Guidance on

Cumulative Risk Assessment of

Pesticide Chemicals That Have a

Common Mechanism of Toxicity

Office of Pesticide Programs

U.S. Environmental Protection Agency

Washington, D.C. 20460

January 14, 2002 
EXECUTIVE SUMMARY 

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, the Food Quality Protection Act (FQPA) imposed upon the Office of Pesticide 

Programs (OPP) the requirement 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 to September 

2000 (USEPA, 2000a; 65 FR 40644), by the FIFRA Scientific Advisory Panel (SAP) in 

September and December 1999 (USEPA, 1999j and 2000g), and by comments offered by 

other external parties at the SAP meetings. Furthermore, OPP has gained experience in 

implementing the draft guidance itself with actual datasets on pesticides that share a 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 may 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. 

ii 
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 uses the guidance described in the document entitled 

General Principles For Performing Aggregate Exposure And Risk Assessments 

(USEPA, 2001h). The aggregate guidance recommends that the risk assessor 

simultaneously consider the exposures from food, drinking water, and 

residential/nonoccupational uses of a pesticide. When the aggregate risk assessments are 

completed for individual chemicals that share a common mechanism of toxicity, OPP will 

consider a 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 has developed a general 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). 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 exposure to food, 

treatment of 100% of crops and tolerance level residues may be assumed for each CMG 

chemical registered for use on a crop. 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. 

iii 
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 should be explained. Thus, all chemicals that were grouped by 

a common mechanism of toxicity should be accounted for (qualitatively or quantitatively) in 

the final assessment. 

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). The guidance recommends use of 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. Departures from the dose-addition approach are appropriate if there 

are data available to support an alternative method. 

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 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. The last step in the doseresponse 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. 

iv 
Detailed exposure scenarios for all of the uses remaining for each pesticide in the CAG 

should 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 are established. The magnitude, frequency, and duration 

for all pertinent exposure pathway/route combinations are determined. These parameters 

take into account appropriate sources of use/usage information, and residues in all 

appropriate media. Any modifying factors necessary for inclusion in the assessment are 

also identified. Where necessary, any appropriate surrogate datasets from other chemicalspecific data, published literature, or generic datasets are considered. A trial run of a 

quantitative cumulative risk is conducted by assigning route- and duration-specific risk 

metrics. The outputs of this trial run are evaluated and a sensitivity analysis is conducted. 

Subpopulations or life stages of concern are assessed. A final quantitative cumulative risk 

assessment can then be conducted. 

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 

should be 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 

subpopulations (with particular attention to children). The basis for group uncertainty and 

FQPA safety factors should be explained. 

v 
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 

OPP’s risk assessments, OPP will depart from its policy where the facts or circumstances 

warrant. In such cases, OPP 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 group of pesticides, or that the circumstances surrounding a specific risk assessment 

demonstrate that a policy should be modified or abandoned. The cumulative risk 

assessment process will continue to evolve after this guidance is published. Thus, the 

Agency may update this guidance or provide supplementary materials as appropriate. 

vi 
TABLE OF CONTENTS

EXECUTIVE SUMMARY ............................................... ii

Abbreviations and Acronyms .......................................... 1

Key Terms Used in Document .......................................... 2

Introduction ......................................................... 5

Background ....................................................... 5

History of Guidance ................................................. 6

Scope of Guidance ................................................. 7

Purpose of Guidance ................................................ 7

Objectives of the Cumulative Risk Assessment Process .................... 8

Organization of the Document ......................................... 9

SECTION 1. Identify Common Mechanism Group (CMG) ................... 12

SECTION 2. Identify Potential Exposures ............................... 14

SECTION 3. Characterize And Select Common Mechanism Endpoint(s) ...... 16

3.1Selection and Characterization of Effects Associated with the Common

Mechanism of Toxicity ........................................... 17

3.2Characterization of Route Specificity and Time Course of Effects .......... 19

3.3Characterization of Potential Chemical Interactions ..................... 20

3.4Initial Quantitative Characterization of the Common Effect(s) ............. 20

3.5Characterization of Potential Susceptible Subpopulations or Life Stages to the

Common Mechanism of Toxicity ................................... 20

3.6Characterization of Human Information .............................. 21

3.7Characterization of Data Issues: Adequacy and Quality ................ 22

3.8Weight-of-the-Evidence Evaluation of the Common Effect(s) ............. 22

SECTION 4. Determine the Need for a Comprehensive Cumulative Risk

Assessment ..................................................... 23

4.1Screening Assessment .......................................... 23

4.2When to Conduct a Comprehensive Cumulative Risk Assessment ......... 24

SECTION 5. Determine Candidate Cumulative Assessment Group .......... 27

vii 
SECTION 6. Conduct Dose-Response Analyses and Determine Relative Potencies

and Points of Departure ........................................... 30

6.1Dose Addition: A Method of Combining Cumulative Potency for Common

Mechanism Chemicals ........................................... 31

6.2Determination of the Relative Potency for the CAG ..................... 32

6.2.1 Determination of Toxic Potency .............................. 33

6.2.1.1 Measures of Potency ................................. 33

6.2.1.2 Endpoint and Study Selection ........................... 35

6.2.1.3 Data Collection and Entry .............................. 36

6.2.1.4 Combining Response Data ............................. 36

6.2.1.5 Use of Surrogate Toxicity Data .......................... 36

6.2.1.6 Modeling the Data ................................... 37

6.2.1.7 Interspecies Adjustment of Dose ........................ 38

6.2.1.8 Route-to-Route Extrapolation ........................... 39

6.3Criteria for Selection of an Index Chemical ........................... 39

6.4Determination of a Point of Departure for the CAG ..................... 39

6.5Calculation of Relative Potency Factors.............................. 41

6.6Presenting the Results of the Dose-Response Assessment .............. 41

SECTION 7. Develop Detailed Exposure Scenarios for All Routes and Durations43

7.1 Dietary Food Pathway .......................................... 46

7.2 Dietary Drinking Water Pathway ................................... 46

7.3 Residential and Nonoccupational Pathway .......................... 47

SECTION 8. Establish Exposure Input Parameters ....................... 49

8.1Dietary Food Pathway ........................................... 49

8.2Dietary Drinking Water Pathway ................................... 52

8.3Residential and Other Nonoccupational Pathway ...................... 54

SECTION 9. Conduct Final Cumulative Risk Assessment .................. 56

9.1Time-frame.................................................... 56

9.2Geographic Scale and Site Selection ................................ 57

9.3Subpopulations of Concern ....................................... 60

9.4Constructing the Assessment ..................................... 60

9.5Expression of Cumulative Risk-Combining Multiple-Pathway Risk ......... 61

9.5.1 Dietary Food and Dietary Water Pathway ....................... 61

9.5.2 Residential and Other Nonoccupational Pathways ................ 62

9.6Accumulating the Risk ........................................... 64

viii 
SECTION 10. Conduct Characterization of Cumulative Risk ................ 66

10.1 Risk Characterization Summary ................................. 66

10.2 Describing Uncertainty ........................................ 67

10.3 Application of Uncertainty Factors and the FQPA 10X Safety Factor ..... 68

10.4 Uncertainty With Respect to Exposure Assessment .................. 69

10.4.1 Uncertainties Associated with the Cumulative Food Pathway May Arise 

from the Following Sources .................................. 69

10.4.2 Uncertainties Associated with the Cumulative Water Pathway ....... 69

10.4.3 Uncertainties Associated With The Cumulative Residential Pathway . 70

10.5 Presentation of Results........................................ 72

References ........................................................ 73

ix 
Abbreviations and Acronyms 

BMD Benchmark Dose

BMD10 A Benchmark Dose associated with a 10% response compared to

background 

BMR Benchmark Response 

CAG Cumulative Assessment Group (of chemicals) 

CMG Common Mechanism Group (of chemicals) 

CSFII USDA in the Continuing Survey of Food Intakes by Individuals 

CWS Community Water Systems 

ED10 Effective Dose: central estimate on a dose associated with a 10% response 

adjusted for background 

FQPA Food Quality Protection Act 

FFDCA Federal Food, Drug, and Cosmetic Act 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

GIS Geographical Information System 

LOAEL Lowest-Observed-Adverse-Effect Level 

MOE Margin of Exposure 

NAS National Academy of Sciences 

NAWQA National Water Quality Assessment Program 

NASS National Agricultural Statistics Service 

NOAEL No-Observed-Adverse-Effect Level 

NRC National Research Council 

OPP Office of Pesticide Programs 

ORETF Outdoor Residential Exposure Task Force 

PBTK Physiologically-based toxicokinetic 

PDP USDA’s Pesticide Data Program 

PHED Pesticide Handlers’ Exposure Database 

POD Point of Departure 

RfD Reference Dose 

RPF Relative Potency Factor 

SAP Scientific Advisory Panel 

SOP Standard Operating Procedures 

UF Uncertainty Factor 

USGS US Geological Survey 
Key Terms Used in Document 

Risk-Related Terms: 

Aggregate Risk is the risk associated with all pathways and routes of exposure to a 

single chemical. 

Critical Window of Expression for the Common Mechanism Effect is the time 

from exposure to expression of the common mechanism effect and continues until the 

effect is reversed and the exposed individual has effectively returned to a pre-exposure 

state. 

Cumulative Risk1 is the risk of a common toxic effect associated with concurrent 

exposure by all relevant pathways and routes of exposure to a group of chemicals that 

share a common mechanism of toxicity. 

Cumulative Assessment Group (CAG) is a subset of chemicals selected from a 

common mechanism group for inclusion in a refined quantitative estimate of risk. The 

chemicals in the CAG, as well as their pathways/routes and pesticide uses, are judged 

to have a hazard and exposure potential that could result in the expression of a 

cumulative risk. Thus, negligible contributors are not included in quantifying the risk. 

Dose Additivity is the Agency's assumption when evaluating the joint risk of 

chemicals that are toxicologically similar and act at the same target site. In other words, 

it is assumed that each chemical behaves as a concentration or dilution of every other 

chemical in the CAG (or chemical mixture). The response of the combination is the 

response expected from the equivalent dose of an index chemical. The equivalent dose 

is the sum of the component doses, scaled by each chemical’s toxic potency relative to 

the index chemical. 

1

The definition of cumulative risk used in this document pertains to those chemicals that share a common 

mechanism of toxicity, as interpreted under FQPA. It should be noted that the EPA has, in other 

contexts, defined cumulative risk assessment in a broader manner–“The examination of the accumulation 

(over time, across sources, across routes, etc.) of stressors or exposures that can cause adverse effects, 

and then the integration of the effects these stressors or exposures cause into an estimate and 

characterization of the risk caused to the individual or population by the stressors acting together” 

(USEPA, 2001i). 

2 
A Group Uncertainty Factor for the CAG is applied after estimating the toxicity of 

the group, in order to cover areas of scientific uncertainty that pertain to the group as a 

whole (e.g., intra- and interspecies differences). Most database issues should be dealt 

with on an individual chemical basis. But the quality and completeness of the database 

on the common toxic effect for the group as a whole should be considered in developing 

a group uncertainty factor. Also, consideration of the l FQPA 10X safety factor for 

children should pertain to the common mechanism of toxicity and generally be based on 

the group rather than individual members of the group. 

Index Chemical is the chemical used as the point of reference for standardizing the 

common toxicity of the chemical members of the CAG. The index chemical should have 

a clearly defined dose-response, be well defined for the common mechanism of toxicity, 

and have a toxicological/biological profile for the common toxicity that is representative 

of the CAG. 

A Point of Departure (POD) is a dose that can be considered to be in the range of 

observed responses, without significant extrapolation. A POD can be a data point or an 

estimated point that is derived from observed dose-response data. A POD is used to 

mark the beginning of extrapolation to determine risk associated with lower 

environmentally relevant human exposures. 

Relative Potency Factor (RPF) is a ratio of the toxic potency of a given chemical to 

that of an index chemical in the CAG. Relative potency factors are used to convert 

exposures of all chemicals in the CAG into their exposure equivalents of the index 

chemical. 

Hazard-Related Terms: 

Common Mechanism Group (CMG) is a group of chemicals determined to cause a 

common toxic effect by a common mechanism of toxicity. The CMG is defined using 

the previously released Guidance for Identifying Pesticide Chemicals and Other 

Substances That Have a Common Mechanism of Toxicity (1999a). Not all members of 

a CMG should necessarily be included in a more refined quantitative estimate of 

cumulative risk. 

Common Mechanism of Toxicity pertains to two or more pesticide chemicals or 

other substances that cause a common toxic effect(s) by the same, or essentially the 

same, sequence of major biochemical events (i.e., interpreted as mode of action). 

3
Exposure-Related Terms: 

Concurrent Exposure is interpreted as potential human exposure by all relevant 

pathways, durations, and routes that allows one chemical to add to the exposure of 

another chemical such that the total risk is an estimate of the sum of the exposures to 

the individual chemicals. This includes simultaneous exposures as well as any 

sequential exposures that could contribute to the same joint risk, either by overlapping 

internal doses or by overlapping toxic effects. 

Exposure Scenario is a combination of facts, assumptions, and inferences that 

defines a discrete situation or activity where potential exposures to two or more 

pesticides may occur. The cumulative exposure framework for estimating combined 

exposures is based on exposure to individuals, which represent differing attributes of 

the population (e.g., human activity patterns, place of residence, age) that link route of 

exposure through scenario building. 

Pathway of Exposure is the physical course a pesticide takes from the source to 

the organism exposed (e.g., through food or drinking water consumption or residential 

pesticide uses). 

Route of Exposure is the way a chemical enters an organism after contact (e.g., 

ingestion, inhalation, or dermal absorption). 

4
Introduction 

Background 

Pesticides are regulated under several major Federal statutes: the Federal 

Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and 

Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act on August 3, 

19962. FIFRA requires that substances used as pesticides be registered with the U.S. 

Environmental Protection Agency (EPA) and that these pesticides not cause 

unreasonable adverse effects on humans or the environment. Under the FFDCA, EPA 

sets tolerances (or exemptions from the requirement of a tolerance) for pesticide 

residues on raw agricultural commodities (RACs) or processed foods. The tolerance for 

a pesticide residue represents the maximum legally allowable concentration of the 

residue that can be present in or on a raw agricultural commodity or processed food. In 

order to establish a pesticide tolerance or exemption from a tolerance, EPA must 

determine with reasonable certainty that consumption of RACs and processed foods 

containing residues of that pesticide will not cause harm to humans, especially infants 

and children. 

Historically, EPA has generally evaluated the safety of pesticides on the basis of 

single-chemical and single-exposure pathway scenarios. In 1993, a report by the 

National Research Council (NRC) made several recommendations on how to improve 

the assessment of health risks posed by pesticides in the diets of infants and children 

(NRC, 1993). One recommendation included consideration of all sources of dietary and 

nondietary exposures to pesticides and assessment of risks from exposure to multiple 

pesticides that cause a common toxic effect (an example was provided for five 

organophosphorus pesticides). The Food Quality Protection Act (FQPA) of 1996 

provides that when determining the safety of a pesticide chemical, EPA shall base its 

assessment of the risk posed by the pesticide chemical on aggregate (i.e., total food, 

drinking water, residential, and other nonoccupational) exposure to the pesticide. EPA 

is also required to consider available information concerning the combined toxic effects 

to human health that may result from dietary, residential, or other nonoccupational 

exposure to chemicals that have a common mechanism of toxicity. 

2

For details see The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), 7 U.S.C. §§ 136 et 

seq.,and Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. § 364a. 

5 
History of Guidance 

Over the past several years, a number of external reviews have helped shape OPP's 

cumulative risk assessment guidance. Additional experience in implementing the 

guidance itself with actual datasets on common mechanism pesticides has also led to 

refinements in cumulative risk assessments. 

OPP has repeatedly sought scientific review by the FIFRA Scientific Advisory Panel 

(SAP). In September 1999, OPP first presented the hazard and dose-response 

components of its cumulative guidance document for review by the SAP (USEPA, 

1999k). 

In December 1999, OPP presented to the SAP for comment the exposure and risk 

characterization elements of the guidance (USEPA, 2000g). In addition to the SAP 

reviews on the guidance document itself, OPP has also requested SAP comment on the 

various exposure models and tools being developed for assessing aggregate and 

cumulative risk; Online (USEPA, 2001l). 

Additionally, the concepts and methods that the risk assessor should consider in 

conducting cumulative risk assessments have been applied to actual datasets on 

common mechanism chemicals. In a pilot analysis of 24 organophosphorus (OP) 

pesticides, OPP demonstrated in detail the methods and parameters that should be 

considered in estimating cumulative risk associated with common mechanism pesticides 

by multiple pathways of exposure. The hazard and dose-response assessment and the 

exposure analyses of this pilot analysis were presented to the SAP for comment in 

September and December 2000, respectively (USEPA, 2000i ; USEPA, 2000e; USEPA, 

2001j; and USEPA, 2001k). OPP revised its approach to the dose-response 

assessment of OPs based on comments provided by the September 2000 SAP review 

(USEPA, 2001d). Finally, OPP published in December 2001, its preliminary risk 

assessment on the organophosphorus pesticides, which is based on the general 

methodology described in this guidance (USEPA, 2001m). 

In addition to the SAP reviews, the public has provided comments on OPP’s 

proposed methods and approaches. The draft guidance document for conducting a 

cumulative risk assessment of pesticides that share a common mechanism of toxicity 

was issued for public comment on June 30, 2000 (USEPA, 2000a; 65 FR 40644). 

Later, a technical workshop was held in July 2000 to explain the approaches in the 

guidance document and to hear questions and comments from the public and various 

stakeholder groups. A technical briefing for stakeholder groups was also conducted in 

August 2001 on a dose-response approach for assessing the cumulative risk associated 

with OP pesticides, and OPP held a meeting at the SAP in September 2001 on the 

same subject (USEPA, 2001n). 

The June 2000 Guidance Document has been revised to clearly describe the 

decision logic and elements of the cumulative risk assessment process, taking into 

6
consideration comments offered by the public, SAP, industry organizations, and other 

Government agencies. This revised guidance document maintains the basic principles 

and approaches presented in the June 2000 guidance document. 

Scope of Guidance 

This document is only intended to provide guidance on performing cumulative risk 

assessments for pesticide chemicals that act by a common mechanism of toxicity. EPA 

is working on its approach for the consideration of “other substances” that have a 

common mechanism of toxicity. Until the Agency develops general guidance on this 

issue, EPA will handle this issue on a case-by-case basis. It is anticipated that most 

mechanisms of toxicity that have been elucidated will be consistent with nonlinearity or 

threshold biological phenomena. The dose-response methods presented in this 

guidance are more applicable to these situations. Finally, FFDCA does not regulate 

exposure to workers or effects on non-target wildlife, and thus, this document does not 

present guidance for performing cumulative risk assessments for those areas. 

Purpose of Guidance 

The purpose of this guidance is to set forth the basic assumptions, principles, and 

analytical framework that are recommended for use by OPP risk assessors in 

conducting cumulative risk assessments. It is also intended to inform decision makers 

and the public of the principles and procedures generally followed in the conduct of 

cumulative risk assessments on pesticide chemicals. The process for assembling and 

evaluating information that will constitute a cumulative risk assessment involving food, 

water, residential, and other nonoccupational exposures to multiple pesticides that 

share a common mechanism of toxicity is described in the following sections of this 

document. This guidance is intended to be flexible so as to accommodate a variety of 

common mechanisms and datasets, but not to provide an in-depth discussion of specific 

datasets. Furthermore, it does not impose binding rules on OPP or other parties. OPP 

remains open to consideration of alternative or new approaches to conducting 

cumulative risk assessments. It is important to emphasize that the cumulative risk 

assessment process is at an early stage of development and will continue to evolve 

after this guidance is published. Thus, there will be continued progress on advancing 

methods and tools. The Agency may update this guidance, or provide supplementary 

materials as appropriate, as the toxicological and exposure databases improve to 

accommodate the data needs for cumulative risk assessment, and as the Agency’s 

knowledge increases about mechanisms of toxicity and how chemicals that share a 

common mechanism of toxicity interact with the biological target tissue at known or 

anticipated levels of human exposures. 

Objectives of the Cumulative Risk Assessment Process 

7
A cumulative risk assessment has several objectives. The risk assessor must 

proceed through a complex set of 

evaluations to achieve those objectives. The 

process begins with the identification of a 

group of chemicals that produce a common 

toxic effect(s) by a common mechanism of 

toxicity. Careful attention should be given to 

the time dimensions of the toxic effects and 

exposure. The mechanism of toxicity, 

pesticide exposure patterns, and treatment 

scenarios will determine the populations of 

concern. This multichemical, multipathway 

risk assessment should identify subgroups 

(particularly children) that may be 

disproportionately at risk to the common 

mechanism of toxicity, and the major 

pathways and routes of exposure and 

chemicals that are driving the associated 

risk. 

It is important to keep in mind that a 

Objectives of a Cumulative Risk Assessment 

<Define the characteristics of the exposure to a

group of chemicals that act by a common

mechanism of toxicity

<Estimate multichemical, multipathway risks

reflecting real-world exposure to pesticides,

including the changing patterns of residue levels as

they relate to differences in location, time, and

co-occurrence

<Identify significant contributors to risk

<Characterize the confidence in the conclusions

and the uncertainties encountered in the

assessment

<Facilitate a greater understanding of the potential

results of changes in pesticide uses and possible

mitigation activities

cumulative risk assessment differs from the single-chemical aggregate risk assessment 

both in focus and purpose. The relationship of pesticides as alternatives or 

complementary products is not considered in single-chemical aggregate analyses. 

Therefore, one cannot simply sum the aggregate risk estimates for the group of 

chemicals shown to have a common mechanism of toxicity to produce a cumulative risk 

assessment. In addition, aggregate assessments often contain conservative 

assumptions to ensure that they are adequately protective of human health. Care 

should be taken to avoid conservative assumptions that may be compounded in the 

cumulative assessment, inappropriately biasing the risk estimates produced. Attention 

should be focused on exposure estimation for use/pesticide combinations that make up 

the largest and most important sources of risk. The cumulative risk assessment should 

identify the likely exceedance of a cumulative exposure level. When a cumulative risk 

assessment reflects the real-world exposure situation (i.e., multichemical and 

multipathway), it permits the identification of significant contributors of risk so that 

mitigation strategies can be targeted more effectively. 

8
The basic concept underlying cumulative risk assessment is that exposure occurs to 

a hypothetical individual whose demographic characteristics help define exposure 

scenarios. The data concerning this individual should be consistent with those 

characteristics. Risk should be estimated while maintaining the appropriate spatial 

(e.g., location and type of home; urbanization, watershed, or aquifer characteristics), 

temporal (e.g., duration, frequency, and seasonality of exposure; frequency of 

residential pest control), and demographic (e.g., age, gender, reproductive status, 

ethnicity, behaviors) linkages of exposure and toxicology data (ILSI, 1998). Cumulative 

risk assessment proceeds by establishing reasonable exposure scenarios for a 

hypothetical individual and groups of individuals over a specific interval of time. The 

exposure scenarios help to identify populations of concern, and to define critical 

windows of time and routes of exposure that should be linked to the common toxic 

effect. The potential for overlapping exposure to multiple chemicals by multiple 

pathways of exposure should be established. 

Organization of the Document 

The process of conducting a cumulative risk assessment is illustrated in Figure 1. 

The figure describes the series of steps needed to organize and explain the decisions, 

data collection, and evaluations envisioned. Although the steps are organized 

sequentially in the figure, they may actually overlap or occur in parallel, as each piece of 

information and each decision in the process is informed by the others, with some 

elements revisited as a result of subsequent analyses. In other words, the hazard, 

dose-response, and exposure analyses are, in reality, highly interactive and are 

integrated in the overall cumulative risk process. These elements are explained in 

Sections 1through 10 in the body of the document. 

It should be emphasized that the risk 

assessor should refer to several other 

Agency documents for supplementary 

guidance in certain areas integral to the 

cumulative risk assessment process. 

OPP developed Guidance for Identifying 

Pesticide Chemicals and Other 

Substances that have a Common 

Mechanism of Toxicity (USEPA, 1999a). 

General Principles For Performing 

Aggregate Exposure And Risk 

Assessments (USEPA, 2001h) describes 

certain aspects of the exposure 

assessment that must be accounted for in 

developing an integrated, single-chemical 

Examples of Supplementary 

EPA Guidance Documents 

<Guidance for Identifying Pesticide Chemicals and

Other Substances that have a Common Mechanism

of Toxicity (1999a)

< General Principles For Performing Aggregate

Exposure And Risk Assessments (USEPA, 2001h)

<Chemical Mixtures (USEPA, 1986d, 2000j)

<Monte Carlo Analysis (USEPA, 1997a)

<Exposure Factors Handbook (USEPA, 1999d)

<Risk Characterization Handbook(USEPA, 2000c)

<Peer Review Handbook (USEPA, 2000d)

multipathway assessment. Detailed procedures for evaluating specific hazards (e.g., 

cancer, developmental toxicity, reproductive toxicity, neurotoxicity) can be found in the 

Agency’s risk assessment guidelines (see USEPA, 1986a,b,c,d; USEPA, 1991a, 1992, 

9
1996; 1998a; 1999c), and guidance on certain techniques of dose-response analysis 

can be found in the Agency’s Benchmark Dose Technical Guidance Document (USEPA, 

2000b). Risk characterization is a key element in cumulative risk assessment and is 

embodied in this document. Finally, the risk assessor should follow the Agency’s 

policies and practices for the peer review of cumulative risk assessments of common 

mechanism pesticides. 

10
Figure 1. The Cumulative Risk Assessment Process 

Step 1. IDENTIFY COMMON MECHANISM GROUP (CMG) -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. 

Step 2. IDENTIFY POTENTIAL EXPOSURES -For each CMG member, evaluate proposed and registered uses and use 

patterns to identify potential exposure pathways (i.e., food, drinking water, residential) and routes (oral, inhalation, dermal). 

Step 3. CHARACTERIZE AND SELECT COMMON MECHANISM ENDPOINT(S)-For each CMG member, evaluate 

common effects that arise via the common mechanism of toxicity across all exposure routes and durations of interest, 

determine the time-frames of expression for the common toxicity, and evaluate the quality of the dose-response data for 

each CMG member. Recommend endpoints/species/sex that can serve as a uniform basis for determining relative potency. 

Step 4. DETERMINE THE NEED FOR A COMPREHENSIVE CUMULATIVE RISK ASSESSMENT-Consider the number 

and types of possible exposure scenarios in conjunction with the associated residue values available. Evaluate the 

toxicological information on NOAELs and LOAELs collected for the common effect. This evaluation may suggest that a 

screening-level assessment for the CMG will indicate that there is no risk concern for this group of chemicals and no further 

detailed assessment will be necessary. This evaluation may also suggest that a cumulative assessment is simply not 

appropriate at this time. 

Step 5. DETERMINE CANDIDATE CUMULATIVE ASSESSMENT GROUP (CAG)-Select pesticides, pesticide uses, 

routes, and pathways from the CMG that have an exposure and hazard potential to result in cumulative effects for inclusion 

in the quantitative estimates of cumulative risk. 

Step 6. CONDUCT DOSE-RESPONSE ANALYSES AND DETERMINE RELATIVE POTENCIES AND POINTS OF 

DEPARTURE-Select and apply an appropriate dose-response method to evaluate the common mechanism effects and 

determine the relative toxic potencies of the CAG by each exposure route and duration of interest. Determine the point of 

departure(s) for extrapolating the risk of the CAG. 

Step 7. DEVELOP DETAILED EXPOSURE SCENARIOS FOR ALL ROUTES AND DURATIONS-For all of the uses 

remaining for each pesticide in the CAG, determine their role in establishing the magnitude of possible exposures. Decide 

the relative importance of scenarios and the need for their inclusion in a quantitative assessment. Identify populations of 

interest and locations for evaluation in the assessment. Determine the co-occurrence of possible exposure scenarios. 

Step 8. ESTABLISH EXPOSURE INPUT PARAMETERS-Determine magnitude, frequency, and duration for all pertinent 

exposure pathway/route combinations. Identify appropriate sources of use/usage information, residues in all appropriate 

media, and any modifying factors necessary for inclusion in the assessment. Where necessary, identify any appropriate 

surrogate datasets from other chemical-specific data, published literature, or generic datasets. Model any necessary 

exposure parameters for inclusion. 

Step 9. CONDUCT FINAL CUMULATIVE RISK ASSESSMENT-Assign route/duration-specific risk metrics. Conduct trial 

run and evaluate output. Conduct sensitivity analysis. Assess subpopulations of concern, determine group uncertainty and 

FQPA safety factors. 

Step 10. CONDUCT CHARACTERIZATION OF CUMULATIVE RISK-Describe the results and conclusions of the 

cumulative risk analysis, including the relative confidence in toxicity and exposure data sources and model inputs. Discuss 

major areas of uncertainty, the magnitude and direction of likely bias, and the impact on the final assessment. Evaluate the 

risk contributions from each pathway and route individually, as well as in combination. Identify risk contributors with regard 

to pesticide(s), pathway, source, time of year, and impacted subpopulation (with particular attention to children). Conduct 

sensitivity analyses to determine those factors most likely to impact the risk. Determine need for uncertainty and safety 

factors. 

11
SECTION 1. Identify Common Mechanism Group (CMG) 

Step 1. 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. 

Common mechanism of toxicity 

determinations should generally follow 

the weight-of-evidence approach 

described in the Guidance for 

Identifying Pesticide Chemicals and 

Other Substances That Have a 

Common Mechanism of Toxicity 

(USEPA, 1999a). In addition, the 

Agency has developed a framework 

for evaluating a chemical’s mode of 

action (see USEPA, 1999c), which 

offers additional direction for 

establishing a mechanism of toxicity. 

Because separate guidance exists, the 

process for grouping chemicals by a 

common mechanism of toxicity will not 

be described within this document. 

However, a few important points 

follow. 

Application of OPP’s Guidance for Identifying 

Pesticide Chemicals and Other Substances That 

Have a Common Mechanism of Toxicity 

<A Common Mechanism of Toxicity: The

Organophosphate Pesticides (USEPA, 1999e) 

<A Science Policy on a Common Mechanism of

Toxicity: The Carbamate Pesticides and the

Grouping of Carbamate Pesticides with

Organophosphorus Pesticides (USEPA, 1999f)

<The Grouping of a Series of Chloroacetanilide

Pesticides Based on a Common Mechanism of

Toxicity (USEPA, 1997b, 2001b).

<Thiocarbamates: A Determination of the Existence

of a Common Mechanism of Toxicity and a Screening

Level Cumulative Dietary (Food) Risk Assessment

(USEPA, 2001c, 2001o)

<The Determination of Whether the Dithiocarbamate

Pesticides Share a Common Mechanism of Toxicity

(USEPA, 2001e, 2001o)

The Food Quality Protection Act uses the term “mechanism of toxicity,” which is 

defined in the January 29, 1999, Guidance Document and interpreted as mode of 

action–“the major steps leading to an adverse health 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 (with biological targets) that are required in order to describe a 

mechanism of toxicity.”3 The identification of a group of chemicals having a common 

mechanism of toxicity (CMG) will precede analyses for cumulative risk assessments. 

Thus, the assessment for grouping a set of chemicals based on a common mechanism 

3

Since the passage of the FQPA, the term “mechanism of toxicity or action” has taken on a specific 

meaning in Agency-wide guidance documents. In the draft EPA guidelines for carcinogen risk 

assessment, the term “mode of action” is contrasted with “mechanism” which implies a more detailed 

molecular description of events than is meant by mode of action (USEPA, 1999c). The definition of 

“mechanism of toxicity” used in this Guidance and in OPP’s earlier guidance (USEPA, 1999a) is 

equivalent to the definition of the term “mode of action.” 

12 
of toxicity will normally be provided in a separate document issued by OPP prior to 

preparation of a cumulative risk assessment (see examples in text box). Key 

conclusions and toxicity data presented in these reports will be utilized and summarized 

when preparing a cumulative risk assessment report. 

13
SECTION 2. Identify Potential Exposures 

Step 2. For each CMG member, evaluate proposed and registered uses and use 

patterns to identify potential exposure pathways (i.e., food, drinking water, residential) 

and routes (oral, inhalation, dermal). 

Aggregate exposure assessments 

should generally be conducted for each 

member of the CMG before a cumulative 

assessment is attempted. The aggregate 

assessments will identify important 

information concerning pathways and 

routes of exposure for each individual 

pesticide. The exposure and use data from 

the aggregate assessment should be 

evaluated to identify pesticides that have 

uses that are likely to result in significant 

exposures and in overlapping exposures 

with other pesticides. Similarly, those 

pesticides should be identified that are 

unlikely to result in a cumulative risk 

because the uses are limited or the 

expected exposures or effects will not 

overlap. For example, if a pesticide's uses 

are limited to contained methods of 

Aggregate risk assessments on individual 

pesticides will provide useful exposure

information to identify: 

<Registered uses

<Tolerances

<%Reference Dose (RfD) of the single

pesticide

<Significant sources and pathways of

exposure (food, drinking water, residential)

<Use patterns

<Geographic distributions

<Times of application

<Average field trial values 

<Monitoring data

<% Crops treated

application such as bait boxes or gels designed for injection behind baseboards, a 

decision that essentially no exposure is anticipated would likely be made, and if so, the 

pesticide would not be included in the assessment. 

The universe of registered uses of pesticides in the CMG will provide a first cut at 

determining which chemicals should be considered in the hazard analysis (Section 3) 

and the scope of exposure scenarios that require consideration in the cumulative 

assessment. Inherent in the types of uses registered is an understanding of the types 

of exposures to be anticipated. For example, the registration of a pesticide solely for 

application to food crops will result primarily in oral exposure (through the food 

ingested), but also potentially through drinking water as the result of runoff and 

leaching. Residential (dermal and inhalation) exposures should not be of concern in this 

case. 

14
Tolerance information should also provide important details on the anticipated 

magnitude of the exposure. For example, if a pesticide’s tolerances are limit of 

detection tolerances, the magnitude of residues anticipated in food may be found to be 

very small, and may provide justification for excluding the food exposure from the risk 

assessment. Similarly, it is unlikely that two pesticides will be encountered together if 

they are alternatives for each other for the same use and will not be used at the same 

time and place, thereby limiting the concern for co-occurrence. Some products may be 

used as combinations. This information suggests that the two pesticides should be 

considered together at least for a portion of the exposures considered (i.e., exposures 

will overlap). Finally, some products may be considered complementary, and the use of 

one will increase the likelihood of the use of the other. 

15
SECTION 3. Characterize And Select Common Mechanism 

Endpoint(s) 

Step 3. For each CMG member, evaluate common effects that arise via the common 

mechanism of toxicity across all exposure routes and durations of interest, determine 

the time-frames of expression for the common toxicity, and evaluate the quality of the 

dose-response data for each CMG member. Recommend endpoints/species/sex that 

can serve as a uniform basis for determining relative potency. 

Once a series of chemicals has 

been identified that share a common 

mechanism of toxicity (i.e., the CMG), 

further hazard analyses are needed to 

characterize and select the common 

toxic effects4

 that should be considered 

in the cumulative risk assessment. An 

important aspect of this hazard 

assessment is to identify the common 

effects associated with the common 

mechanism, the test species/sex that 

provides the most extensive data on the 

common effects, and the exposure 

routes and durations by which the 

common toxic effects are manifested. 

Key Objectives of the Hazard 

Assessment in Cumulative Risk 

<Identify the common toxic effects pertaining to the

common mechanism for determining the relative toxic

potencies of each chemical

<Identify routes and durations of exposure by which

the common mechanism effects will occur

<Identify the species/strains and sex in which the

common mechanism of toxicity occurs

<Identify the studies that provide the most robust and

extensive datasets for determining cumulative hazard

<Identify potential susceptible subgroups or life stages

An initial quantitative evaluation of the data will help guide the final selection of common 

toxic endpoints and choice of dose-response methodology for determining the relative 

toxic potency5

 among chemical members for quantifying risk (discussed in Section 6). 

4

Common toxic effect is defined in the Guidance for Identifying Pesticide Chemicals and Other 

Substances That Have a Common Mechanism of Toxicity (USEPA, 1999a) as the same toxic effect in or 

at the same anatomical or physiological site or locus (e.g., same organ or tissue). 

5

Relative toxic potency refers to a comparison of the exposure level or dose required for an individual 

chemical to the exposure levels or doses required of other chemicals to cause a common toxic effect of 

an equivalent magnitude by a common mechanism of toxicity. 

16 
3.1Selection and Characterization of Effects Associated with the Common 

Mechanism of Toxicity 

To guide the selection of common mechanism endpoints that will provide a 

scientifically sound basis for determining relative potency of chemicals in a 

cumulative risk assessment, the risk assessor should assess the available data to 

determine the following: 

‘ pertinent and sensitive endpoints associated with the common mechanism 

‘ tissues in which common mechanism effects occur 

‘ species/strain or sex in which the common mechanism occurs noting in 

particular whether there are species/strain or sex differences) 

‘ other, more sensitive toxic effects not related to the common toxic effect 

caused by individual CMG members. 

The above areas of inquiry are important for a number of reasons. First, there 

may be a number of different responses pertaining to the common mechanism of 

toxicity on which the cumulative assessment might be based. Some mechanisms 

will be associated with a cascade of events that lead to the adverse toxic effect. For 

example, certain antithyroid chemicals (e.g., amitrole, mancozeb, ethylene thiourea) 

cause thyroid follicular cell carcinogenesis by disruption of thyroid-pituitary 

homeostasis. This results in chronic reduction in circulating thyroid hormones (T3, 

T4) and increases in thyroid stimulating hormone (TSH), which in turn leads to cell 

proliferation, changes in thyroid weight, and eventually neoplasia (Hurley et al., 

1998). Some mechanisms may not be tissue specific, and the chemicals of interest 

may operate in different tissues. For example, organophosphorus pesticides exert 

neurotoxicity via binding to and phosphorylation of the enzyme acetylcholinesterase 

(AChE), which is found in both the central and peripheral nervous systems (Mileson 

et al., 1998). Therefore, all relevant responses need to be evaluated to identify 

effects pertaining to the common mechanism of toxicity. This will provide the most 

robust basis for determining the relative potency among the chemicals of interest, as 

well as determining which endpoint(s) is most protective of the common mechanism 

of toxicity. 

17
It is important to characterize species and strain differences for the common 

mechanism effects to determine species/strain or sex sensitivities. Furthermore, the 

common mechanism effect(s) from different species/strains and sexes should be 

evaluated so the members of the CMG can determine what response data will 

provide a uniform and common basis for determining the chemicals’ relative 

potencies. As discussed later in Section 6, when estimating cumulative risk, 

response data from the same species, strain, and sex for all the members of the 

CMG is preferred. If there are pronounced species/strain or sex differences among 

the test animals or subjects, and it is unknown which test species responds most like 

humans to the test substances, data from the most sensitive animal should be used 

to determine cumulative risk. When response data in the most sensitive 

species/strain or sex are not available for all the chemicals, this should be accounted 

for in the cumulative assessment or in the characterization of uncertainties (see 

Section 10). 

Another important aspect of the hazard assessment is the characterization of 

other toxicities caused by each CMG member and not related to the common 

mechanism. This evaluation determines whether the common toxic effect is more or 

less sensitive than other toxic effects caused by CMG members. A chemical may be 

encountered that is found to produce several types of toxicities, each by a different 

mechanism. For example, the pesticides acetochlor, alachlor, and butachlor induce 

nasal turbinate tumors by one mechanism (via formation of a tissue reactive 

metabolite, a benzoquinone imine intermediate) and thyroid follicular cell tumors by 

another mechanism (via enhancement of hepatic microsomal enzymes and 

perturbation of thyroid hormone levels) (see USEPA, 1998b, 2001b). Refined 

quantitative estimates should generally focus on common effects that represent the 

principal toxicities for the CMG. Thus, in a situation where a chemical may be 

grouped by several different common mechanisms of toxicity, in quantifying 

cumulative risk that pesticide should be considered for its most sensitive and 

pertinent mechanism of toxicity. 

Another situation may occur in which a CMG member produces another toxic 

effect for which the mechanism of toxicity is not understood. The common 

mechanism effect is expressed only at high doses of the chemical, whereas the 

other toxicity is induced at much lower doses. In this situation, the pesticide could 

be grouped in a CMG that is not based on its principal toxicity. If that pesticide is 

regulated at a much lower exposure level on the basis of a much more protective 

toxic effect, then exposure to this chemical and its common mechanism will be 

limited by the more adverse effect or the effect with the lower regulatory endpoint. 

As discussed in Section 5, it may be appropriate to exclude this chemical in 

quantifying cumulative risk. The basis for excluding a CMG chemical from the 

quantification of risk should be included in the cumulative risk assessment. 

3.2Characterization of Route Specificity and Time Course of Effects 

18
As discussed later (Section 9), the temporal characteristics and route specificity 

of the common mechanism effect are key criteria for defining the exposure scenarios 

of interest. Thus, an important aspect of hazard assessment is to characterize the 

route specificity of and the time course of effects for the common mechanism effects 

by evaluating the following: 

‘ routes of exposure (oral, dermal, inhalation) for which the common effect is 

found 

‘ time to onset and peak effects, duration of effects, and time to recovery (if the 

effect is reversible) of the common effect for each exposure route and 

duration anticipated 

‘ toxicokinetic data that are available to help determine how exposure to the 

CMG relates to dose in the target tissue(s) over a given time frame for the 

exposure routes of interest. 

If a chemical is found to produce route-specific effects for the common 

mechanism (e.g., it is not absorbed dermally), then those routes not pertinent to the 

common mechanism should be eliminated from the exposure scenarios considered 

in the cumulative risk assessment. Understanding the time frames (e.g., time to 

onset and peak effects, recovery time) for the common toxic effect will help 

determine the likelihood of the overlapping of effects given use patterns and likely 

patterns of exposure. For example, if the common mechanism effect is reversible 

and recovery is rapid, accumulation of common toxicity is not likely to occur if 

exposures and duration of effects are separated in time (and thus near-simultaneous 

exposures are necessary for cumulative effect to be seen). On the other hand, if the 

mechanism of toxicity results in persistent toxicity or persistence of tissue residues, 

then simultaneous exposures are not required for the chemicals to act by a common 

mechanism. Understanding the time frames associated with the common toxic 

effect will help guide the exposure analysis in selection of modeling scenarios. 

Toxicokinetic information (e.g., data on absorption, distribution, metabolism, and 

excretion), as well as biological half-life for the chemicals of interest, should be 

considered in defining the route specificity and temporal kinetics of the common 

mechanism for the chemicals of interest. 

19
3.3Characterization of Potential Chemical Interactions 

Cumulative toxicity represents the net change in toxicity that results from the 

combined exposure to multiple chemical substances relative to the toxicity caused 

by each substance alone. Although the nature of cumulative toxicity is often 

identical or similar to an effect caused by one or more of the substances individually, 

cumulative toxicity among chemicals can be manifested in many ways. Exposure to 

multiple chemical substances may result in an additive effect, antagonism, 

synergism, or no change in toxic effect(s) caused by any one of the substances 

alone. Many factors determine whether the cumulative toxicity resulting from 

exposures to pesticides and other chemicals that occur individually as discrete 

residues in multiple sources such as the diet (e.g., fruit, vegetables, meat, milk, 

water), air, or on residential surfaces will be greater than, equal to, or less than the 

toxicity caused by any of the chemicals alone. These factors include exposure 

patterns that result in simultaneous or overlapping exposures, the 

toxicokinetics/dynamics of each substance causing the common toxic effect, the 

duration of the common toxic effect, and the toxicokinetic/dynamic interactions 

between the substances. Information should be considered that allows one to 

discern the precise nature of the interactions that may occur following exposure to a 

group of chemicals that share a common mechanism of toxicity. 

3.4Initial Quantitative Characterization of the Common Effect(s) 

A preliminary quantitative screen of available data for the common toxic effect(s) 

is conducted on all the studies in different animal species/strains/sexes for each 

chemical and for each exposure route/duration of interest. This initial screen will 

help guide and determine the level and scope of the dose-response analysis 

described later in Section 6. 

3.5Characterization of Potential Susceptible Subpopulations or Life Stages to 

the Common Mechanism of Toxicity 

When characterizing hazard potential, attention should be given to 

subpopulations or life stages6

 that may be more susceptible to the common toxic 

effect and mechanism. For example, infants and children may not have fully 

developed metabolic pathways for detoxifying or bioactivating chemicals in a 

common mechanism grouping. In such a case, the dose level that would produce 

an effect in infants and children could proportionally be much lower (or higher) than 

the dose level that would produce the effect in adults. The importance of describing 

the potential increased sensitivity of infants and children is described in Executive 

Order 13045, and Agency guidance is provided in EPA’s Rule Writer’s Guide to 

6

Life stage is used to reflect a stage of development through which an organism passes through rather 

than a condition that may be permanently expressed such as gender or genetic make-up. 

20 
Executive Order 13045: Guidance for Considering Risks to Children During the 

Establishment of Public Health-Based and Risk-Based Standards (USEPA, 1998d). 

3.6Characterization of Human Information 

If available, human information–such as data from epidemiological studies, case 

reports, worker health studies, exposure monitoring studies with humans, and 

toxicokinetic data from clinical studies–can contribute to understanding the common 

mechanism of toxicity and characterize the hazards of the CMG. Used in 

conjunction with experimental animal data, human data may contribute to hazard 

characterization and assessment in several ways. They may: 

‘ add to the mechanistic understanding of the common effect and contribute to 

the weight of the evidence that the common mechanism of toxicity may be 

operative in humans 

‘ contribute to identification of the appropriate common endpoint(s) for use in 

hazard and dose-response assessments 

‘ provide insight into interindividual variability 

‘ identify specific subpopulations at risk 

‘ support an interspecies uncertainty factor more appropriate than the default 

factor of 10 (see Section 10). 

Both the design and the execution of studies with human subjects must be rigorously 

reviewed and found to meet appropriate standards of scientific merit and ethical 

conduct before the resulting information should be relied on in an risk assessment. 

The standards for scientific and ethical acceptability of human studies are currently 

under review. 

21
3.7Characterization of Data Issues: Adequacy and Quality 

Another important aspect of the hazard assessment is the characterization of the 

adequacy and quality of the available data. The risk assessor needs to consider the 

following: 

‘ the reproducibility and consistency of the results for the common- mechanism 

effects among studies in the same laboratory and among studies of different 

laboratories 

‘ the availability of response data for the common toxic effect based on several 

different studies that utilized comparable methodologies and the same 

species, strain, and sex of animals 

‘ the availability of route-specific, time course, and toxicokinetic data 

‘ the experimental design and methods used to conduct the study. 

3.8Weight-of-the-Evidence Evaluation of the Common Effect(s) 

A weight-of-the-evidence approach should be used in addressing and providing 

an integrative assessment that considers the above topic areas and questions. This 

analysis is incorporated in the overall characterization of risk (discussed in Section 

10). It requires a discussion of the characteristics of the data on each chemical in 

the common mechanism of toxicity grouping, and how the strengths and 

weaknesses of the data on each chemical influence confidence in the potential 

cumulative hazard identified for the grouping as a whole. In presenting the weightof-evidence evaluation, the risk assessor should include a summary of: (1) the 

mechanism of toxicity identified for the CMG; (2) the key data on the common 

endpoint of toxicity expressed as a result of a common mechanism; and (3) a 

recommendation of the toxicological endpoint(s) to be considered in the cumulative 

assessment. It should also be noted whether other toxic effects are expressed by 

members of the CMG at lower doses than the common mechanism effect, and 

whether a mechanism of toxicity can be identified for those other toxic effects. An 

evaluation of each member’s toxicological profile should allow the risk assessor to 

make recommendations regarding which chemicals should be included in the 

cumulative risk assessment for a particular common mechanism. The rationale and 

recommendations for excluding a particular chemical, route, or duration of exposure 

should be explained. 

22
SECTION 4. Determine the Need for a Comprehensive Cumulative 

Risk Assessment 

Step 4. Consider the number and types of possible exposure scenarios in conjunction 

with the associated residue values available. Evaluate the toxicological information on 

NOAELs and LOAELs collected for the common effect. This evaluation may suggest 

that a screening-level assessment for the CMG will indicate that there is no risk concern 

for this group of chemicals and no further detailed assessment will be necessary. This 

evaluation may also suggest that a cumulative assessment is simply not appropriate at 

this time. 

4.1Screening Assessment 

Not every cumulative risk assessment needs 

to have the same scope or depth. There may be 

certain CMGs that will require only screeninglevel assessments to decide whether to invest 

resources in collecting and analyzing data for a 

more extensive cumulative risk assessment. 

Screening-level assessments are more likely to 

apply to CMGs that comprise only a few 

chemicals and have low exposure potential given 

use patterns of the pesticides. A screening-level 

assessment for exposures to food, for example, 

might assume treatment of 100% of crops with 

A simple or less data-intensive 

method for evaluating cumulative 

risk may suffice when the CMG has: 

<Small number of chemicals

<Limited pesticide uses (e.g., no

residential uses)

<Low aggregate risks

<Monitoring data show non-detectable

levels of residues

each CMG chemical registered for use on a crop, and assume tolerance-level 

residues for the exposure component rather than a more refined estimate of actual 

residue levels from monitoring. Although modeling dose-response curves to derive 

refined relative potencies and points of departure for the CMG is preferred, margins 

of exposure7

 may be developed using NOAELs when dose response data are not 

amenable to modeling. 

7

A Margin of Exposure (MOE) is a numerical value that characterizes the amount of safety to a toxic 

chemical–a ratio of a toxicological endpoint (usually a NOAEL) to exposure. The MOE is a measure of 

how closely the exposure comes to the NOAEL. 

23 
An example screening-level assessment was conducted on the thiocarbamate 

pesticides (see USEPA, 2001c, 2001o). Thiocarbamates are a subgroup of 

carbamates that induce neuropathology of central or peripheral nerves. Although 

these pesticides could not be grouped by neuropathology as a common mechanism 

of toxicity, neuropathology was the most sensitive effect found for these pesticides. 

Therefore, this endpoint was used in this screening assessment as a conservative 

approach. Conservative estimates of chronic food exposure were conducted under 

a DEEMTM screening analysis with tolerance levels and assuming treatment of 100% 

of crops. 

4.2When to Conduct a Comprehensive Cumulative Risk Assessment 

A CMG generally should not be the subject of a screening-level cumulative risk 

assessment if individual pesticide 

aggregate risk estimates have been 

found to be unacceptable. For 

example, if the individual aggregate 

risks are unacceptable, there is a 

higher likelihood that a CMG may 

pose a cumulative risk, particularly if 

the aggregate assessments were 

based on effects associated with the 

common mechanism of toxicity. In 

addition, a screening assessment is 

unlikely to provide meaningful results 

A more refined cumulative risk assessment 

should be considered when the CMG is: 

<Is composed of a large number of chemicals

<Has widespread pesticide uses 

<Has high aggregate risks

<Has monitoring data showing detectable levels

of residues

or save resources if the CMG consists of a large number of chemicals with 

widespread usage. The likelihood of compounding conservatisms causing an 

unacceptable outcome will increase with increasing numbers of uses. If a 

screening-level assessment does not appear to be reasonable for a CMG, a 

determination must be made as to whether the data for the chemicals in the CMG 

will support a quantitative cumulative risk assessment. This evaluation includes 

consideration of whether the exposure and toxicological data are sufficiently detailed 

to support such an assessment. It also considers the logic of the assessment and 

whether the questions asked by the assessment with regard to overlapping 

exposures are reasonable, and addresses exposure conditions likely to be 

encountered. A number of conditions and considerations to be addressed prior to 

initiating a more refined cumulative risk assessment are listed below. 

24
‘ A cumulative exposure assessment generally should not be conducted 

until an aggregate exposure assessment has been conducted for each 

member of the CMG. 

As stated previously, the aggregate assessments will provide the assessor 

with information needed to define the exposure parameters of the cumulative 

exposure assessment. They will also permit evaluation of the strengths and 

weaknesses of the data that will be used to develop the cumulative risk 

assessment. Examination of aggregate exposure assessments will provide 

important information for directing the decision making process as to whether 

a particular pesticide-source and/or pathway combination should be included 

in the quantitative assessment. Particular attention should be given to 

identifying and including those sources of exposure that are likely to 

contribute significantly to the final exposure estimate. At the same time, 

identifying components that are minor contributors to the final risk estimate is 

critical to bounding the scope of the cumulative exposure assessment and, 

ultimately, the cumulative risk assessment. 

‘ For chemicals where multiple and/or overlapping exposures are likely to 

occur, a further evaluation should be conducted to determine 

qualitatively their likely contribution to the impending cumulative 

exposure assessment. 

Pesticide use patterns greatly affect potential exposure scenarios. By 

evaluating a pesticide's geographic and temporal pattern of use, a qualitative 

profile for each chemical from the CMG can be developed to establish the 

potential routes, durations, frequencies, and relative magnitude of exposure. 

Also, the evaluation of chemical use profiles allows for the identification of 

exposure scenarios that may overlap, co-occur, or vary among chemicals. 

‘ Data availability and quality may also play a role in the determination of 

whether to proceed with a full multipathway cumulative risk 

assessment. 

The quantity of data available may vary among routes and pathways, 

making interpretation of analytical results difficult. For example, ample data 

may exist to provide an estimate of exposure from several pesticides though 

the food pathway; however, pesticide-specific data on residential exposure 

may be scarce or nonexistent, requiring the use of default values to generate 

quantitative estimates. In such a case, the uncertainties for the default values 

may be far in excess of the uncertainties for the exposure in food, and 

combining the two would be problematic. Similarly, where datasets differ in 

quality, i.e., how well they represent real-world concentrations, combining 

exposure assessments may produce misleading results. Generally, 

25
assessment of pesticide exposures from food will be conducted using highly 

refined distributional estimates of residues from monitoring. As a result, the 

estimates will closely reflect anticipated exposures likely to be encountered by 

the public, with limited uncertainty in the results. Estimates of exposure from 

residential sources or pesticide residues in water are anticipated to be less 

certain because they will be the result of indirect estimation procedures using 

calculated residue values. Interpretation of combined results of direct and 

indirect estimation techniques will be complicated by the need to determine if 

a particular source of estimated exposure is biased and over- or underreflecting real-world exposures. The mixing of two major sources of 

uncertainty in a highly complex exposure assessment would make it more 

difficult, if not impossible, to evaluate the source of any apparent exceedance 

of acceptable exposure levels. Where issues of data quality or quantity 

indicate that combining pesticide exposures across multiple routes would 

result in significant uncertainties, exposures that are pathway-specific should 

be combined and the implications considered qualitatively in the risk 

characterization. 

26
SECTION 5. Determine Candidate Cumulative Assessment Group 

Step 5. Select pesticides, pesticide uses, routes, and pathways from the common 

mechanism group (CMG) that have an exposure and hazard potential to result in 

cumulative effects for inclusion in the quantitative estimates of cumulative risk. 

A Cumulative Assessment 

Group (CAG) may be a subset of the 

CMG because not all chemicals 

grouped by a common mechanism 

toxicity may be included in the 

quantitative cumulative risk 

assessment. In general, initial 

cumulative assessments should not 

attempt to quantify risk resulting from 

chemicals with a low hazard potential 

or from minor exposure scenarios, but 

should instead focus on those 

The following could be removed from the 

quantitative cumulative risk assessment: 

<A particular use of the pesticide

<A route of exposure

<A pathway of exposure 

(e.g., residential, drinking water)

<An entire chemical

chemicals and exposure scenarios that are likely to be risk contributors and that may 

require mitigation actions. This focus on likely risk contributors is important because, as 

indicated in the Agency’s Supplementary Guidance for Conducting Health Risk 

Assessment of Chemical Mixtures (USEPA, 2000j), the uncertainties and biases for 

even a small number of chemical components of a mixture can be substantial. When 

cumulative risk is assessed, a large number of chemicals may increase the complexity 

and uncertainty with no substantial change in total exposure. Additionally, including a 

large number of chemicals in the refined quantification of risk also may confound the 

interpretation and utility of the assessment results for risk management decisions. 

In reviewing the initial cumulative assessment, careful attention should be paid to 

any decisions to exclude exposure scenarios in order to evaluate whether the 

exclusions had a meaningful effect on the assessment. The exposure and hazard data 

will serve as a basis for determining which members of the CMG, routes, pathways, and 

pesticide uses should be retained for quantifying cumulative risk. Although an entire 

chemical, a route or pathway of exposure, or a particular use may not be included in the 

final quantitative risk assessment, all chemicals, routes or pathways, and uses should at 

least be qualitatively assessed. It is critical that all CMG chemicals and their exposure 

scenarios are accounted for in the cumulative risk assessment. Thus, the rationale for 

not including an entire CMG pesticide or a particular pesticide use or route/pathway 

combination should be clearly described in the cumulative risk assessment. These 

decisions should be based on consideration of the totality of the hazard, dose-response, 

and exposure data. Although the exclusion of negligible contributors may be prudent, 

caution should be exercised such that d chemicals do not constitute a major portion of 

the total risk. Examples of reasons for not including an entire chemical or an exposure 

27
route/pathway or pesticide use in quantifying risk follow: 

An Entire Chemical: The risk assessor may remove any chemical whose 

contribution from all uses is expected to be negligible. 

‘ The chemical’s common toxic effect is the critical effect, but it shows a very 

low toxic potency for the common toxic effect compared to the other CMG 

members for all routes/durations of interest, and thus a low hazard potential 

for the common mechanism. 

‘ The toxicity upon which the CMG was based is not the principal mechanism 

by which the pesticide exerts its potential adverse effect. The pesticide is 

regulated at a much lower exposure level based upon a much more potent 

toxic effect. For example, some thiocarbamate pesticides are weak 

cholinesterase inhibitors, but have much more serious and irreversible effects 

at dose levels significantly below those that induce cholinesterase inhibition. 

The regulatory endpoints for these pesticides reflect the principal adverse 

effects, which are irreversible. Although these chemicals exhibit 

characteristics of the CMG at very high doses, in the long term, exposure to 

these chemicals will be limited by the effects with the lower regulatory 

endpoint. 

‘ On further detailed analysis, an individual chemical member of a CMG is 

found to exhibit toxicokinetic and pharmacodynamic behavior that is 

substantially different from the other members of the CMG. 

A Particular Pathway/Route or Pesticide Use: Careful removal of scenarios in 

which exposure is very low or nonexistent can serve to focus the cumulative risk 

assessment on exposures that are more likely to be risk contributors. The 

sequential removal of scenarios as a part of a sensitivity analysis will be helpful in 

identifying the important sources of exposure for the cumulative risk assessment, 

accounting for uncertainties in the data inputs, evaluating the impact of any 

assumptions used, and explaining the outcomes of the assessment to risk managers 

and the public. 

‘ Routes that have significantly less (or minimal) toxicity for the common 

mechanism effect(s), or routes for which the common mechanism is not 

expected to occur, should be excluded from the cumulative risk assessment. 

For example, a pesticide may be shown to have negligible dermal absorption. 

28
‘ A particular pathway for a specific chemical in the CMG should be removed if 

it is likely to contribute only a very small percentage of the total exposure in 

the most refined analysis performed. The pesticide-pathway combination 

should be noted in the exposure characterization as present but not included 

in the quantitative exposure assessment. For example, a granular 

formulation of a herbicide that is used for turf treatment would most likely not 

contribute significantly to inhalation exposure. 

‘ A specific pesticide-pathway combination that makes a negligible contribution 

to the exposure assessment should be removed because of limited use or low 

consumption of a treated commodity. For example, a pesticide that is used 

only once per season on one low-consumption food crop or during a period of 

dormancy would be expected to make a negligible contribution to overall 

exposure to the pesticide. 

‘ Exposure scenarios should be removed for situations where there is a rapid 

onset of and recovery from the common toxic effect, and overlapping 

exposures with other pesticides are unlikely to result. Thus, attention should 

be given to concurrent exposure for acute or short-term toxic effects or 

chronic effects mediated through reversible precursor events, compared to 

irreversible chronic effects for which long-term exposure is necessary. 

29
SECTION 6. Conduct Dose-Response Analyses and Determine 

Relative Potencies and Points of Departure 

Step 6. Select and apply an appropriate dose-response method to evaluate the 

common mechanism effects and determine the relative toxic potencies of the CAG by

each exposure route and duration of interest. Determine the point of departure(s) for

extrapolating the risk of the CAG. 

The key objectives of the dose-response analysis of the cumulative assessment 

group (CAG) members are to: 

‘ select a common endpoint to estimate the toxic potency of each chemical in the 

CAG on a consistent and uniform basis 

‘ select a method for estimating the relative potency of each chemical to account 

for the different toxic potencies of the CAG, normalizing the exposure data, and 

determining what fraction of the total risk comes from each chemical for each 

route/duration of exposure 

‘ determine a point of departure for each exposure/duration for extrapolating the 

risk of the CAG. This point should be based on high-quality dose-response data 

and should be near or approaching the background response but yet can be 

reliably said to be due to dosing with the chemical 

‘ evaluate the members of the CAG to determine whether they exhibit 

appropriately similar dose-response curves consistent with the assumption of 

proportionality and dose-additivity. 

The dose-response modeling of multiple common mechanism chemicals for 

determining relative potency and point of departure for the CAG is in an early stage of 

development and experience is limited. It is anticipated that data and methods will 

continue to improve and evolve as more experience is gained in this area. Thus, the 

guidance below is a general framework intended to accommodate advancements in 

methodology and a variety of data situations. For additional guidance, the risk assessor 

should refer to EPA’s Benchmark Dose Technical Guidance Document (USEPA, 

2000b), the Agency’s Supplementary Guidance for Conducting Health Risk

Assessments of Chemical Mixtures (USEPA, 2000j), and the Draft Revisions to the 

EPA’s Guidelines for Carcinogen Risk Assessment (USEPA, 1999c). The July 2001 

dose-response assessment on organophosphorus pesticides (USEPA, 2001d) and the 

FIFRA SAP comments on that analysis (USEPA, 2001n) as well as the December 2001 

preliminary organophosphorus pesticide cumulative risk assessment (USEPA, 2001m). 

6.1Dose Addition: A Method of Combining Cumulative Potency for Common 

30
Mechanism Chemicals 

Several methods are available for combining risks of chemical mixtures. These 

approaches are described in detail in the Agency’s Supplementary Guidance for

Conducting Health Risk Assessment of Chemical Mixtures (USEPA, 2000j). 

Because the focus of this guidance is on the cumulative risk associated with multiple 

chemicals that act by a common mechanism of toxicity and elicit the same common 

toxicity in the same target tissue, only methods that use the concept of dose 

addition8

 will be described. Dose addition is regarded as a reasonable and 

appropriate approach for estimating the cumulative risk associated with exposure to 

common mechanism chemicals. The assumptions and scientific support for use of 

dose addition in the risk assessment of chemical mixtures is discussed in detail in 

USEPA (2000j) and thus will only be dealt with briefly in this guidance. 

The mathematical definition of dose addition requires a constant proportionality 

among the effectiveness of the chemicals (USEPA, 1986d, 2000j; Hertzberg et al., 

1999). In other words, it is assumed that the ratios of toxic potencies among the 

chemicals remain constant along their dose-response curves. As discussed in the 

following paragraph, simple dose addition assumes no chemical interactions. In 

reality, common mechanism chemicals may not behave identically (the exact same 

toxicokinetics and pharmacodynamics). Furthermore, dose addition may be limited 

to some range of exposure conditions (dose level and frequency, as well as route). 

Therefore, dose addition is an Agency default assumption, and when applied it is 

only an approximation of the joint chemical risk. The risk assessor should use an 

alternative approach that is more appropriate when data support an alternative 

approach. 

When applying dose-addition methods, it is assumed that at lower levels of 

exposure typically encountered environmentally no chemical interactions are 

expected (i.e., simple additivity) (USEPA, 1986d, 2000j). When adequate chemical 

interaction data (at low chemical doses near anticipated human exposures) are 

available for the CAG and indicate significant departures from the “no interaction” 

assumption [i.e., interactions showing greater (synergism) or lesser (antagonism)], 

alternative approaches to dose addition should be considered. Although there is 

limited practical experience for incorporating interaction data in chemical mixture 

assessments, the Agency’s supplementary guidance for assessing chemical 

mixtures offers approaches (USEPA, 2000j). 

As indicated above, there are several types of dose addition approaches, and the 

risk assessor can refer to the Agency’s Supplementary Guidance for Conducting 

8

In contrast to dose addition, response addition applies when chemicals act on different systems or 

produce effects that do not influence each other (i.e., each chemical effect is independent) (USEPA, 

2000j). 

31 
Health Risk Assessment of Chemical Mixtures (USEPA, 2000j) for a detailed 

discussion of these approaches. This document will only discuss the Relative 

Potency Factor (RPF) method which applies dose addition. At this time, OPP will 

use the RPF approach for estimating cumulative risk because it can utilize doseresponse information to provide an estimate of the common toxicity, and thus allows 

for the quantification of exposure as it relates to the joint risk of the CAG. However, 

if an alternative approach to the RPF method is more appropriate then that should 

be considered. Briefly, the RPF approach uses an index chemical as the point of 

reference for standardizing the common toxicity of the chemical members of the 

CAG. Relative potency factors (i.e., the ratio of the toxic potency of a given 

chemical to that of the index chemical) are then used to convert exposures of all 

chemicals in the CAG into exposure equivalents of the index chemical. The steps 

involved in the RPF approach are depicted in the accompanying text box and will be 

described in detail below. 

6.2Determination of the Relative Potency for the CAG 

Although the chemical 

members of the CAG produce 

the same common effect(s), they 

will likely have different toxic 

potencies in doing so. Thus, to 

estimate the joint risk of the 

CAG, the different chemical 

potencies must be put on a 

common scale so the exposures 

to the chemicals can be 

normalized. The following steps 

should be taken in applying the 

RPF approach: (1) determine 

Steps in the Relative Potency Factor Approach 

<Determine Toxic Potency of each chemical member

in the CAG by route and duration of interest

<Select an Index Chemical as a reference point to

put each chemical member on a common scale

<Calculate Relative Potency Factors based on the

index chemical’s toxic potency

<Determine the Point of Departure for the index

chemical by routes and durations of interest

the toxic potency of each chemical; (2) select an index chemical to use as the point 

of reference for standardizing the common toxicity of each chemical member; 

(3) calculate RPFs for each chemical member that will be used to normalize their 

exposure; and (4) Finally, a point of departure is determined for the index chemical. 

These steps are explained below. 

32
6.2.1 Determination of Toxic Potency 

The toxic potency for each 

chemical member should be 

calculated using a consistent and 

uniform dataset for the chemical 

group. Thus, to the extent possible 

the toxic potencies of each member 

of the CAG should be based on the 

same common effect derived from 

the similar studies using 

comparable methodologies 

evaluating the same species/strain 

and sex for the exposure 

route/durations of interest. As 

explained below, there are several 

measures of potency, as described 

Principles for Determining the Toxic Potency 

for the Chemicals of Interest 

To the extent possible, toxic potency should be 

based on a uniform point of comparison using: 

<Same common toxic endpoint for all 

exposure routes/durations of interest 

<Same measure of potency for each 

exposure route/duration of interest 

<Same species/strain and sex for all 

exposure routes/durations of interest 

<Studies of comparable methodology 

in Section 6.2.1.1, that can be used to estimate the relative potency of the CAG. 

The same measure should be used for each exposure route of interest to provide 

a consistent and uniform basis to derive relative potencies of the CAG. If mixing 

of species/sexes, endpoints, or measures of potency is necessary, then 

additional uncertainties are introduced to the assessment and must be clearly 

noted, and some characterization of their impact on the total cumulative 

assessment should be given. 

6.2.1.1 Measures of Potency 

There are several measures to 

describe the toxic potency of each 

chemical in the CAG. If the dataset 

for the CAG contains information 

amenable to dose-response 

modeling, the ideal approach for 

determining toxic potency is to use a 

biologically- and toxicokineticallybased model. Although the 

development of these models is 

encouraged, they are not yet 

standard methods and are data 

intensive. Thus, the more likely 

approach taken will be to use a curve 

Approaches to Determine 

Relative Toxic Potencies 

Among the Members of the CAG 

Ideal: Biologically- and Toxicokineticallybased Modeling

Appropriate: Empirical Curve 

Fitting Model

Least Desired: Use of NOAELs

Inappropriate: Use of RfDs from the

single-chemical aggregate assessments

fitting model that is appropriate to the response data. The dose-response 

relationship is described for each member of the CAG with the same 

mathematical model function. A benchmark dose (BMD) then can be derived 

from modeling the dose-response of each chemical to determine each 

33
chemical’s toxic potency. A BMD associated with the same designated level 

or percent of response relative to the control or baseline level of response 

(this is referred to as the benchmark response) should be used all CAG 

members. For purposes of determining relative potency, the BMD should be 

based on a central tendency estimate rather than the 95% lower confidence 

limit on dose. The use of the central tendency on dose is considered 

appropriate when determining relative toxic potencies for multiple chemicals 

which are being normalized to a common scale because the 95% confidence 

limits may result in compounding the conservatism in a multiplicative manner. 

The BMD should represent a response level that is within the observable 

range of the dose-response curves for which the toxicity studies have 

reasonable power to detect. Furthermore, if a BMD is used to determine the 

relative potency of the CAG, then the benchmark response should be the 

same that is used to determine the point of departure for the index chemical 

unless there is justification for use of another benchmark response (discussed 

later in Section 6.2.3.). An alternative approach to using a BMD is use of a 

dose scaling factor (units expressed as inverse of the dose units, e.g., 

mg/kg/day-1) for calculating the absolute potency of each chemical. 

If the data available for the CAG are not amenable to curve fitting, then 

NOAELs may be used as a default approach to approximate the toxic 

potencies of the CAG. This is a less desirable approach with several 

disadvantages. NOAELs do not necessarily reflect the relationship between 

dose and response for a given chemical, nor do they reflect a uniform 

response across different chemicals. The “true” NOAEL may be close to the 

background response level, may be well below the background response 

level, or may approach or be at an effect level not observed owing to the 

dosing levels or the insensitivity of the study. An evaluation of the NOAEL 

versus the LOAEL may provide some insight into how close an empirically 

measured NOAEL approaches the background level of response. If NOAELs 

are not available, use of a LOAEL can be considered. In this case, the 

LOAEL for that chemical should be adjusted by a factor (usually 3- or 10-fold 

as a default adjustment) to estimate the NOAEL. 

34
Finally, determinations of relative potency generally should not be based 

on an individual chemical member’s reference doses (RfD)9

. It is 

inappropriate to use the RfDs previously determined for single-chemical 

assessment for a number of reasons. First, they were derived for a different 

purpose. An RfD is based on an evaluation of all toxicities produced by the 

chemical and on identification of the most sensitive effect occurring in the 

most sensitive species. In cumulative risk assessment, the most sensitive 

endpoint is not necessarily the common toxic effect. Although the RfD effect 

may pertain to the common mechanism, it may not be the endpoint or 

species/sex selected to determine the relative potency of the CAG. Finally, 

RfDs contain uncertainty factors that may differ from those pertaining to the 

common toxic effect. 

6.2.1.2 Endpoint and Study Selection 

A comprehensive review of the data pertaining to the common toxicity in 

different strains and sexes and at various time points should be conducted to 

determine which studies can contribute valid information for the doseresponse analysis. Reasons for excluding specific studies should be 

documented. Following the complete review of the toxicity database, the 

common toxic endpoints and species/strain and sexes that have the most 

extensive databases should be selected to provide a uniform basis to 

determine the relative potencies of the CAG for each route and duration of 

interest. Studies with more dose groups will generally be more useful to 

dose-response modeling and the determination of relative potencies and 

points of departure for the CAG. 

9

A chronic reference dose is defined as an estimate (with uncertainty spanning perhaps an order of 

magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely 

to be without appreciable risk of deleterious effects during a lifetime. OPP also determines RfDs for less 

than lifetime risk assessments (e.g., acute dietary risk). An RfD can be derived from a NOAEL, LOAEL, 

or benchmark dose, with uncertainty factors generally applied to reflect limitations of the data used. RfDs 

are generally used in EPA’s noncancer health assessments. 

A description of the RfD process for single-chemical assessments can be found at EPA’s website for its 

Integrated Risk Information System (USEPA, 1999i) or in Barnes and Dourson (1988). 

35 
6.2.1.3 Data Collection and Entry 

The studies to be used in the dose-response analysis should be fully 

documented. A summary format should be prepared that includes the 

following information: type of study, route, duration, doses evaluated, number 

of animals per dose group, species/strain/sex, and the measured effect for 

each dose group including the mean and standard deviation. Study design 

elements that may influence a chemical’s toxic potency should be noted by 

the risk assessor. Examples include the schedule of intermittent dosing, and 

the vehicle (especially for oral exposures), as well as whether the vehicle 

effects are known to influence the toxic effect of concern. 

6.2.1.4 Combining Response Data 

Estimates of each chemical’s toxic potency for the common effect should 

be derived, if possible, for several relatively consistent studies, as opposed to 

a single study. This may be done by modeling each separate study and then 

combining the resulting potency estimates using appropriate statistical 

methods. The potency estimates from different time measures within and 

across studies may also be combined if appropriate (for example, steady 

state may be reached for a given endpoint). Using more than one study 

and/or more timepoint data has benefits in that it will allow for more robust 

estimates of the central value for the potency of each chemical. If there are 

no differential effects between the two sexes, those datasets may be 

combined. Combining data from multiple studies (or multiple timepoints 

within a study) will allow for a better estimate of the uncertainty associated 

with estimations of relative potency. When results from several studies are 

combined, statistically appropriate methods must be used and justified, and 

the rationale should be clearly presented, including a discussion of the 

variability among the single studies. 

6.2.1.5 Use of Surrogate Toxicity Data 

As stated earlier, it is preferred that determinations of relative potency be 

based on the same species/strain and sex. Where there are inadequate or 

missing data for a chemical(s) for the common toxic effect(s) in the 

species/strain or sex that is selected to estimate the relative potency of the 

CAG, “surrogate” data for a particular endpoint/species/sex for a route or 

duration of exposure may be used if it is appropriate to do so both statistically 

and biologically (i.e., there are no, or minimal, species/strain or sex 

differences). It should be noted that there is limited experience in using 

surrogate data to replace missing datasets to estimate relative potency. An 

example of the use of surrogate data can be found in EPA’s report on dioxins 

and furans (USEPA, 1989 and USEPA, 2000h). The FIFRA SAP 

recommended the following: “The use of surrogate data is reasonable when 

36
the data utilized for the extrapolation are of high quality, and there is an 

adequate understanding of the relationships among the data that are utilized 

for the estimation of the surrogate data. It is imperative that the Agency be 

transparent in why and how the surrogate data are chosen. There should be 

a discussion as to the “degree of confidence” or “level of uncertainty” the 

Agency has in the surrogate data.” (USEPA, 2001j). The risk assessor 

should use these recommendations to guide its analysis. 

6.2.1.6 Modeling the Data 

The selection of a mathematical model structure to fit the data being 

analyzed should be guided by the biology of the common mechanism of 

toxicity, the toxicokinetics of the chemicals, and the observed shapes of their 

dose-response curves and the experimental designs used to generate the 

data. If available, pharmacodynamic and pharmcokinetic data should be 

considered in order to account for tissue concentrations and to aid in defining 

dose-response relationships across different species, routes, and time-frames 

of exposure. 

This guidance does not specify a particular set of models. Rather, the 

goal of mathematical dose-response modeling is to select and fit a model that 

best describes the dose-response of the given datasets for the common 

toxicity, and is descriptive with the biology of the common mechanism. 

Various dose-response models have been used to estimate noncancer and 

cancer dose-response functions (see USEPA, 1999c, 2000b). The risk 

assessor should refer to the EPA’s technical guidance for deriving benchmark 

doses (USEPA, 2000c) for a more detailed discussion of considerations 

concerning the model selection and fitting. The choice of a modeling 

procedure should be done on a case-by-case basis. The assumptions 

underlying the model and application of the model to the common toxicity 

dataset should be clearly explained. Although it is not possible to recommend 

the use of specific models, a few points that should be considered in 

modeling the data follow: 

‘ Modeling of individual animal data is desirable; however, if this is not 

practical, then use of summary data such as means and standard 

deviations can be alternatives 

‘ Care should be taken with modeling high-dose data (particularly 

extreme doses) because the model shape in the low-dose region can 

be influenced by high-dose data 

‘ Log transformation of data should be justified because such a 

transformation may distort the dose-response curve 

37
‘ Data variability should be described by appropriate statistical 

techniques and reflected in the potency estimate (e.g., by weighting 

the data in the fitting procedure) 

‘ Confidence intervals or limits should be included in the analysis 

because they can be valuable for evaluating the influence of variability 

on the potency estimates 

‘ An estimate for the uncertainty of the model used in the analysis 

should be included 

‘ The statistical fitting method used must be clearly described. 

A statistical criterion (e.g., P values) should be used to evaluate how well 

the model describes the data. The rationale for the statistical criteria should 

be justified. The risk assessor should refer to the Benchmark Dose Guidance 

on how to evaluate the goodness of fit (USEPA, 2000b). A failure of a model 

to describe a dataset may be due to a number of possibilities, such as quality 

of the data, limitation of the model, or toxicokinetic and dynamic differences 

for a chemical that may raise doubts as to whether that particular chemical is 

appropriately considered in the CAG. The risk assessor should describe how 

these situations are dealt with in the assessment. If a chemical is to be 

excluded from the CAG for quantifying risk, the biological rationale for this 

exclusion should be presented (see Section 5). 

6.2.1.7 Interspecies Adjustment of Dose 

Ideally, when adequate data are available, the doses used in animal 

studies should be adjusted to equivalent human doses by using 

physiologically-based toxicokinetic (PBTK) models. This approach for dose 

extrapolation between species is not possible for most chemicals given that 

the use of PBTK models requires extensive comparative metabolism and 

toxicokinetic data that rarely exist. In the absence of these data, estimates of 

human equivalent doses are based on science policy defaults. The risk 

assessor should follow current Agency policy for interspecies adjustments of 

dose for cancer and noncancer effects and for ingested doses versus inhaled 

doses (see USEPA, 1999c; 1994). 

38
6.2.1.8 Route-to-Route Extrapolation 

Completeness and reliability of endpoint-specific data may be a particular 

concern for the dermal and inhalation routes. Extrapolations based on 

toxicokinetic models may be reliable enough for use in risk assessments, but 

they are rarely available. Simple extrapolations based on toxicokinetic 

defaults are sometimes unreliable because they assume that both routes are 

toxicokinetically and toxicologically similar. Uncertainty in a cumulative risk 

assessment is compounded with each chemical that lacks route-specific data, 

and too much uncertainty can render an assessment less meaningful. Thus, 

a default-based route-to-route extrapolation should not be included in a 

cumulative risk assessment unless there is a reasonable rationale for doing 

so (see USEPA, 2000j). That justification must be clearly stated. Additional 

guidance on route-to-route extrapolations can be found in EPA’s Inhalation 

Risk Characterizations and the Aggregate Risk Index (USEPA, 1998c). 

6.3Criteria for Selection of an Index Chemical 

As indicated above, the RPF method evaluates the equivalent index chemical 

exposure on its dose-response curve in order to estimate the risk of the CAG. Thus, 

it is essential that the index chemical be well characterized (qualitatively and 

quantitatively) because any imprecision in its data may be compounded with every 

chemical against which it is compared. The most important consideration in 

selecting an index compound is that high-quality dose-response data are available 

for the common toxic effect/species/sex and for the exposure route/pathways of 

interest. Furthermore, the compound should be well characterized for the common 

mechanism of toxicity, and the common mechanism of toxicity should be its principal 

toxicity. The index chemical should have a toxicological profile for the common toxic 

effect(s) that is representative of the other chemical members. It is preferable to 

have one index compound to scale the potencies across all routes/durations of 

interest. 

6.4Determination of a Point of Departure for the CAG 

The last key step in the dose-response analysis is to determine an extrapolation 

point or point of departure for the CAG. A point of departure (POD) is a point 

estimate on the index chemical’s dose-response curve that is used to depart from 

the observed range of empirical response (or incidence) data for extrapolating risk to 

the exposure anticipated in the human population. The POD should be either an 

observed dose or an estimated dose that approximates a “minimally toxic” response 

or a point in the dose-response curve at which a change in response can be reliably 

said to be due to dosing with the chemical. The choice of a POD will depend on the 

quality of the dose-response data and the degree of confidence in the relationship 

between the observed adverse effects or lack thereof. The traditional POD used by 

39
the Agency is a NOAEL. The preferred POD, however, is one derived from 

modeling the dose-response curve of the index chemical to derive a benchmark 

dose (BMD)10 that estimates a pre-specified level of response. The benchmark 

response (BMR) quantifies that level of response. 

As stated earlier, biologically-based or physiologically-based toxicokinetic 

models, which incorporate specific data on kinetic processes, are the most desirable 

approaches for quantifying toxic effects. Although the Agency encourages the 

development of such models, it is unlikely that the data will be available in the near 

term for the required input parameters. Thus, the use of a standard curve-fitting 

model will more likely be the practical approach at this time. The dose-response 

model used for the determination of relative potency should be the same one that 

determines the POD for the index chemical. A 10% effect level (BMD10) has been 

proposed by the Agency as the standard default point of departure for quantal 

endpoints (e.g., tumor responses). For some toxicities, a point of departure other 

than the BMD10 may be appropriate. For example, if statistically significant 

responses for the individual chemicals are lower than the 10% level of change in the 

response, then a lower point of departure (e.g., a BMD5 or 1) may be more appropriate 

for the CAG. For continuous endpoints (e.g., changes in hormonal or enzyme 

levels), the Benchmark Dose Technical Guidance Document (USEPA, 2000b) 

recommends that a dose be selected that would be expected to yield a change in 

the mean equal to one control standard deviation. The choice of a BMD response 

level and the justification for that choice should be provided on a case-by-case 

basis. Both the central estimate (BMD) and the 95% lower confidence limit on a 

dose (BMDL) should be presented to provide the risk manager with the magnitude of 

uncertainty associated with the POD. For interim guidance on modeling and 

deriving a benchmark response for extrapolation, the risk assessor should refer to 

the Agency’s benchmark dose guidance (USEPA, 2000b). 

10The term “benchmark dose” refers to the modeling of both quantal and continuous endpoints, whereas 

the term “effective dose” is typically used to refer only to quantal endpoints. 

40 
6.5Calculation of Relative Potency Factors 

Once the toxic potency of each member of the CAG is determined and an index 

chemical has been selected, relative potency factors (RPFs) may be calculated 

based on the index chemical’s toxic potency. The RPF method11 expresses the toxic 

potency (e.g., BMD or NOAEL) of each CAG chemical in relation to the potency of 

one member in the group selected as the index chemical (e.g., if Chemical Y is onetenth as toxic as the index chemical, the RPF for compound Y is 0.1): 

Equation 6.1: RPFn = Toxic Potency[Index Chemical] ÷ Toxic Potency[Chemical n] 

Using this method, each chemical’s exposure pathway is adjusted by its RPF to 

express it as a toxicity equivalent (TEQ) exposure, and then the exposure 

equivalents are summed. The index chemical’s point of departure is then used to 

determine the margin of exposure for each exposure pathway/route/duration of 

interest, as explained in Section 9.6.3. 

6.6Presenting the Results of the Dose-Response Assessment 

Sufficient information should be provided for others to clearly understand the 

dose-response analysis; for example, a graphic display could be provided of the 

dose-response curves for each CAG member, as well as summary tables of the 

studies used, calculated statistics, estimated toxic potencies, and points of departure 

for each route/duration of interest. The summary table should also include pertinent 

information on the time course of the effects (e.g., steady state, recovery). The 

analysis should discuss or identify the following: 

‘ rationale for the choice of endpoints, selection of studies, and model 

‘ dose-response patterns across endpoints, species/strains, and sexes for 

different routes and durations of exposure 

‘ applicability of results to varying exposure scenarios–issues of route of 

exposure, dose rate, frequency, and duration 

11The toxicity equivalency factor (TEF) approach (described in USEPA, 2000j) is conceptually a more 

rigorous type of RPF approach. In contrast to the more general RPF method, a key assumption of the 

TEF approach is that, for each chemical in the CAG, only one potency adjustment factor is needed 

because it applies to all effects by all routes and all durations (USEPA, 2000j). 

41 
‘ uncertainties, assumptions, adjustments, and defaults related to the approach 

for estimating the toxic potencies for each CAG member 

‘ chemical members that display dose-response curves that are not consistent 

with other members of the CAG (in which case there should be 

accompanying biological and statistical discussion concerning whether they 

are appropriately included in the CAG). 

Finally, the cumulative dose-response assessment should include a discussion 

concerning the applicability of the assumption of dose additivity and proportionality 

of the dose-responses among the CAG. It should be cautioned that studies that are 

likely to be available on the CAG may not have been designed to address the issue 

of dose additivity at low exposures. The FIFRA SAP (USEPA, 2001j) indicated that 

when evaluating the appropriateness of dose addition, substantial reliance would 

have to be placed on what is known about the commonality of the mechanism of 

toxicity for the CAG. The application of dose additivity requires the assumption of no 

toxicologic interactions. Thus, as described in Section 3.3, a literature search should 

be conducted on chemical interactions studies as well as whole-mixture studies for 

the members of the CAG to determine support for or departure from dose addition. 

Furthermore, the mathematical definition of dose addition requires a constant 

proportionality among the effective doses of the chemicals (USEPA, 1986d, 2000j; 

Hertzberg et al., 1999). A statistical examination of whether the dose-response 

curves for each chemical member of the CAG are consistent with the assumption of 

dose additivity should be considered in the analysis. If a mathematical doseresponse model were applied to the CAG to estimate toxic potency, then one could 

also evaluate whether that same model function adequately describes the datasets 

for common toxicity of the CAG. If evidence exists that is judged to disagree with 

dose addition, particularly at low doses, then the chemical(s) in question should be 

re-evaluated for inclusion in the quantification of cumulative risk. 

42
SECTION 7. Develop Detailed Exposure Scenarios for All Routes and 

Durations 

Step 7. For all of the uses remaining for each pesticide in the CAG, determine their role 

in establishing the magnitude of possible exposures. Decide the relative importance of 

scenarios and the need for their inclusion in a quantitative assessment. Identify 

populations of interest and locations for evaluation in the assessment. Determine cooccurrences of possible exposure scenarios. 

After the members of the CAG have been identified, the next step in developing a 

cumulative risk assessment is to elaborate the exposure scenarios resulting from the 

uses for each member compound. This process is described in detail in the General 

Principles For Performing Aggregate Exposure And Risk Assessments (USEPA, 

2001h), and will allow a determination of whether the exposure scenarios identified 

present any likelihood of overlapping exposures. Exposures are considered to overlap if 

chemicals are likely to be encountered from more than one source or pathway within the 

time frame in which the common mechanism effect is still operative from previous CAG 

exposures. The pathways of exposure for a chemical in the CAG may be such that 

overlapping exposure to another chemical will never occur. 

For acute or short-term toxic effects, the evaluation of the likelihood of overlapping 

exposure events may be more difficult if there is rapid onset of and recovery from 

the toxic effect. In such cases, a much more detailed estimation of the time course 

of exposures will be necessary. 

For chronic and cancer effects mediated through reversible precursor events, 

overlapping exposure should also be considered to determine whether durations of 

exposure are sufficient to trigger adverse effects, and to determine whether a 

subsequent exposure will occur before recovery is complete. Where effects are 

reversible, if sufficient time has passed such the recovery can be reasonably 

expected to have occurred, subsequent exposures would be considered to have no 

cumulative effect. The exposed individual has effectively returned to a state as 

though no prior exposure had occurred. 

In the case of chronic and cancer effects for which long-term exposure is necessary 

to cause the effect of concern and for which the effect is irreversible, concurrent 

exposures are not required for the chemicals to act by a common mechanism. The 

risk assessor should assume that each additional exposure will result in an 

accumulation of toxic effect with no potential for recovery. 

43
Single-chemical aggregate assessments should be used to inform the risk assessor 

in designing the cumulative risk assessment. However, a refined, quantitative, 

multipesticide cumulative risk assessment should not be performed by summing singlepesticide aggregate assessments. The cumulative risk assessment should reflect 

linkages and co-occurrences of use between complementary and competing pesticides. 

These factors generally cannot be established from single-chemical aggregate 

assessments because they were not relevant for an aggregate (single-chemical) 

assessment and therefore were not considered. Some of the underlying assumptions 

regarding the use of the toxicity data for a single chemical, such as the endpoint 

selected, may differ markedly from those for a CAG. The selection of typical versus 

high-end use data may differ depending upon whether the assessment focuses on 

multiple pesticides or a single pesticide. The cumulative risk assessment cannot be 

reconstituted from preexisting single-pesticide aggregate assessments, but should be 

conducted beginning anew from the base data. 

Using the data and results from the single-chemical aggregate assessments for the 

members of the CAG, the cumulative risk assessment should be planned with the 

following questions in mind: 

‘ Who is exposed? 

‘ To which chemicals and in what amounts? 

‘ What is the timing of the exposures and do they overlap? 

‘ Do the exposures occur in the same location such that they will be experienced 

together? 

‘ What are the pathways, routes, and duration by which the exposures will occur? 

For example, a mosquito treatment in the Southeast should be matched with other 

potential exposures during the spring and summer in the Southeast. The cumulative 

exposure assessment should be carefully structured to avoid nonsensical combinations, 

such as an individual being subjected to exposure resulting from spraying for black flies 

in Minnesota in the summer and treating for termites in Georgia in the fall. 

44
Three key pathways of exposure to pesticides are the dietary pathways of food and 

drinking water, and the nondietary pathway from exposure in residential and other 

nonoccupational settings. Chemical use patterns greatly affect potential exposure 

scenarios. By evaluating a pesticide's use pattern, a profile for each chemical from the 

CMG can be developed to establish the potential routes, durations, frequencies, and 

magnitude of exposure. Also, the evaluation of chemical use profiles allows for the 

identification of exposure scenarios that may overlap, co-occur, or vary between 

chemicals. 

The time-frame over which an exposure occurs is a key criterion for defining 

scenarios of interest. For example, depending upon the nature of the common toxic 

effect and the use patterns for a pesticide, the assessment may focus on the day an 

item of food is consumed, or extend the time of evaluation over several days following a 

home pesticide use. The time-frame will determine how exposures from different 

pathways and routes will be evaluated. This step depends heavily upon examination of 

the toxicity data, but requires the concurrent determination of what scenarios it is 

appropriate to represent. The nature of the adverse effect from the toxicity data will 

determine the time course over which exposure should be assessed. The consideration 

of the time-frames from the toxicity study should include an evaluation of time to onset 

of effect, impact of dose on time to onset, and time required for reversal of the effect (if 

the effect is reversible) following cessation of exposure. Where exposure scenarios are 

found to be of insufficient duration to trigger the common toxic effect, careful 

consideration may be given to eliminating some of the scenarios from the assessment. 

Duration alone, however, cannot be considered as a criterion for removal in a risk 

assessment because the final exposure that is analyzed in the cumulative risk 

assessment will be an accumulation of exposures from many pathways. Several 

exposures of short duration may overlap to produce a cumulative exposure that 

exceeds an acceptable level. Additional information about time intervals that may be 

useful in the development of exposure assessments can be found in the EPA’s 

Exposure Factor Handbook (USEPA, 1999d). 

45
7.1 Dietary Food Pathway 

OPP has extensive experience in conducting pesticide exposure assessments 

that account for differences in consumption patterns by region of the country and 

season. To a large extent, consumption is independent of geographic region and 

season. This is likely owing, in part, to the widespread distribution of both domestic 

and foreign commodities across the United States and, for many commodities, the 

predominance of storage facilities available for domestic commodities and the 

availability of foreign sources of fresh agricultural commodities throughout the year. 

Similarly, OPP has looked at the patterns of residues from data collected from 

USDA's Pesticide Data Program (PDP) and believes that there is little evidence for 

enough seasonal or spatial variation in pesticide residues to substantially alter OPP 

exposure assessments. 

As a result, exposure to pesticide residues in foods will be considered without 

regard for time of year or geographic location unless specific information indicates 

another approach should be taken. Region-specific exposures from residential uses 

and drinking water will be superimposed on the food exposure estimates. 

7.2 Dietary Drinking Water Pathway 

Exposures in drinking water to individuals should be incorporated into cumulative 

exposure assessments on a local or regional basis. Factoring drinking water 

exposure into the framework already contemplated for food-related exposures 

means developing a "person-by-person" approach to estimating drinking water 

exposure to pesticides over time. Because exposure to pesticides in drinking water 

is a local or a regional concern, and additionally, because the food portion of the 

dietary exposure assessment is being done on an individual basis, each hypothetical 

person included in a cumulative risk assessment should be assigned to a location 

and a drinking water source consistent with that location. 

Once an individual has been associated with a representative drinking water 

source, the available data should be examined for the occurrence and cooccurrence of pesticides in the drinking water source over time. Geographical 

Information System (GIS) tools, cropping and pesticide use information, fate and 

transport data, modeling results, monitoring data, and information on the effects of 

blending and treatment should be used to determine the pesticides most likely to 

occur or co-occur in that water source, and potential pesticide concentrations over 

time. Initially, OPP expects to assume that a person would be exposed only to those 

pesticides that are used in the recharge area above an aquifer for groundwater, or in 

the watershed of the drinking water source for surface water. As a guide to 

determining likely regions upon which to focus risk assessment scrutiny, the risk 

assessor should consider using information such as the National Agricultural 

Statistics Service (NASS) database or data from Doane’s Marketing Service to 

evaluate the use of pesticides in the CAG in areas where more than one of the CAG 

46
pesticides are used. Alternatively, an analysis of cropping patterns and pest 

pressure may be explored to identify likely areas for concentration of effort. 

7.3 Residential and Nonoccupational Pathway 

Applications of pesticides made in and around homes, schools, offices, and other 

public areas may result in potential exposure via the oral, dermal, and inhalation 

routes. Consideration of co-occurrence and linkage of uses where appropriate is 

particularly important for residential uses. Linked uses are those in which two 

products are or may be used in combination, such as dipping a pet and treating the 

carpet of a flea-infested home, or used in such a way that using one product 

substantially increases the probability of using a second product. The recognition 

and maintenance of these potential linkages will be critical in developing realistic 

estimates of exposures to a hypothetical individual with defined demographic 

characteristics. At this time, the understanding of patterns of use is limited, although 

the Agency is aware of efforts to conduct surveys describing the pesticide use 

practices of the U.S. public. Exposure assessments for residential and other 

nonoccupational sources will focus on those use scenarios outlined in the 

Residential Standard Operating Procedures (USEPA, 1999g). 

The factors for consideration in developing reasonable exposure scenarios for 

residential, nonoccupational, and institutional exposures are described in detail in a 

previous EPA document (USEPA, 1999b and USEPA, 2001h). As described in that 

document, the patterns of use for pesticides in residential, nonoccupational, and 

institutional settings are highly dependent upon location, season, dwelling type, and 

a myriad of other factors that impact the behavior of a potential pesticide user. 

Where appropriate, an assessor should link residential pesticide use preferences 

with particular classes or categories of individual, based on data, when performing 

cumulative exposure assessments. Where data are limited in quantity or are of poor 

quality, the residential SOPs should serve as the basis for initial estimates of 

exposure. 

Age/gender/pathway considerations play a role in cumulative assessments 

related to the behavior of individuals. Young children may be exposed to more 

pesticide residues for a variety of reasons. For example, young children engage in 

more hand-to-mouth activity (nondietary ingestion) than do adults. Some national 

surveys of home and garden pesticide usage suggest that more males than females 

treat lawns, whereas females are more likely to treat the interior of the house. 

Consideration of data of this type will aid in developing reasonable and realistic 

cumulative exposure and risk assessment scenarios. 

To the extent possible, the assessment of residential, nonoccupational, and 

institutional use patterns should characterize seasonal and geographic variations, 

and associated pest pressures. Residential uses cannot necessarily be assumed to 

be consistent with or coincide with the large national or broad regional breakouts 

47
currently used in the food exposure assessment arena. For instance, a food 

exposure assessment might cover the entire Pacific Northwest region of the United 

States. However, the coastal regions of Washington and Oregon are more humid 

and have milder temperatures than would be found in Idaho. Thus, residential uses 

of pesticides would likely differ considerably between these two areas because of 

differences in pest pressure, even though they are within the same "region." 

Cumulative risk assessments should reflect use patterns and practices on a scale 

sufficient to capture the variability in pesticide use, but not so large as to 

inappropriately dilute real and significant differences. An example is the very 

localized use of fenthion for mosquito control in parts of southern Florida. This 

pesticide should have only limited consideration in an assessment of other 

organophosphorus pesticides, including those used for mosquito control. In 

addition, a national overlay of market share by region may help to direct the risk 

assessor in determining the CAG to combine on a geographic basis. 

48
SECTION 8. Establish Exposure Input Parameters 

Step 8. Determine magnitude, frequency, and duration for all pertinent exposure 

pathway/route combinations. Identify appropriate sources of use/usage information, 

residues in all appropriate media, and any modifying factors necessary for inclusion in 

the assessment. Where necessary, identify any appropriate surrogate datasets from 

other chemical specific data, published literature, or generic datasets. Model any 

necessary exposure parameters for inclusion. 

The data for the three major sources of pesticide exposure (food, drinking water, 

residential or other nonoccupational) that will be used to develop single-chemical 

aggregate assessments will constitute the majority of the data required to conduct the 

cumulative risk assessment. Strengths and weaknesses inherent in the data for each 

individual chemical assessment will be carried over to the cumulative assessment. In 

addition, the data available for the three sources of exposure may vary widely in 

quantity as well as in their ability to describe the range of the exposures likely to be 

encountered by each pathway. The data that OPP anticipates using for each pathway 

are discussed below. 

8.1Dietary Food Pathway 

The body of information for the food pathway is generally much greater than that 

available for the other 

pathways. Some of the types of 

data and their sources that can 

be used in assessing exposure 

to pesticides in food are 

depicted in the text box. 

Cumulative exposure 

assessments for this pathway 

are anticipated to be accurate 

and refined because of the 

availability of monitoring data 

that will provide a clear picture 

of residues in foods far down 

Sources of Dietary Food Data 

<Continuing Survey of Food Intakes by Individuals

(CSFII) (1994-1996, 1998)

<Field Trial Data (studies submitted to EPA that

are required for registration or re-registration).

<Monitoring Data from USDA's Pesticide 

Data Program (PDP)

<FDA's Surveillance Monitoring Data

<Market Basket Monitoring Data

the chain of commerce. In addition, data defining the consumption patterns for the 

U.S. population have been collected in a number of surveys. Current OPP food risk 

assessments rely upon the food consumption data collected by USDA in the 

Continuing Survey of Food Intakes by Individuals (CSFII). Cumulative exposure 

assessments for residues of pesticides in foods can be performed for each 

hypothetical individual used to estimate the distribution of anticipated exposures. 

Using detailed individual consumption records such as those provided by the CSFII, 

combined with analytical results from monitoring programs such as USDA's PDP 

49
program, a refined exposure estimate can be developed that incorporates the 

likelihood of consuming multiple residues in a single food and the likelihood of 

consuming more than one food that may contain a residue of concern. Food 

exposures will be assumed to be national in scope unless there is evidence to the 

contrary. 

The development of cumulative exposure scenarios may be driven by the 

information contained in the food consumption and residue databases. Cumulative 

assessments should be performed on an individual-by-individual basis in order to 

maintain any necessary linkages and associations between consumption data and 

demographic data. Food consumption data files provide demographic information 

on the region (and urbanization) of residence, the season of response, and 

socioeconomic status of the consumption survey respondents, among others. 

These data may be used in constructing subpopulation characteristics that can be 

matched to appropriate residential and drinking water exposure scenarios. Similarly, 

differences in pesticide use and usage rates that are available from a variety of 

sources may also be related to region, and may permit development of more refined 

and focused individual-based cumulative risk assessments. Regional factors will 

also be important in selecting the appropriate localized drinking water data and 

residential use scenarios to include in the cumulative risk assessment. More 

detailed discussion of the importance of demographic information in structuring a 

risk assessment is presented in EPA’s guidance for performing aggregate risk 

assessments (USEPA, 1999b and USEPA, 2001h). 

Monitoring data are unlikely to be available for all commodities under 

consideration. OPP commonly translates residue data between similar commodities 

that have common cultural practices in order to take full advantage of the available 

monitoring data. This translation process includes an evaluation of treatment rates 

and frequencies to be certain that the assumption of relevance of data between 

commodities is appropriate. 

When residue monitoring information for most food uses of CAG pesticides is 

available, the risk assessor should limit the residue data used in cumulative 

exposure assessment to monitoring data that reflect actual measurements of 

pesticide residues and their co-occurrence. Empirical estimation of co-occurrences 

in a cumulative assessment is critical because the co-occurrence of residues of two 

or more chemicals in a single food item is not necessarily independent; a cooccurrence may be the result of intentional application practices. For example, 

some products are sold as mixtures of pesticides, so the presence of one may be 

correlated with the presence of another. In addition, the rotation of multiple 

pesticides within a single growing season may result in the co-occurrence of 

pesticides. Therefore, the use of monitoring data in which co-occurrence was 

measured may provide the only basis for conducting a cumulative food exposure 

assessment that describes this situation with any degree of certainty. 

50
At this time, OPP does not have adequate methodology to combine monitoring 

data with residue field trial data into cumulative assessments. Although such 

combined data are routinely used in aggregate risk assessments for individual 

pesticides, several factors suggest that use of such data in cumulative risk 

assessments would yield results with unacceptably high uncertainty. First, use of 

residue field trial data presents a conservative picture (i.e., an estimate that errs on 

the side of overstating exposure and risk) of residue levels because use of such data 

is premised on the assumption that all uses of the pesticide occurred at maximum 

label rates. This conservatism would be compounded by the aggregation of such 

conservative values. Second, field trial data do not (and cannot) account for cooccurrence of pesticide residues in single items, and such consideration is a relevant 

aspect of any cumulative assessment. PDP data provide a direct measure of 

concurrent exposure to pesticides, and as such implicitly account for actual usage 

practices. The alternative is to rely upon indirect estimation of likely overlapping 

use, extrapolating from data on use areas, use rates, season of application, and 

many other factors. The combination of conservative residue values with an indirect 

approach to estimating co-occurrences would introduce uncertainty, making the 

cumulative risk assessment less reliable for regulatory purposes. Thus, when OPP 

does not have monitoring information for most food uses of the CAG chemicals, 

OPP may combine the field trial values to produce a bounding estimate of exposure 

by the food pathway that will provide qualitative information about the upper-bound 

exposure and relative contribution of different uses. This approach is similar to the 

screening-level assessment described above in Section 4. Inherent in a bounding 

estimate of this type is the premise that an acceptable risk under these 

circumstances indicates no possibility that an unacceptable risk may pass 

unidentified. However, it is difficult or impossible without further refinement to 

determine whether the indication of an unacceptable risk is real or an artifact of the 

estimation process. In general, the risk assessor should not combine data from 

monitoring with data from field trials because of the qualitative difference in the two 

datasets. 

OPP often has information regarding the impact of food preparation (washing, 

peeling, cooking) to adjust the pesticide residues in raw commodities to reflect 

processing and handling. These data should be applied, where appropriate, to 

monitoring data on a pesticide-specific basis. In addition, data on the percent of the 

crop treated are available to permit estimation of the likelihood that a given pesticide 

has been applied to a commodity. The percent of crop treated should also be 

applied on a pesticide-specific basis taking into account the quality of the data. 

8.2Dietary Drinking Water Pathway 

The dietary food pathway in many cases will be based on higher quality 

monitoring data than for the drinking water (or residential) pathway. Thus, the cooccurrence of pesticide residues in water in most cases will be estimated rather than 

based on monitoring data. Although it is desirable to use direct measurements of 

51
pesticide concentrations in tap water in cumulative exposure assessments, this 

approach may not always be feasible. Pesticide concentrations vary considerably 

across space and time; thus, obtaining an adequate number of tap water samples 

could be prohibitively expensive. Accordingly, the risk assessor should be using a 

combination of monitoring and modeling to develop reasonable approximations of 

pesticide concentrations in tap water. These can include: 

‘ direct measurements of pesticide concentrations at the point of distribution 

from Community Water Systems (i.e., finished water) 

‘ direct measurements of pesticide concentrations prior to treatment (i.e., raw 

water measurements) with adjustments for the effects of blending and 

treatment 

‘ model-based estimates of pesticide concentrations in raw water with 

adjustments for the effects of blending and treatment. 

Corrections for treatment and blending should be made to the extent that they are 

reflected in available data. It is OPP's intent to utilize in a scientifically defensible 

manner all available and relevant monitoring data and modeling results to develop its 

best approximation of pesticide concentrations in tap water over time for use in 

cumulative risk assessments. 

Evidence of the co-occurrence of pesticides within a drinking water source for a 

CAG is a critical piece of information needed prior to making a decision to include 

more than one pesticide in a cumulative drinking water exposure assessment. 

Direct measurements of combinations of pesticides in finished drinking water are 

rarely available. However, U.S. Geological Survey (USGS) and National Water 

Quality Assessment Program (NAWQA) databases do contain information on the cooccurrence of a wide variety of pesticides in ambient surface water, and some 

registrant-sponsored studies provide co-occurrence data for specific compounds in 

drinking water. Further, information on the use of different pesticides within the 

same geographic region, combined with information on the timing of use and the fate 

and transport properties of these pesticides, can also be used to identify pesticides 

that are likely to co-occur. Once the likelihood of co-occurrences has been 

established, the risk assessor should use, where appropriate, a combination of direct 

measurements of pesticide concentrations at the intakes from community water 

systems; direct measurements of pesticide concentrations prior to treatment, with 

adjustments for the effects of blending and treatment; and model-based estimates of 

pesticide concentrations in raw water, with adjustments for the effects of blending 

and treatment, as reasonable approximations of concurring pesticide concentrations 

in tap water. 

For pesticides with sufficient monitoring data in finished drinking water, the risk 

assessor should use these data in cumulative risk assessment to approximate tap 

52
water concentrations over time. In cases where sufficient raw water monitoring data 

are available, the risk assessor should use these data in combination with data on 

the effects of blending and treatment to adjust raw drinking water concentrations to 

approximate tap water concentrations over time. 

For pesticides with insufficient or no monitoring data, concentrations over time 

could be estimated using modeling in combination with pesticide-specific fate and 

transport data. A tiered approach to estimating drinking water concentrations is 

being developed to incorporate model estimates of pesticide concentrations in 

drinking water into aggregate and cumulative risk assessments. The risk assessor 

should generally use the highest tier assessment in quantitative cumulative risk 

assessments. This approach will incorporate multiyear climate data to simulate 

likely rainfall events in selected locations and will retain the temporal nature of the 

data, which is critical for time-based exposure estimates. The sites used in the 

analysis will reflect areas of high pesticide use and vulnerability to ensure that the 

outputs reflect health-protective estimates of potential pesticide concentrations in 

water consistent with use patterns, important cropping systems, and soil 

characteristics of the regions represented. The risk assessor should compare the 

results of modeling with monitoring data for similar compounds to confirm whether 

those pesticide concentrations in raw and/or finished drinking water predicted by 

modeling appear to be consistent with measured values. OPP is developing more 

sophisticated predictive models to approximate pesticide concentrations over time in 

drinking water for cases where monitoring data are scarce or lacking. 

Modeling tools are especially useful and valuable when monitoring data are 

scarce or unavailable. This is often the case for pesticide degradates and always 

the case for pesticides pending registration. Further, and importantly, it is extremely 

difficult to accurately characterize (based on monitoring data alone) peak exposures 

for those pesticides that have acute toxicological endpoints. Thus, given the large 

number of samples that would be needed, developing adequate monitoring 

programs to estimate peak or high-end concentrations could be very difficult. 

53
8.3Residential and Other Nonoccupational Pathway 

Current exposure assessments for residential and other nonoccupational sources 

for single-pesticide assessments are most commonly conducted using the 

Residential Standard Operating Procedures (USEPA, 1999g). This is because of 

the limited amount of chemical-specific generic exposure data that are available to 

support exposure assessments. In the cumulative risk assessment, the SOPs 

generally would not provide the level of detail required to develop a reasonably 

descriptive residential exposure assessment. Rather, the residential SOPs would 

serve as the starting point for developing a set of residential exposure assessments 

that provide a more detailed portrait 

of the anticipated use of each 

pesticide in the residential and 

nonoccupational environment. The 

SOPs will define the scenarios of 

interest and the types of additional 

data required. These data may 

include the range of typical 

application rates, pests of interest 

within a region, likelihood that a 

pesticide will be applied, time of 

application for a given use, 

likelihood and frequency of 

reapplication, concentrations of 

pesticides on surfaces or in air 

Sources of Information for the Estimation of 

Residential Exposure 

<Residential Standard Operating Procedures

(USEPA, 1999g)

<General Principles For Performing Aggregate

Exposure And Risk Assessments (USEPA, 2001h)

<Product Labels

<Exposure Factors Handbook (1999d)

<Monte Carlo Guidance Document (1997a)

<National Home and Garden Use Survey

following application, and dissipation rate for the pesticide after application. 

OPP is exploring the use of surrogate (bridging) data to assess residential 

exposure for pesticides with similar use patterns. This will allow EPA to extrapolate 

from one pesticide, for which high-quality residential exposure data are available, to 

other pesticides, similar to what is done for assessing occupational exposure using 

the Pesticide Handlers’ Exposure Database (PHED) and the Outdoor Residential 

Exposure Task Force (ORETF) dataset. Furthermore, OPP is aware that additional 

data that will increase the ability to estimate residential and institutional exposures 

are being developed by the Residential Exposure Joint Venture, the ORETF, and the 

National Pest Control Association. OPP has developed a pilot cumulative 

assessment on a set of organophosphorus pesticides that demonstrate the concepts 

in data application described here. OPP presented this assessment to the SAP for 

review/comment in December 2000 (USEPA, 2000e). The assessment provides 

tangible examples of how surrogate/bridging data may be used in such an 

assessment. 

54
The factors for consideration in developing reasonable exposure scenarios for 

residential, nonoccupational, and institutional exposures are described in detail in a 

previous EPA guidance document (USEPA, 1999b and USEPA,2001h). The 

patterns of use for pesticides in residential, nonoccupational, and institutional 

settings are highly dependent upon location, season, dwelling type, and other factors 

that impact the behavior of a potential pesticide user. An assessor should use the 

available data in such a way that preserves significant intrinsic links between 

residential pesticide use preferences and types of individual when performing 

cumulative exposure assessments. Where data are limited in quantity or are of poor 

quality, the residential SOPs should serve as the basis for initial estimates of 

exposure. The residential SOPs are by nature designed to produce screening-level 

assessments that are intentionally conservative. Combining exposures for the 

members of the CAG based on this screening-level assessment should be 

approached with caution because of the potential for compounding conservative 

assumptions. Furthermore, as in the case of drinking water, the estimation of cooccurrence and residue levels will not be as refined as it is with the food pathway 

because of the significantly more limited data. 

55
SECTION 9. Conduct Final Cumulative Risk Assessment 

Step 9. Assign route/duration-specific risk metrics. Conduct trial run and evaluate 

output. Conduct sensitivity analysis. Assess subpopulations of concern, determine 

group uncertainty and FQPA safety factors. 

The design of the cumulative risk assessment should include consideration for the 

relevance of the time-frame appropriate to the CAG, how input parameters may 

systematically vary with geographic location and time of year or season, and the 

population of concern in the risk assessment. The data assembled to conduct the 

assessment should be combined in such a manner as to provide a coherent, realistic 

picture of the range of potential risks likely to be encountered by exposed populations 

and their associated probabilities. Inappropriate combinations of data may result in 

nonsensical outputs that are inaccurate and misleading. The use of data in the 

cumulative risk assessment process is described below. 

9.1Time-frame 

A cumulative risk assessment should be conducted using a time-frame 

considering the time to onset of the common mechanism effect and also the time for 

reversibility of the effect (if it is reversible). A major determinant in the selection of 

the time-frame is the condition of expression for the common toxicity by duration and 

route. However, use patterns and likely patterns of exposure will also provide input. 

The risk assessor should assume that pesticides that have food uses may cause 

chronic exposures. Such an assumption is generally appropriate given the nature of 

food distribution and storage in the United States, unless the only uses are highly 

seasonal in nature and the commodities in question are only consumed fresh. For 

products with residential or institutional uses, the time-frames for consideration can 

also be bounded by the period of time over which a likely exposure is anticipated to 

occur. In practice, the assessment should be conducted one time-frame at a time, 

using a rolling time period over the calendar year. In other words, if the critical timeframe for consideration is one week, a cumulative assessment should be performed 

sequentially for individuals on days 1 to 7 of the likely exposure window, then days 2 

to 8, days 3 to 9, and so forth (i.e., a rolling time-frame). This approach is described 

in greater detail in a previous document (USEPA, 1999b and USEPA, 2001h). 

56
9.2Geographic Scale and Site Selection 

The outcome of a cumulative risk assessment will be a group of geographically 

oriented assessments rather than a single national-level assessment as is 

commonly conducted for single-chemical food risk assessments. The construction 

of a multichemical, multipathway assessment can be envisioned as assembling a 

series of clear plastic overlays in different combinations depending upon the 

geographic variability and scale of each component. Each overlay would contain a 

map unit of a different scale depending upon whether a highly localized area (e.g., a 

single watershed) or a much larger area (e.g., as would be used when defining 

residential lawn care uses) was represented. The food risk assessment is a national 

assessment that assumes a random distribution of treated commodities across the 

entire United States, with the potential for added geographic or demographic 

specificity (i.e., a breakout by gender or age) to permit accommodation of 

differences in consumption patterns. This assessment can be envisioned as the 

base over which smaller scale risk assessments for residential/institutional and 

water may be superimposed. Residential/institutional risk assessments should be 

tailored to geographic location because of differences in climate and pest pressure 

that occur across the United States. The differences in climate will reflect 

temperature zones and seasonality variations encountered throughout the country, 

producing geographic areas of interest ranging in size from portions of a few States 

to large multi-State regions. Examination of the range of residential use practices 

and patterns across different geographic regions would provide a means of 

identifying specific regional breakouts, which appropriately account for differing 

patterns of residential use. For example, Maine, Vermont, New Hampshire, and 

Massachusetts might exhibit similar use patterns for residential lawn care products, 

with a relatively short window of application in the late spring to early summer. This 

use area could be overlaid upon a grosser scale of food risks to provide a more 

detailed, smaller scale use area. Finally, the source of drinking water could further 

be superimposed to focus the risk assessment. Consideration of water source and 

its incorporation into a risk assessment is anticipated to produce a much finer scale, 

more localized type of assessment, potentially varying from large urban metropolises 

drawing water from a variety of geographically and hydrographically distant sources 

to smaller areas using highly localized supplies such as single watersheds or wells. 

Conceptually, one way of implementing this type of assessment would be to use GIS 

approaches in conjunction with adequate definition of the distribution of residues in 

drinking water. Sufficient understanding of the regional component of residential 

and institutional pesticide use as well as the nature of the resulting residues would 

be a prerequisite for implementation of such an approach. The output from this 

information would consist of a series of risk assessments reflecting the uses and 

potential exposures specific to that geographic area and similar areas for which it 

may serve as a surrogate. 

A pesticide with a broader use pattern may require drinking water exposure 

assessments that include multiple counties, States, or even a large geographic 

57
region. One approach to such an assessment would combine residue data from 

various drinking water sources if the data are judged to be sufficiently similar through 

appropriate statistical tests. However, pesticide use usually impacts different 

drinking water sources to different degrees. This should be taken into account. For 

example, a particularly vulnerable community water system would be suitable for 

use in estimating the potential drinking water exposure for individuals who drink from 

that system, but should not be the basis for an exposure assessment for individuals 

living nearby and drinking from another, less vulnerable source. In situations where 

residue data from several sources may be combined into one distribution of residue 

data, it is desirable to know the population associated with any specific source 

included in the exposure assessment. 

Knowing the size of the population served by a specific drinking water source 

allows for population-weighted exposure assessments. A population-weighted 

exposure assessment accounts for the probability that a specific portion of the 

population may be more highly exposed than the majority. Depending on the quality 

of the data chosen for the assessment, i.e., how representative they are of actual 

drinking water concentrations, a drinking water assessment for the members of the 

CAG to permit the focus of further risk assessment efforts on areas of greatest 

concern. If, however, a high-end, deterministic screening-level assessment is all 

that is available, it should not be combined with a highly refined food risk 

assessment because of the previously stated concern of obscuring results with 

increasing uncertainty. Rather, the screening-level assessment should be 

considered in the context of its implications relative to a separate, highly refined food 

assessment. 

As stated previously, demographic information available from the food 

consumption and residue databases can be used to characterize potentially exposed 

subpopulations. Each assessment should focus on a single subpopulation for which 

the demographic characteristics have been carefully defined. The age, gender, and 

geographic location of the group included in the investigation of the food exposure 

pathway can be linked with exposure scenarios in the drinking water and residential 

pathways. The individual food consumption records in the database, which also 

contains the demographic and other descriptors, will be used as a basis of 

simulating the consumption patterns of the population or subpopulation of interest. 

The likelihood and frequency assumptions associated with residential scenarios 

could be used to superimpose a pattern of exposures that would reasonably be 

expected to occur throughout the year and is consistent for that individual. 

58
The population subgroups that are most commonly of concern to OPP can be 

defined by a number of factors, including demographics, geographic location, and 

season. Demographic considerations would include age, gender, ethnicity, and any 

other considerations that may be important in evaluating subpopulations with 

potential special susceptibilities. The geographic location of the exposed population 

will be needed to help match geographically-based exposure data (e.g., probability 

of applying a termiticide treatment in the South) to appropriate subpopulations. 

Location may be particularly important in evaluating the impact of water data or 

regional use patterns on anticipated exposures. Geographic location will also be an 

important consideration in evaluating seasonal aspects of residential exposures. 

Highly localized exposures may suggest very different strategies for risk mitigation 

than do exposures that are widely disseminated. The size of the affected 

subpopulation should be estimated where possible. The estimates of percentiles of 

exposure and associated risk should be factored against the target population size 

to determine the magnitude of the risk. The following example may serve to 

illustrate these concepts: 

Herbicide B is used widely on lawns, home gardens, and flower beds as a preemergent agent. There are numerous food uses, but the residue data indicate 

that Herbicide B is not detected in food. The herbicide is widely used by 

commercial lawn services. It has been detected in many urban surface water 

sources as well as in many major surface water bodies in the United States. 

Although the herbicide has widespread use in all areas of the United States, the 

residential use patterns differ according to the different climates. In this scenario, 

the subpopulation of concern cannot be ascertained from the food exposure 

assessment because there is no appreciable exposure from this pathway. The 

use pattern of Herbicide B indicates that recreational activities on lawns are likely 

to be a major source of exposure. Individuals most likely to engage in these 

activities (possibly children) would be the subpopulation of concern. In addition, 

individuals consuming water from surface water sources would require greater 

scrutiny, including evaluation of the efficacy of water treatment to remove 

Herbicide B. Individuals who raise home gardens would be another potential 

group of concern. Finally, the use period of Herbicide B would vary with use 

region based upon climate. The period of the year upon which the assessment 

would focus would vary depending upon location. 

Note that this example scenario does not lead to a highly detailed, multipathway 

quantitative cumulative risk assessment. It does, however, identify subpopulations 

of potential concern. Additional exposure data would be needed to confidently 

estimate multipathway cumulative risk. 

59
9.3Subpopulations of Concern 

Cumulative risk assessments should characterize multiple subpopulations 

depending upon the nature of the common toxicity and the geographic distribution of 

use and attendant exposure. The nature of the common toxic effect will determine 

which portions of the population are susceptible to experiencing the common toxic 

effect in question. For example, males would not be considered a reasonable target 

population for adverse effects related to pregnancy. For a common toxic effect that 

is limited in its applicability, the cumulative assessment should be tailored to focus 

on those groups that are sensitive. Similarly, if the use of a chemical is limited to a 

specific geographic locale, the subpopulation of concern should be selected 

considering potential for exposure in drinking water, appropriate residential and 

institutional use patterns that are reflective of the region under consideration, and 

any peculiarities of food consumption patterns or residue distributions that might 

impact the assessment result. 

9.4Constructing the Assessment 

All of the dose-response 

characteristics (RPFs and PODs), 

exposure data, and exposure 

scenarios should be combined in a 

manner to produce a logical 

outcome consistent with exposures 

likely to be encountered by the 

public. There are several different 

exposure models in different stages 

of development that can integrate 

various pathways while 

simultaneously incorporating the 

time dimensions of the data. 

Currently, the CalendexTM and 

LifeLineTM models are available to 

conduct cumulative risk 

assessments. CalendexTM provides 

a focused, detailed profile of 

potential exposures to individuals 

across a calendar year. LifeLineTM 

focuses on identifying key points in 

a lifetime during which important 

exposure events are likely to occur. 

At this time, LifeLineTM permits 

Models That Can Account for the 

Temporal Aspects of Exposure 

<CalendexTM (Novigen ,2001)-a 

calendar-based, probabilistic approach that can 

integrate different pathways of exposure and 

reflect exposure to discrete individuals on a 

daily basis over a 365-day calendar year 

<LifeLineTM (Hampshire Research Institute, 

2000)-a calendar-based, probabilistic approach 

that models longitudinal aspects of exposure to 

discrete individuals across the a substantial 

portion of a lifetime 

<Cumulative and Aggregate Risk Exposure 

Model (CARES) (ACPA, 1999)-a 

calendar-based, probabilistic approach that can 

integrate different pathways of exposure and 

reflect exposure to discrete individuals on a 

daily basis over a 365-day calendar year 

<Residential Exposure-Year (RExY) 

(InfoSciences) - a calendar-based, probabilistic 

residential tool identifying possible sources of 

exposure and estimating their magnitudes 

incorporation of only a limited number of residential exposure scenarios and does 

not support estimates of exposure from drinking water. Other models such as 

Cumulative and Aggregate Risk Exposure Model (CARES) and RExY (Residential 

60
Exposure-Year) are under development. CARES is being developed to accept a 

variety of inputs and will make the conduct of fully quantitative, cumulative risk 

assessments easier. RExY is being developed to provide a user-friendly means of 

exploring the full range of possible exposures anticipated from the residential uses of 

a CAG and identifying the likely risk contributors. 

The risk assessor should accept and review risk assessments performed with 

those models that have been subjected to the public peer-review process. The 

model selected to perform the cumulative risk assessment should be able to provide 

information concerning a variety of issues of interest and concern to the risk 

assessor, such as the range of possible exposures from each source of pesticide 

exposure and from all sources combined, the risks associated with those exposures, 

the contribution of each pesticide and each application method to the estimated 

exposures, and the difference in exposure among subpopulations of concern. The 

construction of the assessment can be approached on a pathway-specific basis, 

involving separate development of the datasets for food, water, and residential 

exposure. 

9.5Expression of Cumulative Risk-Combining Multiple-Pathway Risk 

The cumulative risk assessment should develop all of the underlying data used 

for a chemical-specific evaluation and more. The same basic procedures used in a 

single-chemical aggregate assessment can be carried over into the cumulative 

framework. These processes are presented briefly below. 

9.5.1 Dietary Food and Dietary Water Pathway 

To derive a cumulative residue, chemical-specific residue (on a food sample or 

estimated to occur in water) is converted to a residue expressed in equivalents of 

the index compound. Any processing factors for foods or treatment impacts for 

water should be factored in just prior to this stage because they will be chemicaland medium-specific. 

61
Equation 9.1: ResidueIE = Residuecompound × PF × RPF 

where: ResidueIE is the compound-specific residue concentration expressed 

as equivalents of the index compound, 

Residuecompound is the compound-specific residue concentration, 

PF is a compound-specific process factor (for food) or treatment factor (for 

water), and 

RPF is the relative potency factor used to normalize the compoundspecific residues to the toxicity of the index compound. This factor 

converts the compound-specific concentration to an index-compoundequivalent basis. 

Once all of the residues for a given food or water sample are converted to index 

compound equivalents, they are summed to give a total cumulative residue value for 

each sample. 

Equation 9.2: Residue Cumulative = ∑ Residue 

CAG 

The residue data, normalized to index equivalents and accumulated for each 

sample, are ready for introduction into a probabilistic risk assessment. 

9.5.2 Residential and Other Nonoccupational Pathways 

Residential and other nonoccupational exposures rely upon estimates of 

exposure that are calculated, drawing upon the equations in the Residential 

SOPs (USEPA, 1999g). These estimates are converted to index equivalent 

exposures as in the dietary portion of the assessment. However, for residential 

and other nonoccupational assessment, the assessor is faced with the added 

complexity of developing datasets for oral, dermal, and inhalation exposures, with 

the ultimate goal of accumulating exposures from all members of the CAG by 

each route in a manner reflecting the potential for exposure to more than one 

chemical within a time-frame. 

62
The assessor develops an inventory of the uses registered for each 

compound. The basic equations from the residential SOPs (i.e., exposure 

scenarios) should be evaluated to identify equation parameters for which 

distributions can be substituted for default values. Distributions should be used 

to the extent possible to introduce the full range of possible exposure 

combinations. Generally, the scenarios under consideration will be addressed by 

the general equation: 

Equation 9.3 Exposure = Contact × Residue 

where, the contact function defines the duration of contact, the portion of the 

body exposed, how much of the available residue can be transferred to the 

body for dermal exposure, and the duration of contact and respiratory 

characteristics of the exposed individual for inhalation exposure. The input 

parameters for each scenario/chemical combination are combined to reflect 

the characteristics of the chemical and its particular application rates, 

frequencies, and seasonal attributes. The dissipation rates, transfer factors, 

and other attributes that reflect the physical-chemical properties of the 

chemical should also be factored into the calculation of residues prior to 

normalization to index equivalents. 

An example of the types of data that can be used to flesh out the many 

complexities of a detailed cumulative residential assessment is presented in the 

document Cumulative Risk: A Case Study of the Estimation of Risk from 24 

Organophosphate Pesticides (USEPA, 2000e). This case study was presented 

to the SAP in December 2000. The section on residential exposure clearly 

demonstrates the types of data that are useful in more fully characterizing the 

potential for pesticide exposure from residential uses. It also illustrates the use 

of generic data, including those generated by task forces or provided in Agency 

publications such as the Exposure Factors Handbook, and the use of chemicalspecific data from one compound to serve as a surrogate for another, similar 

compound. The case study also illustrates the use of survey data to develop 

profiles of activities by users and the frequency with which activities are 

performed. Finally, the case study illustrates the role of professional judgment 

and the importance of regional knowledge and expertise in developing detailed 

scenarios. 

63
9.6Accumulating the Risk 

The risk assessor should express the total pesticide residues for the CAG in 

terms of the Index Chemical (see Section 6). This approach requires conversion of 

the residues of each member of the CAG to concentration equivalents of the index 

chemical. This can be done using RPFs developed to normalize the toxic response 

of each pesticide to the toxicity of the index chemical. The point of departure (e.g., 

an BMD10) for the index chemical is then used to calculate route-specific MOEs for 

the CAG. Generally, the expression of risk from the CAG can be expressed as: 

Equation 9.4 MOE = PODIndex ÷ ∑ Exposure 

Route 

EPA uses margins of exposure (MOE) for aggregating the risk posed by 

exposure to a single pesticide via multiple pathways (USEPA, 1999b and USEPA, 

2001h) and has extended this approach to estimating the cumulative risks of multiple 

chemicals (see USEPA, 2000e). Route-specific MOEs can be used and combined 

to generate a total MOE while preserving the route-specific nature of the risk 

estimates. 

1 

Equation 9.5: 

MOEtotal = 1 1 1 

+ + MOEoral * MOEdermal MOEinhalation 

*Oral is the total oral exposure from food and 

drinking water plus oral, nondietary contacts such as 

hand-to-mouth exposure from residential pesticide 

uses. 

This method is illustrated in Cumulative Risk: A Case Study of the Estimation of 

Risk From 24 Organophosphate Pesticides (USEPA, 2000e). In this method, 

exposure can be calculated on a route-specific basis within a source (e.g., 

residential risk for inhalation, dermal, and oral routes of exposure) and then 

combined across sources of exposure (food, drinking water, residential and other 

nonoccupational pathways). Using a calendar-based exposure model, the 

contributions from each pathway can be calculated simultaneously for every 

exposed individual for every day reflected during the time-frame of the exposure 

estimates. 

In developing a cumulative assessment, the risk assessor must have a clear 

understanding of the probability that one or more exposures to a member of the 

64 
CAG will occur on any given day of the year. This information will permit the risk 

assessor to develop a series of internally consistent individual exposure values 

across the calendar year that provide an understanding of the potential exposures to 

members of the CAG on any given day, and the sources of these exposures. The 

estimated cumulative exposures can be expressed as a family of exposure 

distributions that reflect the changing use patterns of CAG chemicals across the 

year, and for subpopulations of interest. The assessment will permit identification of 

the source of the exposure (pesticide, use pattern, rate, location, time of year) and 

evaluation of the magnitude of exposure and the appropriate subject(s) of any 

mitigation activities. 

65
SECTION 10. Conduct Characterization of Cumulative Risk 

Step 10 . Describe the results and conclusions of the cumulative risk analysis, including 

the relative confidence in toxicity and exposure data sources and model inputs. Discuss 

major areas of uncertainty, the magnitude and direction of likely bias, and the impact on 

the final assessment. Evaluate the risk contributions from each pathway and route 

individually, as well as in combination. Identify risk contributors with regard to 

pesticide(s), pathway, source, time of year, and impacted subpopulation (with particular 

attention to children). Conduct sensitivity analyses to determine those factors most 

likely to impact the risk. Determine need for uncertainty and safety factors. 

Risk characterization is the interpretation phase of the assessment process. It is an 

integrative process that brings together the assessments of hazard, dose response, and 

exposure to characterize risk estimates for the exposure scenarios of interest, and 

presents the major results and conclusions of the risk assessment as well as the 

associated uncertainties. A risk characterization provides a discussion for a diverse 

audience that minimizes the use of technical terms. It is an appraisal of the science that 

supports the risk manager in making public health decisions. Additional guidance on 

risk characterization can be found in the Agency’s Handbook (USEPA, 2000c). 

10.1 Risk Characterization Summary 

A risk characterization 

summary should accompany a 

cumulative risk assessment, and 

should present the conclusions of 

the analysis and include a 

discussion of the significant 

contributors and sources of risk. It 

should provide descriptions of risk 

for the exposed population as a 

whole (i.e., average levels of 

exposure) as well as those 

individuals in the high end of the 

distribution. Important subgroups 

of the population (e.g., children) 

who may be at disproportionate 

risk (e.g., through unique 

susceptibility to the common 

Risk Characterization Summary 

<Statement of purpose, scope, level of 

detail of the assessment

<Pesticides and exposure scenario(s) covered 

<Kinds and quality of data available

<Methods of estimation

<Strengths, limitations, and uncertainties

inherent in data and analysis

<Key assumptions and their potential impact on

the outcome of the assessment

<Significant issues relating to each exposure

pathway and impact on the overall assessment

<Special groups (including children) at

disproportionate risk

mechanism of toxicity, or human activity exposure patterns) should be highlighted. 

Methods of estimation should be described (e.g., deterministic versus probabilistic 

methods, or screening-level exposure methods versus highly refined monitoring data 

reflective of residues close to the point of consumption or contact). As discussed 

66
below, significant uncertainties in the cumulative risk assessment should be 

highlighted. 

As indicated throughout the document, conducting a cumulative risk assessment 

requires the coalescing of a variety of data sets of highly variable characteristics. 

Each source of exposure data, and the data defining potential hazard for each 

pesticide is anticipated to have unique strengths and limitations, resulting in potential 

difficulties in interpretation of the results. As the scenarios for each pathway are 

constructed, the risk assessor is encouraged to maintain a record of the attributes of 

each parameter used as an input into the assessment. These include, but are not 

limited to: estimate of direction and magnitude of bias in the data; data format, e.g., 

point estimate, range as uniform distribution, or descriptive distribution; confidence in 

the data. The risk assessor can use this compilation of data attributes to evaluate 

the potential for bias in the results of the assessment. For example, if the majority of 

data bias is in the conservative direction, the assessment may be determined to err 

on the side of overestimation bias. Where directional bias is mixed, the factors may 

offset and result in a more balanced result. Inclusion of sensitivity analyses to 

determine the impact of particular parameters on the resulting assessment may be 

helpful to determine whether or not directional bias in parameters is of concern. 

10.2 Describing Uncertainty 

The goal of any cumulative analysis should be to produce estimates of exposure 

through the pathways of concern that are health protective but use the available data 

to the greatest extent possible. Uncertainty in the cumulative assessment is also an 

important consideration and should be discussed in at least a qualitative sense 

whenever possible in the assessment. It is only when the uncertainties about the 

cumulative risk estimates can be adequately evaluated and conveyed to risk 

managers, interested parties, and the general public that productive dialogue on 

potential refinements, responses, and mitigation actions can take place. 

Because data are unlikely to permit robust evaluation of all the critical 

parameters needed for a highly refined cumulative risk assessment (e.g., kinetic 

data on the common mechanism of toxicity, descriptive dose-response data for 

chemicals by all routes of interest, monitoring data for all exposure pathways of 

interest), the cumulative assessment should describe the significant sources of 

uncertainty, variability, and limitations inherent in the analysis. Uncertainty should 

be described qualitatively, but also captured quantitatively to the extent possible. No 

definitive standard Agency policy or detailed procedure on how to perform 

uncertainty analysis is available. However, several references in the published 

literature provide useful information on this topic (Hattis and Anderson, 1999; Hattis 

and Minkowitz, 1996; Hattis and Burmaster, 1994; Baird et al., 1996). In evaluating 

uncertainty, unique issues for both the toxicological and exposure inputs into 

calculating risks for each pathway of exposure should be highlighted. The precision 

of each pathway analysis (e.g., food, drinking water, residential and other 

67
nonoccupational sources) should help determine the uncertainty in combining the 

different pathways in the cumulative assessment. The following two sections 

address uncertainty issues with respect to cumulative risk assessment. 

10.3 Application of Uncertainty Factors and the FQPA 10X Safety Factor 

FQPA directs that EPA ensure that there is a reasonable certainty that no harm 

will result to infants and children from aggregate exposure to the pesticide chemical 

residue when setting tolerances. In the case of “threshold effects,” FQPA requires 

“an additional tenfold margin of safety for the pesticide chemical residue, and other 

sources of exposure shall be applied for infants and children to take into account the 

potential pre- and post-natal toxicity and completeness of the data with respect to 

exposure and toxicity to infants and children....[and that] the Administrator may use a 

different margin of safety for the pesticide chemical residue only if, on the basis of 

reliable data, such margin will be safe for infants and children.” This is referred to as 

the FQPA Safety Factor provision. A risk assessment addressing cumulative effects 

of a pesticide chemical residue will have major bearing on OPP’s determination of 

whether the reasonable certainty of no harm finding can be made. Accordingly, 

several of the core aspects of the cumulative assessment, such as the identification 

of the nature of the common toxic effect and the scope of the toxicity and exposure 

databases relative to the cumulative assessment, will need to be considered by OPP 

in applying traditional uncertainty factors as well as determining the need for a 

special FQPA safety factor. Consideration of the FQPA Safety Factor should be 

based on the group rather than on individual members of the group. 

OPP has developed guidance entitled Determination of the Appropriate FQPA 

Safety Factor(s) for Use in the Tolerance-Setting Process that describes the policies 

employed in making determinations regard the FQPA safety factor for single 

chemical risk assessments(USEPA, 1999h, 2001f). Although many of the principles 

in that document apply to a cumulative risk assessment, OPP is preparing a 

separate paper, Consideration of the FQPA Safety Factor and Other Uncertainty 

Factors in Cumulative Risk Assessment of Chemicals Sharing a Common 

Mechanism of Toxicity, that presents the general approach attendant to making 

determinations regarding the traditional uncertainty factors and the FQPA safety 

factor for cumulative risk assessments (USEPA, 2001g). The risk assessor should 

refer to that document. 

68
10.4 Uncertainty With Respect to Exposure Assessment 

Exposures through the food, water, and residential pathways merit consideration 

for their contributions to uncertainty in the cumulative assessment and should be 

discussed. Some examples of potential sources are offered below. As deemed 

appropriate by the risk assessor, they should be described in conjunction with the 

assessors’ best estimate of how they may influence the outcome of the risk 

assessment. Uncertainty about the cumulative exposure assessment also pertains 

to the decision regarding the FQPA safety factor. The risk assessor should refer to 

the separate document entitled Consideration of the FQPA Safety Factor and Other 

Uncertainty Factors in Cumulative Risk Assessment of Chemicals Sharing a 

Common Mechanism of Toxicity (USEPA, 2001g). 

10.4.1 Uncertainties Associated with the Cumulative Food Pathway May 

Arise from the Following Sources 

Although temporal and geographic considerations are being incorporated into 

the cumulative exposure assessment with respect to water and residential 

exposures, these are not generally considered relevant with respect to the food 

pathway for the reasons stated earlier. Exposure to pesticides from foods is 

generally considered on a national basis. OPP does not believe, however, that 

uncertainty due to this treatment of food exposures is significant, and 

recommends that they be considered only in a qualitative sense in the cumulative 

assessment unless data indicates otherwise. Limitations and uncertainties with 

respect to the source of residue data should be considered. Other issues 

involve: (1) how nondetects are treated; (2) how percent crop treated is or is not 

incorporated; (3) to what extent PDP or Total Diet Study data are or are not used; 

and (4) the degree to which residue data are translated to other similar 

commodities (and to what extent those commodities are expected to share 

similar residue profiles). These and other appropriate issues should be 

discussed in the cumulative risk assessment. 

10.4.2 Uncertainties Associated with the Cumulative Water Pathway 

The uncertainties associated with the cumulative water pathway are likely to 

be quite different from those outlined for pesticide exposures from foods. The 

following examples illustrate some sources of uncertainty that should be 

discussed in evaluating the results of the risk assessment. Uncertainties in the 

drinking water portion will most likely be due to the nature of the data source. In 

most instances for the foreseeable future, drinking water data will be derived 

from monitoring-assisted modeling or from PRZM-EXAMS/IR model. The use of 

model-derived data is expected to be a conservative (health-protective) estimate 

of drinking water concentrations that represent high end use sites but do not 

grossly overestimate real-world water concentrations. Some of the potential 

sources of uncertainties associated with use of such data include 

69
physicochemical properties and other parameters (e.g., degradation) of the CAG 

pesticides; rates, frequencies, and patterns of use including the percent of a crop 

within a region that is treated12; the actual co-occurrence of the pesticides in 

water bodies; and potential for degradate formation, persistence, and toxicity. 

Qualitative discussion of these and other factors should be included in the 

cumulative assessment. To the extent possible, comparison to available 

monitoring data should be used to check the model outputs. 

10.4.3 Uncertainties Associated With The Cumulative Residential Pathway 

The uncertainties associated with the cumulative residential pathway will often 

be similar in etiology to those associated with estimation of cumulative exposure 

from water. As with drinking water, estimation of exposure from residential uses 

of pesticides will generally be indirect. For example, sources of uncertainty follow 

below: 

‘ For some pesticides, chemical-specific data or data from the literature 

(including EPA’s Exposure Factors Handbook) will be available and should 

be used to the extent possible. For others, specific data will not be 

available and appropriate professional judgment and expertise will need to 

be applied by the risk analyst in using surrogate data. Where data 

distribution fitting or other distribution analysis is performed, or where 

limited data cause the assessor to rely upon a uniform distribution, the 

impact of these analyses on the outcome of the assessment should be 

described. The reasons for the selection of a particular distribution should 

be provided along with a discussion as to the uncertainties associated with 

this decision. Specific factors or inputs in which distributional assumptions 

may be necessary include among others, transfer coefficients, crossformulation exposure assumptions, turf transferable residues, various 

aspects and components of hand-to-mouth behavior of toddlers, and lawn 

sizes. 

12For a regional analysis, such factors as soil characteristics, precipitation, and evapotranspiration will 

likely, of necessity, be averaged across a watershed and uncertainty would be associated with any such 

spatial homogenization. 

70 
‘ For some behavior patterns, data from the literature (including EPA’s 

Exposure Factors Handbook) will be available and should be used to the 

extent possible. Distributions of behavioral patterns (e.g., hand-to-mouth 

activity of toddlers) and durations of exposure (e.g., time spent on lawn) 

can be obtained from the Exposure Factors Handbook or the open 

literature. Significant uncertainties may still remain, owing in part to the 

limited number of studies available. The impact of any modeling of human 

behavior on the results of the assessment should be discussed. 

‘ Few data exist on the probability of concurrent uses of pesticides, whether 

complementary (e.g., flea treatment of lawn and simultaneous flea 

treatment of a residence) or competitive (e.g., if one member of a CAG is 

used one time in the March to May time frame to treat lawns for grubs, 

how likely is it that a second member of the CAG will be used on that 

same lawn at a later application window). For the foreseeable future, this 

aspect of residential pesticide exposure is likely to be modeled on the 

basis of use information. The impact of this process on the cumulative 

risk assessment should be discussed. 

‘ In certain instances where data on the CAG chemicals of interest are not 

available or are of limited utility, surrogate chemicals or formulations can 

be used in the cumulative assessment. Uncertainties associated with this 

translation should be discussed. 

In any risk assessment, there will be numerous identified and unidentified 

uncertainties. Assessment of cumulative exposures to pesticides is no 

exception. The risk assessor should be aware of and communicate these 

uncertainties to the risk manager. Sensitivity analyses will provide direction as to 

where best to focus resources and efforts to improve the quality and quantity of 

data to inform the risk assessment process. 

71
10.5 Presentation of Results 

The outcome of a cumulative risk assessment usually will not be a single 

estimate of risk. Rather, it will contain a series of estimates that represent time and 

geographically dependent distributions and estimates of risk from exposure to more 

than one common mechanism pesticide from the same source, and the combined 

risk to multiple pathways and routes of exposure. The values will be unitless, 

cumulative MOEs or a comparison to the index chemical’s point of departure. 

Cumulative risk values should be expressed only as whole numbers and not as 

fractional values so as not to imply greater precision than actually exists. Results 

should be presented for different age groups (e.g., the 18+ adult, various children’s 

ages, women of child-bearing age), and an evaluation of the impact of the behavior 

of different age groups on exposure should be provided. The risk assessor should 

present MOEs as a range of percentiles of exposure for the risk manager, with an 

explanation of the significance of each percentile. 

Decisions regarding the acceptability of a particular outcome will require 

evaluation of the entire data set used in the assessment, including the decisions 

regarding the group uncertainty factor and the relationship of the toxicological 

response in the test species to the anticipated human response. In other words, a 

halving of the cumulative MOE does not necessarily indicate a doubling of risk 

potential. The MOE outcome should be compared to or incorporate the group 

uncertainty factors (e.g., intra- and interspecies uncertainty factors), and if 

necessary, the FQPA safety factor. A cumulative MOE or cumulative %POD should 

be carefully interpreted in the context of the supporting information, magnitude and 

direction of biases, assumptions used, and attendant uncertainties. 

72
References 

ACPA. 1999. Cumulative and Aggregate Risk Evaluation System: CARES. 

Conceptual Model. American Crop Protection Association. Washington, DC. Available: 

http://www.alphacares.org/ 

Baird SJS, Cohen JT, Graham JD, Shlyakhter AI, Evans JS. 1996. “Noncancer Risk 

Assessment: a Probabilistic Alternative to Current Practice.” Hum Ecol Risk Assess 

2:78-99. 

Barnes DG, Dourson M. 1988. “Reference Dose (RfD): Description and Use in Health 

Risk Assessments.” Regul Toxicol Pharmacol 8:471-486. 

Hampshire Research Institute. 2000. “Overview of the Fundamentals of Version 1.0 of 

LifeLineTM Software for Modeling Aggregate and Cumulative Exposures to Pesticides;” 

September 2000. Hampshire Research Institute, Alexandria, VA. Available: 

http://www.epa.gov/scipoly/sap/2000/#september 

Hattis D, Anderson E. 1999. “What Should Be the Implications of Uncertainty, 

Variability, and Inherent “Biases”/”Conservatism” for Risk Management Decision 

Making”? Risk Anal 19:95-107. 

Hattis D, Burmaster DE. 1994. Assessment of Variability and Uncertainty Distributions 

for Practical Risk Analyses. Risk Anal 14:713-730. 

Hattis D, Minkowitz WS. 1996. “Risk Evaluation: Criteria Arising from Legal Traditions 

and Experience with Quantitative Risk Assessment in the United States.” Environ 

Toxicol Pharmacol 2:103-109. 

Hertzberg RC, Rice G, Teuschler LK. 1999. “Methods for Health Risk Assessment of 

Combustion Mixtures.” In: Hazardous Waste Incineration: Evaluating the Human 

Health and Environmental Risks. Roberts S, Team C, Bean J, (eds.) CAC Press LC, 

pp. 105-148. 

Hurley PM, Hil RN, Whiting RJ. 1998. “Mode of Carcinogenic Action of Pesticides 

Inducing Thyroid Follicular Cell Tumors in Rodents.” Environ Health Perspect 

106:(8):437-445. 

International Life Sciences Institute. 1998. Report. “Aggregate Exposure Assessment 

Workshop.” Available: http://www.ilsi.org/ 

73
Mileson B.E., Chambers J.E., Chen W.L. et al., 1998. “Common Mechanism of Toxicity: 

a Case Study of Organophosphorus Pesticides.” Toxicol Sci 41:8-20. 

National Research Council. 1993. Pesticides in the Diets of Infants and Children, 

Committee on Pesticides in the Diets of Infants and Children, Board on Agriculture and 

Board on Environmental Studies and Toxicology, Commission on Life Sciences, 

National Research Council, National Academy Press, Washington, DC. 

Novigen Sciences, Inc. 2001. “CALENDEXTM.” Online. Available: 

http://www.novigensci.com/calendex.html 

U.S. Environmental Protection Agency. 1986a. “Guidelines for Mutagenicity Risk 

Assessment;” September, 1986. EPA/630/R-98/003. National Center for 

Environmental Assessment, Office of Research & Development, Washington, DC. 

51 FR 34006. Available: http://www.epa.gov/ncea/raf/pdfs/mutagen2.pdf 

U.S. Environmental Protection Agency. 1986b. “Guidelines for Carcinogen Risk 

Assessment;” September, 1986. EPA/630/R-00/004. National Center for 

Environmental Assessment, Office of Research & Development, Washington, DC. 

51 FR 33992. Available: http://www.epa.gov/ncea/raf/car2sab/guidelines_1986.pdf 

U.S. Environmental Protection Agency. 1986c. “Guidelines for the Health Assessment 

of Suspect Developmental Toxicants;” September, 1986. National Center for 

Environmental Assessment, Office of Research & Development, Washington, DC. 

51 FR 34028. 

U.S. Environmental Protection Agency. 1986d. “Guidelines for the Health Risk 

Assessment of Chemical Mixtures;” September, 1986. EPA/630/R-98/002. National 

Center for Environmental Assessment, Office of Research & Development, Washington, 

DC. 51 FR 34014. Available: 

http://www.epa.gov/ncea/raf/pdfs/chem_mix/chemmix_1986.pdf 

U.S. Environmental Protection Agency. 1989. “Interim Procedures for Estimating Risks 

Associated with Exposures to Mixtures of Chlorinated Dibenzo-p-Dioxins and 

-Dibenzofurans (CDDs and CDFs) and 1989 Update;” October 1986. 

EPA/625/3/R-89/016. National Center for Environmental Assessment, Office of 

Research & Development, Washington, DC. 

U.S. Environmental Protection Agency. 1991a. “Guidelines for Developmental Toxicity 

Risk Assessment;” December 1991. EPA/600/FR-1/001. National Center for 

Environmental Assessment, Office of Research & Development, Washington, DC. 

56 FR 63798. Available: http://www.epa.gov/ncea/raf/pdfs/devtox.pdf 

U.S. Environmental Protection Agency. 1992. “Guidelines for Exposure Assessment;” 

May 29, 1992. EPA/600Z-92/001. National Center for Environmental Assessment, 

74
Office of Research & Development, Washington, DC. 57 FR 22888. Available: 

htp://www.epa.gov/NCEA/exposure.htm 

U.S. Environmental Protection Agency. 1994. “Methods for Derivation of Inhalation 

Reference Concentrations and Application of Inhalation Dosimetry;” October 1994. 

EPA/600/8-90/066F. Office of Research and Development. Washington, DC. 

Available: http://www.epa.gov/clariton/clhtml/pubtitle.html 

U.S. Environmental Protection Agency. 1996. “Guidelines for Reproductive Toxicity 

Risk Assessment;” October 1996. EPA/630/R-96/009. National Center for 

Environmental Assessment, Office of Research & Development, Washington, DC. 

61 FR 56273. Available: http://www.epa.gov/nceawww1/raf/pdfs/repro51.pdf 

U.S. Environmental Protection Agency. 1997a. “Guiding Principles for Monte Carlo 

Analysis;” March 1997. EPA/630/R-97/001. National Center for Environmental 

Assessment, Office of Research & Development, Washington, DC. Available: 

http://www.epa.gov/ncea/monteabs.htm 

U.S. Environmental Protection Agency. 1997b. Background Document Presented to 

the FIFRA Scientific Advisory Panel at the March 1997 Public Meeting. “The Grouping 

of a Series of Chloroacetanilide Pesticides Based on a Common Mechanism of 

Toxicity.” Office of Pesticide Programs, Office of Prevention, Pesticides, and Toxic 

Substances. Washington, DC. Available: 

http://www.epa.gov/scipoly/sap/1997/march/mechan_f.pdf 

U.S. Environmental Protection Agency. 1998a. “Guidelines for Neurotoxicity Risk 

Assessment;” April 1998. EPA/630/R-95/001F. National Center for Environmental 

Assessment, Office of Research & Development, Washington, DC. 60 FR 26926. 

Available: http://www.epa.gov/ncea/nurotox.htm 

U.S. Environmental Protection Agency. 1998b. “Assessment of Thyroid Follicular Cell 

Tumors;” March 1998. EPA/630/R-97/002. National Center for Environmental 

Assessment, Office of Research & Development, Washington, DC. Available: 

http://www.epa.gov/ncea/pdfs/thyroid.pdf 

U.S. Environmental Protection Agency. 1998c. Memorandum from John Whalen and 

Hugh Pettigrew to M. Stasikowski. “Inhalation Risk Characterizations and the 

Aggregate Risk Index;” November 25, 1998. Health Effects Division, Office of Pesticide 

Programs, Office of Prevention, Pesticides, and Toxic Substances. Washington, DC. 

75
U.S. Environmental Protection Agency. 1998d. Rule Writer’s Guide to Executive Order 

13045: Guidance for Considering Risks to Children During the Establishment of Public 

Health-Based and Risk-Based Standards ; November 1998. Office of Children’s Health 

Protection. Washington, DC. Online. Available: 

http://www.epa.gov/children/whatwe/rrguide.pdf 

U.S. Environmental Protection Agency. 1999a. “Guidance for Identifying Pesticide 

Chemicals and Other Substances That Have a Common Mechanism of Toxicity;” 

January 29, 1999. Office of Pesticide Programs, Office of Prevention, Pesticides, and 

Toxic Substances, Washington, D.C. Available: 

http://www.epa.gov/fedrgstr/EPA-PEST/1999/February/Day-05/ 

U.S. Environmental Protection Agency. 1999b. Draft Document. “Guidance for 

Performing Aggregate Exposure and Risk Assessments;” October 29, 1999. Office of 

Pesticide Programs, Office of Prevention, Pesticides, and Toxic Substances, 

Washington, D.C. 64 FR 61343. Available: 

http://www.epa.gov/fedrgstr/EPA-PEST/1999/November/Day-10/. 

U.S. Environmental Protection Agency. 1999c. Review Draft. “Guidelines for 

Carcinogen Risk Assessment;” July 1999. NCEA-F-0644. National Center for 

Environmental Assessment, Office of Research & Development, Washington, DC. 

Available: http://www.epa.gov/ncea/raf/pdfs/cancer_gls.pdf 

U.S. Environmental Protection Agency. 1999d. “Exposure Factors Handbook;” 

February 1999. EPA/600C-99/001. National Center for Environmental Assessment, 

Office of Research & Development, Washington, DC. Available: 

http://www.epa.gov/ncea/exposfac.htm 

U.S. Environmental Protection Agency. 1999e. “Guidance for Identifying Pesticide 

Chemicals and Other Substances That Have a Common Mechanism of Toxicity;” 

January 29, 1999. Office of Pesticide Programs, Office of Prevention, Pesticides, and 

Toxic Substances. Washington, DC. Available: 

http://www.epa.gov/oppfead1/trac/science/#common 

U.S. Environmental Protection Agency. 1999f. Draft Document. “A Science Policy on 

A Common Mechanism of Toxicity: the Carbamate Pesticides and the Grouping of 

Carbamate with the Organophosphorus Pesticides;” August 30, 1999. Office of 

Pesticide Programs, Office of Prevention, Pesticides, and Toxic Substances. 

Washington, DC. Available: 

http://www.epa.gov/scipoly/sap/1999/september/carbam.pdf. 

76
U.S. Environmental Protection Agency. 1999g. Draft Document. “Standard Operating 

Procedures (SOPs) for Residential Exposure Assessments;” December 19, 1997. 

Office of Pesticide Programs, Office of Prevention, Pesticides, and Toxic Substances, 

Washington, D.C. Available: http://www.epa.gov/pesticides/trac/science/trac6a05.pdf 

U.S. Environmental Protection Agency. 1999h. Draft Document. The Office of 

Pesticide Programs’ Policy on Determination of the Appropriate FQPA Safety Factor(s) 

for Use in the Tolerance-Setting Process; May 10, 1999. Office of Pesticide Programs, 

Office of Prevention, Pesticides, and Toxic Substances. Washington, DC. Available: 

http://www.epa.gov/oppfead1/trac/science/#10-fold 

U.S. Environmental Protection Agency. 1999i. Glossary of IRIS Terms. October 1999. 

Online. National Center for Environmental Assessment, Office of Research and 

Development. Washington, DC. Available: http://www.epa.gov/iris/gloss8.htm 

U.S. Environmental Protection Agency. 1999j. Report from Session II of the FIFRA 

Scientific Advisory Panel Meeting of September 23, 1999. “Proposed Guidance for 

Conducting Cumulative Hazard Assessments for Pesticides that have a Common 

Mechanism of Toxicity;” November 18, 1999. FIFRA Scientific Advisory Panel, Office of 

Science Coordination and Policy, Office of Prevention, Pesticides and Toxic 

Substances. Washington, DC. SAP Report 99-05D. Available: 

http://www.epa.gov/scipoly/sap/2000/September/ 

U.S. Environmental Protection Agency. 1999k. Draft Document. “Proposed Guidance 

on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common 

Mechanism of Toxicity;” August 27, 1999. Office of Pesticide Programs, Office of 

Prevention, Pesticides, and Toxic Substances. Washington, DC. Available: 

http://www.epa.gov/scipoly/sap/1999/september/cumdoc.pdf 

U.S. Environmental Protection Agency. 2000a. Public Comment Draft. “Proposed 

Guidance on Cumulative Risk Assessment of Pesticide Chemicals that Have a Common 

Mechanism of Toxicity;” June 22, 2000. 65 FR 40644. Office of Pesticide Programs, 

Office of Prevention, Pesticides, and Toxic Substances. Washington, DC. Available: 

www.epa.gov/fedrgstr/EPA-PEST/2000/June/Day-30/6049.pdf 

U.S. Environmental Protection Agency. 2000b. External Review Draft. “Benchmark 

Dose Technical Guidance Document;” October 2000. EPA/630/R-00/001. National 

Center for Environmental Assessment, Office of Research & Development, Washington, 

DC. Available: http://www.epa.gov/NCEA/bnchmrk/bmds_peer.htm 

77
U.S. Environmental Protection Agency. 2000c. “Science Policy Council Handbook: 

Risk Characterization;” December 2000. EPA 100-B-00-002. Science Policy Council, 

Office of Research and Development. Washington, DC. Available: 

http://www.epa.gov/ORD/spc/rchandbk.pdf 

U.S. Environmental Protection Agency. 2000d. “Science Policy Council Handbook: 

Peer Review,” 2nd Edition; December 2000. EPA 100-B-00-001. Science Policy 

Council, Office of Research and Development. Washington, DC. Available: 

http://www.epa.gov/ORD/spc/prhandbk.pdf 

U.S. Environmental Protection Agency. 2000e. Draft Document. “Cumulative Risk: A 

Case Study of the Estimation of Risk from 24 Organophosphate Pesticides;” November 

9, 2000. Office of Pesticide Programs, Office of Prevention, Pesticides, and Toxic 

Substances. Washington, DC. Available: 

http://www.epa.gov/scipoly/sap/2000/December/sap_casestudy2.pdf 

U.S. Environmental Protection Agency. 2000g. Report from Session II of the FIFRA 

Scientific Advisory Panel Meeting of December 8-9, 1999. “Cumulative Risk 

Assessment Methodology Issues of Pesticide Substances that Have a Common 

Mechanism of Toxicity;” February 4, 2000. FIFRA Scientific Advisory Panel, Office of 

Science Coordination and Policy, Office of Prevention, Pesticides and Toxic 

Substances. Washington, DC. SAP Report 99-06B. Available: 

http://www.epa.gov/scipoly/sap/2000/December 

U.S. Environmental Protection Agency. 2000h. Draft Document. Dioxin 

Reassessment. National Center for Environmental Assessment, Office of Research 

and Development. Washington, DC. Available: 

http://cfpub.epa.gov/ncea/cfm/dioxreass.cfm 

U.S. Environmental Protection Agency. 2000i. Issue Paper for the FIFRA Scientific 

Advisory Panel Review. “Endpoint Selection and Determination of Relative Potency in 

Cumulative Hazard and Dose-Response Assessment: A Pilot Study of 

Organophosphorus Pesticide Chemicals;” September 5, 2000. Office of Pesticide 

Programs, Office of Prevention, Pesticides, and Toxic Substances. Available: 

http://www.epa.gov/scipoly/sap/2000/September/cumulative_hazard.pdf 

U.S. Environmental Protection Agency. 2000j. “Supplementary Guidance for 

Conducting Health Risk Assessment of Chemical Mixtures;” August 1, 2000. USEPA 

EPA/630/R-00/002. National Center for Environmental Assessment, Office of Research 

& Development, Washington, DC. 51 FR 34014. Available: 

http://www.epa.gov/NCEA/raf/chem_mix.htm 

78
U.S. Environmental Protection Agency. 2001b. “The Grouping of a Series of 

Chloroacetanilide Pesticides Based on a Common Mechanism of Toxicity;” June 

7, 2001. Office of Pesticide Programs, Office of Prevention, Pesticides, and Toxic 

Substances. Washington, DC. Available: 

http://www.epa.gov/oppfead1/cb/csb_page/updates/chloroa.pdf 

U.S. Environmental Protection Agency. 2001c. “Thiocarbamates: A Determination of 

the Existence of a Common Mechanism of Toxicity and a Screening Level Cumulative 

Dietary (Food) Risk Assessment ;” in preparation. Office of Pesticide Programs, Office 

of Prevention, Pesticides, and Toxic Substances. Washington, DC. Will Be Available: 

http://www.epa.gov/oppfead1/trac/science/#common 

U.S. Environmental Protection Agency. 2001d. “Preliminary Cumulative Hazard and

Dose Response Assessment for Organophosphorus Pesticides: Determination of

Relative Potency and Points of Departure for Cholinesterase Inhibition;” July 31, 2001.

Office of Pesticide Programs, Office of Prevention, Pesticides and Toxic Substances. 

Washington, DC. Available: 

http://www.epa.gov/scipoly/sap/index.htm#september

U.S. Environmental Protection Agency. 2001e. The Determination of Whether the 

Dithiocarbamate Pesticides Share a Common Mechanism of Toxicity. Office of 

Pesticide Programs, Office of Prevention, Pesticides, and Toxic Substances. 

Washington, DC. Will Be Available: 

http://www.epa.gov/oppfead1/trac/science/#common 

USEPA. 2001f. “Determination of the Appropriate FQPA Safety Factor(s) for Use in the 

Tolerance-Setting Process;” in preparation. Office of Pesticide Programs, Office of 

Prevention, Pesticides, and Toxic Substances. Will Be Available: 

http://www.epa.gov/oppfead1/trac/science/#10-fold 

U.S. Environmental Protection Agency. 2001g. Draft Document. “Consideration of the 

FQPA Safety Factor and Other Uncertainty Factors in Cumulative Risk Assessment of 

Chemicals Sharing a Common Mechanism of Toxicity;” in preparation. Office of 

Pesticide Programs, Office of Prevention, Pesticides, and Toxic Substances. 

Washington, DC. Will Be Available: http://www.epa.gov/oppfead1/trac/science/#10-fold 

U.S. Environmental Protection Agency. 2001h. “General Principles For Performing 

Aggregate Exposure And Risk Assessments;” November 14, 2001. Office of Pesticide 

Programs, Office of Prevention, Pesticides, and Toxic Substances. Washington, DC. 

Available: http://www.epa.gov/oppfead1/trac/science/#non-occupational 

79
U.S. Environmental Protection Agency. 2001i. Review Draft. “Framework for 

Cumulative Risk Assessment;” August 2, 2001. Office of Research and Development, 

National Center for Environmental Assessment. NCEA-F-1098. Available: 

http://www.epa.gov/ncea/raf/frmwrkcra.htm 

U.S. Environmental Protection Agency. 2001j. Report from the FIFRA Scientific 

Advisory Panel Meeting of September 27, 2000. “End Point Selection and 

Determination of Relative Potency in Cumulative Hazard Assessment: A Pilot Study of 

Organophosphorus Pesticide Chemicals;” March 21, 2001. FIFRA Scientific Advisory 

Panel, Office of Science Coordination and Policy, Office of Prevention, Pesticides and 

Toxic Substances. Washington, DC. SAP Report 2000-0X. Available: 

http://www.epa.gov/scipoly/sap/2000/September/ 

U.S. Environmental Protection Agency. 2001k. Report from Session II of the FIFRA 

Scientific Advisory Panel Meeting of December 7-8, 2000. “Case Study of the 

Cumulative Risk of 24 Organophosphate Pesticides; Cumulative Risk Assessment 

Method for Dietary Food Exposure; Cumulative Risk Assessment for Residential 

Exposure; Cumulative Risk Assessment for Drinking Water; Integrated Cumulative Risk 

Assessment;” May 8, 2001. FIFRA Scientific Advisory Panel, Office of Science 

Coordination and Policy, Office of Prevention, Pesticides and Toxic Substances. 

Washington, DC. SAP Report 2001-06. Available: 

http://www.epa.gov/scipoly/sap/2001/December/ 

U.S. Environmental Protection Agency. 2001l. “Cumulative Risk Assessment: 

Developing the Methods Available Papers and Where They May be Located;” June 

21, 2001. Online. Available: 

http://www.epa.gov/pesticides/cumulative/Cum_Risk_AssessmentDTM.htm 

U.S. Environmental Protection Agency. 2001m. “Organophosphate Pesticides: 

Preliminary OP Cumulative Risk Assessment;” December 3, 2001. Office of Pesticide 

Programs, Office of Prevention, Pesticides and Toxic Substances. Washington, DC. 

Available: http://www.epa.gov/pesticides/cumulative/pra-op/ 

U.S. Environmental Protection Agency. 2001n. Report from the FIFRA Scientific 

Advisory Panel Meeting of September 5-6, 2001. “Preliminary Cumulative Hazard and 

Dose Response Assessment for Organophosphorus Pesticides: Determination of 

Relative Potency and Points of Departure for Cholinesterase Inhibition;” September 11, 

2001. FIFRA Scientific Advisory Panel, Office of Science Coordination and Policy, 

Office of Prevention, Pesticides and Toxic Substances. Washington, DC. Available: 

http://www.epa.gov/scipoly/sap/index.htm#september 

80
U.S. Environmental Protection Agency. 2001o. Issue Papers for the FIFRA Scientific 

Advisory Panel Review. “Thiocarbamates: A Screening Level Cumulative Dietary 

(Food) Risk Assessment,” August 17, 2001 and “The Grouping of a Series of 

Dithiocarbamate Pesticides Based on a Common Mechanism of Toxicity,” August 17, 

2001. Office of Pesticide Programs, Office of Prevention, Pesticides, and Toxic 

Substances. Washington, DC. Available: 

http://www.epa.gov/scipoly/sap/index.htm#september7 

81