Establishing a Common Mechanism Grouping & in CRA

A CRA begins with the identification of a group of pesticide chemicals, referred to as a CMG, 

that induce a common toxic effect by a common mechanism of toxicity. OPP has guidance 

documents for designating CMGs (USEPA 1999) and for developing CRAs (USEPA 2002). These 

documents provide definitions for some key concepts:

• OPP’s CMG guidance defines mechanism of toxicity as the major steps leading to a toxic 

effect following interaction of a pesticide with biological targets. All steps leading to an 

effect do not need to be specifically understood. Rather, it is the identification of the 

crucial events following chemical interaction that are required in order to describe a 

mechanism of toxicity. For example, a mechanism of toxicity may be described by 

knowing the following: a chemical binds to a given biological target in vitro, and causes 

the receptor-related molecular response; in vivo it also leads to the molecular response 

and causes a number of intervening biological and morphological steps that result in an 

adverse effect. 

This definition of mechanism of toxicity is similar to the concept of mode of action 

(MOA) as defined by EPA’s Cancer Guidelines (USEPA, 2005) and other international 

efforts thru OECD and WHO (Boobis et al., 2008; Seed et al., 2005; Sonich-Mullin et al., 

2001; Meek et al, 2014). In addition, the term, adverse outcome pathway (AOP), has 

been introduced (Ankley et al., 2010). An AOP links a molecular initiating event (MIE) to 

progressive levels of biological organization at the individual or population level. As 

such, although the terminology is different, the concepts are similar---an AOP is 

conceptually similar to establishing key events in a MOA or for establishing a CMG under 

the FFDCA. In this document, both terms (MOA and AOP) are used.

• A common mechanism of toxicity as defined in EPA’s CMG and CRA guidance pertains

to two or more pesticide chemicals or other substances that cause a common toxic 

effect to human health by the same, or essentially the same, sequence of major 

biochemical events. Hence, the underlying basis of the toxicity is the same, or 

essentially the same, for each pesticide chemical. A CMG is a group of pesticides which 

share a common mechanism of toxicity.

• A common mechanism endpoint(s) is/are those common toxic effect(s) which are 

pertinent and sensitive endpoints associated with the common mechanism which will 

provide a scientifically sound basis for determining relative potency of chemicals in a 

CRA.
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• Candidate common mechanism group or candidate CMG represents a group of 

pesticides for which toxicological information on chemical structure, apical endpoint, 

pesticidal MOA and/or mammalian mechanistic information suggest the potential for a 

common mechanism of toxicity but do not have adequate data for establishing key 

events in a pathway as described in the MOA/AOP framework (e.g., lack of dose or 

temporal concordance of proposed key events).

3.0. Cumulative Risk Screening Analysis 

A screening-level assessment applies more conservative approaches and health protective 

overestimates of toxicity and/or exposure than would a refined CRA conducted using the 2002 

CRA guidance. The screening analysis for CRA described in this guidance begins with an

evaluation of the toxicological knowledgebase available on a particular group of pesticides 

derived from experimental toxicology studies submitted for pesticide registration and from the 

scientific literature. If the toxicological characterization of potential for common mechanism

suggests a candidate CMG may be established, then a screening-level toxicology and exposure 

analysis may be conducted to provide an initial screen for multiple pesticide exposure. 

Together, the initial toxicological and exposure analyses lead to different options for next steps 

described below. 

3.1. Toxicological determination of whether a CMG or Candidate CMG can be Established

3.1.1. Toxicological Considerations in Determining a Candidate CMG 

The 1999 CMG guidance indicates that evaluating a group of pesticides for potential common 

mechanism of toxicity begins with several considerations: chemical structural similarity, 

toxicological profile, and information on MOA/AOP. The screening approach uses the same 

considerations. The degree of available information will vary across pesticides. For some, there 

is extensive knowledge of MOA/AOP while for others, little to no information is known on how 

they interact with biological targets in any taxa. In other words, little to no information is 

known on the pesticidal MOA or mammalian MOA/AOP. For such pesticides, the available data 

needs to be carefully considered before conducting a cumulative screening evaluation. 

3.1.1.1. Chemical Structural Similarity

Shared chemical structure may be a good starting point for considering a group of chemicals. In 

many cases, shared chemical structure may translate to shared toxicophore3 and ultimately to a 

common mechanism of toxicity. However, shared chemical structure does not guarantee a 

shared toxicological profile. Chemical structure needs to be evaluated in combination with 

other considerations. Shared chemical structure is not solely sufficient as support for 

considering a candidate CMG.

 3 A toxicophore is a feature or group within a chemical structure that is associated with toxic properties
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3.1.1.2. Hazard Profile

As part of CRA screening efforts, reviewers conduct an initial review of the experimental 

toxicology data from data submitted for pesticide registration and from the scientific literature 

for a particular group of pesticides, if needed. 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 

making4. 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 open literature review guidance (U.S. EPA 2012a), are starting to reflect 

this progression in the agency’s process. 

The reviewer evaluates data on all available durations of effects, routes of exposure, species

tested, and potentially sensitive lifestages. The target organ(s), adverse effects/apical

outcome(s), and pharmacokinetic properties are identified and compared among the group 

members. Specifically, the reviewer is evaluating the extent to which common patterns of 

effects are observed among members of a potential class. Those effects at lower doses, 

particularly those used in deriving points of departure (PoDs) for single pesticide risk 

assessment, get more weight in the screening analysis than high dose effects. Toxic effects 

related to specific target sites (e.g., particular enzyme or other protein, hormone) or target 

tissues (e.g., thyroid, blood) are preferred over non-specific effects (e.g., changes in body 

weight or food consumption) since specific effects are more likely to be derived from common 

toxicity pathway than non-specific ones. Non-specific toxic effects, unless tied to a MOA/AOP 

or testable hypothesis related to a potential MOA/AOP, would not support a candidate CMG.

In most cases, common apical outcome will not be used as the sole factor in determining a 

candidate CMG for screening purposes. For example, all neurotoxic pesticides will not be 

grouped into a single group for screening purposes. Neurotoxicity is mediated through multiple 

pathways and under the FFDCA only those which share a common pathway are combined. 

Therefore, it is inappropriate to include all neurotoxic pesticides in a single candidate group for 

cumulative screening. Similarly, all pesticides which cause liver or kidney toxicity will not be 

combined in a candidate CMGs since liver and kidney toxicity is often the result of repeated 

exposure to high doses which overwhelm the biological system; moreover, kidney and liver 

effects can occur from multiple pathways. Common adverse effects to the liver and kidney will 

be evaluated carefully in the context of knowledge of mammalian MOA/AOP and chemical 

structure.

 4 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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3.1.1.3. MOA/AOP/Common Mechanism of Toxicity

Across different pesticide classes, a range of mechanistic information is available.

Data & knowledge of mammalian MOA/AOP and related information on pharmacokinetics for 

individual members of the pesticide class provides the strongest information and is the 

foundation for establishing a CMG. The CMG guidance describes this process in detail; only key 

information is summarized here. 

Use of the modified Bradford Hill Criteria like those described in the MOA framework (USEPA, 

2005; Boobis et al., 2008; Seed et al., 2005; Sonich-Mullin et al., 2001) provides the 

organizational tool for evaluating the availability of data and describing the key events and dose 

response and temporal concordance linkage of those key events leading from exposure to 

adverse health outcomes. Specifically, the modified Bradford Hill Criteria are used to evaluate 

the experimental support that establishes key events within a MOA or an AOP, and explicitly 

considers such concepts as strength, consistency, dose response, temporal concordance and 

biological plausibility in a weight of evidence (WoE) analysis. The ability to establish the 

MOA/AOP across representative chemicals within the group is a key determinant for 

establishing a CMG. 

With respect to screening for candidate CMGs, existing knowledge of an established MOA/AOPs 

for one or more individual members of the group is a strong starting point. The mechanistic 

information and apical outcomes for the remaining candidate CMG member(s) can then be 

used to compare with similar information on those with the more robust data. For those 

classes where no members have an established MOA/AOPs but some limited mechanistic 

information is available, a determination is made about the extent to which a testable 

hypothesis can be described. 

For pesticide classes which lack data on the mammalian MOA/AOP, information on the 

pesticidal MOA may provide a useful a starting point in for purposes of screening. 

Consideration of the pesticidal MOA needs to be done with caution as some pesticidal MOAs 

may not be relevant to humans or have unknown relevance. For example, the sulfonyl urea 

(SUs) herbicides share the ability to inhibit acetolactate synthase (ALS), an enzyme that 

catalyzes the biosynthesis of three branched-chain amino acids (valine, leucine, and isoleucine), 

all of which are essential for plant growth. Mammals have ALS but its function in mammals is 

unknown. In toxicity studies with SUs, effects are generally observed at very high doses (at or 

near the limit dose for many SUs). In addition the SUs do not show a common toxicological 

profile; instead target organs vary among this class. Thus, the toxicological profile of the SUs 

does not support a candidate CMG determination.

3.1.2. Drawing Conclusions from CMG Screening Analysis and Options for Further CRA 

OPP will conduct a WoE analysis to evaluate all relevant scientific information, as described in 

3.1.1, along with the strengths and limitations of the evidence. Use of the MOA/AOP 
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framework provides the organizing principles (e.g., dose concordance, temporal concordance, 

specificity, biological plausibility, etc) for assessing the degree to which the available evidence 

does or does not support common toxicological profile(s) and the degree to which data support 

establishing a set of key events. As shown in Figure 1, this analysis can lead to various options 

for next steps (Figure 1).

Option 1: Conclusion of No Common Mechanism, No Further CRA Work is Necessary: 

• For some pesticide groups, the pesticides do not share a similar toxicological profile and 

no further cumulative evaluation is necessary. 

• For other groups, although the pesticide members may share some chemical or 

toxicological characteristics (e.g., chemical structure or apical endpoint), the 

toxicological database does not support a testable hypothesis for a common mechanism 

of action. In these cases, the Agency will conclude that no common mechanism of 

toxicity exists for this group of pesticides and that no CRA will be conducted. 

Option 2: Candidate CMG can be formed; Screening-Level Exposure Analysis is Conducted: 

Candidate CMGs are groups of pesticides that have shared characteristics to support a testable 

hypothesis for a common mechanism of action or sufficient toxicological data to suggest a 

common pathway but do not have adequate data for establishing key events in a pathway as 

described in the MOA/AOP framework (e.g., lack of dose or temporal concordance of proposed 

key events). For these, a screening-level exposure analysis will be conducted as described in 

section 3.2 below. 

Option 3: CMG can be established: Sufficient mechanistic data are available to support 

establishing a set of key events in a pathway and thus support developing a science policy 

establishing a CMG; such policy may be developed according to the 1999 CMG guidance 

document. Following the development of that science policy, a CRA will be conducted. This 

CRA would follow the CRA guidance and thus no additional information is provided in this 

document.
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Figure 1. Draft, Schematic for the Cumulative Risk Assessment Screening Framework
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3.2. CRA Screening on a Candidate CMG 

If a candidate CMG can be formed (Option 2), the Agency will generally proceed to a CRA 

screening-level analysis as described below. 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

(USEPA, 2002b; USEPA, 2004; USEPA 2014). 

3.2.1. Toxicology Evaluation in CRA Screening 

Consistent with the Agency’s mixture risk assessment guidance (USEPA, 1986; USEPA, 2000), 

OPP assumes dose additivity in CRA unless data are available to support an alternative 

approach. Then OPP will evaluate the toxicological database for dose response data to identify 

an index chemical and to develop screening-level relative potency factors (RPFs) and PODs for 

purposes of screening exposure analysis. As noted in the 2002 CRA guidance, it is preferred 

that an 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 . Similarly 

in the screening analysis, the index chemical will be selected based on an evaluation of the 

available data in the toxicological databases for all chemicals in a candidate CMG. Therefore, 

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 routes of interest. The

data and mathematical approach used in the derivation of the screening RPFs and PODs should 

be described and include a characterization of their refinement (or lack thereof). Screeninglevel RPFs and PODs should, to the extent possible, be related to hypothesized MOA/AOP and 

the common toxic effect for the class. 

While under the 2002 CRA guidance, an important component in cumulative hazard assessment 

is the derivation of a uniform measure of dose response such that the potency of each CMG 

member is accurately assessed, in this screening-level cumulative analyses, RPFs and PODs may 

vary in their level of refinement. For example, these toxicity values may be derived from the 

PODs from single chemical risk assessments, from no-observed-adverse-effect levels (NOAELs) 

or lowest-observed-adverse-effect levels (LOAELs) from specific toxicology studies or possibly 

benchmark doses (BMDs). In some analyses, the same value may be used for each chemical in 

the candidate group. 

3.2.2. Exposure Considerations in CRA Screening 

The screening process continues by evaluating the exposure and risk potential using the most 

recent single chemical risk assessments. Evaluation of these risk assessments includes

consideration of the registered use patterns, level of refinement, and overall risk profiles of the 

candidate CMG being considered. 
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3.2.2.1. Use Pattern

Defining and comparing the use patterns of the chemicals within a candidate CMG is an

important task. The range of food and residential uses for the chemicals within the candidate 

CMG is characterized. One key consideration is the extent to which food uses for the candidate 

CMG pesticide chemicals are similar (e.g., all the pesticide chemicals have a registered apple or 

corn use) or wide-ranging. Another important consideration is if the candidate CMG chemicals 

have residential uses. Given that pesticide chemicals within a same class are likely to control 

similar pests, evaluation of the use patterns and use sites may allow for the co-occurrence of 

candidate CMG pesticide chemicals to be considered. 

3.2.2.2. Level of Refinement for Single Pesticide Chemical Risk Assessment

Determining the level of refinement used in each single pesticide chemical risk assessment is a 

key task when working through the screening analysis. For example, in evaluating the single 

pesticide chemical dietary exposure assessments, it is important to characterize the type of 

data used to define food residues [i.e., tolerance levels, field trial data, or the Pesticide Data 

Program (PDP) data], whether or not percent crop treated information was incorporated, 

whether processing data was incorporated, and what model(s) were utilized to estimate 

drinking water concentrations. Additionally, determination of the use of chemical-specific 

exposure or transferable residue data in the single chemical residential assessments should be 

considered. When combining individual chemical-specific exposure assessments, comparison 

of the levels of refinement across the pesticide chemicals within the candidate CMG should be 

considered in the interpretation of the screening evaluation.

3.2.2.3. Single Pesticide Chemical Aggregate Assessment Risk Profile

Determining the risk profile for each single pesticide chemical risk assessment is also a key task 

in the screening analysis. It is important to consider the relative contributions of each exposure 

pathway (e.g., food, drinking water, and residential exposure) as well as the overall aggregate 

risk picture for each pesticide chemical. This analysis can suggest areas of refinement which 

might have the greatest impact on the screening evaluation.

3.2.3. Tiered Approach for Cumulative Screening-Level Dietary Exposure Analysis 

This section presents a variety of approaches that could be considered for screening-level 

analysis of cumulative risks of a candidate CMG. These approaches are presented in a tiered 

manner attempting to account for the resources that are required to conduct the analysis. If a 

minimal resource approach can be used and cumulative screening risks are acceptable, there is 

no need to perform more refined approaches. As such, the reviewer follows through the tiers 

described below until the screening risk does not exceed the level of concern.

The starting point for the screening-level cumulative analysis is to use the exposure values 

derived from the single pesticide chemical assessments, regardless of level of refinement or 
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difference in levels of refinement across the pesticide chemical candidate CMGs; therefore, 

considering the levels of refinement will be a key component in interpreting the screening 

results. Most food exposure assessments that are conducted by OPP for conventional pesticides 

are unrefined, relying on tolerance level residues and assuming 100% of the crop is treated. 

However, in cases where risks have been identified and refinements are needed, OPP’s general 

policy is to refine only to the degree that risks of concern have been mitigated. Consequently, 

often, single pesticide chemical dietary assessment are unrefined or only partially refined. Any 

refinements discussed in the dietary tiers below would be in addition to those already in place 

in the single pesticide chemical assessments. Consideration should be given to the inclusion of 

potential refinements, such as percent crop treated and/or monitoring data when using the 

tiered approach outlined below. Conceptually, the reviewer will systematically work through 

the tiers described below and stop refinements at the point when the dietary risk does not 

exceed the level of concern. 

• Tier 1: Combined food and water exposures from the most recent single pesticide 

chemical risk assessment(s) are extracted, RPF scaled, and summed. This exposure

value is then compared to the POD of the reference chemical. While this method 

considers the relative toxicity of each member of the candidate CMG pesticide 

chemicals, this approach is still likely to significantly overestimate the cumulative risk 

picture. Tier 1 assumes complete co-occurrence of both food and drinking water 

residues. 

• Tier 2: In Tier 2, food residues are handled the same as in Tier 1, above. However, Tier 

2 addresses the unlikely co-occurrence of high-end residues in drinking water. To 

accomplish this, drinking water residues are removed from all single pesticide chemical 

dietary exposure assessments. The single highest RPF-scaled modeled water exposure 

scenario from among the members of the candidate CMG is identified and is combined 

with the RPF-adjusted combined food exposures. While requiring additional resource 

expenditure, this approach incorporates relative toxicities and more appropriately 

addresses drinking water exposure, while still overestimating exposure by assuming 

complete co-occurrence of food residues. 

• Tier 3: In tier 3, water residues are handled as in tier 2. However, an attempt is made to 

refine co-occurrence of food residues. Only the pesticide that has the highest RPFscaled exposure would be used for a given crop/commodity. For example if multiple 

pesticides are used on apples, only the chemical that yields the highest RPF-scaled 

exposure would be included in the cumulative screening evaluation. The assumption is 

that growers would not use multiple pesticide chemicals from the same pesticide 

chemical class in the same season. While requiring further resource expenditure, this 

approach incorporates relative toxicities and begins to address the unlikely cooccurrence of candidate CMG pesticide residues in food and/or water. However, this 

screening-level assessment likely still uses modelled drinking water residue estimates 

and may not actually include monitoring data for foods, thus still overestimating the 

cumulative risk picture. 

• Any further level of refinement beyond Tier 3 would involve extensive resources and is 

beyond a screening-level evaluation. 
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3.2.4. Tiered Approach for Cumulative Screening-Level Residential Exposure Analysis 

 

As noted above the single pesticide chemical risk assessments provide the primary source of 

residential exposure information for the cumulative screening-level residential assessment. 

Most residential exposure assessments that are conducted by OPP are unrefined. Specifically, 

they often include high-end, default assumptions with regards to surface residues (e.g., turf 

residues, indoor surface residues, etc.). In addition, they rarely utilize survey data in order to 

determine co-occurrence of exposure scenarios. Any differences in terms of level of refinement 

when considering these single pesticide chemical residential exposure assessments together 

will need to be characterized by the reviewer. Any refinements discussed in the residential 

tiers below would be in addition to those already in place in the single pesticide chemical 

assessments. These residential exposures would then be scaled using the screening-level RPFs 

and PODs and summed. Conceptually, the reviewer will systematically work through the tiers 

described below and stop refinements at the point when the residential risk does not exceed

the level of concern. 

• Tier 1: Unrefined Assessment. Residential exposures from the most recent risk 

assessment(s) are extracted then RPF-scaled and summed. This assessment utilizes any 

chemical specific surface residue data consistent with its use in each single pesticide 

chemical assessment but does not translate the data to the members of the candidate 

CMG. In summing these exposures, this assessment assumes that all residential 

exposure for each individual scenario (e.g., turf, pet, and indoor residential exposures) is 

to the single pesticide chemical in the CMG with the highest risk (i.e., lowest margin of 

exposure or MOE) for that scenario. For example, if there are three chemicals in the 

candidate CMG with pet uses, it is conservatively assumed that all pet use exposure 

occurs via the chemical with the highest risk. With respect to co-occurrence of exposure 

scenarios, the assumption is complete co-exposure for all of the available exposure 

scenarios (e.g., turf, pet, and indoor residential exposures) without any related cooccurrence refinements.

• Tier 2: Refine Surface Residue Assumptions. Residential exposures from the most 

recent risk assessment(s) are extracted and it is determined if each assessment uses any 

pesticide chemical specific surface residue data (e.g., turf residues, indoor surface 

residues, etc.). If such data is utilized then the exposures are not altered. If such data is 

not utilized, then the chemical-specific data that results in the highest surface residue 

for that exposure scenario is translated and used in refined residential exposure 

estimates. For example, if three chemical-specific indoor residue studies are available 

for a candidate CMG that contains seven chemicals, the indoor residue study that 

results in the highest residue would be translated to the four chemicals in the class for 

which there are not chemical-specific indoor residue studies. These residential 

exposures are then RPF-scaled and summed. In summing these exposures, this 

assessment still assumes that all residential exposure for each individual scenario (e.g., 

turf, pet, and indoor residential exposures) is to the single pesticide chemical in the 

CMG with the highest risk (i.e., lowest MOE) for that scenario. With respect to co-
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occurrence of exposure scenarios, the assumption is complete co-exposure for all of the 

available exposure scenarios (e.g., turf, pet, and indoor residential exposures) without 

any related co-exposure refinements. 

• Tier 3: Refine Co-occurrence Across Exposure Scenarios. In Tier 3, the same refinements 

regarding the surface residue data are incorporated. These residential exposures are 

then RPF-scaled and summed. In summing these exposures, this assessment still 

assumes that all residential exposure for each scenario (e.g., turf, pet, and indoor 

residential exposures) is to the single pesticide with the highest risk (i.e., lowest MOE)

for that scenario. The Tier 3 assessment would determine the co-occurrence of the 

available exposure scenarios (e.g., turf, pet, and indoor residential exposures) using 

available survey data to determine the probability of turf, pet, and/or indoor uses cooccurring in the same time period. 

• Any further level of refinement beyond Tier 3 would involve extensive resources and is 

beyond a screening-level evaluation (See Figure 1). 

3.2.5. Cumulative Screening-Level Multi-Pathway Exposure Analysis 

As noted in the dietary and residential exposure sections above, the reviewer will systematically

work through the dietary and residential exposure tiers and stop refinements at the point when 

the risks are less than the level of concern. The same stepwise approach should be taken for 

combining dietary and residential exposures. Initially, the reviewer would take the appropriate 

refined level dietary exposure point estimate and deterministically aggregate it with the 

appropriate refined level residential exposure point estimate. This means that the reviewer 

may be aggregating a more refined dietary exposure with a less refined residential exposure 

(i.e., Tier 3 dietary with a Tier 1 residential). In some cases, this aggregate exposure may result 

in risks that exceed the level of concern, which may result in the need to further refine either 

the dietary or residential exposure component.

In instances where screening-level cumulative risks are below the level of concern, the 

cumulative screening is considered complete and no additional toxicology and/or exposure 

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

changes. There may be cases where screening-level risks are still above the level of concern at 

the highest Tiers described above. Refinements beyond this point would result in an exposure 

analysis that is no longer considered ‘screening-level.’ As such, the Agency will consider 

whether additional toxicology data are needed to further describe the MOA/AOP of the 

candidate CMG to help inform whether a more refined CRA as described by the 2002 guidance 

is warranted. If additional information or further refinement are deemed not warranted, the 

findings of the screening-level analysis will have the same weight as results of any CRA 

conducted under the 2002 guidance. 

4.0. Screening-Level Cumulative Analysis & Recommendations for Next Steps 

This guidance document is intended to assist Agency scientists and regulators in fulfilling the 

obligations of section 408(b)(2)(D)(v) to consider available information concerning cumulative 
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effects of pesticides and other substances that have a common mechanism of toxicity. This 

guidance document presents a screening-level approach to evaluate whether currently 

available toxicology information support establishing a candidate CMG and if so, describes a 

screening-level approach with more refined tiers for assessing the potential cumulative risk of 

that candidate CMG. The screening-level cumulative approach described here uses pointestimate aggregate methodology combined with conservative assumptions of high-end dietary 

(food and water) exposure with high-end residential exposure while assuming co-occurrence of 

dietary and residential exposure. The Agency considers this approach to be highly conservative. 

The screening-level approach presented in section 3 of this document does not specifically 

address incorporation of various potential CRA refinements, which help provide more accurate 

estimates of human risk such as PBPK modeling, probabilistic exposure modeling, and spatial or 

temporal considerations. These refinements are generally resource intensive, may require 

large amounts of toxicology and exposure data, and can involve sophisticated modelling. 

However, if a screening-level CRA is performed and risks do not exceed the level of concern, 

then there is no need to invest the resources in further refinement at that time. This CRA 

screening-level approach will ultimately allow the Agency to address the FFDCA requirements

to consider available information concerning cumulative effects of pesticides having a common 

mechanism of toxicity while efficiently using resources. 
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5.0. References

Ankley, GT; Bennett, RS; Erickson, RJ; et al. (2010). Adverse outcome pathways: a conceptual 

framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem

29(3):730−741.

Boobis, AR; Doe, JE; Heinrich-Hirsch, B; et al. (2008) IPCS framework for analyzing the relevance 

of a noncancer mode of action for humans. Crit Rev Toxicol 38:87−96.

Meek, M.E., Boobis, A.R., Crofton, K.M., Heinemeyer, G., Raaij, M.V., Vickers, C., Risk 

assessment of combined exposure to multiple chemicals: A WHO/IPCS framework, Regulatory 

Toxicology and Pharmacology (2011), doi: 10.1016/j.yrtph.2011.03.010. 

Meek ME, Boobis A, Cote I, Dellarco V, Fotakis G, Munn S, Seed J, Vickers C. 2014. New 

developments in the evolution and application of the WHO/IPCS framework on mode of 

action/species concordance analysis. J Appl Toxicol. 2014 Jan; 34(1):1-18.

Seed, J; Carney, EW; Corley, RA; et al. 2005. Overview: using mode of action and life stage 

information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol 

35(8−9):664−672.

Sonich-Mullin, C; Fielder, R; Wiltse, J; et al. 2001. IPCS conceptual framework for evaluating a 

mode of action for chemical carcinogenesis. Regul Toxicol Pharmacol 34:146−152.

U.S. Environmental Protection Agency (USEPA). 1986. Guidelines for the Health Risk 

Assessment of Chemical Mixtures. U.S. Environmental Protection Agency, Office of Research 

and Development, Washington, DC. September. EPA/630/R-98/002.

U.S. Environmental Protection Agency (USEPA). 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. Environmental Protection Agency (USEPA). 2000. Supplementary Guidance for Conducting 

Health Risk Assessment of Chemical Mixtures. U.S. Environmental Protection Agency, Risk 

Assessment Forum, Washington, DC. EPA/630/R-00/002. Available 

at http://www.epa.gov/ncea/raf/pdfs/chem_mix/chem_mix_08_2001.pdf.

U.S. Environmental Protection Agency (USEPA). 2001. “Guidance on Cumulative Risk 

Assessment of Pesticide Chemicals that Have a Common Mechanism of Toxicity.” Office of 

Pesticide Programs, Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental 

Protection Agency. Washington, DC. Available: http://www.epa.gov/oppfead1/trac/science/
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U.S. Environmental Protection Agency (USEPA). 2002a. “Guidance on Cumulative Risk 

Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity”; January 14, 

2002. Available: http://www.epa.gov/pesticides/trac/science/cumulative_guidance.pdf

U.S. Environmental Protection Agency (USEPA). 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. Environmental Protection Agency (USEPA). 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. Environmental Protection Agency (USEPA). 2005. Guidelines for carcinogen risk 

assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register 

70(66):17765−17817. Available online at http://www.epa.gov/raf.

U.S. Environmental Protection Agency (USEPA). 2012a. Guidance for considering and using open 

literature toxicity studies to support human health risk 

assessment. http://www.epa.gov/pesticides/science/lit-studies.pdf

U.S. Environmental Protection Agency (USEPA). 2012b. Standard Operating Procedures for 

Residential Pesticide Exposure Assessment (Residential SOPs). Available online 

at http://www.epa.gov/opp00001/science/residential-exposure-sop.html

U.S. Environmental Protection Agency (USEPA). 2014. Guidance for Applying Quantitative Data 

to Develop Data-Derived Extrapolation Factors for Interspecies and Intraspecies Extrapolation. 

http://www2.epa.gov/osa/guidance-applying-quantitative-data-develop-data-derivedextrapolation-factors-interspecies-and